endothelin-1 and Hypertension--Pulmonary

endothelin-1 has been researched along with Hypertension--Pulmonary* in 579 studies

Reviews

81 review(s) available for endothelin-1 and Hypertension--Pulmonary

ArticleYear
Insights into Endothelin Receptors in Pulmonary Hypertension.
    International journal of molecular sciences, 2023, Jun-16, Volume: 24, Issue:12

    Pulmonary hypertension (PH) is a disease which affects the cardiopulmonary system; it is defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg as measured by right heart catheterization at rest, and is caused by complex and diverse mechanisms. In response to stimuli such as hypoxia and ischemia, the expression and synthesis of endothelin (ET) increase, leading to the activation of various signaling pathways downstream of it and producing effects such as the induction of abnormal vascular proliferation during the development of the disease. This paper reviews the regulation of endothelin receptors and their pathways in normal physiological processes and disease processes, and describes the mechanistic roles of ET receptor antagonists that are currently approved and used in clinical studies. Current clinical researches on ET are focused on the development of multi-target combinations and novel delivery methods to improve efficacy and patient compliance while reducing side effects. In this review, future research directions and trends of ET targets are described, including monotherapy and precision medicine.

    Topics: Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension, Pulmonary; Lung; Receptors, Endothelin

2023
Potassium Channels as Therapeutic Targets in Pulmonary Arterial Hypertension.
    Biomolecules, 2022, Sep-22, Volume: 12, Issue:10

    Pulmonary arterial hypertension (PAH) is a devastating disease with high morbidity and mortality. Deleterious remodeling in the pulmonary arterial system leads to irreversible arterial constriction and elevated pulmonary arterial pressures, right heart failure, and eventually death. The difficulty in treating PAH stems in part from the complex nature of disease pathogenesis, with several signaling compounds known to be involved (e.g., endothelin-1, prostacyclins) which are indeed targets of PAH therapy. Over the last decade, potassium channelopathies were established as novel causes of PAH. More specifically, loss-of-function mutations in the

    Topics: Channelopathies; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; KATP Channels; Nerve Tissue Proteins; Potassium; Potassium Channels, Tandem Pore Domain; Potassium Channels, Voltage-Gated; Prostaglandins I; Pulmonary Arterial Hypertension

2022
5-HTT, BMPR2, EDN1, ENG, KCNA5 gene polymorphisms and susceptibility to pulmonary arterial hypertension: A meta-analysis.
    Gene, 2019, Jan-05, Volume: 680

    The influence of 5-HTT, BMPR2, EDN1, ENG, KCNA5 genes polymorphisms on susceptibility of pulmonary arterial hypertension remains uncertain. This meta-analysis is conducted for further study.. We conducted a literature search on PubMed and ISI web of science databases for searching relevant articles until November 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. A total of 17 articles with 2631 PAH subjects and 5139 controls were included in the final meta-analysis. Statistical software Stata13.0 was used for data-analysis.. A significant relationship was found between the 5-HTT L/S polymorphism and PAH in all the genetic models [LL vs. SS: OR = 1.60, 95% CI, 1.11-2.32; LS vs. SS: OR = 1.55, 95% CI, 1.10-2.21; (LS + LL) vs. SS: OR = 1.56, 95% CI, 1.13-2.17; L vs. S: OR = 1.32, 95% CI, 1.08-1.62]. There were also associations of the SERT L/S polymorphism with IPAH and PAH in COPD [IPAH L/S: OR = 1.26, 95% CI, 1.01-1.57; PAH in COPD L/S: OR = 1.42, 95% CI, 1.04-1.94]. In addition, the results showed a statistically significant association between EDN1 rs5370 polymorphism and the risk of PAH in all the genetic models [TT vs. GG: OR = 3.32, 95% CI, 1.30-8.51; TG vs. GG: OR = 2.68, 95% CI, 1.54-4.66; (TG + TT) vs. GG: OR = 2.82, 95% CI, 1.69-4.71; T vs. G: OR = 2.43, 95% CI, 1.60-3.68]. However, the significant association was not found between BMPR2 rs1061157, KCNA5 rs10744676, ENG rs3739817 polymorphisms and the risk of PAH (all p > 0.05).. 5-HTT L/S polymorphism and END1 rs5370 polymorphism were correlated with significantly increased risk of PAH. Moreover, L allele in 5-HTT gene increased susceptibility to IPAH and PAH in COPD.

    Topics: Adult; Aged; Bone Morphogenetic Protein Receptors, Type II; Endoglin; Endothelin-1; Gene Regulatory Networks; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Kv1.5 Potassium Channel; Middle Aged; Polymorphism, Single Nucleotide; Serotonin Plasma Membrane Transport Proteins; Young Adult

2019
Titration of pulmonary arterial hypertension therapeutics: Experience-based recommendations.
    Respiratory medicine, 2018, Volume: 143

    The availability of new medications has improved exercise capacity, enhanced quality of life, and extended time to clinical worsening in patients with pulmonary arterial hypertension (PAH). For many of these medications, careful individualized dose titration is required to maximize therapeutic effectiveness while minimizing side effects. In addition, specific routes of administration, including intravenous (IV), subcutaneous (SC), and inhaled administration may present additional challenges for patients and healthcare providers. These challenges include the possibility of catheter-related infections (IV), infusion site pain (SC), and adherence to frequent dosing schedules (inhaled). Temporary discontinuations may require re-titration and, in some cases, may even be life threatening. Here, based on our clinical experience, we provide our recommendations for dose titration schemes for PAH medications that require individualized dosing in adult patients, including agents acting on the endothelin-1 pathway (bosentan and ambrisentan), the prostacyclin pathway (epoprostenol, treprostinil, and selexipag), and the nitric oxide pathway (tadalafil and the soluble guanylate cyclase stimulator riociguat). A case study that illustrates the application of best practices for PAH medication dose titration in a real-world setting is presented. Good two-way communication between specialty pharmacies and other healthcare providers promotes optimal medication usage and patient health. Experience has shown that slow, cautious up-titration is generally associated with better long-term outcomes. In all cases, patient education, frequent monitoring and careful management of side effects, and treatment adherence are critical.

    Topics: Drug Administration Schedule; Endothelin Receptor Antagonists; Endothelin-1; Epoprostenol; Evidence-Based Medicine; Female; Humans; Hypertension, Pulmonary; Middle Aged; Nitric Oxide

2018
Research advances in pathogenesis and prophylactic measures of acute high altitude illness.
    Respiratory medicine, 2018, Volume: 145

    After ascent to high altitude (≥2500 m), the inability of the human body to adapt to the hypobaric and hypoxia environment can induce tissue hypoxia, then a series of high altitude illnesses including acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE) would develop. Symptoms of AMS include headache, dizziness, nausea, and vomiting; HAPE is characterized by orthopnea, breathlessness at rest, cough, pink frothy sputum, and results in obvious pulmonary edema that poses significant harm to people; HACE is characterized by ataxia and decreased consciousness, leading to coma and brain herniation which would be fatal if not treated promptly. This review article provides a current understanding of the pathophysiology of these three forms of high altitude illness and elaborates the current prevention and treatment measures of these diseases.

    Topics: Acetazolamide; Acute Disease; Altitude Sickness; Calcium Channel Blockers; Carbonic Anhydrase Inhibitors; Cytokines; Dexamethasone; Endothelin-1; Hemodynamics; Humans; Hypertension, Pulmonary; Inflammation Mediators; Nifedipine; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pulmonary Alveoli; Sildenafil Citrate

2018
Pulmonary Arterial Hypertension Complicating Congenital Heart Disease: Advances in Therapy.
    Seminars in respiratory and critical care medicine, 2017, Volume: 38, Issue:5

    Topics: Antihypertensive Agents; Combined Modality Therapy; Endothelin-1; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Survival; Tomography, X-Ray Computed

2017
Medical therapies for pulmonary arterial hypertension.
    Heart failure reviews, 2016, Volume: 21, Issue:3

    Pulmonary Arterial hypertension (PAH) is a chronic and progressive disease characterized by an increase in pulmonary vascular resistance due to severe remodeling of the small pulmonary arteries. In PAH, the endothelial cells fail to maintain their homeostatic balance, with the consequent impaired production of vasodilators and over-expression of vasoconstrictors and proliferators. Current treatment of PAH is based on the discovery of three main pathways of endothelial dysfunction (prostacyclin, nitric oxide and endothelin-1), and includes drugs such as prostacyclin analogs, phosphodiesterase-5 inhibitors and endothelin receptor antagonists (ERAs). Recently approved drugs that act through these classic pathways include riociguat (cyclic GMP stimulator) and macitentan (a tissue specific dual ERA). However, several new drugs and new pathways are under study. New targeted therapies include tyrosine kinase inhibitors, Rho kinase inhibitors and serotonin receptor blockers. There are now ten drugs approved for the treatment of PAH that, alone or in combination, have changed the natural history of this disease. The new drugs will allow us to further modified the patients' life expectancy and move towards a cure.

    Topics: Drug Therapy, Combination; Drugs, Investigational; Endothelin Receptor Antagonists; Endothelin-1; Epoprostenol; Humans; Hypertension, Pulmonary; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides

2016
Factors associated with pulmonary hypertension and long-term survival in bronchiectasis subjects.
    Respiratory medicine, 2016, Volume: 119

    The development of pulmonary hypertension (PH) and its effect on long-term survival in bronchiectasis subjects has not been explored. The present study aims to analyze the factors associated with PH and its effect on long-term survival in bronchiectasis subjects.. We prospectively evaluated 23 bronchiectasis subjects without PH and 16 with PH, as well as 20 healthy volunteers.. Bronchiectasis subjects with PH were more hypoxemic and had a greater number of involved lobes in high resolution computed tomography (HRCT) than did the bronchiectasis subjects without PH (P < 0.001 and P < 0.001, respectively). At three years, the survival rate was 95.7% for bronchiectasis subjects without PH and 56.3% for bronchiectasis with PH, and at 5 years, these rates were 95.7% and 62.5%, respectively (P = 0.002). Multivariate Cox regression analysis revealed that only the Medical Research Council (MRC) dyspnea score was independently related to poor survival in all bronchiectasis subjects (hazard ratio: 6.98; 95% CI: 2.41-20.23; P < 0.00001).. Subjects with PH are more hypoxemic and have a greater number of involvements in the lobes of the lungs. Bronchiectasis subjects with PH have worse survival than do bronchiectasis subjects without PH. MRC dyspnea score is an independent predictor of long-term survival.

    Topics: Adult; Bronchiectasis; Clinical Trials as Topic; Dyspnea; Echocardiography, Doppler; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Oxygen; Patient Outcome Assessment; Prospective Studies; Risk Factors; Survival Rate; Tomography, X-Ray Computed; Turkey; Ventricular Dysfunction, Right

2016
Treatment-related biomarkers in pulmonary hypertension.
    American journal of respiratory cell and molecular biology, 2015, Volume: 52, Issue:6

    Significant advances in the treatment of pulmonary arterial hypertension (PAH) over the last two decades have led to the introduction of multiple classes of oral therapy, but the disease remains devastating for many patients. Disease progression, in spite of oral monotherapy, is a major problem, and alternative therapy, such as infusion of prostacyclins, is cumbersome and carries considerable potential morbidity. Use of combination oral therapy, including drugs from both the endothelin receptor antagonist and phosphodiesterase-5 inhibitor classes, has increased, and there is some evidence to support this approach. Given the multiple options now available in pulmonary hypertension (PH) therapy, biomarkers to guide treatment decisions could be helpful. Here, we review the evidence for and against the clinical use of molecular biomarkers relevant to PH pathogenesis, emphasizing assayable markers that may also inform more rational selection of agents that influence pathways targeted by treatment. We emphasize the interactive nature of changes in mediators and messengers, such as endothelin-1, prostacyclin, brain natriuretic peptide (which has demonstrated biomarker utility), nitric oxide derivatives, and cyclic guanosine monophosphate, which play important roles in processes central to progression of PAH, such as vascular remodeling, vasoconstriction, and maladaptive right ventricular changes, and are relevant to its therapy. Accordingly, we propose that the identification and use of a molecular biomarker panel that assays these molecules in parallel and serially might, if validated, better inform unique patient phenotypes, prognosis, and the rational selection and titration of combination oral and other therapy in individual patients with PH/PAH.

    Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Biomarkers; Cyclic AMP; Cyclic GMP; Endothelin-1; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Nitric Oxide; S-Nitrosothiols; Treatment Outcome

2015
Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension.
    Reproductive toxicology (Elmsford, N.Y.), 2015, Aug-15, Volume: 56

    The Pregnancy Prevention Program (PPP) is in place to prevent drug-induced developmental malformations. Remarkably, among the ten PPP-enlisted drugs are three endothelin-1 (ET-1) receptor antagonists (ERA's: ambrisentan, bosentan and macitentan), which are approved for the treatment of Pulmonary Arterial Hypertension (PAH). This review describes the effects of ERA's in PAH pathobiology and cardiopulmonary fetal development. While ERA's hamper pathological remodeling of the pulmonary vasculature and as such exert beneficial effects in PAH, they disturb fetal development of cardiopulmonary tissues. By blocking ET-1-mediated positive inotropic effects and myocardial fetal gene induction, ERA's may affect right ventricular adaptation to the increased pulmonary vascular resistance in both the fetus and the adult PAH patient.

    Topics: Animals; Antihypertensive Agents; Arterial Pressure; Endothelin Receptor Antagonists; Endothelin-1; Female; Fetal Heart; Fetus; Gene Expression Regulation, Developmental; Heart Ventricles; Humans; Hypertension, Pulmonary; Pregnancy; Pregnancy Complications, Cardiovascular; Pulmonary Artery; Receptors, Endothelin; Risk Assessment; Signal Transduction; Vascular Remodeling

2015
Current state of endothelin receptor antagonism in hypertension and pulmonary hypertension.
    Therapeutic advances in cardiovascular disease, 2014, Volume: 8, Issue:5

    Endothelin 1 (ET-1), a potent vasoconstrictive substance, was discovered in 1988 by Yanagisawa and colleagues, and since then, a quarter of a century has passed. Understanding the biology of ET-1 has rapidly developed by characterizing the components of its receptors and processing enzymes. Numerous studies have revealed not only physiological but also various pathophysiological roles of the ET system. At first, ET-1 was the attractive and promising target for the treatment of hypertension owing to its potent vasoconstrictive nature and a variety of ET receptor antagonists (ERAs) were studied. However, the clinical application to treat hypertension was disappointing because of the side effects, including liver toxicity and fluid retention. On the other hand, ERAs have been established as orphan drugs for the treatment of pulmonary arterial hypertension and improved the prognosis of patients. Furthermore, multipotency of the ET system in the pathogenesis of multiple diseases has led to the development of translational research not only in the field of hypertension but in a variety of fields. Furthermore, a range of studies are ongoing to apply ERAs to clinical situations. In this article, we review the pathophysiological roles of the ET system in hypertension and pulmonary hypertension and the potential of ET receptor antagonism for the treatment of these diseases.

    Topics: Animals; Antihypertensive Agents; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension; Hypertension, Pulmonary; Prognosis; Receptors, Endothelin; Translational Research, Biomedical

2014
Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12.
    British journal of pharmacology, 2014, Volume: 171, Issue:24

    Since the discovery of endothelin (ET)-1 in 1988, the main components of the signalling pathway have become established, comprising three structurally similar endogenous 21-amino acid peptides, ET-1, ET-2 and ET-3, that activate two GPCRs, ETA and ETB . Our aim in this review is to highlight the recent progress in ET research. The ET-like domain peptide, corresponding to prepro-ET-193-166 , has been proposed to be co-synthesized and released with ET-1, to modulate the actions of the peptide. ET-1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long-lasting action. To date, the major therapeutic strategy to block the unwanted actions of ET in disease, principally in pulmonary arterial hypertension, has been to use antagonists that are selective for the ETA receptor (ambrisentan) or that block both receptor subtypes (bosentan). Macitentan represents the next generation of antagonists, being more potent than bosentan, with longer receptor occupancy and it is converted to an active metabolite; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy. A second strategy is now being more widely tested in clinical trials and uses combined inhibitors of ET-converting enzyme and neutral endopeptidase such as SLV306 (daglutril). A third strategy based on activating the ETB receptor, has led to the renaissance of the modified peptide agonist IRL1620 as a clinical candidate in delivering anti-tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions. Finally, we discuss biased signalling, epigenetic regulation and targeting with monoclonal antibodies as prospective new areas for ET research.

    Topics: Antineoplastic Agents; Aspartic Acid Endopeptidases; Benzazepines; Bosentan; Endothelin A Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelin-3; Endothelin-Converting Enzymes; Endothelins; Epigenesis, Genetic; Humans; Hypertension, Pulmonary; Metalloendopeptidases; Neoplasms; Peptide Fragments; Phenylpropionates; Pyridazines; Pyrimidines; Receptor, Endothelin B; Sulfonamides; Vasodilator Agents

2014
The role of endothelin system in cardiovascular disease and the potential therapeutic perspectives of its inhibition.
    Current topics in medicinal chemistry, 2013, Volume: 13, Issue:2

    Since its identification in 1988 and the recognition of its primary role as a potent vasoconstrictor, endothelin has been extensively studied and is now considered as a ubiquitous protein, involved in important aspects of human homeostasis as well as in several pathophysiological pathways, mostly associated with cardiovascular disease. From an evolutionary point of view, endothelin consists a primitive molecule with the rare characteristic of being exactly the same in all mammals, thus permitting scientists to perform experiments in animals and doing predictions for humans. The understanding of its contribution to the genesis, evolution and maintenance of disease through activation of special receptor subtypes has led to the development of both selective and unselective receptor antagonists. Despite the disappointing results of these antagonists in the field of heart failure, almost from the initial animal trials of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension, it has been demonstrated that the drug leads at least to hemodynamic and clinical improvement of the patients, thus receiving official approval for the management of this rare but eventually lethal disease. Resistant hypertension is another area where endothelin receptor blockers might potentially play a role, while the pathophysiological role of endothelin in atherosclerotic coronary artery disease is well-established and the relative research goes on. The main goal of this review is to describe the endothelin system and mostly to enlighten its role in pathophysiologic pathways, as well to state the relative research in the various fields of cardiovascular disease and also highlight its prognostic significance wherever there exists one.

    Topics: Animals; Atherosclerosis; Atrial Fibrillation; Bosentan; Cardiovascular Diseases; Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension, Pulmonary; Phenylpropionates; Predictive Value of Tests; Pyridazines; Receptors, Endothelin; Sulfonamides

2013
Mechanisms and drug therapy of pulmonary hypertension at high altitude.
    High altitude medicine & biology, 2013, Volume: 14, Issue:2

    Pulmonary vasoconstriction represents a physiological adaptive mechanism to high altitude. If exaggerated, however, it is associated with important morbidity and mortality. Recent mechanistic studies using short-term acute high altitude exposure have provided insight into the importance of defective vascular endothelial and respiratory epithelial nitric oxide (NO) synthesis, increased endothelin-1 bioavailability, and overactivation of the sympathetic nervous system in causing exaggerated hypoxic pulmonary hypertension in humans. Based on these studies, drugs that increase NO bioavailability, attenuate endothelin-1 induced pulmonary vasoconstriction, or prevent exaggerated sympathetic activation have been shown to be useful for the treatment/prevention of exaggerated pulmonary hypertension during acute short-term high altitude exposure. The mechanisms underpinning chronic pulmonary hypertension in high altitude dwellers are less well understood, but recent evidence suggests that they differ in some aspects from those involved in short-term adaptation to high altitude. These differences have consequences for the choice of the treatment for chronic pulmonary hypertension at high altitude. Finally, recent data indicate that fetal programming of pulmonary vascular dysfunction in offspring of preeclampsia and children generated by assisted reproductive technologies represents a novel and frequent cause of pulmonary hypertension at high altitude. In animal models of fetal programming of hypoxic pulmonary hypertension, epigenetic mechanisms play a role, and targeting of these mechanisms with drugs lowers pulmonary artery pressure. If epigenetic mechanisms also are operational in the fetal programming of pulmonary vascular dysfunction in humans, such drugs may become novel tools for the treatment of hypoxic pulmonary hypertension.

    Topics: Acute Disease; Adaptation, Physiological; Altitude Sickness; Anti-Inflammatory Agents; Antihypertensive Agents; Biomarkers; Chronic Disease; Endothelin-1; Female; Fetal Development; Foramen Ovale, Patent; Humans; Hypertension, Pulmonary; Nitric Oxide; Oxidative Stress; Pre-Eclampsia; Pregnancy; Pulmonary Edema; Risk Factors; Sympathetic Nervous System; Vasodilator Agents

2013
Vasoactive peptides and the pathogenesis of pulmonary hypertension: role and potential therapeutic application.
    Handbook of experimental pharmacology, 2013, Volume: 218

    Pulmonary hypertension (PH) is a debilitating disease with a dismal prognosis. Recent advances in therapy (e.g. prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors), whilst significantly improving survival, simply delay the inexorable progression of the disease. An array of endogenous vasoconstrictors and vasodilators coordinates to maintain pulmonary vascular homeostasis and morphological integrity, and an imbalance in the expression and function of these mediators precipitates PH and related lung diseases. The vasodilator peptides, including natriuretic peptides, vasoactive intestinal peptide, calcitonin gene-related peptide and adrenomedullin, trigger the production of cyclic nucleotides (e.g. cGMP and cAMP) in many pulmonary cell types, which in tandem exert a multifaceted protection against the pathogenesis of PH, encompassing vasodilatation, inhibition of vascular smooth muscle proliferation, anti-inflammatory and anti-fibrotic effects and salutary actions on the right ventricle. This coordinated beneficial activity underpins a contemporary perception that to advance treatment of PH it is necessary to offset multiple disease mechanisms (i.e. the pulmonary vasoconstriction, pulmonary vascular remodelling, right ventricular dysfunction). Thus, there is considerable potential for harnessing the favourable activity of peptide mediators to offer a novel, efficacious therapeutic approach in PH.

    Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Endothelin-1; Humans; Hypertension, Pulmonary; Natriuretic Peptides; Peptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide

2013
Vascular remodeling in pulmonary hypertension.
    Journal of molecular medicine (Berlin, Germany), 2013, Volume: 91, Issue:3

    Pulmonary hypertension is a complex, progressive condition arising from a variety of genetic and pathogenic causes. Patients present with a spectrum of histologic and pathophysiological features, likely reflecting the diversity in underlying pathogenesis. It is widely recognized that structural alterations in the vascular wall contribute to all forms of pulmonary hypertension. Features characteristic of the remodeled vasculature in patients with pulmonary hypertension include increased stiffening of the elastic proximal pulmonary arteries, thickening of the intimal and/or medial layer of muscular arteries, development of vaso-occlusive lesions, and the appearance of cells expressing smooth muscle-specific markers in normally non-muscular small diameter vessels, resulting from proliferation and migration of pulmonary arterial smooth muscle cells and cellular transdifferentiation. The development of several animal models of pulmonary hypertension has provided the means to explore the mechanistic underpinnings of pulmonary vascular remodeling, although none of the experimental models currently used entirely replicates the pulmonary arterial hypertension observed in patients. Herein, we provide an overview of the histological abnormalities observed in humans with pulmonary hypertension and in preclinical models and discuss insights gained regarding several key signaling pathways contributing to the remodeling process. In particular, we will focus on the roles of ion homeostasis, endothelin-1, serotonin, bone morphogenetic proteins, Rho kinase, and hypoxia-inducible factor 1 in pulmonary arterial smooth muscle and endothelial cells, highlighting areas of cross-talk between these pathways and potentials for therapeutic targeting.

    Topics: Animals; Bone Morphogenetic Proteins; Disease Models, Animal; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Hypoxia-Inducible Factor 1; Mice; Pulmonary Artery; Rats; rho-Associated Kinases; Serotonin; Signal Transduction

2013
Right ventricular adaptation and maladaptation in chronic pulmonary arterial hypertension.
    Cardiology clinics, 2012, Volume: 30, Issue:2

    The right ventricle (RV) is not well suited to chronic pressure overload and often fails to adequately compensate. Mechanisms that allow the RV to respond to acute pressure overload often become maladaptive and contribute to its failure, including the effects of pulmonary hypertension on RV myocardial perfusion, the influence of interventricular dependence on RV function, and metabolic shifts in the RV myocardium from fatty acid to glycolysis. Medications to treat pulmonary hypertension have focused on pulmonary vasodilatation. Their effects on RV function may determine their effectiveness. How new medications affect right ventricular performance must be addressed.

    Topics: Adaptation, Physiological; Calcium Channel Blockers; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Exercise; Familial Primary Pulmonary Hypertension; Heart Failure; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Ventricular Dysfunction, Right; Ventricular Remodeling

2012
Endothelin receptor antagonists for the treatment of pulmonary artery hypertension.
    Life sciences, 2012, Oct-15, Volume: 91, Issue:13-14

    The demonstration that endothelin production is upregulated in pulmonary artery hypertension (PAH) served as the rationale for developing endothelin-receptor antagonists (ERAs) as a treatment for PAH. This article reviews the primary studies demonstrating efficacy of ERAs in PAH.. Multicenter, placebo-controlled trials and open-label extension studies.. Two orally active ERAs are currently approved for the treatment of PAH - the dual receptor antagonist bosentan, and the more selective ET(A) receptor antagonist ambrisentan-based on multicenter randomized clinical trials demonstrating efficacy and safety. Long-term experience with both agents supports maintenance of therapeutic effects in most patients. Adverse effects, including altered liver function and edema may occur and require careful monitoring.. Despite failure to demonstrate efficacy of ERAs in other cardiopulmonary conditions, ERAs have a major role in the treatment algorithm for PAH.

    Topics: Administration, Oral; Animals; Antihypertensive Agents; Bosentan; Drug Design; Drug Monitoring; Endothelin Receptor Antagonists; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Sulfonamides

2012
Pulmonary hypertension in left heart disease.
    European respiratory review : an official journal of the European Respiratory Society, 2012, Dec-01, Volume: 21, Issue:126

    Pulmonary hypertension (PH) is a frequent complication of left heart disease arising from a wide range of cardiac disorders. In the clinical classification, PH associated with left heart disease is classified as Group 2, which includes left heart systolic dysfunction, left heart diastolic dysfunction and left heart valvular disease. In the past, rheumatic mitral valve disease was the most common cause of PH in left heart disease; however, today it is more likely to be associated with hypertensive and/or ischaemic heart disease. As the incidence of these conditions is increasing, the number of patients presenting with PH is also increasing and, today, left heart disease represents the most frequent cause of PH. The development of PH in patients with left heart disease is associated with poor prognosis. However, despite the increasingly large number of patients affected and the impact of PH on outcome, there are currently no specific treatment options for these patients. This review gives an overview of the pathophysiology and epidemiology of PH associated with left heart disease, and discusses the challenges associated with its management and treatment.

    Topics: Antihypertensive Agents; Bosentan; Echocardiography, Doppler; Electrocardiography; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Exercise Test; Heart Valve Prosthesis; Humans; Hypertension, Pulmonary; Mitral Valve; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pulmonary Wedge Pressure; Radiography, Thoracic; Stroke Volume; Sulfonamides; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Left; Weight Loss

2012
Pathways in pulmonary arterial hypertension: the future is here.
    European respiratory review : an official journal of the European Respiratory Society, 2012, Dec-01, Volume: 21, Issue:126

    It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options currently available for the management of PAH all act on one of these mechanistic pathways. However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options. This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH.

    Topics: Acetamides; Animals; Antihypertensive Agents; Benzamides; Clinical Trials as Topic; Drugs, Investigational; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Epoprostenol; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Lisuride; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Serotonin Antagonists; Sulfonamides

2012
Key role of the RhoA/Rho kinase system in pulmonary hypertension.
    Pulmonary pharmacology & therapeutics, 2011, Volume: 24, Issue:1

    Pulmonary hypertension (PH) is a general term comprising a spectrum of pulmonary hypertensive disorders which have in common an elevation of mean pulmonary arterial pressure (mPAP). The prototypical form of the disease, termed pulmonary arterial hypertension (PAH), is a rare but lethal syndrome with a complex aetiology characterised by increased pulmonary vascular resistance (PVR) and progressive elevation of mPAP; patients generally die from heart failure. Current therapies are inadequate and median survival is less than three years. PH due to chronic hypoxia (CH) is a condition separate from PAH and is strongly associated with chronic obstructive pulmonary disease (COPD). An early event in the pathogenesis of this form of PH is hypoxic pulmonary vasoconstriction (HPV), an acute homeostatic process that maintains the ventilation-perfusion ratio during alveolar hypoxia. The mechanisms underlying HPV remain controversial, but RhoA/Rho kinase (ROK)-mediated Ca²+-sensitisation is considered important. Increasing evidence also implicates RhoA/ROK in PASMC proliferation, inflammatory cell recruitment and the regulation of cell motility, all of which are involved in the pulmonary vascular remodelling occurring in all forms of PH. ROK is therefore a potential therapeutic target in treating PH of various aetiologies. Here, we examine current concepts regarding the aetiology of PAH and also PH due to CH, focusing on the contribution that RhoA/ROK-mediated processes may make to their development and on ROK inhibitors as potential therapies.

    Topics: Animals; Bone Morphogenetic Protein Receptors, Type II; Cell Proliferation; Endothelin-1; Humans; Hypertension, Pulmonary; Hypoxia; Muscle, Smooth, Vascular; NFATC Transcription Factors; rho-Associated Kinases; rhoA GTP-Binding Protein; Serotonin; Vasoconstriction

2011
Pulmonary hypertension in sarcoidosis: a review.
    Respirology (Carlton, Vic.), 2011, Volume: 16, Issue:1

    Pulmonary hypertension (PH) is a well-recognized complication of sarcoidosis. Patients with sarcoidosis-associated PH (SAPH) have poorer functional status and greater supplemental oxygen requirements than sarcoidosis patients without PH, and are more likely to be listed for lung transplantation. PH is an independent risk factor for mortality in sarcoidosis patients awaiting lung transplantation. The pathophysiology of SAPH is complex, with multiple mechanisms contributing to pathogenesis, including the fibrous destruction of the pulmonary vascular bed, extrinsic compression of the central pulmonary vessels and an intrinsic vasculopathy. Recognition of SAPH may be delayed as it can be masked by the clinical picture of underlying pulmonary sarcoidosis, and right heart catheter remains the gold-standard for diagnosis. Management of SAPH is based on reversal of resting hypoxaemia, treatment of comorbidities and treatment of the underlying sarcoidosis. The use of corticosteroids in SAPH is controversial. Specific PH therapy is not routinely recommended in SAPH as there are no successful placebo-controlled trials, although there is limited data to suggest that endothelin receptor antagonists and phosphodiesterase-5 inhibitors may be useful.

    Topics: Cardiomyopathies; Endothelin-1; Humans; Hypertension, Pulmonary; Lung; Natriuretic Peptide, Brain; Sarcoidosis, Pulmonary; Ultrasonography; Vasoconstriction

2011
Bosentan for the treatment of adult pulmonary hypertension.
    Future cardiology, 2011, Volume: 7, Issue:1

    Pulmonary hypertension is a severe progressive disease with a marked morbidity and a high mortality attributed to right heart failure. Bosentan, a dual endothelin receptor antagonist, is an effective and well-tolerated oral therapy for the management of pulmonary arterial hypertension (PAH; WHO group 1 pulmonary hypertension). Bosentan improves cardiopulmonary hemodynamics, exercise capacity, WHO functional class and quality of life, as well as delaying time to clinical worsening in patients with PAH. This article reviews the role of endothelin-1 in the pathogenesis and progression of PAH, the diagnosis of PAH and the pharmacology of bosentan, and summarizes the current available evidence for the safety and efficacy of bosentan for the treatment of PAH as a monotherapy and combination therapy, as well as its role in the management of other forms of pulmonary hypertension.

    Topics: Antihypertensive Agents; Bosentan; Comorbidity; Disease Progression; Endothelin Receptor Antagonists; Endothelin-1; Exercise Tolerance; Hemodynamics; Humans; Hypertension, Pulmonary; Prognosis; Quality of Life; Receptors, Endothelin; Sulfonamides

2011
The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension.
    Pharmacological research, 2011, Volume: 63, Issue:6

    The term pulmonary arterial hypertension (PAH) describes a rare group of diseases characterized by raised pulmonary vascular resistance, resulting from vascular remodelling in the pre-capillary resistance arterioles (< 100 mm). Left untreated, patients die from right heart failure, with a mortality approaching most serious cancers. Endothelin-1(ET-1) is not only a potent vasoconstrictor, but causes proliferation of many of the vascular cells involved in vascular remodelling. Although produced mainly by the vascular endothelium, other cells such as smooth muscle, fibroblasts and macrophages are known sources of ET-1 when these cells are challenged by relevant stimuli. Plasma ET-1 levels are raised in patients with PAH and correlate with important clinical outcomes. Furthermore, ET-1 receptor antagonism has been demonstrated to improve both morbidity and mortality in conditions associated with PAH. We review the literature supporting the role for ET-1 in the pathogenesis of PAH.

    Topics: Animals; Clinical Trials as Topic; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Receptors, Endothelin; Vascular Resistance

2011
Genomics of pulmonary arterial hypertension: implications for therapy.
    Heart failure clinics, 2010, Volume: 6, Issue:1

    Pulmonary arterial hypertension (PAH) remains a vexing clinical disease with no cure. Despite advances and the discovery of a gene (BMPR2) associated with many of the hereditary forms of the disease, and some cases not previously known to be inherited, the reasons for mutations in this gene as a cause remain somewhat elusive. Clearly, a complex interplay exists between genetic alterations, environmental exposures (including infections), and disease development. This article addresses the advances in the genetics of PAH, including the identification of genetic etiologies and modulators, and the role of genetics in predicting disease progression and targeting therapeutics.

    Topics: Animals; Biomarkers; Bone Morphogenetic Protein Receptors, Type II; Disease Progression; Endothelin-1; Gene Expression; Humans; Hypertension, Pulmonary; Nitric Oxide; Oligonucleotide Array Sequence Analysis; Proteomics; Vasodilation

2010
The role of Endothelin-1 in obstructive sleep apnea syndrome and pulmonary arterial hypertension: pathogenesis and Endothelin-1 antagonists.
    Current medicinal chemistry, 2010, Volume: 17, Issue:11

    Obstructive Sleep Apnea Syndrome (OSAS) is a recognized risk factor for cardiovascular disorders and in some cases is complicated with Pulmonary Arterial Hypertension (PAH), as the endothelium is affected. Recent studies provide strong evidence for endothelial dysfunction in obstructive sleep apnea. The resultant vasoconstriction, abnormal cell proliferation and hyper-coagulability may lead to the initiation or progression of atherosclerotic cardiovascular and cerebrovascular disorders, which are frequently encountered in OSA patients. While the currently available therapies for OSAS, such as Continuous Positive Airway Pressure therapy (CPAP therapy), improve endothelial dysfunction, they are not well-tolerated by patients. CPAP therapy can reduce nocturnal hypoxemias and decrease noradrenaline circulating levels, but does not affect ET-1 plasma levels. Potent and selective Endothelin-1 receptor antagonists have been developed and have shown promising results in the treatment of cardiovascular diseases such as pulmonary arterial hypertension, acute and chronic heart failure, hypertension, renal failure, and atherosclerosis. However, results are often contrasting and complicated because of the tissue-specific vasoconstrictor actions of Endothelin-B receptors and the fact that endothelin is an autocrine and paracrine factor whose activity is difficult to measure in vivo.

    Topics: Continuous Positive Airway Pressure; Endothelin-1; Humans; Hypertension, Pulmonary; Receptors, Endothelin; Sleep Apnea, Obstructive

2010
Pulmonary hypertension in children: a historical overview.
    Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies, 2010, Volume: 11, Issue:2 Suppl

    Pulmonary arterial hypertension in children contributes significantly to morbidity and mortality in diverse pediatric cardiac, lung, hematologic, and other diseases. Pulmonary arterial hypertension is generally a disease of small pulmonary arteries characterized by vascular narrowing due to high-tone and abnormal vasoreactivity, structural remodeling of the vessel wall, intraluminal obstruction, and decreased vascular growth and surface area. Without therapy, high pulmonary vascular resistance contributes to progressive right ventricular failure, low cardiac output, and death. Advances in basic pulmonary vascular biology over the last few decades have led directly to several novel therapies, which have significantly expanded therapeutic choices and have led to improved survival and quality of life of many children with pulmonary arterial hypertension. Despite these improvements, long-term outcomes in many settings remain guarded and substantial challenges persist, especially with regard to understanding mechanisms and approach to structural remodeling of severe pulmonary arterial hypertension.

    Topics: Antihypertensive Agents; Child; Endothelin-1; Humans; Hypertension, Pulmonary; Nitric Oxide; Pulmonary Artery; Quality of Life; Vascular Resistance; Vasodilator Agents

2010
[Endothelin antagonists and their role in pharmacotherapy].
    Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego, 2010, Volume: 28, Issue:167

    Endotelina (ET-1) is the polypeptide about wide spectrum of physiological effects, involved in pathophysiology of cardiovascular and neoplastic diseases. Thus, ET-1 blocking becomes modern therapeutic target. The endothelin receptor antagonists (ERA)--sentans are the intensely studied agents, already approved for an alternative pulmonary hypertension therapy and hormone-resistant prostate cancer treatment. The promising results of conducted clinical trials suggest the possible extension of ERA application in other clinical entities in the close future. The article shortly describes present studied endothelin receptor antagonists and rationale for their introduction to the general clinical practice.

    Topics: Animals; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Male; Prostatic Neoplasms

2010
[Pulmonary arterial hypertension related to systemic sclerosis in 2008].
    Journal des maladies vasculaires, 2009, Volume: 34, Issue:1

    Systemic sclerosis-related pulmonary arterial hypertension (PAH) is a severe disease affecting about 1000 patients in France. In 2008, all scleroderma patients are screened for PAH by a yearly cardiac Doppler ultrasonography. The pathogenesis of systemic sclerosis-related PAH is poorly known but it seems that besides common arteriolar remodeling (media hypertrophy, intimal thickening, endothelial proliferation), venular lesions suggesting obstructive venous disease and inflammatory lesions may be also be involved. Prostacyclin and analogues, phosphodiesterase-5 inhibitors (sildenafil) and endothelin-1 receptor antagonists are proposed as specific treatments for systemic sclerosis-related PAH. Unlike bosentan, which is non-selective, inhibiting both ETA and ETB receptors, sodium sitaxentan is highly selective for ETA receptors; this could favor pulmonary vasodilation.

    Topics: Altitude; Antihypertensive Agents; Bosentan; Echocardiography; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; France; Humans; Hypertension, Pulmonary; Hypoxia; Oxygen; Phosphodiesterase 5 Inhibitors; Prognosis; Scleroderma, Systemic; Sulfonamides

2009
Endothelin receptor blockade in the management of pulmonary arterial hypertension: selective and dual antagonism.
    Respiratory medicine, 2009, Volume: 103, Issue:7

    Various treatments approved by the United States Food and Drug Administration for the management of pulmonary arterial hypertension (PAH) target three of the many pathways implicated in the development of PAH: prostacyclin-, endothelin-1 (ET-1)-, and nitric oxide-mediated pathways. The objectives of this manuscript are to provide background information on the role of ET-1 in the pathogenesis of PAH, to provide theoretical considerations for the advantages and disadvantages of dual vs single endothelin receptor antagonists (ERAs) for the management of PAH, and to describe the clinical study results from randomized, double-blind, placebo-controlled trials for the various ERAs. ET receptors (ET(A) and ET(B)) have different densities and distributions throughout the body and are dynamically regulated, such that blockade of ET(A) and ET(B) receptors may have different results in normal vs pathological conditions. Although differences in biological effects can be found in studies of isolated cells, blood vessels and animal models, clinical treatment studies have not identified clear differences in efficacy among the various ERAs. The main differences appear to be in safety profiles, with a greater frequency of serum liver function abnormalities occurring with the available dual ET(A)/ET(B) antagonist, and possibly higher rates of peripheral edema noted with selective ET(A) agents. Head-to-head studies will be necessary to resolve the question of whether single vs dual blockade produces better clinical results with fewer side effects in patients with PAH.

    Topics: Endothelial Cells; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Pulmonary Artery; Randomized Controlled Trials as Topic; Receptor Cross-Talk; Receptor, Endothelin A; Receptor, Endothelin B; United States; Vasoconstriction; Vasodilation

2009
The science of endothelin-1 and endothelin receptor antagonists in the management of pulmonary arterial hypertension: current understanding and future studies.
    European journal of clinical investigation, 2009, Volume: 39 Suppl 2

    Pathological vascular remodelling is a key contributor to the symptomatology of pulmonary arterial hypertension (PAH), and reversing this process may offer the best hope for improving this debilitating condition. The vascular remodelling process is believed to be due to endothelial cell dysfunction and to involve altered production of endothelial cell-derived vasoactive mediators. The observation that circulating plasma levels of the vasoactive peptide endothelin (ET)-1 are raised in patients with PAH, and that ET-1 production is increased in the pulmonary tissue of affected individuals, makes it a particularly interesting target for a therapeutic intervention in PAH. Clinical trials with ET receptor antagonists (ETRAs) show that they provide symptomatic benefit in patients with PAH, thereby proving the clinical relevance of the ET system as a therapeutic target. In this paper, we review the role of ET-1 together with the available data on the roles of the specific ET receptors and ETRAs in PAH. In particular, we discuss the possible role of ET receptor selectivity in the vascular remodelling process in PAH and whether selective ET(A) or nonselective ET(A)/ET(B) blockade offers the greatest potential to improve symptoms and alter the clinical course of the disease.

    Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Randomized Controlled Trials as Topic; Vasodilation

2009
Pulmonary hypertension complicating congenital heart disease.
    Current cardiology reports, 2009, Volume: 11, Issue:4

    Congenital heart disease can predispose individuals to pulmonary vascular remodeling as a result of the abnormality in pulmonary blood flow and pressure that accompanies the specific congenital defect being considered. Pulmonary arterial hypertension associated with congenital heart defects is an important determinant of functional capacity and survival, especially when the Eisenmenger's state of reversed shunt is present. The likelihood of right ventricular dysfunction and failure increases with the degree of pulmonary artery pressure. Thus, the aim of disease management in this patient population should be to prevent or improve right heart failure. Current therapies that modify the progression of pulmonary vascular disease-including endothelin-1 receptor antagonists, phosphodiesterase-5 inhibitors, and prostanoids-should be considered carefully in patients with congenital heart disease-associated pulmonary hypertension. The risks and benefits of altering the balance of pulmonary vascular resistance to systemic vascular resistance must be weighed for each patient.

    Topics: Antihypertensive Agents; Endothelin-1; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Randomized Controlled Trials as Topic; Survival; Ventricular Dysfunction, Right

2009
The endothelin system in pulmonary and renal vasculopathy: les liaisons dangereuses.
    European respiratory review : an official journal of the European Respiratory Society, 2009, Volume: 18, Issue:114

    Endothelial cells regulate vascular tone largely by the actions of endothelin-1. Endothelin-1 is a potent vasoconstrictor, with effects that are dependent on the receptors to which it binds as well as their location. Endothelin-1 dysregulation is implicated in pathological conditions, including those of the pulmonary vasculature and the kidney. In this review, we describe the physiology and actions of endothelin-1 in lung and renal tissues and discuss therapies that disrupt these interactions in disease states. We provide an overview of the current clinical progress of these targeted agents and provide perspectives on the treatment of pulmonary and renal diseases with endothelin receptor antagonists.

    Topics: Endothelin A Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Hypertension, Renal

2009
Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter?
    European heart journal, 2008, Volume: 29, Issue:16

    Treatment options for pulmonary arterial hypertension (PAH) have considerably improved in the past few years. Endothelin (ET)-receptor antagonism has been established as a first-line option for the majority of PAH patients. Endothelin-receptor antagonists (ETRAs) comprise sulfonamide and non-sulfonamide agents with different affinities for ET-receptor subtypes (ET(A) and ET(B)), and the focus of development has shifted from drugs with less selectivity to those with high selectivity. There is ongoing debate as to whether selective or non-selective ET-receptor antagonism is more beneficial in the treatment of PAH. This paper reviews the current evidence from experimental and clinical studies obtained from a thorough literature search focusing on the three marketed drugs bosentan, sitaxentan, and ambrisentan. A clinically meaningful difference among the three approved ETRAs with respect to their ET-receptor selectivity could not be demonstrated to date. Therefore, in clinical practice, other features are likely to be of greater relevance when considering treatment, such as the potential for serious drug-drug interactions, convenience of dosing schedule, or rates of limiting side effects. These characteristics bear more relation to the chemical or pharmacological properties of the drugs than to receptor selectivity itself.

    Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Male; Phenylpropionates; Pulmonary Artery; Pyridazines; Randomized Controlled Trials as Topic; Sulfonamides; Thiophenes; Treatment Outcome; Vascular Resistance; Walking

2008
Bosentan for idiopathic pulmonary fibrosis.
    Current opinion in investigational drugs (London, England : 2000), 2008, Volume: 9, Issue:11

    Idiopathic pulmonary fibrosis (IPF) is a debilitating, fatal, chronic fibrosing lung disease with no known effective therapy. Endothelin-1 may underlie the pathogenesis of lung fibrosis, therefore it was hypothesized that the oral dual endothelin receptor antagonist bosentan may have efficacy for the treatment of IPF. The BUILD-1 study evaluated the efficacy, safety and tolerability of bosentan in patients with IPF. Bosentan was associated with a trend toward delayed time to disease progression or death and improvement in quality-of-life, both of which were more pronounced in patients with a biopsy-confirmed IPF diagnosis. These observations are being investigated in the ongoing BUILD-3 trial.

    Topics: Animals; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Pulmonary Fibrosis; Randomized Controlled Trials as Topic; Sulfonamides

2008
Management of pulmonary arterial hypertension with a focus on combination therapies.
    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 2007, Volume: 26, Issue:5

    Pulmonary arterial hypertension (PAH) is a rare but frequently fatal condition marked by vasoconstriction and vascular remodeling within small pulmonary arteries. The pathobiology of PAH involves imbalances in a multitude of endogenous mediators, which promote aberrant cellular growth, vasoconstriction and hemostasis within the pulmonary vascular tree. The mechanisms promoting these pathologic effects are complex. This complexity is highlighted by the many overlapping secondary messenger systems through which these mediators work. In light of this natural redundancy, it is not surprising that many of the drugs used to treat PAH, which have shown short-term efficacy, fall "short of the mark" in reversing or halting the progression of this disease in the long run. This very redundancy in pathways makes the case for the use of combination of drugs with differing mechanisms of action to treat PAH. Similar to what is now accepted as the standard of care for the treatment of cancer and left ventricular dysfunction, combination therapy has the greatest promise for inducing the most complete vascular remodeling of the pulmonary vasculature by "shutting down" as many of these pathologic pathways as possible. Combination therapies involving existing therapies or new agents with improved pharmacokinetic and/or pharmacodynamic properties represent an emerging clinical paradigm for patients with sub-optimally managed disease. As emerging data in this field of therapy comes to fruition, further reductions in the morbidity and mortality associated with PAH will manifest. The goal of this report is to review the philosophy of combination therapy and present the available data in this area of study.

    Topics: Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Endothelin-1; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Piperazines; Pulmonary Artery; Purines; Randomized Controlled Trials as Topic; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Analysis

2007
[Bosentan for treatment of heart failure].
    Nihon rinsho. Japanese journal of clinical medicine, 2007, May-28, Volume: 65 Suppl 5

    Topics: Animals; Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Sulfonamides; Ventricular Remodeling

2007
A review of pulmonary arterial hypertension: role of ambrisentan.
    Vascular health and risk management, 2007, Volume: 3, Issue:1

    Pulmonary arterial hypertension (PAH) is a rare fatal disease. Current disease-specific therapeutic interventions in PAH target 1 of 3 established pathways in disease pathobiology: prostacyclin, nitric oxide, and endothelin-1. Endothelin receptor antagonists (ERAs) act on the endothelin pathway by blocking binding of endothelin-1 to its receptors (endothelin type-A [ET(A)] and/or type-B [ET(B)]) on the surface of endothelial and smooth muscle cells. Ambrisentan is an oral, once-daily, ET(A)-selective ERA in development for the treatment of PAH. In Phase 3 clinical trials in patients with PAH, ambrisentan (2.5-10 mg orally once-daily) improved exercise capacity, Borg dyspnea index, time to clinical worsening, WHO functional class, and quality of life compared with placebo. Ambrisentan provided durable (at least 2 years) improvement in exercise capacity in a Phase 2 long-term extension study. Ambrisentan was well tolerated with a lower incidence and severity of liver function test abnormalities compared with the ET(A)/ET(B) ERA, bosentan, and the ET(A)-selective ERA, sitaxsentan. Ambrisentan does not induce or inhibit P450 enzymes; therefore, ambrisentan is unlikely to affect the pharmacokinetics of P450-metabolized drugs. The demonstration of clinical efficacy, low incidence of acute hepatic toxicity, and low risk of drug-drug interactions support the role of ambrisentan for the treatment of PAH.

    Topics: Endothelin Receptor Antagonists; Endothelin-1; Exercise; Humans; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Phenylpropionates; Pulmonary Wedge Pressure; Pyridazines; Receptors, Endothelin; Treatment Outcome; Vascular Resistance

2007
Pediatric pulmonary hypertension: Roles of endothelin-1 and nitric oxide.
    Clinical hemorheology and microcirculation, 2007, Volume: 37, Issue:1-2

    An increasing number of studies implicate oxidative stress in the development of endothelial dysfunction and the pathogenesis of cardiovascular disease. Further, this oxidative stress has been shown to be associated with alterations in both the endothelin-1 (ET-1) and nitric oxide (NO) signaling pathways such that bioavailable NO is decreased and ET-1 signaling is potentiated. However, recent data, from our groups and others, have shown that oxidative stress, ET-1, and NO are co-regulated in a complex fashion that appears to be dependent on the cellular levels of each species. Thus, when ROS levels are transiently elevated, NO signaling is potentiated through transcriptional, post-transcriptional, and post-translational mechanisms. However, in pediatric pulmonary hypertensive disorders, when reactive oxygen species (ROS) increases are sustained by ET-1 mediated activation of smooth muscle cell ET(A) subtype receptors, NOS gene expression and NO signaling are reduced. Further, increases in oxidative stress can stimulate both the expression of the ET-1 gene and the secretion of the ET-1 peptide. Thus, this manuscript will review the available data regarding the interaction of NO, ET-1, and ROS in the endothelial dysfunction of pediatric pulmonary hypertension. In addition, we will suggest avenues of both basic and clinical research that will be important to develop novel pulmonary hypertension treatment and prevention strategies.

    Topics: Child; Endothelin-1; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Nitric Oxide; Oxidative Stress; Reactive Oxygen Species

2007
Review of bosentan in the management of pulmonary arterial hypertension.
    Vascular health and risk management, 2007, Volume: 3, Issue:6

    The dual endothelin receptor antagonist, bosentan, is an orally active therapy, which is effective in the treatment of pulmonary arterial hypertension (PAH). This review critically appraises the evidence for the efficacy of bosentan in idiopathic and familial PAH, in PAH associated with connective tissue disease and in PAH which may develop in association with other conditions. Data from the pivotal placebo controlled studies and their open labeled extensions as well as long term survival and quality of life data is presented. Data is also presented on the potential benefit of bosentan in patients with inoperable chronic thromboembolic pulmonary hypertension. The safety and tolerability of bosentan as well as drug interactions are discussed. Dosage recommendations in adults and pediatrics are presented. An algorithm is provided to guide the reader in monitoring potential increases in alanine and aspartate transaminase levels that may occur with bosentan use and the dose adjustments that are recommended as a result of any increase in the levels of these enzymes are shown. Finally, the role of bosentan as part of combination therapy in PAH is examined.

    Topics: Antihypertensive Agents; Bosentan; Connective Tissue Diseases; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Endothelin-1; Humans; Hypertension, Pulmonary; Pediatrics; Quality of Life; Sulfonamides

2007
Pulmonary arterial hypertension.
    Current opinion in critical care, 2006, Volume: 12, Issue:3

    The prevalence of pulmonary arterial hypertension is rising worldwide. Significant progress in our understanding of the pathobiology of pulmonary arterial hypertension has resulted in a shift from vasodilator therapy to the development of specific drugs targeting seminal molecular derangements of this disorder. This review highlights the recent advances in treatment and provides directions for the future care.. Induction of endothelin-1 and decreased transcription of nitric oxide and prostacyclin leads to pulmonary vasoconstriction that triggers several downstream molecular events which result in pulmonary vascular remodeling. Treatment with endothelin receptor antagonists, prostanoids and phosphodiesterase-5 inhibitors that prevent breakdown of cGMP have all demonstrated benefits in prospective, randomized, controlled trials of pulmonary arterial hypertension patients. Future strategies will combine these therapies to explore whether targeting more than one pathway provides synergistic long-term benefit.. Treatment guidelines developed by the American College of Chest Physicians aim to ensure that evidence-based approaches are practiced. Because of genetic heterogeneity in treatment effects and outcomes among patients, pharmacogenetics which will study polymorphisms that modulate the response to treatment will enable physicians to deliver cost-effective, tailored treatments for all pulmonary arterial hypertension patients in the future.

    Topics: Antihypertensive Agents; Drug Therapy, Combination; Endothelin-1; Epoprostenol; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Nitric Oxide; Pulmonary Artery; Randomized Controlled Trials as Topic

2006
Current understanding of the role of bosentan in inoperable chronic thromboembolic pulmonary hypertension.
    Expert opinion on pharmacotherapy, 2006, Volume: 7, Issue:9

    Chronic thromboembolic pulmonary hypertension may occur in the context of incomplete lysis of acute pulmonary emboli, resulting in the obstruction of pulmonary blood flow, as well as progressive right ventricular dysfunction and failure. The treatment of choice for this condition is surgical removal of the obstructing material. However, in many patients, surgery is not possible due to either an unfavourable distribution of the disease, the development of a concurrent small vessel pulmonary arteriopathy, or the presence of significant comorbid conditions. There is increasing evidence that the medical therapies that are used in other forms of pulmonary hypertension may also be effective in inoperable chronic thromboembolic pulmonary hypertension. This article examines the rationale for the use of the oral dual endothelin receptor antagonist bosentan in this life-threatening condition.

    Topics: Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Drug Administration Schedule; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Receptors, Endothelin; Sulfonamides

2006
Pulmonary hypertension in chronic dialysis patients with arteriovenous fistula: pathogenesis and therapeutic prospective.
    Current opinion in nephrology and hypertension, 2006, Volume: 15, Issue:4

    End-stage renal disease patients receiving chronic haemodialysis via arteriovenous access often develop various cardiovascular complications, including vascular calcification, cardiac-vascular calcification and atherosclerotic coronary disease. This review describes recently published studies that demonstrate a high incidence of pulmonary hypertension among patients with end-stage renal disease receiving long-term haemodialysis via a surgical arteriovenous fistula. Both end-stage renal disease and long-term haemodialysis via arteriovenous fistula may be involved in the pathogenesis of pulmonary hypertension by affecting pulmonary vascular resistance and cardiac output.. Morbidity and mortality from cardiovascular disease are greatly increased in patients on maintenance haemodialysis therapy. Using Doppler echocardiography, we found a significant increase in cardiac output in 40% of chronic haemodialysis patients, probably related to the large arteriovenous access or altered vascular resistance as a result of the local vascular tone and function expressed by the imbalance between vasodilators such as nitric oxide, and vasoconstrictors such as endothelin-1.. We propose different potential mechanisms as explanations for the development of pulmonary hypertension. Hormonal and metabolic derangement associated with end-stage renal disease might lead to pulmonary arterial vasoconstriction and an increase in pulmonary vascular resistance. Pulmonary arterial pressure may be further increased by high cardiac output resulting from the arteriole-venous access itself, worsened by commonly occurring anaemia and fluid overload.

    Topics: Adult; Aged; Blood Pressure; Calcinosis; Cardiac Output; Echocardiography, Doppler; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Pulmonary Artery; Renal Dialysis; Time Factors; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

2006
[Endothelin].
    Nihon rinsho. Japanese journal of clinical medicine, 2006, Volume: 64 Suppl 5

    Topics: Animals; Antihypertensive Agents; Bosentan; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension; Hypertension, Pulmonary; Receptors, Endothelin; Sulfonamides

2006
Dual ET(A)/ET(B) vs. selective ET(A) endothelin receptor antagonism in patients with pulmonary hypertension.
    European journal of clinical investigation, 2006, Volume: 36 Suppl 3

    Since the identification of endothelin as a key mediator in the pathogenesis of several diseases, including pulmonary arterial hypertension (PAH), the pharmacologic control of the activated endothelin system with endothelin receptor antagonists (ETRA) has been a major therapeutic achievement for the treatment of patients with PAH. To date, dual ET(A)/ET(B) and selective ET(A) receptor antagonists have clinically been evaluated. To answer the question of whether selective or dual ETRA is preferable in patients with PAH, experimental and clinical data with relevance to the pulmonary circulation are reviewed in this article. Whereas experimental and clinical data provide unambiguous evidence that ET(A) receptors mediate the detrimental effects of ET-1, such as vasoconstriction and cell proliferation, the elucidation of the role of ET(B) receptors has been more complex. It has been shown that there is a subpopulation of ET(B) receptors on smooth muscle cells and fibroblasts mediating vasoconstriction and proliferation. On the contrary, there is clear evidence that endothelial ET(B) receptors continue to mediate vasodilation, vasoprotection and ET-1 clearance despite the pathology associated with pulmonary hypertension. More difficult to assess is the net effect of these mechanisms in patients to be treated with ETRA. When considering the available data from controlled clinical trials, nonselectivity does not appear to carry a relevant clinical benefit for the treatment of patients with PAH when compared with selective ET(A) receptor antagonism.

    Topics: Antihypertensive Agents; Bosentan; Cell Division; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Isoxazoles; Lung; Pulmonary Fibrosis; Sulfonamides; Thiophenes; Vasoconstriction; Vasodilation

2006
Endothelin and endothelin receptor antagonism in portopulmonary hypertension.
    European journal of clinical investigation, 2006, Volume: 36 Suppl 3

    Portopulmonary hypertension (PPHT) is a rare but devastating complication in patients with portal hypertension, characterized by pulmonary arterial obliterative disease with a concomitant rise in pulmonary vascular resistance. A broad body of evidence has accumulated, indicating that endothelin (ET) peptides and their cognate receptors are causally involved in the pathophysiology of pulmonary arterial hypertension (PAH) owing to different aetiologies, including PPHT. In addition, the ET system may be involved in hepatic fibrotic remodelling and portal hypertension. Several experimental models have provided evidence that ET receptor antagonism may have therapeutic potential in PPHT. Initial experience has accumulated during the last 2 years, suggesting that targeting the ET system may have beneficial effects in the clinical setting. In these studies, the orally active, dual ET receptor antagonist bosentan improved pulmonary haemodynamics and functional capacity. These effects were sustained and occurred in the absence of adverse events. If these observations can be corroborated by controlled clinical trials, bosentan would offer several advantages over available therapies, which have major drawbacks owing to their invasive and demanding mode of application.

    Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Liver Transplantation; Pulmonary Circulation; Sulfonamides; Treatment Outcome

2006
Oxidative and nitrosative stress in pediatric pulmonary hypertension: roles of endothelin-1 and nitric oxide.
    Vascular pharmacology, 2006, Volume: 45, Issue:5

    An increasing number of studies implicate oxidative stress in the development of endothelial dysfunction and the pathogenesis of cardiovascular disease. Further, this oxidative stress has been shown to be associated with alterations in both the endothelin-1 (ET-1) and nitric oxide (NO) signaling pathways such that bioavailable NO is decreased and ET-1 signaling is potentiated. However, recent data, from our groups and others, have shown that oxidative stress, ET-1, and NO are co-regulated in a complex fashion that appears to be dependent on the cellular levels of each species. Thus, when ROS levels are transiently elevated, NO signaling is potentiated through transcriptional, post-transcriptional, and post-translational mechanisms. However, in pediatric pulmonary hypertensive disorders, when reactive oxygen species (ROS) increases are sustained by ET-1 mediated activation of smooth muscle cell ET(A) subtype receptors, NOS gene expression and NO signaling are reduced. Further, increases in oxidative stress can stimulate both the expression of the ET-1 gene and the secretion of the ET-1 peptide. Finally, the addition of exogenous NO, and increasingly utilized therapy for pulmonary hypertension, can also lead to increases ROS generation via the activation of ROS generating enzymes and through the induction of mitochondrial dysfunction. Thus, this manuscript will review the available data regarding the interaction of oxidative and nitrosative stress, endothelial dysfunction, and its role in the pathophysiology of pediatric pulmonary hypertension. In addition, we will suggest avenues of both basic and clinical research that will be important to develop novel pulmonary hypertension treatment and prevention strategies, and resolve some of the remaining clinical issues regarding the use of NO augmentation.

    Topics: Administration, Inhalation; Animals; Child; Child, Preschool; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Nitric Oxide; Nitric Oxide Donors; Nitrosation; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species; Vascular Resistance

2006
Pharmacologic treatment for pulmonary arterial hypertension.
    Current opinion in cardiology, 2006, Volume: 21, Issue:6

    Pulmonary arterial hypertension (PAH) has been a disease with limited treatment options and poor prognosis. This article reviews the recent advances that took place in the medical management of PAH.. Sildenafil is a type 5 cGMP-specific phosphodiesterase inhibitor originally developed to treat erectile dysfunction. Multiple uncontrolled and randomized controlled trials have proven that it is useful in the treatment of PAH and it was approved by the US Food and Drug Administration. The switch from continuous intravenous infusion of epoprostenol to subcutaneous infusion of treprostinil has been proven feasible and safe. Bosentan has been shown effective as a monotherapy and it also improves survival in patients with functional classes III and IV. In smaller clinical trials bosentan has improved symptoms in different forms of PAH. Combinations of drugs of different classes such as prostanoids, endothelin receptor blockers and sildenafil are tested, and such a strategy improves both symptoms and survival. Animal models and anecdotal clinical experience suggest the possibility of using imatinib mesylate in PAH.. With the approval of sildenafil, treatment options for this difficult disease have improved significantly. Combinations of drugs of different groups are promising and need further exploration.

    Topics: Antihypertensive Agents; Bosentan; Disease Progression; Drug Therapy, Combination; Endothelin-1; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Prognosis; Prostaglandins; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

2006
Pulmonary hypertension in high-altitude dwellers: novel mechanisms, unsuspected predisposing factors.
    Advances in experimental medicine and biology, 2006, Volume: 588

    Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease states in general. Over the past decade, studies involving short-term hypoxic exposure have greatly advanced our knowledge regarding underlying mechanisms and predisposing events of hypoxic pulmonary hypertension. Studies in high altitude pulmonary edema (HAPE)-prone subjects, a condition characterized by exaggerated hypoxic pulmonary hypertension, have provided evidence for the central role of pulmonary vascular endothelial and respiratory epithelial nitric oxide (NO) for pulmonary artery pressure homeostasis. More recently, it has been shown that pathological events during the perinatal period (possibly by impairing pulmonary NO synthesis), predispose to exaggerated hypoxic pulmonary hypertension later in life. In an attempt to translate some of this new knowledge to the understanding of underlying mechanisms and predisposing events of chronic hypoxic pulmonary hypertension, we have recently initiated a series of studies among high-risk subpopulations (experiments of nature) of high-altitude dwellers. These studies have allowed to identify novel risk factors and underlying mechanisms that may predispose to sustained hypoxic pulmonary hypertension. The aim of this article is to briefly review this new data, and demonstrate that insufficient NO synthesis/bioavailability, possibly related in part to augmented oxidative stress, may represent an important underlying mechanism predisposing to pulmonary hypertension in high-altitude dwellers.

    Topics: Altitude; Altitude Sickness; Blood Pressure; Disease Susceptibility; Down Syndrome; Endothelin-1; Humans; Hypertension; Hypertension, Pulmonary; Models, Biological; Mountaineering; Nitric Oxide; Polycythemia; Pulmonary Artery; Pulmonary Circulation

2006
[Treatment of pulmonary arterial hypertension: endothelin-receptor antagonists].
    Deutsche medizinische Wochenschrift (1946), 2006, Dec-08, Volume: 131, Issue:49 Suppl 9

    Endothelin-1 (ET-1) is of significance in the pathophysiology and prognosis of pulmonary hypertension (PHT). Bosentan, an endothelin-receptor antagonist, currently plays a central role in the treatment of PHT, because it improves exercise capacity, hemodynamics, clinical symptoms and right ventricular function, achieving a survival duration of 2- 3 years. Bosentan causes an increase of transaminases in about 10% of patients, but this effect is reversible on dosage reduction or discontinuing the medication. However, transaminases should be measured every 4 weeks while patients are on bosentan. Almost all current guidelines list bosentan as of equal value to sildenafil or prostacyclin analogues in the first-line treatment of patients in NYHA functional class III and also, with narrower indications, of those in class IV.

    Topics: Algorithms; Antihypertensive Agents; Bosentan; Drug Interactions; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Pyridazines; Sulfonamides; Survival Rate; Thiophenes

2006
Endothelin receptor antagonism in pulmonary arterial hypertension--a role for selective ET(A) inhibition?
    Current medical research and opinion, 2006, Volume: 22, Issue:12

    Pulmonary arterial hypertension (PAH) develops from an abnormal interaction between the endothelium and smooth muscle cells in the pulmonary arteries and is characterized by a progressive increase in pulmonary vascular resistance resulting from vascular remodeling, vasoconstriction, and cellular proliferation. A rapidly progressive disease with limited therapeutic options, PAH may progress to right ventricular failure and death. Endothelin (ET-1), a potent vasoconstrictor, has vascular remodeling properties that contribute to the acceleration of the disease. ET-1 predominantly binds to two receptors, endothelin-A (ET(A)) and endothelin-B (ET(B)) receptors. ET(A) receptors are found on smooth muscle cells only and, when activated, induce vasoconstriction and cellular proliferation. ET(B) receptors on smooth muscle cells, when activated, cause vasoconstriction, whereas those on endothelial cells produce vasodilation and clear circulating ET-1. Therefore, a clinically important question arises as to whether selective ET(A) receptor antagonism is superior to nonselective dual-receptor antagonism in the treatment of PAH.. To review clinical trials that studied safety and efficacy of various endothelin receptor antagonists (ETRAs) for the treatment of PAH and address the rationale for the use of either a nonselective or a selective ETRA.. Nonselective blockade of both ET receptors with the ETRA bosentan has demonstrated benefit in PAH, as have sitaxsentan and ambrisentan, two investigational agents with more selectivity for the ET(A) receptor. Data from placebo-controlled studies and long-term, open-label studies suggest that all ETRAs have similar efficacy, though there is some evidence suggesting that selective ETRAs may have a safer profile.. Both selective and nonselective ETRAs have proven to be efficacious in treatment of PAH patients, and selective ETRAs may have a slightly safer profile. However, because PAH is a rare disease and trials have relatively small numbers of patients, it is difficult to quantify the magnitude of the difference between the different agents.

    Topics: Clinical Trials as Topic; Endothelin A Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Sulfonamides; Thiophenes

2006
[Endothelium pharmacology in pulmonary hypertension].
    Kardiologia polska, 2005, Volume: 63, Issue:4 Suppl 2

    The dysfunction of lung endothelium is crucial in the development of pulmonary hypertension. Dysfunction of endothelial synthesis of prostacyclin (PGI2) and nitric oxide (NO) and increased activity of endothelin 1 (ET-1) are connected to the progress of the disease. In this review the authors describe three major mediators of pulmonary endothelium: NO, PGI2 and ET-1. Their role in pulmonary hypertension and possibilities of pharmacological modulation of their activity are also discussed.

    Topics: Animals; Calcium Channel Blockers; Disease Progression; Endothelin-1; Endothelium; Epoprostenol; Humans; Hypertension, Pulmonary; Lung; Nitric Oxide; Phosphodiesterase Inhibitors; Platelet Aggregation Inhibitors

2005
Endothelin-1 in congenital heart disease.
    Pediatric research, 2005, Volume: 57, Issue:5 Pt 2

    Endothelin-1 (ET-1) is a 21-amino acid polypeptide produced primarily by vascular endothelial cells. First discovered in 1988 as a potent vasoconstrictor, it has subsequently been appreciated to participate in several biologic activities, including vascular smooth muscle proliferation, fibrosis, cardiac and vascular hypertrophy, and inflammation. Increasing data demonstrate alterations in ET-1 signaling in newborns, infants, and children with congenital heart defects that are associated with alterations in pulmonary blood flow. This review outlines the pathophysiologic role of the ET-1 cascade in the development of altered pulmonary vascular tone and reactivity that occurs with congenital heart disease and its repair, following the use of cardiopulmonary bypass. In addition, therapeutic implications for the use of novel ET receptor antagonists will be emphasized.

    Topics: Animals; Cardiopulmonary Bypass; Child, Preschool; Endothelin Receptor Antagonists; Endothelin-1; Heart Diseases; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Inflammation; Models, Biological; Peptides; Pulmonary Circulation; Pulmonary Veins; Signal Transduction; Vasoconstrictor Agents

2005
Endothelin antagonism in pulmonary hypertension, heart failure, and beyond.
    Heart (British Cardiac Society), 2005, Volume: 91, Issue:6

    Topics: Aspartic Acid Endopeptidases; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Heart Failure; Humans; Hypertension, Pulmonary; Metalloendopeptidases; Receptors, Endothelin

2005
Endothelin antagonism in pulmonary arterial hypertension.
    Seminars in respiratory and critical care medicine, 2005, Volume: 26, Issue:4

    The pathobiology of pulmonary arterial hypertension (PAH) reflects a multifactorial process and complex evolution that involves dysfunction of underlying cellular pathways and mediators. Among these, the endothelin system has been shown to be important in the pathogenesis of PAH. Endothelin-1 (ET-1), which is found in high levels in PAH, is a known potent vasoconstrictor with proliferative vascular remodeling properties. Left unchecked, endothelin excess, along with other derangements, may contribute to the development and perpetuation of PAH. There is now substantial evidence from clinical trials and long-term data that monotherapy with an endothelin receptor antagonist (ERA) is a beneficial, therapeutic approach in PAH. Combination therapy of an ERA with a prostanoid or phosphodiesterase-5 inhibitor, two drug classes that have different mechanisms of action, is conceptually appealing, but the evidence for its efficacy and safety are still being investigated. This review provides an overview of endothelin biology and the clinical use of ERAs for the treatment of PAH. The use of ERAs for other forms of pulmonary hypertension will not be reviewed here.

    Topics: Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Epoprostenol; Humans; Hypertension, Pulmonary; Isoxazoles; Piperazines; Pulmonary Artery; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes

2005
[Endothelin].
    Nihon rinsho. Japanese journal of clinical medicine, 2005, Volume: 63 Suppl 8

    Topics: Animals; Arteriosclerosis; Biomarkers; Bosentan; Diagnostic Techniques, Endocrine; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Receptors, Endothelin; Reference Values; Sulfonamides

2005
[Pharmacological characteristics and clinical efficacy of bosentan].
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 2005, Volume: 126, Issue:6

    Topics: Animals; Antihypertensive Agents; Bosentan; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; In Vitro Techniques; Nitric Oxide Synthase; Randomized Controlled Trials as Topic; Sulfonamides; Vasoconstriction

2005
The endothelin system in pulmonary arterial hypertension.
    Cardiovascular research, 2004, Feb-01, Volume: 61, Issue:2

    Endothelin-1 (ET-1), a peptide produced primarily by vascular endothelial cells, was discovered in 1980 and it was characterized as a powerful vasoconstrictor and mitogen for smooth muscle. ET-1 binds to two types of receptors, ETA and ETB: ETA-receptors are found in smooth muscle cells, whereas ETB-receptors are localized on both endothelial cells and in smooth muscle cells. Activation of ETA- and ETB-receptors on smooth muscle cells mediates the vasoconstrictive and mitogenic effects of ET-1. Stimulation of endothelial ETB-receptors promotes ET-1 clearance and activation of NO and prostacyclin release. Pulmonary arterial hypertension (PAH) is a severe condition characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. An activation of the ET-1 system has been demonstrated in both plasma and lung tissues of PAH patients as well as in animal models of PAH. The most efficient way to antagonize the ET-1 system is the use of ET-1 receptor antagonists that can block either ETA- or ETA- and ETB-receptors. These drugs are effective in animal models of PAH and have been tested in multiple clinical trials in patients with PAH. Bosentan, an orally active, dual ET-1 receptor antagonist has been shown to improve symptoms, exercise capacity, hemodynamics, echocardiographic parameters and the outcome of patients with severe PAH, and it has been approved for clinical use in many countries. The selective ETA-receptor antagonist sitaxentan has improved exercise capacity and hemodynamics of PAH patients in two preliminary studies. The main side effect of ET-1 antagonists is the increase of liver enzymes likely due to an accumulation of bile salts cytotoxic to hepatocytes. Additional trials with these drugs are currently ongoing. In conclusion, the hypothesis that the ET-1 system over-activation can be successfully antagonised in patients with PAH has been clearly demonstrated.

    Topics: Animals; Bosentan; Endothelial Cells; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Infant, Newborn; Isoxazoles; Models, Animal; Muscle, Smooth, Vascular; Pulmonary Circulation; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Thiophenes

2004
Bosentan: a novel agent for the treatment of pulmonary arterial hypertension.
    International journal of clinical practice, 2004, Volume: 58, Issue:1

    Pulmonary arterial hypertension (PAH) is a progressive disease that, without treatment, ultimately results in right heart failure and death. For the majority of patients with advanced PAH, therapy requires cumbersome drug delivery devices with serious side effects. Endothelin, a potent endogenous vasoconstrictor, is increased in individuals with PAH. The development of bosentan, a novel, well-tolerated, orally active endothelin antagonist, has significantly changed the therapeutic approach to PAH. Recent clinical trials have demonstrated that treatment with bosentan produces favourable effects on cardiopulmonary haemodynamics, exercise capacity, WHO functional class and time to clinical worsening in PAH.

    Topics: Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Randomized Controlled Trials as Topic; Sulfonamides

2004
Endothelin receptor antagonists in pulmonary arterial hypertension.
    Journal of the American College of Cardiology, 2004, Jun-16, Volume: 43, Issue:12 Suppl S

    Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations have clearly shown that endothelin (ET)-1 is overexpressed in several forms of pulmonary vascular disease and likely plays a significant pathogenetic role in the development and progression of pulmonary vasculopathy. Oral endothelin receptor antagonists (ERAs) have been shown to improve pulmonary hemodynamics, exercise capacity, functional status, and clinical outcome in several randomized placebo-controlled trials. Bosentan, a dual-receptor antagonist, is approved by the U.S. Food and Drug Administration for class III and IV patients with PAH, based on two phase III trials. In addition to its efficacy as sole therapy, bosentan may have a role as part of a combination of drugs such as a prostanoid or sildenafil. The selective endothelin receptor-A antagonists sitaxsentan and ambrisentan are currently undergoing investigation.

    Topics: Endothelin Receptor Antagonists; Endothelin-1; Forecasting; Humans; Hypertension, Pulmonary; Pulmonary Artery; Randomized Controlled Trials as Topic

2004
HIV-related pulmonary hypertension. From pathogenesis to clinical aspects.
    Acta cardiologica, 2004, Volume: 59, Issue:3

    HIV-related pulmonary hypertension (HIV-PH) is a cardiovascular complication of HIV infection that has been recognized in the last years with increasing frequency. HIV-related pulmonary hypertension is a clinical disorder which carries a bad prognosis. While a direct HIV infection of the pulmonary vessels in the pathogenesis of this disorder was not demonstrated, currently a multifactorial pathogenesis of this disease could be hypothesized. Echocardiography has been found to be the most useful screening imaging modality for the diagnosis of HIV-PH, with a high predictive negative value and a low positive predictive value. For this reason Doppler echocardiography is not the gold standard in the diagnosis of HIV-PH. The treatment of HIV-PH is complex and controversial. To date, no study determining the agent of choice for the treatment of this disease exists. Different studies have shown variable results in patiens with HIV-PH treated with highly active antiretroviral therapy (HAART) but only HAART seems not to be effective in lowering pulmonary hypertension in these patients, and in some patients, HIV-PH develops in spite of a previous HAART. It seems reasonable in HIV-PH patients that a treatment with oral vasodilator drugs can improve the adherence of a long-lasting and complex antiretroviral therapy.

    Topics: Cytokines; Echocardiography; Endothelin-1; HIV Infections; Humans; Hypertension, Pulmonary; Prognosis; Survival Analysis

2004
[Pulmonary hypertension in chronic obstructive lung disease].
    Problemy tuberkuleza i boleznei legkikh, 2004, Issue:11

    Topics: Electrocardiography; Endothelin-1; Humans; Hypertension, Pulmonary; Hypoxia; Lung; Magnetic Resonance Imaging; Nitric Oxide; Pulmonary Disease, Chronic Obstructive; Radiography; Spirometry

2004
Primary pulmonary hypertension: an overview of epidemiology and pathogenesis.
    Cleveland Clinic journal of medicine, 2003, Volume: 70 Suppl 1

    Pulmonary arterial hypertension (PAH) refers to a group of diseases characterized by high pulmonary artery pressure of unknown mechanism. Primary pulmonary hypertension (PPH) is the idiopathic subset of PAH that affects a mostly young population and is more common in females than in males. A familial form of PPH accounts for about 6% of cases, and its autosomal dominant gene was recently identified. Pulmonary arterial hypertension is histologically characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, and thrombosis in situ. The pathogenesis of PAH remains unclear. Elevated pulmonary vascular resistance seems to result from an imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling. Nitric oxide, a locally produced selective pulmonary vasodilator, appears to play a central role in the pathobiology of PAH.

    Topics: Endothelial Growth Factors; Endothelin-1; Endothelium, Vascular; Female; Global Health; Humans; Hypertension, Pulmonary; Male; Muscle, Smooth, Vascular; Nitric Oxide; Prostaglandins; Retrospective Studies; Sex Factors; Thrombosis

2003
The endothelin system in pulmonary hypertension.
    Canadian journal of physiology and pharmacology, 2003, Volume: 81, Issue:6

    Pulmonary hypertension (PH) may result from numerous clinical entities affecting the pulmonary circulation primarily or secondarily. It is recognized that vascular endothelial dysfunction contributes to the development and perpetuation of PH by creating an imbalance between vasodilating and antiproliferative forces and between vasoconstrictive and proliferative forces. In that context, endothelin-1 (ET-1) overproduction was rapidly targeted as a plausible contributor to the pathogenesis of PH. The lung is recognized as the major site for ET production and clearance. In all animal models of PH studied, circulating plasma ET-1 levels are elevated, accompanied by an increase in lung tissue expression of the peptide. The use of selective ETA and dual ETA-ETB receptor antagonists in these models both in prevention and in therapeutic studies have confirmed the contribution of ET-1 to the rise in pulmonary vascular tone, pulmonary medial hypertrophy, and right ventricular hypertrophy. This is found consistently in models affecting the pulmonary circulation primarily or producing PH secondarily. Recent clinical trials in patients with pulmonary arterial hypertension have confirmed the therapeutic effectiveness of ET-receptor antagonists in humans. We offer a systematic review of the pathogenic role of the ET system in the development of PH as well as the rationale behind the preclinical and ongoing clinical trials with this new class of agents.

    Topics: Animals; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Receptors, Endothelin; Sulfonamides

2003
The pathogenesis of HIV-associated pulmonary hypertension.
    Advances in cardiology, 2003, Volume: 40

    Topics: Comorbidity; Endothelin-1; Epoprostenol; HIV Infections; Humans; Hypertension, Pulmonary; Nitric Oxide; Vasoconstriction

2003
Role of reactive oxygen species in vascular remodeling associated with pulmonary hypertension.
    Antioxidants & redox signaling, 2003, Volume: 5, Issue:6

    Several manifestations of neonatal pulmonary hypertension are associated with vascular remodeling, resulting in increased muscularity of the small pulmonary arteries. Abnormal structural development of the pulmonary vasculature has been implicated in persistent pulmonary hypertension of the newborn (PPHN). Increased plasma levels of the vasoconstrictor endothelin-1 (ET-1) have been demonstrated in patients with PPHN, which is likely to contribute to hypertension. In addition, several studies have identified a role for ET-1 in the proliferation of vascular smooth muscle cells (SMCs), suggesting that ET-1 may also be involved in the vascular remodeling characteristic of this disease. However, the mechanisms of ET-1-induced SMC proliferation are unclear and appear to differ between cells from different origins within the vasculature. In SMCs isolated from fetal pulmonary arterial cells, ET-1 stimulated proliferation via an induction of reactive species (ROS). Furthermore, other lines of evidence have demonstrated the involvement of ROS in ET-1-stimulated SMC growth, suggesting that ROS may be a common factor in the mechanisms involved. This review discusses the potential roles for ROS in the abnormal pulmonary vascular development characteristic of PPHN, and the treatment strategies arising from our increasing knowledge of the molecular mechanisms involved.

    Topics: Animals; Antioxidants; Cell Division; Endothelin-1; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Models, Biological; Nitric Oxide; Nitric Oxide Donors; Pulmonary Artery; Reactive Oxygen Species; Receptors, Endothelin; Vascular Diseases

2003
Targeting mediators of vascular injury in scleroderma.
    Current opinion in rheumatology, 2002, Volume: 14, Issue:6

    Increasing evidence suggests that the vasculopathy of scleroderma is mediated by a number of soluble factors and involves a complex interaction between endothelial cells, smooth muscle cells, extracellular matrix, intravascular coagulation factors, and circulating cells. Novel therapeutic approaches beyond vasodilator therapy are being developed by recognizing important molecular pathways involved in scleroderma vascular disease. The success of this strategy is most evident in pulmonary hypertension, an often fatal complication of scleroderma. In this article, the authors explore therapies for scleroderma that target endothelial cells, smooth muscle cells, reactive oxygen species, and circulating blood cells. The authors highlight clinical trials that have investigated the role of prostacyclin (and its analogues) and bosentan in managing scleroderma-related pulmonary hypertension. Finally, the authors look at the potential role of biomarkers as surrogate indicators of active vascular disease in scleroderma.

    Topics: Antihypertensive Agents; Biomarkers; Bosentan; Clinical Trials as Topic; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Reactive Oxygen Species; Scleroderma, Systemic; Sulfonamides

2002
Therapeutic potential for endothelin receptor antagonists in cardiovascular disorders.
    American journal of cardiovascular drugs : drugs, devices, and other interventions, 2001, Volume: 1, Issue:4

    The endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These peptides are converted by endothelin-converting enzymes (ECE-1 and -2) from 'big endothelins' originating from large preproendothelin peptides cleaved by endopeptidases. Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ET(A) and ET(B) receptors on vascular smooth muscle cells. In contrast, ET(B )receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin. Additionally, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial hypertension, atherosclerosis, and heart failure. In patients with atherosclerotic vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of cardiovascular disease. In arterial hypertension, they prevent vascular and myocardial hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in atherosclerosis due to hypercholesterolemia. In experimental myocardial ischemia, treatment with an ET receptor antagonist reduced infarct size and prevented left ventricular remodeling after myocardial infarction. Most impressively, treatment with the selective ET(A) receptor antagonist BQ123 significantly improved survival in an experimental model of heart failure. In many clinical conditions, such as congestive heart failure, both mixed ET(A/B )as well as selective ET(A) receptor antagonism ameliorates the clinical status of patients, i.e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ET(A/B) receptor antagonist effectively lowered arterial blood pressure in patients with arterial hypertension. In patients with primary pulmonary hypertension or pulmonary hypertension related to scleroderma, treatment with a mixed ET(A/B) receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomize

    Topics: Animals; Arteriosclerosis; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Myocardial Infarction; Renal Insufficiency

2001
Novel therapeutics for the treatment of paediatric pulmonary arterial hypertension.
    Expert opinion on investigational drugs, 2001, Volume: 10, Issue:5

    The treatment of paediatric pulmonary arterial hypertension is challenging due to the serious nature of the disease, its rapid progression and the limited treatment options available. However, recent advances in the treatment of pulmonary arterial hypertension may offer significant improvements for patients suffering from this condition. Novel treatment options include prostacyclin analogues and endothelin receptor antagonists. A comprehensive review of the newer agents, with an emphasis on the pathobiology/pathophysiology of pulmonary arterial hypertension provides insight into future management of paediatric pulmonary arterial hypertension.

    Topics: Child; Endothelin Receptor Antagonists; Endothelin-1; Epoprostenol; Humans; Hypertension, Pulmonary; Vasodilator Agents

2001
[Fawn-Hooded Rat; an animal model of development of pulmonary hypertension].
    Nihon rinsho. Japanese journal of clinical medicine, 2001, Volume: 59, Issue:6

    The Fawn-Hooded Rat (FHR) spontaneously develops pulmonary hypertension (PH) at sea level, and an increased severity of this disease is observed upon exposure to mild hypoxia. A recent report suggested that lung hypoplasia with decreased alveolarization and altered vascular growth led by the decreased activity of endothelial nitric oxide synthase may contribute to the development of PH in the FHR. Exposure to mild hypoxia (P1O2 = 120 mmHg) leads to severe PH in FHR but not in Tester Moriyama rat, a strain that has a serotonin platelet storage-pool deficiency (PSPD) similar to that of the FHR. A serotonin PSPD does not appear to predispose FHR to PH. Endothelin-1 (ET-1) mRNA and peptide levels are increased in the hypertensive lungs of mildly hypoxic FHR. ET-1 may at least partly contribute to the development of PH in this strain.

    Topics: Animals; Disease Models, Animal; DNA-Binding Proteins; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Nuclear Proteins; Rats; RNA, Messenger; Serotonin; Transcription Factors

2001
Endothelin receptor antagonists and cardiovascular diseases of aging.
    Drugs & aging, 2001, Volume: 18, Issue:6

    Our understanding of the role of the endothelin system in human cardiovascular physiology and pathophysiology has evolved very rapidly since the initial description of its constituent parts in 1988. Endothelin-1 (ET-1) is the predominant endothelin isoform in the human cardiovascular system and has potent vasoconstrictor, mitogenic and antinatriuretic properties which have implicated it in the pathophysiology of a number of cardiovascular diseases. The effects of ET-1 have been shown to be mediated by 2 principal endothelin receptor subtypes: ET(A) and ET(B). The development of a range of peptidic and nonpeptidic endothelin receptor antagonists represents an exciting breakthrough in human cardiovascular therapeutics. Two main classes of endothelin receptor antagonist have been developed for possible human therapeutic use: ET(A)-selective and nonselective antagonists. Extensive laboratory and clinical research with these agents has highlighted their promise in various cardiovascular diseases. Randomised, placebo-controlled clinical trials have yielded very encouraging results in patients with hypertension and chronic heart failure with more preliminary data suggesting a possible role in the treatment and prevention of atherosclerosis and stroke. Much more research is needed, however, before endothelin receptor antagonists can be considered for clinical use.

    Topics: Aged; Animal Population Groups; Animals; Arteriosclerosis; Cardiovascular Diseases; Drugs, Investigational; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Receptors, Endothelin; Stroke

2001
Reciprocal regulation of endothelin-1 and nitric oxide: relevance in the physiology and pathology of the cardiovascular system.
    International review of cytology, 2001, Volume: 209

    The endothelium plays a crucial role in the regulation of cardiovascular structure and function by releasing several mediators in response to biochemical and physical stimuli. These mediators are grouped into two classes: (1) endothelium-derived constricting factors (EDCFs) and (2) endothelium-derived relaxing factors (EDRFs), the roles of which are considered to be detrimental and beneficial, respectively. Endothelin-1 (ET-1) and nitric oxide (NO) are the prototypes of EDCFs and EDRFs, respectively, and their effects on the cardiovascular system have been studied in depth. Numerous conditions characterized by an impaired availability of NO have been found to be associated with enhanced synthesis of ET-1, and vice versa, thereby suggesting that these two factors have a reciprocal regulation. Experimental studies have provided evidence that ET-1 may exert a bidirectional effect by either enhancing NO production via ETB receptors located in endothelial cells or blunting it via ETA receptors prevalently located in the vascular smooth muscle cells. Conversely, NO was found to inhibit ET-1 synthesis in different cell types. In vitro and in vivo studies have started to unravel the molecular mechanisms involved in this complex interaction. It has been clarified that several factors affect in opposite directions the transcription of preproET-1 and NO-synthase genes, nuclear factor-KB and peroxisome proliferator-activated receptors playing a key role in these regulatory mechanisms. ET-1 and NO interplay seems to have a great relevance in the physiological regulation of vascular tone and blood pressure, as well as in vascular remodeling. Moreover, an imbalance between ET-1 and NO systems may underly the mechanisms involved in the pathogenesis of systemic and pulmonary hypertension and atherosclerosis.

    Topics: Animals; Arteriosclerosis; Cardiovascular Physiological Phenomena; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Models, Biological; NF-kappa B; Nitric Oxide; Protein Precursors; Receptor, Endothelin A; Receptors, Cytoplasmic and Nuclear; Receptors, Endothelin; Signal Transduction; Transcription Factors

2001
Therapeutic potential of endothelin receptor antagonists and nitric oxide donors in pulmonary hypertension.
    Expert opinion on investigational drugs, 2001, Volume: 10, Issue:7

    Pulmonary hypertension can occur idiopathically as a primary disorder of the pulmonary circulation or more commonly, it can exist as a haemodynamic manifestation of a wide variety of pulmonary and cardiovascular diseases, including acute lung injury, chronic obstructive lung disease, congenital heart disease, mitral stenosis, chronic left-sided congestive heart failure and connective tissue diseases such as scleroderma. Pulmonary hypertension is associated with changes in vascular tone as well as vascular structure, with the relative contribution of each dependent upon the aetiology of the increased pulmonary vascular resistance. Most currently available treatments utilise anticoagulants as well as vasodilator drugs that only attenuate the vasoconstrictive component of the disease. The latter category includes oral calcium channel blockers, iv. and aerosolised prostacyclin analogues and inhaled nitric oxide but all three classes of vasodilators have disadvantages and limitations. Treatment with vasodilators is often ineffective in patients with longstanding pulmonary hypertension in which structural changes contribute significantly to the pulmonary hypertension, blood flow obstruction and right heart failure. In view of the immense clinical need, new therapies are being developed by pharmaceutical companies to treat pulmonary hypertension. This update will focus on the current development status of endothelin receptor antagonists and nitric oxide donors for the treatment of pulmonary hypertension.

    Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Nitric Oxide; Nitric Oxide Donors; Treatment Outcome

2001
Endothelin and pulmonary hypertension.
    Journal of cardiovascular pharmacology, 2000, Volume: 35, Issue:4 Suppl 2

    Biochemical and molecular biological evidence indicates that endothelin (ET)-1 and its receptors are selectively upregulated in the lung during exposure to hypoxia, while functional evidence indicates that ET-1 is a major mediator of hypoxia-induced pulmonary vasoconstriction and vascular remodeling. Hypoxia stimulates ET-1 gene transcription and peptide synthesis in cultured endothelial cells, and plasma ET-1 levels are increased in patients with primary pulmonary hypertension, and in humans exposed to high altitude, while immunoreactive ET-1 and ET-1 mRNA levels are increased in pulmonary artery endothelial cells of patients with primary pulmonary hypertension. Rats exposed to normobaric hypoxia exhibit increased pulmonary artery pressure, increased ET-1 peptide levels in plasma and lung, and selective increases in steady-state ET-1 and ET(A) and ET(B) receptor mRNA levels in lung but not in organs perfused by the systemic vasculature. The observations that both ET-1 and its major vascular smooth-muscle cell receptor are upregulated in response to hypoxia suggest that ET-1 may be a mediator of hypoxia-induced pulmonary hypertension. Moreover, hypoxic pulmonary vasoconstriction and vascular remodeling can be prevented and reversed by administration of either an ET(A)-selective or a combined ET(A) and ET(B) receptor antagonist. These findings support the hypothesis that endogenous ET-1 plays a major role in hypoxic pulmonary vasoconstriction/hypertension, right heart hypertrophy, and pulmonary vascular remodeling and suggest that ET-receptor blockers may be useful in the treatment and prevention of hypoxic pulmonary hypertension in humans.

    Topics: Animals; Cells, Cultured; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Hypoxia; Rats; Receptors, Endothelin; Vasoconstriction

2000
Endothelial dysfunction in the pulmonary vascular bed.
    The American journal of the medical sciences, 2000, Volume: 320, Issue:4

    The pulmonary endothelium modulates vascular tone by the release of endothelium-derived constricting (EDCF) and relaxing (EDRF) factors, among them endothelin-1, nitric oxide, prostacyclin, and putative endothelium-derived hyperpolarizing factors. Abnormalities in EDCF and EDRF generation have been demonstrated in a number of cardiopulmonary disease states, such as primary and secondary pulmonary hypertension, chronic obstructive lung disease, cardiopulmonary bypass, and congestive heart failure. An imbalance between EDCF and EDRF, termed "pulmonary endothelial dysfunction," may contribute to the alteration in vascular tone characteristic of pulmonary disease. The following review summarizes the present knowledge of the role of EDCF and EDRF in such processes with major focus on pulmonary endothelial dysfunction in hypoxia-induced pulmonary hypertension.

    Topics: Animals; Antihypertensive Agents; Atrasentan; Bosentan; Controlled Clinical Trials as Topic; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Epoprostenol; Heart Failure; Humans; Hypertension, Pulmonary; Hypoxia; Lung Diseases, Obstructive; Nitric Oxide; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Circulation; Pyrrolidines; Receptors, Endothelin; RNA, Messenger; Sulfonamides; Time Factors; Vasoconstriction; Vasodilation

2000
Putative mediator role of endothelin-1 in asthma and other lung diseases.
    Clinical and experimental pharmacology & physiology, 1999, Volume: 26, Issue:2

    1. There is an increasing amount of research to implicate endothelin (ET)-1, a member of a family of 21 amino acid peptides, as a potentially important mediator in pulmonary diseases, in particular asthma and pulmonary hypertension. Thus, ET-1 fits several of the standard criteria that need to be fulfilled for a pathophysiologically relevant substance. 2. Endothelin-1 is present in abundance in human lung: the major loci for ET-1 are the epithelium, endothelium, endocrine cells and inflammatory cells. Furthermore, the receptors that mediate the biological effects of ET-1, the ETA and ETB receptor subtypes, are found in human lung, predominantly in airway smooth muscle, and vascular smooth muscle and, to a lesser extent, nerves. There is no change in the relative proportions of ETA and ETB receptors in asthmatic versus non-asthmatic bronchial smooth muscle and peripheral lung. 3. Several studies have shown that ET-1 mimics several of the features of asthma (including bronchospasm, airway remodelling, inflammatory cell recruitment and activation, oedema, mucus secretion, airway hyperreactivity and dysfunction in neuronal inputs); however, some other reports are at odds with these findings. 4. Endothelin-1 mimics the two classical features of pulmonary hypertension (pulmonary vascular constriction and remodelling), which is often a serious complication of chronic obstructive pulmonary disease. 5. Intranasal ET-1 produces several of the symptoms of allergic rhinitis. 6. There are several reports of increased levels and/or expression of ET in patients with many pulmonary disorders, in particular asthma or pulmonary hypertension, with some evidence of a correlation between ET amounts and disease severity; however, other studies do not confirm these observations. 7. Despite these intriguing data in support of a pathophysiological role of ET-1 in lung disease, the definitive test and most difficult criteria to fulfil, the clinical evaluation of ET receptor antagonists or ET synthesis inhibitors, has still to be conducted. Only after these pivotal data are available will we be able to determine definitively whether ET-1 is a pathophysiologically important mediator in lung diseases or merely an interesting peptide with several effects in the pulmonary system.

    Topics: Asthma; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Lung Diseases; Molecular Mimicry; Receptors, Endothelin

1999
Endothelin-1 and serotonin: mediators of primary and secondary pulmonary hypertension?
    The Journal of laboratory and clinical medicine, 1999, Volume: 134, Issue:2

    Topics: Endothelin-1; Humans; Hypertension, Pulmonary; Serotonin

1999
Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling.
    Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.), 1999, Volume: 221, Issue:4

    Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.

    Topics: Animals; Arteriosclerosis; Cardiovascular Diseases; Cardiovascular System; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Rats; Vasoconstrictor Agents

1999
Role of endothelial and smooth muscle cells in the physiopathology and treatment management of pulmonary hypertension.
    Cardiovascular research, 1999, Volume: 44, Issue:2

    Pulmonary hypertension can occur either as primary or secondary disease following cardiac or pulmonary illnesses. In either cases, histological lung biopsies reveal vascular remodelling i.e. smooth muscle cells proliferation with medial hypertrophy, arteriolar muscularization and endothelial cell proliferation. Subsequent intimal thickening, fibrosis and in situ thrombosis, altogether lead to vaso-occlusive alterations referred to as plexiform lesions. Theories concerning the detailed physiopathology of pulmonary hypertension have focused on endothelial and smooth muscle cells' chemical factors production and response to different mediators. The endothelium produces vasoconstrictor and growth-promoting factor such as endothelin-1 (ET-1) as well as vasodilator and growth-inhibitor factors like prostacyclin and nitric oxide (NO). ET-1 has been noted in high concentrations in some clinical cases and experimental models of pulmonary hypertension, coupled with ET-1 receptors' modulation and altered endothelin converting enzyme activities, suggesting their active role in both arteriolar vasoconstriction and occlusion. Vascular thrombosis which has been noted by pathologists in pulmonary hypertension, could be related to an imbalance between thrombotic inducing factors (such as anti-phospholipid antibodies, ET-1 and thromboxane) and decreased fibrinolytic activity and antiaggregant endothelial factors (like prostacyclin, NO, thrombomodulin). The discovery of an endothelial cells' monoclonal proliferation in plexiform lesions of patients with primary pulmonary hypertension may reinforce the cellular proliferation hypothesis to understand the histopathology of this disease. In view of these new findings, the treatments available for pulmonary hypertension have been expanded from the previously employed oxygen therapy, calcium-channel blockers and anticoagulants, to intravenous prostacyclin analogues (epoprostenol) and inhaled nitric oxide.

    Topics: Antibodies, Antiphospholipid; Endothelial Growth Factors; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Hypertension, Pulmonary; Lymphokines; Muscle, Smooth, Vascular; Nitric Oxide; Prostaglandins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

1999
Endothelin in the pulmonary circulation with special reference to hypoxic pulmonary vasoconstriction.
    Scandinavian cardiovascular journal. Supplement, 1997, Volume: 46

    1. The experimental model using periods of ventilation with a gas mixture containing 10% oxygen in the anesthetized pig was found to induce HPV that was reproducible and remained stable for up to two hours. 2. Intrapulmonary infusion of ET-1 during normoxia resulted in a dose-dependent increase in the SVR with a concomitant decrease in CO and rise in PVR. Infusion of ET-3 and S6c evoked similar responses, but of a considerably smaller magnitude. The dose-dependent systemic vasoconstriction evoked by ET-1 infusion was reduced after administration of the combined ETA and ETB receptor antagonist bosentan as well as the selective ETA receptor blockers BMS-182874 and TBC-11251 indicating that this effect is primarily mediated by ETA receptors. ETA receptors are present in porcine pulmonary arteries, since BMS-182874 caused a rightward shift of the concentration-response curve to ET-1 in vitro. 3. Administration of selective ETA- or combined ETA and ETB antagonists but not of a selective ETB antagonist reduced the SVR in normoxic pigs, indicating that ET acting through ETA receptors contributes to systemic vascular tone in the pig. In addition, ETA selective and non-selective ETA and ETB antagonists produced a reduction of PVR, although this effect was less consistent than the influence on SVR. This indicates that ETA receptors may contribute to basal pulmonary vascular tone. The plasma levels of ET-1 increased following the non-selective ET receptor antagonist bosentan but were unaffected by selective ETA receptor antagonism. 4. Intrapulmonary infusion of ET-1 produced in low doses a pulmonary vasodilatation during HPV in the pig. This pulmonary vasodilatory effect was also evident when ET-3 or S6c was infused. The pulmonary vasodilatory effect of ET-1 infusion was abolished following administration of the selective ETB receptor antagonist BQ-788, indicating that the pulmonary vasodilatory effect of ET in HPV in the pig is mediated by ETB receptors. Higher doses of ET-1 infusion during HPV resulted in systemic and pulmonary vasoconstriction. 5. Both combined ETA and ETB blockade using bosentan and selective ETA receptor inhibition using BMS-182874 or TBC-11251 reduced the development of HPV in the pig. In addition, bolus injection of TBC-11251 reversed already established HPV. Selective ETB receptor antagonism had no effect on HPV. These findings suggest that ETA receptor activation contributes to HPV in the pig. 6. The concentration-dependent contraction evok

    Topics: Adult; Animals; Child; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Endothelins; Endothelium, Vascular; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Pulmonary Circulation; Receptors, Endothelin; Swine; Vasoconstriction

1997
[The clinical significance of endothelin].
    Duodecim; laaketieteellinen aikakauskirja, 1997, Volume: 113, Issue:8

    Topics: Animals; Arteriosclerosis; Endothelin-1; Endothelin-2; Endothelin-3; Endothelins; Heart Failure; Humans; Hypertension, Pulmonary; Primary Prevention; Prognosis; Vasoconstriction

1997

Trials

24 trial(s) available for endothelin-1 and Hypertension--Pulmonary

ArticleYear
The neurohormonal basis of pulmonary hypertension in heart failure with preserved ejection fraction.
    European heart journal, 2019, 12-01, Volume: 40, Issue:45

    Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve.. Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = -0.52 and -0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s' and e' tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e', r = -0.59 and -0.67, both P < 0.001), reduced cardiac output responses to exercise (r = -0.59 and -0.61, both P < 0.0001), and more severely impaired peak VO2 (r = -0.60 and -0.67, both P < 0.0001).. Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype.. NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search.

    Topics: Aged; Arterial Pressure; Atrial Natriuretic Factor; Case-Control Studies; Cross-Sectional Studies; Echocardiography; Endothelin-1; Exercise; Exercise Tolerance; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen Consumption; Peptide Fragments; Prospective Studies; Pulmonary Artery; Stroke Volume

2019
Pharmacokinetic-pharmacodynamic relationships of macitentan, a new endothelin receptor antagonist, after multiple dosing in healthy Korean subjects.
    American journal of cardiovascular drugs : drugs, devices, and other interventions, 2014, Volume: 14, Issue:5

    Macitentan is a novel dual endothelin (ET)-1 receptor antagonist to be used in patients with pulmonary arterial hypertension. This study aimed to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of macitentan after administration of multiple doses to healthy Korean male subjects.. A randomized, double-blind, placebo-controlled, multiple-ascending dose study was performed in 30 healthy male subjects receiving oral macitentan (3, 10, or 30 mg) or placebo once daily for 10 days. Plasma concentrations of macitentan, its active metabolite ACT-13277, and ET-1 were evaluated. Safety and tolerability measurements were conducted throughout the study.. The concentration-time profile of macitentan was characterized by slow absorption (median time to maximum plasma concentration [t(max)] 9-10 h) and slow elimination (mean elimination half-life [t ½] 11-15 h). After repeated doses of 3, 10, and 30 mg of macitentan over the course of 10 days, the peak concentration (C(max)) increased as the dose increased and the area under the plasma concentration-time curve during the dosing interval (AUC(τ)) increased in a dose-proportional manner. Plasma concentrations showed approximately 1.5- to 1.9-fold accumulation on day 10 compared with day 1. ACT-132577 showed higher levels of exposure than macitentan, its mean half-life was 46-48 h, and it accumulated 7- to 12-fold. Macitentan increased plasma ET-1 concentrations at all doses tested and was well tolerated and elicited no serious adverse events.. Multiple oral doses of 3, 10, and 30 mg of macitentan were well tolerated in healthy Korean subjects, and its pharmacokinetics correlated positively with ET-1 concentrations.

    Topics: Adult; Antihypertensive Agents; Asian People; Dose-Response Relationship, Drug; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrimidines; Receptor, Endothelin A; Sulfonamides; Young Adult

2014
Plasma endothelin-1 and nitric oxide correlate with ligustrazine alleviation of pulmonary artery hypertension in patients of chronic cor pulmonale from high altitude plateau during acute exacerbation.
    Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 2014, Volume: 30, Issue:6

    To explore the mechanisms involved in the ligustrazine alleviation of the pulmonary artery hypertension (PAH) in patients of chronic obstructive pulmonary disease (COPD) associated with chronic cor pulmonale (CCP) during exacerbation.. Seventy patients of COPD and CCP with acute exacerbation were randomly and equally divided into control group and treatment group. The control group received standard treatment with antibiotics, antiasthmatic and expectorant medications, and oxygenation; and the ligustrazine treatment group received ligustrazine treatment (80 mg/d; i.v.; for 2 weeks) in addition to the standard treatment. Before and at the end of 2 week treatment, the clinic responses of the two regimens were evaluated, plasma levels of endothelin-1 (ET-1) and nitric oxide (NO) were determined; arterial oxygen partial pressure (PaO2, mean pulmonary arterial pressure (mPAP), outflow tract of right ventricle (RVOT), and internal diameter of right ventricle (RV) were measured.. Good clinic benefits were achieved in both the standard and ligustrazine regimens, plasma level of ET-1, values of mPAP, RV and RVOT decreased significantly, plasma level of NO and PaO2 values decreased (all P < 0.01 vs pre-treatment to all parameters). Compared with the control group, ligustrazine greatly enhanced the clinic efficacy from 77.1% to 97.1% (P < 0.05), and also resulted in more significant changes of all these parameters (P < 0.01 vs control group for all parameters). For both groups, the levels of plasma ET-1 were positively correlated with values of mPAP, RVOT, and RV (r = 0.710, 0.853, and 0.766, respectively, all P = 0.000), and negatively correlated with plasma NO and PaO2 (r = - 0.823, and - 0.752, respectively, all P = 0.000).. Ligustrazine is effective in treating pulmonary artery hypertension during acute exacerbation of COPD and CCP in patients from the plateau area. The observed changes in the plasma levels of NO and ET-1 in response to ligustrazine treatment suggest that ligustrazine may act through the selective effect on pulmonary blood vessels to enhance the synthesis and release of NO and suppress those of ET-1 from lung vascular endothelial cells, thus reducing pulmonary artery pressure and decreasing pulmonary arterial hypertension.

    Topics: Altitude; Blood Gas Analysis; Chronic Disease; Endothelin-1; Humans; Hypertension, Pulmonary; Nitric Oxide; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pyrazines; Respiration

2014
Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects.
    Journal of clinical pharmacology, 2013, Volume: 53, Issue:11

    This multiple-ascending-dose study investigated safety, tolerability, pharmacokinetics, and pharmacodynamics, of macitentan, a new endothelin receptor antagonist (ERA) with sustained receptor binding and enhanced tissue penetration properties compared to other ERAs. Healthy male subjects (n = 32) received once daily oral doses of macitentan (1 - 30 mg) or placebo for 10 days. Administration of macitentan was safe and well tolerated. Macitentan had no effect on bile salts, suggesting an improved liver safety profile. The multiple-dose pharmacokinetics of macitentan were dose-proportional and were characterized by a median tmax and apparent elimination half-life varying from 6.0 to 8.5 and 14.3 to 18.5 hours, respectively, for the different doses and minimal accumulation. ACT-132577, a metabolite with lower potency than macitentan, had a half-life of about 48 hours and accumulated approximately 8.5-fold. Compared to placebo, administration of macitentan caused a dose-dependent increase in plasma ET-1 with maximum effects attained at 10 mg. A small dose-dependent increase in the 6β-hydroxycortisol/cortisol urinary excretion ratio was observed, although there were no statistically significant differences between treatments including placebo. Effects of macitentan on cytochrome P450 enzyme 3A4 should be further evaluated in dedicated studies. The present results support investigation of macitentan in the management of pulmonary arterial hypertension and ET-1-dependent pathologies.

    Topics: Adult; Bile Acids and Salts; Dose-Response Relationship, Drug; Double-Blind Method; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hydrocortisone; Hypertension, Pulmonary; Male; Middle Aged; Pyrimidines; Sulfonamides; Young Adult

2013
[Use of nebivolol in patients with idiopathic pulmonary hypertension: results of the pilot study].
    Terapevticheskii arkhiv, 2012, Volume: 84, Issue:12

    To study the impact of 24-week therapy with nebivolol in a dose of 5 mg/day on the clinical and functional status of patients with idiopathic pulmonary hypertension (IPH), echocardiographic parameters, and blood levels of vasoactive mediators and nitric oxide (NO) metabolite.. During continuous standard therapy comprising dihydropyridine calcium antagonists, warfarin, and diuretics, 12 patients with IPH and functional class (FC) II-III received nebivolol in a dose of 5 mg/day for 24 weeks. According to the data of right heart catheterization, all the patients had a positive acute pharmacological test with a vasodilator (NO). Six-minute walk test (6'WT), estimation of the Borg dyspnea index (BDI) and FC, transthoracic echocardiography (EchoCG), and measurements of the levels of NO metabolites, endothelin-1, (ET-1), thromboxane B2 (TxB2), and 6-keto-prostaglandin F1alpha (6-ketoPG F1alpha) were done at baseline and after 12 and 24 weeks of the therapy.. Following 24-week nebivolol treatment, there was a statistically significant increase in 6'WT distance (from 473 +/- 47.6 to 516.7 +/- 58.4 m; p < 0.0001) and a drop in BDI (from 3.4 +/- 2.2 to 1.1 +/- 0.7; p < 0.05) and FC (from 2.9 +/- 0.4 to 1.7 +/- 0.2; p < 0.05). Doppler EchoCG showed that pulmonary artery systolic pressure statistically significantly decreased (91.6 +/- 30 to 78.3 +/- 39 mm Hg; p = 0.05) at 12 weeks and slightly increased up to 83.2 +/- 32.4 mm Hg at 24 weeks. After 24-week treatment, the anteroposterior dimensions of the right ventricle (RV) statistically significantly reduced (from 4.4 +/- 0.6 to 3.8 +/- 1.2 cm; p < 0.05). The other EchoCG parameters remained substantially unchanged. There was a statistically reduction in the level of ET-1 (from 2.99 +/- 1.1 to 2.17 +/- 0.8 micromol/l; p < 0.05). The concentrations of 6-ketoPG Fla, TxB2, and NO metabolite remained substantially unchanged at 24 weeks of treatment with nebivolol. There were no adverse reactions requiring that the dose of the drug be discontinued or reduced. Heart rate tended to be lower at a 24-week follow-up. All the patients continued taking nebivolol after completion of the study.. Therapy with nebivolol in a dose of 5 mg/day for 24 weeks led to a significant functional improvement in the patients with IPH and reductions in RV dimensions and blood ET-1 levels. The therapy did not cause adverse reactions.

    Topics: Adult; Benzopyrans; Drug Monitoring; Echocardiography, Doppler; Endothelin-1; Ethanolamines; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nebivolol; Nitric Oxide; Pilot Projects; Severity of Illness Index; Treatment Outcome; Vasodilator Agents

2012
Gene expression of endothelin-1 and its receptors in the heart of broiler chickens with T(3)-induced pulmonary hypertension.
    Research in veterinary science, 2011, Volume: 91, Issue:3

    To investigate the effect of T(3)-induced pulmonary hypertension on endothelin (ET) production and genes expression of ET-1, ET(A) and ET(B) receptors (ET(A)R and ET(B)R) during rearing, semiquantitative RT-PCR and enzyme immunometric assay were performed in the heart ventricles and serum, respectively. The ET-1 and its receptor genes were expressed in the right and left ventricles of control and T(3)-treated broilers at 12, 28 and 49 days of age. There were significant (P<0.05) reductions of the relative amounts of ET-1 (in both ventricles) and ET(A)R (in the right ventricle) mRNAs at 28 and 49 days of age, in T(3)-treated broilers compared to controls. The relative amounts of ET(B)R mRNA in the right and left ventricles did not significantly differ between control and T(3)-treated broilers at any age. The serum level of ET was significantly (P<0.05) increased in T(3)-treated chickens at 28 and 49 days of age when compared with that of the control. It is concluded that ET-1, ET(A)R and ET(B)R genes are normally expressed in the heart ventricles of broilers. It is likely that increased serum level of ET and decreased ET-1/ET(A)R genes expression in the ventricles are involved in the heart dysfunction of broiler chickens with developmental pulmonary hypertension.

    Topics: Animals; Chickens; Endothelin-1; Gene Expression Regulation; Hypertension, Pulmonary; Immunoenzyme Techniques; Myocardium; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Triiodothyronine

2011
Genistein attenuates low temperature induced pulmonary hypertension in broiler chicks by modulating endothelial function.
    European journal of pharmacology, 2010, Dec-15, Volume: 649, Issue:1-3

    Pulmonary arterial hypertension is characterized by high pulmonary blood pressure, vascular remodeling and right ventricular hypertrophy. In the present study, we investigated whether genistein would prevent the development of low temperature-induced pulmonary hypertension in broilers. Hemodynamic parameters, vascular remodeling, the expression of endothelial nitric oxide and endothelin-1 content in lung tissue were evaluated. The results demonstrated that genistein significantly reduced pulmonary arterial hypertension and suppressed pulmonary arterial vascular remodeling without affecting broilers' performance. The beneficial effects appeared to be mediated by restoring endothelial function especially endothelial nitric oxide and endothelin-1, two critical vasoactive molecules that associated with the development of hypertension. Genistein supplementation might be a potential therapeutic strategy for the treatment of pulmonary hypertension.

    Topics: Animals; Ascites; Chickens; Cold Temperature; Cyclic GMP; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Genistein; Hemodynamics; Hypertension, Pulmonary; Lung; Male; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Pericardial Effusion; Phytoestrogens; Poultry Diseases; Weight Gain

2010
Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension.
    Clinical science (London, England : 1979), 2009, Volume: 116, Issue:6

    PH (pulmonary hypertension) often complicates the disease course of patients with COPD (chronic obstructive pulmonary disease) and is an indication of a worse prognosis. In the present study, we assessed whether pravastatin administration was effective in improving PH and exercise capacity in COPD patients with PH, and whether the pulmonary protection was mediated by inhibiting ET-1 (endothelin-1) production. In a double-blind parallel design, 53 COPD patients with PH were randomly assigned to receive either placebo or pravastatin (40 mg/day) over a period of 6 months at a medical centre. Baseline characteristics were similar in both groups. The exercise time remained stable throughout the study in the placebo group. After 6 months, the exercise time significantly increased 52% from 660+/-352 to 1006+/-316 s (P<0.0001) in pravastatin-treated patients. With pravastatin, echocardiographically derived systolic PAP (pulmonary artery pressure) decreased significantly from 47+/-8 to 40+/-6 mmHg. There was significant improvement in the Borg dyspnoea score after administering pravastatin. Despite unchanged plasma ET-1 levels throughout the study, urinary excretion of the peptide was decreased and significantly correlated with an improvement in exercise time in pravastatin-treated patients (r=-0.47, P=0.01). In conclusion, pravastatin significantly improved exercise tolerance, and decreased PH and dyspnoea during exercise in COPD patients with PH, probably by inhibiting ET-1 synthesis.

    Topics: Adult; Aged; Aged, 80 and over; Endothelin-1; Exercise Tolerance; Female; Hemodynamics; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Lipids; Male; Middle Aged; Pravastatin; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

2009
Endothelin-1 messenger [corrected] ribonucleic acid expression in pulmonary hypertensive and nonhypertensive chickens.
    Poultry science, 2008, Volume: 87, Issue:7

    Four hundred 1-d-old Cobb broilers were distributed in 3 groups: group A comprised broilers maintained under natural hypobaric hypoxia (Bogotá, Colombia); group B comprised broilers under relative normoxia (Villavicencio, Colombia); and group C comprised broilers maintained at 460 m above sea level (Villavicencio, Colombia) from d 1 to 25 of age, and then moved to 2,638 m above sea level (Bogotá, Colombia). Broilers were designated as nonpulmonary hypertensive (NPHB) and pulmonary hypertensive (PHB), to estimate possible differences between them in the lung expression of endothelin 1 (ET-1) mRNA at 24 and 42 d of age. In group A, 12 NPHB and 12 PHB were used for determination of ET-1 mRNA expression at 42 d. In group B, nonPHB were found, and therefore, ET-1 mRNA expression was detected in 48 NPHB, 24 of them in each age group (24 and 42 d). In group C, only NPHB were encountered at 42 and 53 d, and ET-1 mRNA expression was determined at 42 d in 24 birds. The ET-1 mRNA levels of PHB of group A at 42 d were significantly higher than the correspondent ones in NPHB of groups A (P < 0.001) and C (P < 0.05) at the same age. No differences in ET-1 mRNA expression were encountered between NPHB of groups A and B at 42 d (P > 0.05). However, ET-1 mRNA expression was higher in group C than the correspondent one in NPHB of groups A and B at 42 d (P < 0.001). The present data suggest that ET-1 may play a major role in pulmonary hypertension pathophysiology. It is possible that chickens should be exposed to hypobaric hypoxia before d 24, as a requisite to develop pulmonary hypertension. These results might provide clues for future studies in pulmonary vasoconstriction and vascular remodeling.

    Topics: Aging; Altitude; Animals; Chickens; Endothelin-1; Gene Expression Regulation; Hypertension, Pulmonary; Hypoxia; Lung; Male; Poultry Diseases; RNA, Messenger

2008
Secondary pulmonary hypertension: haemodynamic effects of torasemide versus furosemide.
    Clinical drug investigation, 2008, Volume: 28, Issue:1

    Experimental data have demonstrated controversial results regarding loop diuretics and their influence on the pulmonary vasculature. The aim of this pilot study was to compare the effect of torasemide versus furosemide on systemic and pulmonary haemodynamics in patients with secondary pulmonary hypertension.. Twenty-one patients were enrolled in this double-blind, randomized trial: the furosemide group (n = 11) received 40 mg intravenously (IV) and 80 mg orally whereas the torasemide group (n = 10) received 20 mg IV and 20 mg orally. Haemodynamic variables were documented and endothelin-1 and arterial angiotensin-II plasma levels were simultaneously analysed at baseline (T0), 5 minutes after IV administration (T1), at baseline prior to oral administration (T2), and 60 minutes after oral administration (T3).. Cardiac output (relative treatment effect over time between groups; p = 0.03) increased significantly in the torasemide group compared with the furosemide group. In the furosemide group, a significant increase in arterial angiotensin-II (AT-II) plasma levels was observed compared with the torasemide group (relative treatment effect over time between groups; p = 0.031).. Torasemide increased cardiac output (relative treatment effect over the time), whereas treatment with furosemide significantly increased arterial AT-II plasma levels. A possible explanation for these findings might be activation of the renin-angiotensin system by furosemide. However, the underlying pathomechanism remains to be established and evidence from an adequately powered trial is needed to determine if furosemide aggravates cardiac function by increasing AT-II plasma levels.

    Topics: Administration, Oral; Aged; Angiotensin II; Antihypertensive Agents; Cardiac Output; Diuretics; Dose-Response Relationship, Drug; Double-Blind Method; Endothelin-1; Female; Furosemide; Hemodynamics; Humans; Hypertension, Pulmonary; Injections, Intravenous; Lung; Male; Middle Aged; Pilot Projects; Prospective Studies; Stroke Volume; Sulfonamides; Torsemide; Treatment Outcome

2008
Improvement of vascular endothelial function using the oral endothelin receptor antagonist bosentan in patients with systemic sclerosis.
    Arthritis and rheumatism, 2007, Volume: 56, Issue:6

    Increased endothelin activity may play a role in the pathogenesis of vascular injury, a primary feature of systemic sclerosis (SSc; scleroderma). Our goal was to test the hypothesis that treatment with the oral endothelin receptor antagonist bosentan might improve vascular endothelial function in SSc patients.. A 4-week, prospective, parallel-group study compared 12 SSc patients who did not receive bosentan treatment with 12 patients who did receive treatment (125 mg/day) for pulmonary hypertension and/or digital ulcers. There were no differences in demographic and clinical characteristics or medications between the 2 groups. Baseline endothelial dysfunction was documented by decreased brachial artery ultrasound-derived flow-mediated dilation (FMD%; <5.5). Pulse wave analysis, venous occlusion plethysmography, and measurement of serum vascular markers were performed in parallel.. FMD%, the main end point, increased significantly from a mean +/- SD of 3.1 +/- 1.3% to 8.4 +/- 2.6% after 4 weeks of bosentan treatment (P < 0.001, compared with a change from 2.4 +/- 1.6% to 2.4 +/- 2.2% in control patients). Arterial blood pressure, endothelium-independent vascular function, augmentation index, peripheral flow reserve, as well as circulating intercellular adhesion molecule 1, E-selectin, vascular endothelial growth factor, and endothelin 1 were not significantly affected by bosentan treatment. In patients continuously treated for 4 months, during which the dosage of bosentan remained at 125 mg/day (n = 5) or increased to 250 mg/day (n = 5), the 4-week results remained unchanged.. Small doses of bosentan improve endothelial function without affecting hemodynamic parameters or endothelial activation-related processes, thus supporting a direct, reversible effect of endothelin in SSc-associated vascular injury. A long-term, controlled trial to examine the potentially global clinical benefit of endothelin receptor blockade in patients with early SSc may be warranted.

    Topics: Administration, Oral; Adult; Aged; Bosentan; Brachial Artery; Dose-Response Relationship, Drug; E-Selectin; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension, Pulmonary; Intercellular Adhesion Molecule-1; Male; Middle Aged; Prospective Studies; Regional Blood Flow; Scleroderma, Systemic; Sulfonamides; Ultrasonography; Vascular Endothelial Growth Factor A; Vasodilation

2007
Role of endothelin-1 in exposure to high altitude: Acute Mountain Sickness and Endothelin-1 (ACME-1) study.
    Circulation, 2006, Sep-26, Volume: 114, Issue:13

    The degree of pulmonary hypertension in healthy subjects exposed to acute hypobaric hypoxia at high altitude was found to be related to increased plasma endothelin (ET)-1. The aim of the present study was to investigate the effects of ET-1 antagonism on pulmonary hypertension, renal water, and sodium balance under acute and prolonged exposure to high-altitude-associated hypoxia.. In a double-blind fashion, healthy volunteers were randomly assigned to receive bosentan (62.5 mg for 1 day and 125 mg for the following 2 days; n=10) or placebo (n=10) at sea level and after rapid ascent to high altitude (4559 m). At sea level, bosentan did not induce any significant changes in hemodynamic or renal parameters. At altitude, bosentan induced a significant reduction of systolic pulmonary artery pressure (21+/-7 versus 31+/-7 mm Hg, P<0.03) and a mild increase in arterial oxygen saturation versus placebo after just 1 day of treatment. However, both urinary volume and free water clearance (H2OCl/glomerular filtration rate) were significantly reduced versus placebo after 2 days of ET-1 antagonism (1100+/-200 versus 1610+/-590 mL; -6.7+/-3.5 versus -1.8+/-4.8 mL/min, P<0.05 versus placebo for both). Sodium clearance and segmental tubular function were not significantly affected by bosentan administration.. The present results indicate that the early beneficial effect of ET-1 antagonism on pulmonary blood pressure is followed by an impairment in volume adaptation. These findings must be considered for the prevention and treatment of acute mountain sickness.

    Topics: Acute Disease; Adaptation, Physiological; Adult; Altitude; Altitude Sickness; Arginine Vasopressin; Bosentan; Creatinine; Diuresis; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension, Pulmonary; Hypoxia; Kidney; Kidney Diseases; Male; Middle Aged; Muscle, Smooth, Vascular; Osmolar Concentration; Oxygen; Potassium Channels, Voltage-Gated; Pulmonary Artery; Pulmonary Edema; Receptors, Endothelin; Sulfonamides; Vasoconstriction

2006
[Effects of hemofiltration modifies during extracorporeal circulation in the surgery of pulmonary hypertension with congenital heart defects on endothelin level and the ratio of pulmonary pressure/systemic pressure ].
    Zhonghua yi xue za zhi, 2004, Sep-17, Volume: 84, Issue:18

    Topics: Adolescent; Adult; Blood Pressure; Cardiopulmonary Bypass; Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Hemofiltration; Humans; Hypertension, Pulmonary; Infant; Male

2004
Nitric oxide inhalation modulates endothelin-1 plasma concentration gradients following left ventricular assist device implantation.
    Journal of cardiovascular pharmacology, 2004, Volume: 44 Suppl 1

    Inhaled nitric oxide (iNO) therapy is an effective treatment of pulmonary hypertension following left ventricular assist device (LVAD) implantation. As iNO may also modulate circulating endothelin-1 (ET-1) and big endothelin following LVAD implantation, we investigated the effects of iNO on ET-1 and big endothelin plasma concentration gradients. In order to assist weaning from cardiopulmonary bypass, iNO was administered to 15 consecutive patients with secondary pulmonary hypertension following implantation of a LVAD. Central venous, pulmonary arterial and arterial ET-1 and big endothelin plasma levels were measured preoperatively, on cardiopulmonary bypass prior to iNO administration, 12, 24 and 48 hours postoperatively, and 72 hours after weaning from iNO. The ET-1 gradients between central venous and pulmonary arterial plasma levels decreased significantly with time, and there was a trend for lower arterial-pulmonary arterial plasma concentration gradients. Big endothelin plasma concentration gradients were not altered significantly. The decrease in ET-1 plasma concentration gradients during and after iNO administration may reflect a restoration of the physiologic balance between the different vascular beds. This provides further evidence that intermittent iNO therapy may modulate ET-1 after LVAD implantation.

    Topics: Administration, Inhalation; Antihypertensive Agents; Blood Pressure; Cardiac Output, Low; Cardiopulmonary Bypass; Central Venous Pressure; Down-Regulation; Endothelin-1; Female; Heart Failure; Heart-Assist Devices; Humans; Hypertension, Pulmonary; Intraoperative Care; Male; Middle Aged; Nitric Oxide; Time Factors; Treatment Outcome; Ventricular Dysfunction, Right

2004
Influence of inhaled iloprost on transpulmonary gradient of big endothelin in patients with pulmonary hypertension.
    Circulation, 2003, Mar-25, Volume: 107, Issue:11

    The pulmonary circulation is an important site for the production and clearance of endothelin (ET)-1, a potent vasoactive and mitogenic peptide. In healthy individuals, 40% to 50% of circulating ET-1 is removed on each passage through the lungs resulting in an arteriovenous ratio of <1, whereas many patients with pulmonary arterial hypertension (PAH) have ratios >1, indicating reduced clearance or increased release of endothelin. The influence of inhaled prostanoids on endothelin clearance is unknown.. In a prospective investigation, plasma concentrations of big endothelin-1 (big ET-1, Elisa) were measured in 15 patients with pulmonary hypertension undergoing right heart catheterization with iloprost inhalation (4 m, 11 f, aged 35 to 75 years, mean pulmonary arterial pressure (PAPm) 54+/-2.3 mm Hg, pulmonary vascular resistance (PVR) 1061+/-141 dyn x sec x cm(-5)). There was a significant transpulmonary gradient for big ET-1 with 31% +/-11% higher concentrations in the radial artery than in the pulmonary artery (P<0.001). After inhalation of iloprost a significant decrease in the AV-ratio from 1.31+/-0.11 to 0.92+/-0.06 (P<0.007) was observed. The pulmonary net release of 3.10+/-0.65 pmol/min big ET-1 at baseline decreased to -1.24+/-1.32 pmol/min (P=0.013) within 15 minutes indicating a restored balance. Patients under long-term treatment with iloprost (n=7) tended to have a lower net release and AV-ratio for big ET-1 than patients without pretreatment.. An increase in pulmonary clearance of big-ET could be a mechanism contributing to the beneficial effects of inhaled prostanoids in the treatment of PAH.

    Topics: Administration, Inhalation; Adult; Aged; Endothelin-1; Endothelins; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Protein Precursors; Pulmonary Circulation

2003
Modulation of circulating endothelin-1 and big endothelin by nitric oxide inhalation following left ventricular assist device implantation.
    Circulation, 2003, Sep-09, Volume: 108 Suppl 1

    Inhaled nitric oxide (iNO) is an established therapy in the treatment of pulmonary hypertension and right ventricular dysfunction following left ventricular assist device implantation. Since it is known that endothelin-1 contributes to pulmonary hypertension, and nitric oxide modulates endothelin-1 synthesis in vitro, we investigated the effects of iNO on circulating endothelin-1 and big endothelin following left ventricular assist device implantation.. On weaning from cardiopulmonary bypass, 15 consecutive patients with secondary pulmonary hypertension after implantation of a left ventricular assist device were treated with iNO. Endothelin-1 and big endothelin plasma levels were measured preoperatively, on cardiopulmonary bypass prior to iNO, 12, 24, and 48 hour postoperatively, and 72 hour after cessation of iNO. Endothelin-1 levels were increased preoperatively (1.05+/-0.20 fmol/L), and were highest on cardiopulmonary bypass (1.65+/-0.27 fmol/L). During iNO therapy endothelin-1 and big endothelin decreased significantly (endothelin-1: 12 hour 1.24+/-0.18, 24 hour 0.93+/-0.20, and 48 hour 0.81+/-0.14 fmol/L); they were lowest 72 hour post-iNO (endothelin-1: 0.56+/-0.09 fmol/L). Plasma endothelin-1 concentrations and iNO dose were inversely correlated (r=-0.657, P<0.015). A significant correlation was also found between endothelin-1 versus PA pressures and PVR/SVR ratio, but not with CI and SVR.. Since it is known that endothelin-1 mediates pulmonary hypertension, we suggest a 2-fold effect of iNO therapy: firstly, a selective vasodilation of the pulmonary vasculature; and secondly, iNO mediated modulation of endothelin-1.

    Topics: Administration, Inhalation; Adult; Aged; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Female; Heart-Assist Devices; Hemodynamics; Humans; Hypertension, Pulmonary; Kinetics; Male; Middle Aged; Nitric Oxide; Protein Precursors

2003
[Levels of plasma endothelin, nitric oxide and atrial natriuretic peptide after cardiopulmonary bypass and influence of inhaled nitric oxide in patients with ventricular septal defect and pulmonary hypertension].
    Zhonghua wai ke za zhi [Chinese journal of surgery], 2002, Volume: 40, Issue:4

    To assess the changes of the levels of plasma endothelin (ET-1), nitric oxide (NO) and atrial natriuretic peptide (ANP) after cardiopulmonary bypass (CPB) and the influence of inhaled nitric oxide in patients with ventricular septal defect (VSD) and pulmonary hypertension (PH).. Sixty patients with VSD were enrolled in this study. They were divided into 2 groups: group A [no-PH group, mean pulmonary artery pressure (mPAP) < 20 mm Hg (1 mm Hg = 0.133 kPa) n = 20] and group B (PH group, mPAP > 20 mm Hg, n = 40). Group B was subdivided into two groups by randomized block, group B(1) (inhaled NO group, n = 20) and group B(2) (contrast group, n = 20). The plasma ET-1, NO, ANP concentrations were assayed at 24 h pre-operation and 0 h, 1 h, 5 h, 12 h, 24 h, 48 h after CPB.. The preoperative plasma ET-1, NO and ANP concentrations in group B were significantly higher than those in group A. In three groups, the plasma ET-1 concentration at 0 h after CPB was significantly higher than that at 24 h pre-operation, and the plasma NO concentration at 0 h after CPB was significantly lower than that at 24 h pre-operation. In group B, the plasma ANP concentration at 0 h after CPB was significantly higher than that at 24 h pre-operation. After CPB, the plasma ET-1 concentration in group B(1) decreased faster than that in group B(2), and the plasma NO concentration in group B(1) increased faster than that in group B(2). In group B, the preoperative plasma ET-1 concentration negatively correlated with the preoperative plasma NO concentration and positively correlated with the preoperative ANP concentration.. The broken dynamic balance of ET-1/NO may take part in generation and development of pulmonary hypertension. ANP acts as a favorable physiological regulating factor in the pathogenesis of pulmonary hypertension. CPB can regulate the level of ET-1 up and NO and ANP down while inhaled NO can cause the level of ET-1 down and the level of NO up.

    Topics: Administration, Inhalation; Atrial Natriuretic Factor; Cardiopulmonary Bypass; Child, Preschool; Endothelin-1; Female; Heart Septal Defects; Humans; Hypertension, Pulmonary; Male; Nitric Oxide

2002
Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension.
    Circulation, 2002, Mar-05, Volume: 105, Issue:9

    The pulmonary circulation is an important site for the production and clearance of endothelin (ET)-1, a potent vasoactive and mitogenic peptide. Increased plasma ET-1 levels are observed in pulmonary arterial hypertension (PHT) and may contribute to the regulation of pulmonary vascular resistance, as well as to proliferative changes in the pulmonary vascular bed.. We prospectively assessed changes in plasma big ET-1 levels and changes in ET(A) and ET(B) receptor gene expression in 14 consecutive patients undergoing pulmonary thromboendarterectomy for thromboembolic PHT. Plasma big ET-1 levels were higher in patients with PHT (median, 2.2 pg/mL; 25th to 75th percentile, 1.5 to 3.0 pg/mL) compared with age-matched controls (median, 1.2 pg/mL; 25th to 75th percentile, 1.0 to 1.4 pg/mL; P=0.002). In addition to increased plasma big ET-1 levels, selective upregulation of ET(B) receptor mRNA transcripts and immunoreactive protein in the pulmonary artery was observed in the patients; however, ET(A) receptor gene expression was unaffected.. These data suggest that changes in the ET signaling system in PHT caused by thromboembolic disease are not limited to an increased production of ET-1: they also affect ET receptor gene expression.

    Topics: Endarterectomy; Endothelin-1; Endothelins; Female; Fluorescent Antibody Technique; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies; Protein Precursors; Pulmonary Artery; Pulmonary Embolism; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

2002
Usefulness of endothelin-1 concentration in capillary blood in patients with mitral stenosis as a predictor of regression of pulmonary hypertension after mitral valve replacement or valvuloplasty.
    The American journal of cardiology, 2002, Jul-15, Volume: 90, Issue:2

    Topics: Adult; Aged; Capillaries; Catheterization; Endothelin-1; Heart Valve Prosthesis Implantation; Humans; Hypertension, Pulmonary; Middle Aged; Mitral Valve Stenosis; Predictive Value of Tests; Pulmonary Circulation; Remission Induction

2002
Endothelin receptor subtype A blockade selectively reduces pulmonary pressure after cardiopulmonary bypass.
    The Journal of thoracic and cardiovascular surgery, 2001, Volume: 122, Issue:2

    The bioactive peptide endothelin-1 is elevated during and after cardiopulmonary bypass and exerts cardiovascular effects through its 2 receptor subtypes, endothelin-1A and endothelin-1B. Increased endothelin-1A receptor stimulation after cardiopulmonary bypass can cause increased pulmonary vascular resistance and modulate myocardial contractility. However, whether and to what degree selective endothelin-1A blockade influences these parameters in the postbypass setting is not completely understood.. Our objective was to measure left ventricular function and hemodynamics in a porcine model of cardiopulmonary bypass after selective blockade of endothelin-1A.. Adult pigs (n = 23) underwent 90 minutes of cardiopulmonary bypass and were randomized 30 minutes after bypass to receive a selective endothelin-1A antagonist (TBC 11251, 10 mg/kg; n = 13) or saline vehicle (n = 10).. After bypass and before randomization, pulmonary vascular resistance rose nearly 4-fold, and left ventricular preload recruitable stroke work fell to one third of baseline values (both P <.05). In the vehicle group pulmonary vascular resistance continued to rise, and preload recruitable stroke work remained reduced. However, after endothelin-1A blockade, the rise in pulmonary vascular resistance was significantly blunted compared with that in the vehicle group. Moreover, the reduction in pulmonary vascular resistance with endothelin-1A blockade was achieved without a significant change in systemic perfusion pressures.. The present study demonstrated that increased activity of the endothelin-1A receptor likely contributes to alterations in pulmonary vascular resistance in the postbypass setting. Selective endothelin-1A blockade may provide a means to selectively decrease pulmonary vascular resistance without significant effects on systemic hemodynamics.

    Topics: Analysis of Variance; Animals; Cardiopulmonary Bypass; Disease Models, Animal; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Isoxazoles; Pulmonary Circulation; Receptors, Endothelin; Swine; Thiophenes; Vascular Resistance; Ventricular Function, Left

2001
[Observation on short-term effects of Angelica injection on chronic obstructive pulmonary disease patients with pulmonary hypertension].
    Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine, 2000, Volume: 20, Issue:3

    To study the effects of 25% Angelica sinensis injection on hemodynamics, endothelin-1 (ET-1), angiotensin-II (AT-II), endogenous digitalis-like factor (EDF), pulmonary function and arterial blood gas in the patients with chronic obstructive pulmonary disease (COPD) complicated pulmonary hypertension.. Sixty COPD patients complicated with pulmonary hypertension in remission stage were randomly divided into two groups, 30 cases in each. The Angelica group and the control group were treated with Angelica sinensis injection and 5% glucose injection (250 ml, intravenous dripping per day for 10 days) respectively. It was designed to investigate the changes of hemodynamics, ET-1, AT-II, EDF, pulmonary function and arterial blood gas.. The levels of mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), blood ET-1, AT-II and EDF were reduced by (18 +/- 5)%, (27 +/- 8)%, (20 +/- 6)%, (36 +/- 9)%, (38 +/- 11)% respectively, and PaO2 was increased in Angelica group (P < 0.05 or P < 0.01). There were insignificant differences of the above parameters in the control group, and no changes of pulmonary function in both groups.. Twenty-five Percent of Angelica injection can improve pulmonary hemodynamics through influencing the metabolism of ET-1, AT-II and EDF as well as increase PaO2 of the body.

    Topics: Aged; Angiotensin II; Drugs, Chinese Herbal; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Vasodilator Agents

2000
Dilutional and modified ultrafiltration reduces pulmonary hypertension after operations for congenital heart disease: a prospective randomized study.
    The Journal of thoracic and cardiovascular surgery, 1998, Volume: 115, Issue:3

    A prospective randomized study was performed to test whether removal of endothelin-1, by ultrafiltration techniques, will reduce pulmonary hypertension after operations for congenital heart disease.. Twenty-four patients with pulmonary hypertension (systolic pulmonary/systemic arterial pressure ratio > 60%) undergoing cardiac operations were randomized into a control group (n = 12) having conventional ultrafiltration and an experimental group (n = 12) undergoing dilutional ultrafiltration during and modified ultrafiltration after cardiopulmonary bypass. Plasma endothelin-1, nitric oxide metabolites, and cyclic guanosine monophosphate were assayed before bypass, 10 minutes into bypass, after bypass, and 0, 3, 6, and 12 hours after the operation in both groups, as well as in the ultrafiltrates and after modified ultrafiltration in the experimental group. Both groups received alpha-blockers (chlorpromazine and/or prazosin) postoperatively using the same guidelines.. The ultrafiltrates contained significant amounts of endothelin-1 (1.81 +/- 0.86 pg/ml, dilutional, and 6.44 +/- 1.82 pg/ml, modified ultrafiltrate). Endothelin-1 and the pulmonary/systemic pressure ratio were significantly lower in experimental compared with control patients. Nitric oxide metabolites and cyclic guanosine monophosphate increased similarly in both groups for 12 hours after the operation (p = not significant). Three of 12 control patients (25%) but no experimental patients had pulmonary hypertensive crises (p = 0.07). The experimental patients required significantly less ventilatory support (67 +/- 47 hours vs 178 +/- 139 hours for control patients, p = 0.048).. Dilutional and modified ultrafiltration reduce endothelin-1 and the pulmonary/systemic pressure ratio postoperatively and may become an important adjunct for preventing pulmonary hypertension after operations for congenital heart disease in high-risk patients.

    Topics: Cardiopulmonary Bypass; Cyclic GMP; Endothelin-1; Female; Heart Defects, Congenital; Hemofiltration; Humans; Hypertension, Pulmonary; Infant; Male; Nitric Oxide; Postoperative Complications; Prospective Studies

1998
Plasma levels of nitric oxide products and endothelin in pulmonary hypertension with congenital heart disease.
    Acta paediatrica (Oslo, Norway : 1992), 1998, Volume: 87, Issue:6

    Topics: Biomarkers; Cardiac Catheterization; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Radioimmunoassay; Sensitivity and Specificity

1998
Local and peripheral plasma endothelin-1 in pulmonary hypertension secondary to chronic obstructive pulmonary disease.
    Respiration; international review of thoracic diseases, 1998, Volume: 65, Issue:4

    Endothelin-1 (ET-1) has been described to have crucial effects in the initiation and evolution of pulmonary hypertension (PH) secondary to cardiac disorders. However, the precise role of ET-1 in PH induced by chronic obstructive pulmonary disease (COPD) is not yet clear. The objective of this cross-sectional study was to determine the local and peripheral plasma ET-1 profile of COPD patients with or without PH. Twenty-six COPD patients with clinical and/or laboratory findings suspicious of PH, and 20 healthy smoker volunteers constituted the study population. Patients were allocated to PH (n = 17) and non-PH (n = 9) groups according to their pulmonary artery pressures determined by right-heart catheterization. Plasma ET-1 samples, obtained from the main pulmonary artery (mixed venous blood) and peripheral blood (radial artery and brachial vein), were assessed by radioimmunoassay. Brachial vein ET-1 levels were within normal ranges in PH (2.7 +/- 0.5 pg/ml) and non-PH (3.2 +/- 0. 7 pg/ml) COPD patients compared with that of the controls (4.4 +/- 0. 1 pg/ml). Likewise, radial artery ET-1 levels in PH (3.3 +/- 0.7 pg/ml) and non-PH (2.9 +/- 0.8 pg/ml) groups, and in controls (3.4 +/- 1.1 pg/ml) were also comparable. The pulmonary artery ET-1 concentration of the PH group (13.6 +/- 3.7 pg/ml) was higher than that of the non-PH group (2.2 +/- 0.4 pg/ml) and that of the peripheral blood levels of controls. Elevated pulmonary artery ET-1 in the PH group was inversely correlated only with PaO2 levels. These results could be taken as an evidence of a local role of ET-1 in COPD-induced PH, but it remains to be clarified whether ET-1 is a marker or a mediator of PH in COPD.

    Topics: Adult; Aged; Biomarkers; Blood Gas Analysis; Cross-Sectional Studies; Endothelin-1; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Middle Aged; Multivariate Analysis; Respiratory Function Tests; Sensitivity and Specificity; Statistics, Nonparametric

1998

Other Studies

474 other study(ies) available for endothelin-1 and Hypertension--Pulmonary

ArticleYear
The Effect of Exercise on Endothelin 1 Level in Patients With Pulmonary Hypertension.
    Current problems in cardiology, 2023, Volume: 48, Issue:5

    Topics: Endothelin-1; Exercise; Humans; Hypertension, Pulmonary

2023
Histopathological Evaluation of Pulmonary Thromboendarterectomy Specimens of Chronic Thromboembolic Pulmonary Hypertension.
    Journal of atherosclerosis and thrombosis, 2023, Nov-01, Volume: 30, Issue:11

    Chronic thromboembolic pulmonary hypertension (CTEPH) is a condition with a poor prognosis in which the pulmonary arteries are occluded by organized thrombi. Pulmonary thromboendarterectomy (PEA) is an effective treatment for CTEPH; however, the literature on its histopathological examination is lacking. This study aimed to investigate the histopathological findings and protein and gene expression in PEA specimens, establish an optimal histopathological evaluation method, and clarify the mechanisms of thrombus organization and disease progression in CTEPH.. In total, 50 patients with CTEPH who underwent PEA were analyzed. The patients were categorized according to their clinical data into two groups: good and poor postoperative courses. The relationship between their histopathological findings and the clinical course was examined. Immunohistochemical studies confirmed the expression of oxidants, antioxidants, and smooth muscle cell (SMC) differentiation markers and their changes during the progression of thrombus organization. The mRNA expression analysis of 102 samples from 27 cases included oxidants, antioxidants, and vasoconstrictor endothelin-1.. In the PEA specimens, colander-like lesions (aggregations of recanalized blood vessels with well-differentiated SMCs) were significantly more common in the good postoperative course group than in the poor postoperative course group; analysis of proteins and genes proposed that oxidative and antioxidant mechanisms were involved. In the colander-like lesions, there was an increase in endothelin-1 mRNA and protein expression of endothelin receptor A.. Colander-like lesions in PEA specimens must be identified. Additionally, SMC differentiation in recanalized vessels and the expression of vasoconstrictors and their receptors may contribute to the progression of CTEPH.

    Topics: Chronic Disease; Endarterectomy; Endothelin-1; Humans; Hypertension, Pulmonary; Oxidants; Pulmonary Embolism; RNA, Messenger; Thrombosis

2023
Serum expression of Rho kinase, endothelin-1, and nitric oxide in pediatric patients with congenital heart disease accompanied by pulmonary hypertension.
    Asian journal of surgery, 2022, Volume: 45, Issue:1

    Topics: Child; Endothelin-1; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Nitric Oxide; rho-Associated Kinases

2022
Correlation between hs-CRP, IL-6, IL-10, ET-1, and Chronic Obstructive Pulmonary Disease Combined with Pulmonary Hypertension.
    Journal of healthcare engineering, 2022, Volume: 2022

    Topics: C-Reactive Protein; Endothelin-1; Humans; Hypertension, Pulmonary; Interleukin-10; Interleukin-6; Oxygen; Pulmonary Disease, Chronic Obstructive

2022
Evaluation of acute phase proteins, adiponectin and endothelin-1 to determine vascular damage in dogs with heartworm disease (Dirofilaria immitis), before and after adulticide treatment.
    Veterinary parasitology, 2022, Volume: 309

    Previous studies have shown the existence of an acute phase response in dogs with heartworm (Dirofilaria immitis), probably caused by the vascular inflammation that occurs during the pathogenesis of this disease. In addition, it has been seen that this acute phase response persists after finishing treatment, especially in dogs with pulmonary hypertension (PH). Furthermore, echocardiographic studies have shown that PH and endarteritis appear to persist for at least 10 months after completion of adulticide treatment, suggesting that the vascular changes in these dogs may not be reversible. Therefore, the objective of this study was to evaluate the serum concentrations of different positive acute phase proteins (APP) [C reactive-protein (CRP), haptoglobin and ferritin] and negative APP (albumin and paraoxonase-1 (PON-1)), and the usefulness of the endothelin-1 (ET-1) and adiponectin, in dogs infected by D. immitis to evaluate their usefulness as diagnostic biomarkers of vascular damage and PH and their progression throughout therapy up to 7 months after the end of adulticide treatment. Twenty-five heartworm-infected dogs received adulticide treatment, and serum measurements were performed on the day of diagnosis (day 0), day of discharge (day 90), and 6 months after discharge (day 270). In addition, presence or absence of PH was also echocardiographically determined using the Right Pulmonary Artery Distensibility Index. PH was present in 44% of the dogs on day 0 and day 90, and in 48% of dogs on day 270. Alterations were observed in the concentrations of all APP throughout the study, persisting the alterations in PON-1 and ferritin on day 270. Depending on the presence or absence of PH, CRP showed significant differences throughout the study, as did ET-1. On the other hand, adiponectin did not show variations throughout the study, so it did not seem a useful marker in this disease. These results could reflect the possible persistence of vascular inflammation up to 7 months after finishing treatment, whether or not there was PH, and consolidate the study of APP as useful markers in heartworm disease. Moreover, persistent PH could be the consequent clinical manifestation in dogs with more severe vascular alterations so the study of APP, especially CRP, and ET-1 could be especially advantageous in these patients in the early evaluation of the disease, as well as for the determination of disease severity, monitoring therapeutic responses, and predicting outcomes

    Topics: Acute-Phase Proteins; Acute-Phase Reaction; Adiponectin; Animals; Biomarkers; C-Reactive Protein; Dirofilaria immitis; Dirofilariasis; Dog Diseases; Dogs; Endothelin-1; Ferritins; Hypertension, Pulmonary

2022
Endothelin-1 alters BMP signaling to promote proliferation of pulmonary artery smooth muscle cells.
    Canadian journal of physiology and pharmacology, 2022, Oct-01, Volume: 100, Issue:10

    Pulmonary arterial hypertension (PAH) is characterized by abnormal outgrowth of pulmonary artery smooth muscle cells (PASMCs) of the media. Abundant expression of endothelin-1 (ET-1) and activated p38 mitogen-activated protein kinase (p38MAPK) has been observed in PAH patients. p38MAPK has been implicated in cell proliferation. An unspecified disturbance in bone morphogenetic protein (BMP) signaling may be involved in the development of PAH. Type I receptors (BMPR1A and BMPR1B) and type II receptor (BMPR2) transduce signals via two distinct pathways, i.e., canonical and non-canonical pathways, activating Smad1/5/8 and p38MAPK, respectively. BMPR1B expression was previously reported to be enhanced in the PASMCs of patients with idiopathic PAH. BMP15 binds specifically to BMPR1B. We assessed the effects of ET-1 on BMP receptor expression and cell proliferation. BMP2 increased BMPR1B expression in human PASMCs after pretreatment with ET-1 in vitro. Although BMP2 alone did not affect PASMC proliferation, BMP2 treatment after ET-1 pretreatment significantly accelerated PASMC proliferation. PH-797804, a selective p38MAPK inhibitor, abrogated this proliferation. Similarly, after ET-1 pretreatment, BMP15 significantly accelerated the proliferation of PASMCs, whereas stimulation with BMP15 alone did not. In conclusion, in PASMCs, ET-1 exposure under pathological conditions alters BMP signaling to activate p38MAPK, resulting in cell proliferation.

    Topics: Bone Morphogenetic Proteins; Cell Proliferation; Cells, Cultured; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Pulmonary Artery

2022
Changes in Some Vascular Biomarkers in Patients with Severe COVID-19 with Various Degrees of Pulmonary Hypertension.
    Bulletin of experimental biology and medicine, 2022, Volume: 173, Issue:4

    The aim of the study was to evaluate the levels of cardiac biomarkers endothelin 1, B-natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (Nt-proBNP), NO

    Topics: Biomarkers; COVID-19; Endothelin-1; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Nitrates; Nitrites; Nitrogen Dioxide; Oxygen; Peptide Fragments

2022
Microrna-486-5P Regulates Human Pulmonary Artery Smooth Muscle Cell Migration via Endothelin-1.
    International journal of molecular sciences, 2022, Sep-08, Volume: 23, Issue:18

    Pulmonary arterial hypertension (PAH) is a fatal or life-threatening disorder characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance. Abnormal vascular remodeling, including the proliferation and phenotypic modulation of pulmonary artery smooth muscle cells (PASMCs), represents the most critical pathological change during PAH development. Previous studies showed that miR-486 could reduce apoptosis in different cells; however, the role of miR-486 in PAH development or HPASMC proliferation and migration remains unclear. After 6 h of hypoxia treatment, miR-486-5p was significantly upregulated in HPASMCs. We found that miR-486-5p could upregulate the expression and secretion of ET-1. Furthermore, transfection with a miR-486-5p mimic could induce HPASMC proliferation and migration. We also found that miRNA-486-5p could downregulate the expression of SMAD2 and the phosphorylation of SMAD3. According to previous studies, the loss of SMAD3 may play an important role in miRNA-486-5p-induced HPASMC proliferation. Although the role of miRNA-486-5p in PAH in in vivo models still requires further investigation and confirmation, our findings show the potential roles and effects of miR-486-5p during PAH development.

    Topics: Cell Movement; Cell Proliferation; Cells, Cultured; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; MicroRNAs; Myocytes, Smooth Muscle; Pulmonary Arterial Hypertension; Pulmonary Artery

2022
Changes in ET-1, Plasma Neuropeptide Y, and CGRP in Child Patients With Congenital Heart Disease Complicated With Pulmonary Hypertension Before and After Operation.
    Clinical pediatrics, 2021, Volume: 60, Issue:1

    This study aims to explore the changes in endothelin-1 (ET-1), plasma neuropeptide Y, and calcitonin gene-related peptide (CGRP) in child patients before and after operation. A total of 80 child patients with congenital heart disease (CHD) complicated with pulmonary hypertension (PH) were enrolled and divided into control group (n = 40, conservative treatment for various reasons) and observation group (n = 40, active preoperative preparation and timely operative intervention) according to different treatments. There were positive correlations between systolic pulmonary arterial pressure (sPAP) and ET-1, plasma neuropeptide Y, while negative correlation between sPAP and CGRP. In conclusion, our data demonstrate that the levels of ET-1, plasma neuropeptide Y, and CGRP in PH-CHD were significantly changed after interventions, which provides new leads as alternative biomarkers to assess the efficacy of treatments against PH-CHD.

    Topics: Calcitonin Gene-Related Peptide; Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Neuropeptide Y; Postoperative Period; Preoperative Period

2021
Characteristics and long-term survival of patients with chronic thromboembolic pulmonary hypertension in China.
    Respirology (Carlton, Vic.), 2021, Volume: 26, Issue:2

    The purpose of this study was to report the characteristics and long-term survival of patients with CTEPH treated in three distinct ways: PEA, BPA and medical therapy.. Patients diagnosed with CTEPH were included in the registry that was set up in 18 centres from August 2009 to July 2018. The characteristics and survival of patients with CTEPH receiving the different treatments were reported. Prognostic factors were evaluated by Cox regression model.. A total of 593 patients with CTEPH were included. Eighty-one patients were treated with PEA, 61 with BPA and 451 with drugs. The estimated survival rates at 1, 3, 5 and 8 years were, respectively, 95.2%, 84.6%, 73.4% and 66.6% in all patients; 92.6%, 89.6%, 87.5% and 80.2% in surgical patients; and 95.4%, 88.3%, 71.0% and 64.1% in medically treated patients. The estimated survival rates at 1, 3, 5 and 7 years in patients treated with BPA were 96.7%, 88.1%, 70.0% and 70.0%, respectively. For all patients, PEA was an independent predictor of survival. Other independent risk factors were CHD, cardiac index, PVR, big endothelin-1, APE and 6MWD.. This is the first multicentre prospective registry reporting baseline characteristics and estimated survival of patients with CTEPH in China. The long-term survival rates are similar to those of patients in the international and Spanish registries. PEA is an independent predictor of survival.

    Topics: Angioplasty, Balloon; China; Chronic Disease; Endarterectomy; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Multivariate Analysis; Pulmonary Embolism; Registries; Risk Factors; Survival Analysis; Time Factors; Treatment Outcome

2021
Therapeutic inhibition of HIF-2α reverses polycythemia and pulmonary hypertension in murine models of human diseases.
    Blood, 2021, 05-06, Volume: 137, Issue:18

    Polycythemia and pulmonary hypertension are 2 human diseases for which better therapies are needed. Upregulation of hypoxia-inducible factor-2α (HIF-2α) and its target genes, erythropoietin (EPO) and endothelin-1, causes polycythemia and pulmonary hypertension in patients with Chuvash polycythemia who are homozygous for the R200W mutation in the von Hippel Lindau (VHL) gene and in a murine mouse model of Chuvash polycythemia that bears the same homozygous VhlR200W mutation. Moreover, the aged VhlR200W mice developed pulmonary fibrosis, most likely due to the increased expression of Cxcl-12, another Hif-2α target. Patients with mutations in iron regulatory protein 1 (IRP1) also develop polycythemia, and Irp1-knockout (Irp1-KO) mice exhibit polycythemia, pulmonary hypertension, and cardiac fibrosis attributable to translational derepression of Hif-2α, and the resultant high expression of the Hif-2α targets EPO, endothelin-1, and Cxcl-12. In this study, we inactivated Hif-2α with the second-generation allosteric HIF-2α inhibitor MK-6482 in VhlR200W, Irp1-KO, and double-mutant VhlR200W;Irp1-KO mice. MK-6482 treatment decreased EPO production and reversed polycythemia in all 3 mouse models. Drug treatment also decreased right ventricular pressure and mitigated pulmonary hypertension in VhlR200W, Irp1-KO, and VhlR200W;Irp1-KO mice to near normal wild-type levels and normalized the movement of the cardiac interventricular septum in VhlR200Wmice. MK-6482 treatment reduced the increased expression of Cxcl-12, which, in association with CXCR4, mediates fibrocyte influx into the lungs, potentially causing pulmonary fibrosis. Our results suggest that oral intake of MK-6482 could represent a new approach to treatment of patients with polycythemia, pulmonary hypertension, pulmonary fibrosis, and complications caused by elevated expression of HIF-2α.

    Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Endothelin-1; Erythropoietin; Female; Gene Expression Regulation; Hypertension, Pulmonary; Iron Regulatory Protein 1; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Polycythemia; Sulfones; Von Hippel-Lindau Tumor Suppressor Protein

2021
In vivo assessment of a single adenine mutation in 5'UTR of Endothelin-1 gene in paediatric cases with severe pulmonary hypertension: an observational study.
    BMC research notes, 2021, May-19, Volume: 14, Issue:1

    Endothelin-1 plays an important role in the pathogenesis of severe pulmonary hypertension. The + 139 'A', adenine insertion variant in 5'UTR of edn1 gene has been reported to be associated with increased expression of Endothelin-1 in vitro. The aim of present study was to explore the association of this variant with the circulating levels of Endothelin-1 in vivo using archived DNA and plasma samples from 38 paediatric congenital heart disease (cyanotic and acyanotic) patients with severe pulmonary hypertension.. The plasma Endothelin-1 levels were highly varied ranging from 1.63 to75.16 pg/ml. The + 139 'A' insertion variant in 5'UTR of edn1 was seen in 8 out of 38 cases with only one acyanotic sample demonstrating homozygosity of inserted 'A' allele at + 139 site (4A/4A genotype). The plasma Endothelin-1 levels in children with homozygous variant 3A/3A genotype were comparable in cyanotic and acyanotic groups. Lone 4A/4A acyanotic sample had ET-1 levels similar to the median value of ET-1 associated with 3A/3A genotype and was absent in cyanotic group presumably due to deleterious higher ET-1 levels. The discussed observations, limited by the small sample size, are suggestive of homozygous adenine insertion variant posing a risk in cyanotic babies with Severe Pulmonary Hypertension.

    Topics: 5' Untranslated Regions; Adenine; Child; Endothelin-1; Humans; Hypertension, Pulmonary; Mutation

2021
C1q/TNF-related protein-9 ameliorates hypoxia-induced pulmonary hypertension by regulating secretion of endothelin-1 and nitric oxide mediated by AMPK in rats.
    Scientific reports, 2021, 05-31, Volume: 11, Issue:1

    Injury/dysfunction of the endothelium of pulmonary arteries contributes to hypoxia-induced pulmonary hypertension (HPH). We investigated whether C1q/tumor necrosis factor-related protein-9 (CTRP9), a newly identified cardiovascular agent, has protective roles in the development of HPH. HPH was induced in adult male rats by chronic hypobaric hypoxia. CTRP9 overexpression by adeno-associated virus (AAV)-CTRP9 transfection attenuated the increases in right ventricular systolic pressure, right ventricular hypertrophy index, and pulmonary arterial remodeling of rats under hypoxia. Importantly, CTRP9 overexpression improved endothelium-dependent vasodilation in pulmonary arterioles in HPH rats. CTRP9 overexpression enhanced expression of phosphorylated 5'-adenosine monophosphate-activated protein kinase (p-AMPK) and phosphorylated endothelial nitric oxide synthase (p-eNOS), and reduced phosphorylated extracellular signal-regulated protein kinase (p-ERK1/2) expression in pulmonary microvascular endothelial cells (PMVECs) of HPH rats. In cultured PMVECs, CTRP9 not only preserved the decrease of AMPK and eNOS phosphorylation level and nitric oxide (NO) production induced by hypoxia, but also blocked the increase in hypoxia-induced ERK1/2 phosphorylation level and endothelin (ET)-1 production. Furthermore, the effects of CTRP9 were interrupted by inhibitors or knockdown of AMPK. CTRP9 enhances NO production and reduces ET-1 production by regulating AMPK activation. CTRP9 could be a target for HPH.

    Topics: Adenylate Kinase; Adiponectin; Animals; Cells, Cultured; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; MAP Kinase Signaling System; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Rats

2021
Activated Endothelial TGFβ1 Signaling Promotes Venous Thrombus Nonresolution in Mice Via Endothelin-1: Potential Role for Chronic Thromboembolic Pulmonary Hypertension.
    Circulation research, 2020, 01-17, Volume: 126, Issue:2

    Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by defective thrombus resolution, pulmonary artery obstruction, and vasculopathy. TGFβ (transforming growth factor-β) signaling mutations have been implicated in pulmonary arterial hypertension, whereas the role of TGFβ in the pathophysiology of CTEPH is unknown.. To determine whether defective TGFβ signaling in endothelial cells contributes to thrombus nonresolution and fibrosis.. Venous thrombosis was induced by inferior vena cava ligation in mice with genetic deletion of TGFβ1 in platelets (Plt.TGFβ-KO) or TGFβ type II receptors in endothelial cells (End.TGFβRII-KO). Pulmonary endarterectomy specimens from CTEPH patients were analyzed using immunohistochemistry. Primary human and mouse endothelial cells were studied using confocal microscopy, quantitative polymerase chain reaction, and Western blot. Absence of TGFβ1 in platelets did not alter platelet number or function but was associated with faster venous thrombus resolution, whereas endothelial TGFβRII deletion resulted in larger, more fibrotic and higher vascularized venous thrombi. Increased circulating active TGFβ1 levels, endothelial TGFβRI/ALK1 (activin receptor-like kinase), and TGFβRI/ALK5 expression were detected in End.TGFβRII-KO mice, and activated TGFβ signaling was present in vessel-rich areas of CTEPH specimens. CTEPH-endothelial cells and murine endothelial cells lacking TGFβRII simultaneously expressed endothelial and mesenchymal markers and transcription factors regulating endothelial-to-mesenchymal transition, similar to TGFβ1-stimulated endothelial cells. Mechanistically, increased endothelin-1 levels were detected in TGFβRII-KO endothelial cells, murine venous thrombi, or endarterectomy specimens and plasma of CTEPH patients, and endothelin-1 overexpression was prevented by inhibition of ALK5, and to a lesser extent of ALK1. ALK5 inhibition and endothelin receptor antagonization inhibited mesenchymal lineage conversion in TGFβ1-exposed human and murine endothelial cells and improved venous thrombus resolution and pulmonary vaso-occlusions in End.TGFβRII-KO mice.. Endothelial TGFβ1 signaling via type I receptors and endothelin-1 contribute to mesenchymal lineage transition and thrombofibrosis, which were prevented by blocking endothelin receptors. Our findings may have relevant implications for the prevention and management of CTEPH.

    Topics: Activin Receptors, Type II; Aged; Aged, 80 and over; Animals; Blood Platelets; Endothelin-1; Female; Human Umbilical Vein Endothelial Cells; Humans; Hypertension, Pulmonary; Male; Mice; Mutation; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Signal Transduction; Transforming Growth Factor beta; Venae Cavae; Venous Thrombosis

2020
Endothelin 1: A Potential Prognostic Biomarker for Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension?
    Cardiology, 2020, Volume: 145, Issue:4

    Topics: Biomarkers; Endothelin-1; Heart Failure; Hospitalization; Humans; Hypertension, Pulmonary; Prognosis; Stroke Volume

2020
Periostin: A Potential Therapeutic Target For Pulmonary Hypertension?
    Circulation research, 2020, 10-09, Volume: 127, Issue:9

    POSTN (Periostin) is an ECM (extracellular matrix) protein involved in tissue remodeling in response to injury and a contributing factor in tumorigenesis, suggesting that POSTN plays a role in the pathogenesis of pulmonary hypertension (PH).. We aimed to gain insight into the mechanistic contribution of POSTN in experimental mouse models of PH and correlate these findings with PH in humans.. We used genetic epistasis approaches in human pulmonary artery endothelial cells (hPAECs), human pulmonary artery smooth muscle cells, and experimental mouse models of PH (Sugen 5416/hypoxia or chronic hypoxia) to discern the role of POSTN and its relationship to HIF (hypoxia-inducible factor)-1α signaling. We found that POSTN expression was correlated with the extent of PH in mouse models and in humans. Decreasing POSTN improved hemodynamic and cardiac responses in PH mice, blunted the release of growth factors and HIF-1α, and reversed the downregulated BMPR (bone morphogenetic protein receptor)-2 expression in hPAECs from patients with PH, whereas increasing POSTIN had the opposite effects and induced a hyperproliferative and promigratory phenotype in both hPAECs and human pulmonary artery smooth muscle cells. Overexpression of POSTN-induced activation of HIFs and increased the production of ET (endothelin)-1 and VEGF (vascular endothelial growth factor) in hPAECs. SiRNA-mediated knockdown of HIF-1α abolished the proangiogenic effect of POSTN. Blockade of TrkB (tyrosine kinase receptor B) attenuated the effect of POSTN on HIF-1α expression, while inhibition of HIF-1α reduced the expression of POSTN and TrkB. These results suggest that hPAECs produce POSTN via a HIF-1α-dependent mechanism.. Our study reveals that POSTN expression is increased in human and animal models of PH and fosters PH development via a positive feedback loop between HIF-1α and POSTN during hypoxia. We propose that manipulating POSTIN expression may be an efficacious therapeutic target in the treatment of PH. Our results also suggest that POSTN may serve as a biomarker to estimate the severity of PH.

    Topics: Animals; Biomarkers; Bone Morphogenetic Protein Receptors, Type II; Cell Adhesion Molecules; Cell Hypoxia; Cell Movement; Cell Proliferation; Disease Models, Animal; Endothelial Cells; Endothelin-1; Humans; Hypertension, Pulmonary; Hypoxia-Inducible Factor 1, alpha Subunit; Indoles; Membrane Glycoproteins; Mice; Myocytes, Smooth Muscle; Protein-Tyrosine Kinases; Pulmonary Artery; Pyrroles; Receptor, trkB; Vascular Endothelial Growth Factor A

2020
Treatment-related biomarkers in pulmonary hypertension patients on oral therapies.
    Respiratory research, 2020, Nov-19, Volume: 21, Issue:1

    Multiple classes of oral therapy are available for the treatment of pulmonary arterial hypertension (PAH), but there is little to guide clinicians in choosing a specific regimen or therapeutic class. We aimed to investigate whether treatment-relevant blood biomarkers can predict therapy response in prevalent PAH patients.. This prospective cohort study longitudinally assessed biomarkers along the endothelin-1 (ET-1) and nitric oxide (cGMP, ADMA, SDMA, nitrite, and S-nitrosohemoglobin) pathways along with the cGMP/NT-proBNP ratio over 12 months in patients with WHO Group 1 PAH on oral PAH-specific therapies. The relationship between biomarkers and 6MWD at the same and future visits was examined using mixed linear regression models adjusted for age. As cGMP can be elevated when NT-proBNP is elevated, we also tested the relationship between 6MWD and the cGMP/NT-pro BNP ratio. Patients with PAH with concomitant heart or lung disease or chronic thromboembolic pulmonary hypertension (CTEPH) were included in a sensitivity analysis.. The study cohort included 58 patients with PAH treated with either an endothelin receptor antagonist (27.6%), phosphodiesterase-5 inhibitor (25.9%) or a combination of the two (43.1%). Among biomarkers along the current therapeutic pathways, ET-1 and the cGMP/NT-proBNP ratio associated with same visit 6MWD (p = 0.02 and p = 0.03 respectively), and ET-1 predicted future 6MWD (p = 0.02). ET-1 (p = 0.01) and cGMP/NT-proBNP ratio (p = 0.04) also predicted future 6MWD in the larger cohort (n = 108) of PAH patients with concomitant left heart disease (n = 17), lung disease (n = 20), or CTEPH (n = 13). Finally, in the larger cohort, SDMA associated with 6MWD at the same visit (p = 0.01) in all subgroups and ADMA associated with 6MWD in PAH patients with concomitant lung disease (p = 0.03) and PAH patients on ERA therapy (p = 0.01).. ET-1, cGMP/NTproBNP ratio, and dimethylarginines ADMA and SDMA are mediators along pathways targeted by oral PAH therapies that associate with or predict 6MWD.

    Topics: Administration, Oral; Aged; Biomarkers; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Longitudinal Studies; Male; Middle Aged; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Prospective Studies; Treatment Outcome

2020
PBI-4050 reduces pulmonary hypertension, lung fibrosis, and right ventricular dysfunction in heart failure.
    Cardiovascular research, 2020, 01-01, Volume: 116, Issue:1

    Heart failure with reduced ejection fraction (HFrEF) causes lung remodelling with myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome with pulmonary hypertension (PH) and right ventricular (RV) dysfunction. PBI-4050 is a first-in-class anti-fibrotic, anti-inflammatory, and anti-proliferative compound. The present study evaluated the therapeutic impact of PBI-4050 on PH in an HFrEF model.. HFrEF was induced after myocardial infarction (MI) in rats. Two weeks later, sham-operated and MI groups received PBI-4050 (200 mg/kg/day by gavage) or saline for 3 weeks. Animals were analysed according to infarct size as large (≥30% left ventricle) or medium MI (<30%). Large MI caused PH and RV hypertrophy (RVH) with a restrictive lung syndrome. PBI-4050 did not adversely affect left ventricular (LV) function but markedly reduced PH and RVH and improved RV dysfunction. PBI-4050 reduced lung remodelling and improved respiratory compliance with decreased lung fibrosis, alveolar wall cellular proliferation and α-smooth muscle actin expression. The increased expression of endothelin-1 (ET-1), transforming growth factor beta (TGF-β), interleukin-6 (IL-6) and of tissue inhibitor of metalloprotease-1 in the lungs from HFrEF were reduced with PBI-4050 therapy. Activation of isolated human lung fibroblasts (HLFs) to a myofibroblastic pro-fibrogenic phenotype was markedly reduced by PBI-4050. The fatty acid receptor GPR84 was increased in HFrEF lungs and in activated HLFs, and reduced by PBI-4050. GPR84 agonists activated fibrogenesis in HLFs and finally, PBI-4050 reduced ERK1/2 phosphorylation.. PBI-4050 reduces PH and RVH in HFrEF by decreasing lung fibrosis and remodelling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function. A contributing mechanism involves reducing the activation of lung fibroblasts by IL-6, TGF-β, and ET-1 by antagonism of GPR84 and reduced ERK1/2 phosphorylation. PBI-4050 is a novel promising therapy for targeting lung remodelling in group II PH.

    Topics: Acetates; Animals; Cells, Cultured; Disease Models, Animal; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Fibrosis; Heart Failure; Heart Ventricles; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Interleukin-6; Lung; Male; Phosphorylation; Pulmonary Fibrosis; Rats, Wistar; Receptors, G-Protein-Coupled; Signal Transduction; Transforming Growth Factor beta; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Remodeling

2020
The prognosis value of C-reactive protein and endothelin-1 in chronic obstructive pulmonary disease patients with pulmonary artery pressure.
    Pakistan journal of pharmaceutical sciences, 2019, Volume: 32, Issue:4

    Chronic Obstructive Pulmonary Disease (COPD), which is caused by various proinflammatory cytokines, will present some kinds of complication with progression such as Pulmonary Artery Hypertension (PAH). CRP (C-Reactive Protein) and ET-1(Endotheline-1) play pivotal function in inflammatory responses. The aim of this study is to investigate the prognosis value of CRP and ET-1 in COPD patients with pulmonary artery hypertension. CRP and ET-1 were measured in the plasma, sputum and exhaled breath condensate (EBC) of 55 COPD patients, 75 COPD patients with PAH and 57 healthy controls. Then, we analyzed the influence of these two proteins on the lung function, pulmonary artery pressure, exercise capacity and other clinical indices. The amount of CRP and ET-1 were the highest in COPD patients with PAH, followed by the COPD patients and the healthy controls. And there were statistically significant differences (p<0.05). The amount of CRP and ET-1 were negatively correlated with the lung function and exercise capacity, positively correlated with the pulmonary artery pressure. CRP and ET-1 are two valuable indicators in the diagnosis of COPD patients with PAH in clinic.

    Topics: Aged; Biomarkers; Body Mass Index; Breath Tests; C-Reactive Protein; Case-Control Studies; Endothelin-1; Exercise; Female; Humans; Hypertension, Pulmonary; Male; Prognosis; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Smoking; Sputum

2019
Effect of Rho kinase inhibitor fasudil on the expression ET-1 and NO in rats with hypoxic pulmonary hypertension.
    Clinical hemorheology and microcirculation, 2019, Volume: 71, Issue:1

    This study aims to study the effect of Rho kinase inhibitor fasudil on the expression endothelin-1 (ET-1) and nitric oxide (NO) in rats with hypoxic pulmonary hypertension (HPH).. Twenty-four male SD rats were randomly divided into three groups: control group, model group (HPH group) and HPH+fasudil group. The rat HPH model was established by intermittent hypoxia (IH) at atmospheric pressure. Mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index (RVHI), ET-1 and NO levels, and pulmonary vascular structural changes were observed in all groups.. MPAP, RVHI and ET-1 levels were significantly higher in HPH group than in control group, while NO was significantly lower than in control group. In addition, mPAP, RVHI and ET-1 were significantly lower in the HPH+fasudil group than in the HPH group. In the HPH group, ET-1 level was significantly and positively correlated with mPAP and RVHI, NO was negatively correlated with mPAP and RVHI levels, and ET-1 level was significantly and negatively correlated with NO level. In the HPH group, pulmonary arteriolar walls were generally thickened, and lumen stenosis was obvious; while after fasudil treatment, pulmonary arteriolar wall thickening and stenosis degree were significantly reduced.. Fasudil can significantly reduce ET-l level and increase NO level in HPH rats, suppressing the development of pulmonary arterial hypertension.

    Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Male; Nitric Oxide; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley

2019
S-nitrosation impairs KLF4 activity and instigates endothelial dysfunction in pulmonary arterial hypertension.
    Redox biology, 2019, Volume: 21

    Krüppel-like factor 4 (KLF4) is a transcription factor with conserved zinc finger domains. As an essential regulator of vascular homeostasis, KLF4 exerts a protective effect in endothelial cells (ECs), including regulating vasodilation, inflammation, coagulation and oxidative stress. However, the underlying mechanisms modifying KLF4 activity in mediating vascular function remain poorly understood. Recently, essential roles for S-nitrosation have been implicated in many pathophysiologic processes of cardiovascular disease. Here, we demonstrated that KLF4 could undergo S-nitrosation in response to nitrosative stress in ECs, leading to the decreased nuclear localization with compromised transactivity. Mass-spectrometry and site-directed mutagenesis revealed that S-nitrosation modified KLF4 predominantly at Cys437. Functionally, KLF4 dependent vasodilatory response was impaired after S-nitrosoglutathione (GSNO) treatment. In ECs, endothelin-1 (ET-1) induced KLF4 S-nitrosation, which was inhibited by an endothelin receptor antagonist Bosentan. In hypoxia-induced rat model of pulmonary arterial hypertension (PAH), S-nitrosated KLF4 (SNO-KLF4) was significantly increased in lung tissues, along with decreased nuclear localization of KLF4. In summary, we demonstrated that S-nitrosation is a novel mechanism for the post-translational modification of KLF4 in ECs. Moreover, these findings suggested that KLF4 S-nitrosation may be implicated in the pathogenesis of vascular dysfunction and diseases such as PAH.

    Topics: Animals; Cysteine; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Hypertension, Pulmonary; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Male; Protein Transport; Rats; Recombinant Proteins; Transcription, Genetic; Vasodilation

2019
Magnesium attenuates endothelin-1-induced vasoreactivity and enhances vasodilatation in mouse pulmonary arteries: Modulation by chronic hypoxic pulmonary hypertension.
    Experimental physiology, 2018, 04-01, Volume: 103, Issue:4

    What is the central question of this study? The central goal of this study was to elucidate the role of magnesium in the regulation of pulmonary vascular reactivity in relationship to hypoxic pulmonary hypertension. What is the main finding and its importance? We found that magnesium is essential for normal vasoreactivity of the pulmonary artery. Increasing the magnesium concentration attenuates vasoconstriction and improves vasodilatation via release of nitric oxide. Pulmonary hypertension is associated with endothelial dysfunction resulting in the suppression of magnesium modulation of vasodilatation. These results provide evidence that magnesium is important for the modulation of pulmonary vascular function.. Pulmonary hypertension (PH) is characterized by enhanced vasoreactivity and sustained pulmonary vasoconstriction, arising from aberrant Ca

    Topics: Animals; Endothelin-1; Endothelium, Vascular; Hypertension, Pulmonary; Hypoxia; Magnesium; Male; Mice; Mice, Inbred ICR; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitric Oxide; Pulmonary Artery; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

2018
Actin polymerization contributes to enhanced pulmonary vasoconstrictor reactivity after chronic hypoxia.
    American journal of physiology. Heart and circulatory physiology, 2018, 05-01, Volume: 314, Issue:5

    Chronic hypoxia (CH) augments basal and endothelin-1 (ET-1)-induced pulmonary vasoconstrictor reactivity through reactive oxygen species (ROS) generation and RhoA/Rho kinase (ROCK)-dependent myofilament Ca

    Topics: Actin Cytoskeleton; Actin Depolymerizing Factors; Actins; Animals; Chronic Disease; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Oxidative Stress; Phosphorylation; Polymerization; Pulmonary Artery; Rats, Sprague-Dawley; rho GTP-Binding Proteins; rho-Associated Kinases; Vascular Remodeling; Vasoconstriction; Vasoconstrictor Agents

2018
Lung Function, Inflammation, and Endothelin-1 in Congenital Heart Disease-Associated Pulmonary Arterial Hypertension.
    Journal of the American Heart Association, 2018, 02-14, Volume: 7, Issue:4

    Breathlessness is the most common symptom in people with pulmonary arterial hypertension and congenital heart disease (CHD-APAH), previously thought to be caused by worsening PAH, but perhaps also by inflammation and abnormalities of lung function. We studied lung function and airway inflammation in patients with CHD-APAH and compared the results with controls.. Raised biomarkers for inflammation were found in CHD-APAH. Significant abnormalities in airway physiology may contribute to the dyspnea but are not driven by inflammation as assessed by circulating and sputum cytokines. A relationship between increased serum endothelin-1 and airway dysfunction may relate to its bronchoconstrictive properties.

    Topics: Adult; Biomarkers; Bronchoconstriction; Case-Control Studies; Databases, Factual; Dyspnea; Endothelin-1; Exercise Tolerance; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Inflammation Mediators; Lung; Male; Middle Aged; Plethysmography, Whole Body; Pneumonia; Risk Factors; Spirometry; Sputum; Up-Regulation; Walk Test

2018
NMDA-Type Glutamate Receptor Activation Promotes Vascular Remodeling and Pulmonary Arterial Hypertension.
    Circulation, 2018, 05-29, Volume: 137, Issue:22

    Excessive proliferation and apoptosis resistance in pulmonary vascular cells underlie vascular remodeling in pulmonary arterial hypertension (PAH). Specific treatments for PAH exist, mostly targeting endothelial dysfunction, but high pulmonary arterial pressure still causes heart failure and death. Pulmonary vascular remodeling may be driven by metabolic reprogramming of vascular cells to increase glutaminolysis and glutamate production. The. We assessed the status of the glutamate-NMDAR axis in the pulmonary arteries of patients with PAH and controls through mass spectrometry imaging, Western blotting, and immunohistochemistry. We measured the glutamate release from cultured pulmonary vascular cells using enzymatic assays and analyzed NMDAR regulation/phosphorylation through Western blot experiments. The effect of NMDAR blockade on human pulmonary arterial smooth muscle cell proliferation was determined using a BrdU incorporation assay. We assessed the role of NMDARs in vascular remodeling associated to pulmonary hypertension, in both smooth muscle-specific NMDAR knockout mice exposed to chronic hypoxia and the monocrotaline rat model of pulmonary hypertension using NMDAR blockers.. We report glutamate accumulation, upregulation of the NMDAR, and NMDAR engagement reflected by increases in GluN1-subunit phosphorylation in the pulmonary arteries of human patients with PAH. K. These results reveal a dysregulation of the glutamate-NMDAR axis in the pulmonary arteries of patients with PAH and identify vascular NMDARs as targets for antiremodeling treatments in PAH.

    Topics: Animals; Apoptosis; Calcium; Cell Proliferation; Disease Models, Animal; Dizocilpine Maleate; Endothelin-1; Glutamic Acid; Humans; Hypertension, Pulmonary; Lung; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Potassium Channels, Voltage-Gated; Rats; Receptors, Endothelin; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Vascular Remodeling

2018
Early versus late cardiac remodeling during right ventricular pressure load and impact of preventive versus rescue therapy with endothelin-1 receptor blockers.
    Journal of applied physiology (Bethesda, Md. : 1985), 2018, 05-01, Volume: 124, Issue:5

    Pulmonary artery banding (PAB) causes right ventricular (RV) dysfunction, biventricular fibrosis, and apoptosis, which are attenuated by endothelin-1 receptor blockade (ERB). Little is known about the time course of remodeling and whether early versus late ERB confers improved outcome. PAB was performed in five groups of rabbits: Shams, 3-wk PAB (3W), 6-wk PAB (6W), 6-wk PAB + ERB administered from day 1 (6WERB1), and 6-wk PAB + ERB administered from day 21 (6WERB21). Biventricular development of profibrotic molecular signaling, fibrosis, apoptosis, and conductance catheter and echocardiography function were studied. Thirty-three rabbits [ n = 6-7 per group; 3.00 (0.23) kg, mean (SD)] developed half to full systemic RV pressures. Biventricular profibrotic signaling and collagen deposition [RV collagen: Shams 3.8 (0.58) vs. 3W 8.69 (2.52) vs. 6W 8.83 (4.02)%, P < 0.005] and apoptosis [RV: Shams 8.32 (3.2) vs. 3W 55.95 (47.55) vs. 6W 38.85 (17.26) apoptotic cells per microfield, P < 0.0005] increased with PAB. Early and late ERB attenuated fibrosis [RV: 6WERB1 5.55 (1.18), 6WERB21 5.63 (0.72)%] and apoptosis [RV: 6WERB1 11.1 (5.25), 6WERB21 20.24 (7.16) apoptotic cells per microfield, P < 0.0001 vs. 6W]. RV dimensions progressively increased at 3W and 6W and decreased with early ERB [end-diastolic dimensions: Shams 0.4 (0.13) vs. 3W 0.55 (0.78) vs. 6W 0.78 (0.25) vs. 6WERB1 0.71 (0.26) vs. 6WERB21 0.49 (0.23) cm, P < 0.05]. Despite increased RV contractility with PAB [RV end-systolic pressure-volume relationship: Shams 3.76 (1.76) vs. 3W 12.21 (3.44) vs. 6W 19.4 (6.88) mmHg/ml], biventricular function and cardiac output [Shams 196.1 (39.73) vs. 3W 149.9 (34.82) vs. 6W 151 (31.69) ml/min] worsened in PAB groups and improved with early and late ERB [6WERB1 202.8 (26.8), 6WERB21 194.8 (36.93) ml/min, P < 0.05 vs. PAB]. In conclusion, RV pressure overload induces early biventricular fibrosis, apoptosis, remodeling, and dysfunction that worsens with persistent RV hypertension. This remodeling is attenuated by early and late ERB. NEW & NOTEWORTHY Our results in a rabbit model of progressive right ventricular (RV) pressure loading indicate that biventricular fibrosis, apoptosis, and dysfunction are already present when RV hypertension is reached at 3 wk of progressive pulmonary artery banding. These findings worsen with persistent RV hypertension to 6 wk and are attenuated with both early and late endothelin-1 receptor blockade, with some advantages to early thera

    Topics: Animals; Apoptosis; Echocardiography; Endothelin A Receptor Antagonists; Endothelin-1; Fibrosis; Heart Ventricles; Hypertension, Pulmonary; Male; Rabbits; Receptor, Endothelin A; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Pressure; Ventricular Remodeling

2018
Cardioprotective effect of cerium oxide nanoparticles in monocrotaline rat model of pulmonary hypertension: A possible implication of endothelin-1.
    Life sciences, 2018, May-15, Volume: 201

    Cerium oxide nanoparticles (CeO. Pulmonary hypertension was induced in albino rats by a single subcutaneous injection of MCT (60 mg/kg). Rats received either single CeO. CeO

    Topics: Animals; Apoptosis; Cardiotonic Agents; Cerium; Electrocardiography; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Nanoparticles; Nucleosides; Organ Size; Oxidative Stress; Poisons; Rats; Rats, Sprague-Dawley; Respiratory Function Tests; Triazoles

2018
Transient Receptor Potential Melastatin-8 Activation Induces Relaxation of Pulmonary Artery by Inhibition of Store-Operated Calcium Entry in Normoxic and Chronic Hypoxic Pulmonary Hypertensive Rats.
    The Journal of pharmacology and experimental therapeutics, 2018, Volume: 365, Issue:3

    Pulmonary hypertension (PH) is characterized by enhanced vasoconstriction and vascular remodeling, which are attributable to the alteration of Ca

    Topics: Animals; Biological Transport; Calcium; Cell Hypoxia; Endothelin-1; Gene Expression Regulation; Hypertension, Pulmonary; Male; Myocytes, Smooth Muscle; Pulmonary Artery; Pyrimidinones; Rats; Rats, Sprague-Dawley; TRPC Cation Channels; TRPM Cation Channels; Vasoconstriction; Vasodilation

2018
Unraveling endothelin-1 induced hypercontractility of human pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension.
    PloS one, 2018, Volume: 13, Issue:4

    Contraction of human pulmonary artery smooth muscle cells (HPASMC) isolated from pulmonary arterial hypertensive (PAH) and normal (non-PAH) subject lungs was determined and measured with real-time electrical impedance. Treatment of HPASMC with vasoactive peptides, endothelin-1 (ET-1) and bradykinin (BK) but not angiotensin II, induced a temporal decrease in the electrical impedance profile mirroring constrictive morphological change of the cells which typically was more robust in PAH as opposed to non-PAH cells. Inhibition with LIMKi3 and a cofilin targeted motif mimicking cell permeable peptide (MMCPP) had no effect on ET-1 induced HPASMC contraction indicating a negligible role for these actin regulatory proteins. On the other hand, a MMCPP blocking the activity of caldesmon reduced ET-1 promoted contraction pointing to a regulatory role of this protein and its activation pathway in HPASMC contraction. Inhibition of this MEK/ERK/p90RSK pathway, which is an upstream regulator of caldesmon phosphorylation, reduced ET-1 induced cell contraction. While the regulation of ET-1 induced cell contraction was found to be similar in PAH and non-PAH cells, a key difference was the response to pharmacological inhibitors and to siRNA knockdown of Rho kinases (ROCK1/ROCK2). The PAH cells required much higher concentrations of inhibitors to abrogate ET-1 induced contractions and their contraction was not affected by siRNA against either ROCK1 or ROCK2. Lastly, blocking of L-type and T-type Ca2+ channels had no effect on ET-1 or BK induced contraction. However, inhibiting the activity of the sarcoplasmic reticulum Ca2+ ATPase blunted ET-1 and BK induced HPASMC contraction in both PAH and non-PAH derived HPASMC. In summary, our findings here together with previous communications illustrate similarities and differences in the regulation PAH and non-PAH smooth muscle cell contraction relating to calcium translocation, RhoA/ROCK signaling and the activity of caldesmon. These findings may provide useful tools in achieving the regulation of the vascular hypercontractility taking place in PAH.

    Topics: Actin Depolymerizing Factors; Bradykinin; Electric Impedance; Endothelin-1; Gene Knockdown Techniques; Humans; Hypertension, Pulmonary; Lim Kinases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulmonary Artery; rho-Associated Kinases; Vasoconstriction

2018
3,7-Bis(2-hydroxyethyl)icaritin, a potent inhibitor of phosphodiesterase-5, prevents monocrotaline-induced pulmonary arterial hypertension via NO/cGMP activation in rats.
    European journal of pharmacology, 2018, Jun-15, Volume: 829

    Pulmonary arterial hypertension (PAH) is a chronic progressive disease which leads to elevated pulmonary arterial pressure and right heart failure. 3,7-Bis(2-hydroxyethyl)icaritin (ICT), an icariin derivatives, was reported to have potent inhibitory activity on phosphodiesterase type 5 (PDE5) which plays a crucial role in the pathogenesis of PAH. The present study was designed to investigate the effects of ICT on monocrotaline (MCT)-induced PAH rat model and reveal the underlying mechanism. MCT-induced PAH rat models were established with intragastric administration of ICT (10, 20, 40 mg/kg/d), Icariin (ICA) (40 mg/kg/d) and Sildenafil (25 mg/kg/d). The mean pulmonary arterial pressure (mPAP) and right ventricle hypertrophy index (RVHI) were measured. Pulmonary artery remodeling was assessed by H&E staining. Blood and lung tissue were collected to evaluate the level of endothelin 1 (ET-1), nitric oxide (NO), and cyclic guanosine monophosphate (cGMP). The expressions endothelial nitric oxide synthase (eNOS) and PDE5A in lung tissues were determined by Western blot analysis. The results showed that ICT reduced RVHI and mPAP, and reversed lung vascular remodeling in rats with MCT-induced PAH. ICT also reversed MCT-induced ET-1 elevation, NO and cGMP reduction in serum or lung tissue. Moreover, ICT administration significantly induced eNOS activation and PDE5A inhibition. ICT with lower dose had better effects than ICA. In summary, ICT is more effective in preventing MCT-induced PAH in rats via NO/cGMP activation compared with ICA. These findings demonstrate a novel mechanism of the action of ICT that may have value in prevention of PAH.

    Topics: Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelin-1; Flavonoids; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Rats; Rats, Sprague-Dawley; Vascular Remodeling

2018
Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response.
    Molecules (Basel, Switzerland), 2018, May-26, Volume: 23, Issue:6

    Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. Several studies have demonstrated that betaine possesses outstanding anti-inflammatory effects. However, whether betaine exerts protective effects on PAH by inhibiting inflammatory responses in the lungs needs to be explored. To test our hypothesis, we aimed to investigate the effects of betaine on monocrotaline-induced PAH in rats and attempted to further clarify the possible mechanisms.. PAH was induced by monocrotaline (50 mg/kg) and oral administration of betaine (100, 200, and 400 mg/kg/day). The mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricle hypertrophy index were used to evaluate the development of PAH. Hematoxylin and eosin staining and Masson staining were performed to measure the extents of vascular remodeling and proliferation in fibrous tissue. Monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were also detected by immunohistochemical staining. Nuclear factor-κB (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β) were assessed by Western blot.. This study showed that betaine improved the abnormalities in right ventricular systolic pressure, mean pulmonary arterial pressure, right ventricle hypertrophy index, and pulmonary arterial remodeling induced by monocrotaline compared with the PAH group. The levels of MCP-1 and ET-1 also decreased. Western blot indicated that the protein expression levels of NF-κB, TNF-α, and IL-1β significantly decreased (. Our study demonstrated that betaine attenuated PAH through its anti-inflammatory effects. Hence, the present data may offer novel targets and promising pharmacological perspectives for treating monocrotaline-induced PAH.

    Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Betaine; Biomarkers; Chemokine CCL2; Cytokines; Disease Models, Animal; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Immunohistochemistry; Inflammation Mediators; Male; Monocrotaline; Myocardium; NF-kappa B; Pulmonary Artery; Rats

2018
Connexin 43 Plays a Role in Pulmonary Vascular Reactivity in Mice.
    International journal of molecular sciences, 2018, 06-27, Volume: 19, Issue:7

    Pulmonary arterial hypertension (PAH) is a chronic condition characterized by vascular remodeling and increased vaso-reactivity. PAH is more common in females than in males (~3:1). Connexin (Cx)43 has been shown to be involved in cellular communication within the pulmonary vasculature. Therefore, we investigated the role of Cx43 in pulmonary vascular reactivity using

    Topics: Animals; Connexin 43; Endothelin-1; Female; Gap Junctions; Genotype; Hypertension, Pulmonary; Isoproterenol; Male; Mice; Mice, Inbred C57BL; Muscle Relaxation; Nitric Oxide; Pulmonary Artery; Real-Time Polymerase Chain Reaction; Serotonin

2018
Study on sildenafil combined with inhalational nitric oxide therapy on the curative effects and serum levels of HIF-1α, ET-1, and calcium in neonatal pulmonary hypertension.
    European review for medical and pharmacological sciences, 2018, Volume: 22, Issue:14

    To explore the effect of sildenafil combined with inhalational nitric oxide (NO) therapy on the curative effects and serum levels of hypoxia-inducible factor (HIF)-1α, endothelin-1 (ET-1), and calcium in persistent pulmonary hypertension of the newborn (PPHN).. Eighty-six patients with neonatal pulmonary hypertension treated in Xuzhou Children's Hospital from March 2015 to February 2016 were randomly divided into the observation group and control group, treated with sildenafil and sildenafil combined with inhalational NO, respectively. The clinical efficacy of newborns in the two groups was compared. Fraction of inspiration O2 (FiO2), Oxygen Index (OI), blood oxygen partial pressure (PaO2), blood oxygen saturation (SpO2), and pulmonary arterial pressure of newborns in the two groups were compared before treatment and 2 h, 12 h, and 24 h after treatment. The serum levels of HIF-1α, ET-1, and calcium of patients in the two groups were compared before treatment and 3, 5, 7 days after treatment.. The total effective rate of the observation group (95.34%) was significantly higher than that of the control group (74.41%) (p<0.05). After treatment, FiO2, OI, and pulmonary arterial pressure of patients in the two groups decreased, and the decrease in the observation group was significantly lower than in the control group (p<0.05). After treatment, PaO2 and SpO2 of patients in the observation group were higher than those of the control group. The levels of HIF-1α and ET-1 of patients in the two groups decreased and were significantly lower in the observation group compared with the control group. The levels of calcium of patients in the two groups increased and were significantly higher in the observation group than the control group (p<0.05).. Sildenafil combined with inhalational NO therapy for neonatal pulmonary hypertension can quickly improve oxygenation, effectively reduce pulmonary arterial hypertension, and is worthy of clinical application.

    Topics: Administration, Inhalation; Calcium; Drug Therapy, Combination; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia-Inducible Factor 1, alpha Subunit; Infant, Newborn; Male; Nitric Oxide; Oxygen; Sildenafil Citrate

2018
High preoperative plasma endothelin-1 levels are associated with increased acute kidney injury risk after pulmonary endarterectomy.
    Journal of nephrology, 2018, Volume: 31, Issue:6

    The only curative treatment for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). PEA requires cardiopulmonary bypass (CPB) which is associated with a high acute kidney injury (AKI) risk. Circulating endothelin-1 (ET-1) levels are elevated in CTEPH, and ET-1 plays a pivotal role in AKI. Because AKI is burdened by high morbidity and mortality, we aimed to evaluate the association between preoperative ET-1 and the risk to develop AKI in CTEPH individuals who undergo PEA. We also evaluated the association of AKI and ET-1 with kidney function and mortality at 1 year after PEA.. In 385 consecutive patients diagnosed with CTEPH who underwent PEA at the Foundation IRCC Policlinico San Matteo (Pavia, Italy) from January 2009 to April 2015, we assessed preoperative circulating ET-1 by ELISA and identified presence of AKI based on 2012 KDIGO criteria.. AKI occurred in 26.5% of the 347 patients included in the analysis, and was independently associated with preoperative ET-1 (p = 0.008), body mass index (BMI) (p = 0.022), male gender (p = 0.005) and duration of CPB (p = 0.002). At 1-year post PEA, estimated glomerular filtration rate (eGFR) significantly improved in patients who did not develop AKI [ΔeGFR 5.6 ml/min/1.73 m. Perioperative AKI is associated with higher preoperative circulating ET-1 and it negatively influences long-term kidney function in patients with CTEPH who undergo PEA.

    Topics: Acute Kidney Injury; Aged; Biomarkers; Endarterectomy; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension, Pulmonary; Italy; Kidney; Male; Middle Aged; Predictive Value of Tests; Pulmonary Embolism; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Up-Regulation

2018
Pulmonary microvascular remodeling in chronic thrombo-embolic pulmonary hypertension.
    American journal of physiology. Lung cellular and molecular physiology, 2018, 12-01, Volume: 315, Issue:6

    Pulmonary vascular remodeling in pulmonary arterial hypertension involves perturbations in the nitric oxide (NO) and endothelin-1 (ET-1) pathways. However, the implications of pulmonary vascular remodeling and these pathways remain unclear in chronic thrombo-embolic pulmonary hypertension (CTEPH). The objective of the present study was to characterize changes in microvascular morphology and function, focussing on the ET-1 and NO pathways, in a CTEPH swine model. Swine were chronically instrumented and received up to five pulmonary embolizations by microsphere infusion, whereas endothelial dysfunction was induced by daily administration of the endothelial NO synthase inhibitor N

    Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelin-1; Hypertension, Pulmonary; Lung; Microvessels; Nitric Oxide; Pulmonary Artery; Pulmonary Circulation; Pulmonary Embolism; rho-Associated Kinases; Swine; Vasoconstriction

2018
Potential Role of Endothelin in Early Vascular Aging.
    Current hypertension reviews, 2017, Volume: 13, Issue:1

    Early vascular aging is a process associated with gradual alterations in the vessels, regarding their structure and function, taking a more rapid course than normal biological aging in the arteries. In the presence of cardiovascular disease, these age-associated alterations are accelerated, contributing in the appearance or the progression of cardiovascular disease, such as high blood pressure, dyslipidemia, smoking and diabetes. Endothelin-1 (ET-1) is the most abundant and important endothelin produced by vascular cells. ET-1 exerts its biological actions through the activation of two receptors: ETA and ETB. Many important functions are mediated by the activation of these receptors, such as cardiovascular remodeling, vasoconstriction, cell proliferation and differentiation, production of extracellular matrix, and water and sodium secretion control. ETA receptor seems to participate in the pathogenesis and development of diseases, such as diabetes, atherosclerosis, systemic and pulmonary hypertension, and cardiac remodeling after myocardial ischemia, whereas ETB receptor seems to prevent the overstimulation of ETA receptor, acting as a clearance receptor. Increased ET-1 system activity may contribute to vascular dysfunction in aging via multiple pathways, such as direct hemodynamic effects, vascular oxidative stress, inflammatory activity, mitogenic stimulation of the vascular smooth muscle cells and fibrotic processes. Endothelin receptor antagonists were considered to be used for the treatment of some diseases like hypertension, diabetes and chronic kidney disease. However, besides pulmonary hypertension, this class is not in clinical use because of the side effects and the availability of safer drugs for the treatment of these diseases.

    Topics: Aging; Blood Vessels; Cardiovascular Diseases; Disease Progression; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction

2017
Role of microRNA-130a in the pathogeneses of obstructive sleep apnea hypopnea syndrome-associated pulmonary hypertension by targeting the GAX gene.
    Medicine, 2017, Volume: 96, Issue:20

    The purpose of this study was to elucidate the role of microRNA-130a (miR-130a) in obstructive sleep apnea hypopnea syndrome (OSAHS)-associated pulmonary hypertension (PHT) by targeting the growth arrest-specific homeobox (GAX) gene.. A total of 108 patients with OSAHS-associated PHT were recruited as the OSAHS-associated PHT group and 110 healthy individuals were randomly selected as the normal control group. Human umbilical vein endothelial cells (HUVECs) were selected and divided into the control, miR-130a mimic, mimic negative control (NC), miR-130a inhibitor, and inhibitor-NC groups. The dual luciferase reporter gene assay was used to identify the relationship between miR-130a and the GAX gene. The quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were applied for the relative expressions of miR-130a and the mRNA and protein expressions of GAX. Serum levels of endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), nitric oxide (NO), and super oxide dismutase (SOD) were detected. Cell apoptosis and angiogenic activity were analyzed by flow cytometry and cell tube formation assay.. GAX was a target gene of miR-130a. Compared with the normal control group, the relative expression of miR-130a and the serum levels of ET-1 and VEGF were increased, whereas the mRNA expression of GAX and the serum levels of NO and SOD were decreased in the OSAHS-associated PHT group. Compared with the control, mimic-NC, and inhibitor-NC groups, the relative expressions of miR-130a in the miR-130a mimic group were enhanced, whereas the expression of miR-130a in the miR-130a inhibitor group was reduced. However, the mRNA and protein expressions of GAX showed an opposite trend in the miR-130a mimic and miR-130a inhibitor groups. In comparison to the control, mimic-NC, and inhibitor-NC groups, the miR-130a mimic group had an increase of ET-1 and VEGF expressions, whereas the expressions of NO and SOD were reduced. However, the miR-130a inhibitor group exhibited an opposite trend. The apoptosis rate and tube formation number in the miR-130a mimic group were obviously increased, whereas the miR-130a inhibitor group showed an obvious decrease.. These data provided strong evidence that miR-130a may be involved in the progression of OSAHS-associated PHT by down-regulating GAX gene.

    Topics: Apoptosis; Biomarkers; Cells, Cultured; Down-Regulation; Endothelin-1; Female; Homeodomain Proteins; Human Umbilical Vein Endothelial Cells; Humans; Hypertension, Pulmonary; Male; MicroRNAs; Middle Aged; Nitric Oxide; Random Allocation; RNA, Messenger; Sleep Apnea, Obstructive; Superoxide Dismutase; Transfection; Vascular Endothelial Growth Factor A

2017
Contribution of reactive oxygen species to the pathogenesis of pulmonary arterial hypertension.
    PloS one, 2017, Volume: 12, Issue:6

    Pulmonary arterial hypertension is associated with a decreased antioxidant capacity. However, neither the contribution of reactive oxygen species to pulmonary vasoconstrictor sensitivity, nor the therapeutic efficacy of antioxidant strategies in this setting are known. We hypothesized that reactive oxygen species play a central role in mediating both vasoconstrictor and arterial remodeling components of severe pulmonary arterial hypertension. We examined the effect of the chemical antioxidant, TEMPOL, on right ventricular systolic pressure, vascular remodeling, and enhanced vasoconstrictor reactivity in both chronic hypoxia and hypoxia/SU5416 rat models of pulmonary hypertension. SU5416 is a vascular endothelial growth factor receptor antagonist and the combination of chronic hypoxia/SU5416 produces a model of severe pulmonary arterial hypertension with vascular plexiform lesions/fibrosis that is not present with chronic hypoxia alone. The major findings from this study are: 1) compared to hypoxia alone, hypoxia/SU5416 exposure caused more severe pulmonary hypertension, right ventricular hypertrophy, adventitial lesion formation, and greater vasoconstrictor sensitivity through a superoxide and Rho kinase-dependent Ca2+ sensitization mechanism. 2) Chronic hypoxia increased medial muscularization and superoxide levels, however there was no effect of SU5416 to augment these responses. 3) Treatment with TEMPOL decreased right ventricular systolic pressure in both hypoxia and hypoxia/SU5416 groups. 4) This effect of TEMPOL was associated with normalization of vasoconstrictor responses, but not arterial remodeling. Rather, medial hypertrophy and adventitial fibrotic lesion formation were more pronounced following chronic TEMPOL treatment in hypoxia/SU5416 rats. Our findings support a major role for reactive oxygen species in mediating enhanced vasoconstrictor reactivity and pulmonary hypertension in both chronic hypoxia and hypoxia/SU5416 rat models, despite a paradoxical effect of antioxidant therapy to exacerbate arterial remodeling in animals with severe pulmonary arterial hypertension in the hypoxia/SU5416 model.

    Topics: Animals; Calcium; Cells, Cultured; Cyclic N-Oxides; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Spin Labels; Superoxides; Vasoconstriction

2017
Autoimmune disease mouse model exhibits pulmonary arterial hypertension.
    PloS one, 2017, Volume: 12, Issue:9

    Pulmonary arterial hypertension is often associated with connective tissue disease. Although there are some animal models of pulmonary hypertension, an autoimmune disease-based model has not yet been reported. MRL/lpr mice, which have hypergammaglobulinemia, produce various autoimmune antibodies, and develop vasculitis and nephritis spontaneously. However, little is known about pulmonary circulation in these mice. In the present study, we examined the pulmonary arterial pressure in MRL/lpr mice.. We used female MRL/lpr mice aged between 12 and 14 weeks. Fluorescent immunostaining showed that there was no deposition of immunoglobulin or C3 in the lung tissue of the MRL/lpr mice. Elevation of interferon-γ and interleukin-6 was recognized in the lung tissue of the MRL/lpr mice. Right ventricular systolic pressure, Fulton index and the ratio of right ventricular weight to body weight in the MRL/lpr mice were significantly higher than those in wild type mice with same background (C57BL/6). The medial smooth muscle area and the proportion of muscularized vessels in the lung tissue of the MRL/lpr mice were larger than those of the C57BL/6 mice. Western blot analysis demonstrated markedly elevated levels of prepro-endothelin-1 and survivin as well as decreased endothelial nitric oxide synthase phosphorylation in the lung tissue of the MRL/lpr mice. Terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling assay showed the resistance against apoptosis of pulmonary arterial smooth muscle cells in the MRL/lpr mice.. We showed that MRL/lpr mice were complicated with pulmonary hypertension. MRL/lpr mice appeared to be a useful model for studying the mechanism of pulmonary hypertension associated with connective tissue diseases.

    Topics: Animals; Apoptosis; Autoimmune Diseases; Blood Pressure; Complement C3; Cytokines; Disease Models, Animal; Endothelin-1; Heart Ventricles; Hypertension, Pulmonary; Immunoglobulin G; Inhibitor of Apoptosis Proteins; Lung; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Myocytes, Smooth Muscle; Nitric Oxide Synthase Type III; Pulmonary Artery; Repressor Proteins; Survivin

2017
Roles of hypoxia-inducible factor-1α and its target genes in neonatal hypoxic pulmonary hypertension.
    European review for medical and pharmacological sciences, 2017, Volume: 21, Issue:18

    To investigate the role of hypoxia-inducible factor-1α and its target genes in hypoxic pulmonary hypertension in neonates.. A total of 117 newborns were selected and divided into two groups for clinical experiments: 85 cases in the hypoxic pulmonary hypertension (HPH) group, including mild, moderate and severe subgroups, and 32 cases in the case-control group. ELISA was used to detect the serum HIF-1α, endothelin-1 (ET-1) and adrenomedullin (ADM) levels, and echocardiography was used to detect the dynamic changes in pulmonary artery systolic pressure (PASP), right ventricular ejection fraction (RVEF), tricuspid E peak and A peak ratio (E/A) and right ventricular Tei index.. The average PASP level of the HPH group was significantly higher than that of the control group at 1 d and 3 d after birth (p < 0.05). The average PASP level was still higher in the severe HPH group than that in the control group at 7 d after birth, while the average levels in the mild and moderate HPH groups recovered to the normal. Compared with those in control group, RVEF and E/A of the tricuspid valve were decreased significantly in severe HPH patients (p < 0.05). The Tei indexes of the right ventricle were significantly higher in the mild, moderate and severe HPH groups than those in control group and the right ventricular Tei index was positively correlated with PASP. The levels of serum ADM, HHH-1α and ET-1 in all the three HPH subgroups were significantly higher than those in the control group at 1 d after birth and showed positive correlations with PASP (p < 0.05), except that serum ADM in mild HPH showed no obvious difference from the control group. The levels of serum HIF-1α and ADM in the severe HPH group and the ET-1 levels in the moderate and severe groups were increased significantly at 3 d after birth (p < 0.05).. The PASP level in neonates with HPH is related to the serum HIF-1α, ET-1 and ADM levels, indicating that hypoxia can increase the level of HIF-1α, which in turn will enhance the expression of downstream target genes ET-1 and ADM, further leading to pulmonary hypertension. The right ventricular Tei index can be used to sensitively detect right ventricular dysfunction of mild, moderate and severe HPH groups.

    Topics: Adrenomedullin; Animals; Case-Control Studies; Echocardiography; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Infant, Newborn; Male; Pulmonary Artery; Ventricular Dysfunction, Right; Ventricular Function, Right

2017
miR-200c regulates endothelin-1 induced PASMCs abnormal proliferation and apoptosis.
    IUBMB life, 2017, Volume: 69, Issue:11

    miR-200c is an antioncogene in multiple tumors. However, its function in the pathogenesis of pulmonary arterial hypertension (PAH) has not been thoroughly investigated nor understood. In this study, we discovered that miR-200c was able to substantially upregulate in pulmonary arterial smooth muscle cells (PASMCs) treated with endothelin-1 (ET-1). miR-200c also induced cell proliferation and suppressed cell apoptosis in PASMCs in vitro. However, miR-200c had no effect on G1/S/G2 transitions during the cell cycle. Furthermore, we identified miR-200c as a new regulator of the microtubule associated protein 2 (MAP-2) and zinc finger E-box binding homeobox1 (ZEB-1) in PASMCs. miR-200c inhibited MAP-2 and ZEB-1 expression by directly binding to their 3'-untranslated regions(3'UTR) according to luciferase assay results. Our findings provide novel insights into the mechanisms of PAH pathogenesis and potential molecular biomarkers for PAH diagnosis and treatment. © 2017 IUBMB Life, 69(11):877-886, 2017.

    Topics: 3' Untranslated Regions; Apoptosis; Binding Sites; Cell Hypoxia; Cell Proliferation; Cells, Cultured; Endothelin-1; Gene Expression Profiling; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Hypoxia-Inducible Factor 1, alpha Subunit; MicroRNAs; Microtubule-Associated Proteins; Models, Biological; Myocytes, Smooth Muscle; Oligonucleotide Array Sequence Analysis; Pulmonary Artery; Signal Transduction; Zinc Finger E-box-Binding Homeobox 1

2017
Peroxisome Proliferator-Activated Receptor γ Regulates the V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog 1/microRNA-27a Axis to Reduce Endothelin-1 and Endothelial Dysfunction in the Sickle Cell Mouse Lung.
    American journal of respiratory cell and molecular biology, 2017, Volume: 56, Issue:1

    Pulmonary hypertension (PH), a serious complication of sickle cell disease (SCD), causes significant morbidity and mortality. Although a recent study determined that hemin release during hemolysis triggers endothelial dysfunction in SCD, the pathogenesis of SCD-PH remains incompletely defined. This study examines peroxisome proliferator-activated receptor γ (PPARγ) regulation in SCD-PH and endothelial dysfunction. PH and right ventricular hypertrophy were studied in Townes humanized sickle cell (SS) and littermate control (AA) mice. In parallel studies, SS or AA mice were gavaged with the PPARγ agonist, rosiglitazone (RSG), 10 mg/kg/day, or vehicle for 10 days. In vitro, human pulmonary artery endothelial cells (HPAECs) were treated with vehicle or hemin for 72 hours, and selected HPAECs were treated with RSG. SS mice developed PH and right ventricular hypertrophy associated with reduced lung levels of PPARγ and increased levels of microRNA-27a (miR-27a), v-ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS1), endothelin-1 (ET-1), and markers of endothelial dysfunction (platelet/endothelial cell adhesion molecule 1 and E selectin). HPAECs treated with hemin had increased ETS1, miR-27a, ET-1, and endothelial dysfunction and decreased PPARγ levels. These derangements were attenuated by ETS1 knockdown, inhibition of miR-27a, or PPARγ overexpression. In SS mouse lung or in hemin-treated HPAECs, activation of PPARγ with RSG attenuated reductions in PPARγ and increases in miR-27a, ET-1, and markers of endothelial dysfunction. In SCD-PH pathogenesis, ETS1 stimulates increases in miR-27a levels that reduce PPARγ and increase ET-1 and endothelial dysfunction. PPARγ activation attenuated SCD-associated signaling derangements, suggesting a novel therapeutic approach to attenuate SCD-PH pathogenesis.

    Topics: Anemia, Sickle Cell; Animals; Blood Pressure; Endothelial Cells; Endothelin-1; Gene Knockdown Techniques; Hemin; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Ligands; Lung; Mice; MicroRNAs; Models, Biological; PPAR gamma; Proto-Oncogene Protein c-ets-1; Pulmonary Artery; Rosiglitazone; Systole; Thiazolidinediones; Up-Regulation

2017
[Protective effects of heat shock protein 70 against hypoxic pulmonary hypertension in neonatal rats].
    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 2017, Volume: 19, Issue:1

    To investigate the protective effect of heat shock protein 70 (HSP70) against hypoxic pulmonary hypertension (HPH) in neonatal rats.. A total of 128 neonatal rats were randomly divided into blank control group, HPH model group, empty virus group, and HSP70 group, with 32 rats in each group. Before the establishment of an HPH model, the rats in the blank control group and HPH model group were given caudal vein injection of 5 μL sterile saline, those in the empty virus group were given caudal vein injection of 5 μL Ad-GFP (1 010 PFU/mL), and those in the HSP70 group were given caudal vein injection of 5 μL Ad-HSP70 (1 010 PFU/mL). HPH model was prepared in the HPH model, empty virus, and HSP70 groups after transfection. At 3, 7, 10, and 14 days after model establishment, a multi-channel physiological recorder was used to record mean pulmonary arterial pressure (mPAP), optical and electron microscopes were used to observe the structure and remodeling parameters of pulmonary vessels, and Western blot was used to measure the protein expression of HSP70, hypoxia-inducible factor-1α (HIF-1α), endothelin-1 (ET-1), and inducible nitric oxide synthase (iNOS) in lung tissues.. At 3, 7, 10, and 14 days after model establishment, the HPH model group and the empty virus group had a significantly higher mPAP than the blank control group (P<0.05). On days 7 and 10 of hypoxia, the blank control group and the HSP70 group had significantly lower MA% and MT% than the HPH model group and the empty virus group (P<0.01); on day 14 of hypoxia, the HPH model group, empty virus group, and HSP70 group had similar MA% and MT% (P>0.05), but had significantly higher MA% and MT% than the blank control group (P<0.01). On days 3, 7 and 10 of hypoxia, the HSP70 group had significantly higher protein expression of HSP70 than the HPH model group, empty virus group, and blank control group (P<0.01); the HSP70 group had significantly lower expression of HIF-1α, ET-1, and iNOS than the HPH model group and the empty virus group (P<0.05) and similar expression of HIF-1α, ET-1, and iNOS as the blank control group (P>0.05).. In neonatal rats with HPH, HSP70 transfection can increase the expression of HSP70 in lung tissues, downregulate the expression of HIF-1α, ET-1, and iNOS, alleviate pulmonary vascular remodeling, and reduce pulmonary artery pressure; therefore, it may become a new strategy for the treatment of HPH in neonates.

    Topics: Animals; Disease Models, Animal; Endothelin-1; HSP70 Heat-Shock Proteins; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Nitric Oxide Synthase Type II; Pulmonary Artery; Rats; Rats, Wistar; Transfection

2017
Effects of aerobic exercise training on metabolism of nitric oxide and endothelin-1 in lung parenchyma of rats with pulmonary arterial hypertension.
    Molecular and cellular biochemistry, 2017, Volume: 429, Issue:1-2

    Topics: Animals; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Male; Monocrotaline; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrites; Parenchymal Tissue; Physical Conditioning, Animal; Rats; Rats, Wistar; Vascular Resistance

2017
In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension.
    Cancer chemotherapy and pharmacology, 2017, Volume: 79, Issue:4

    Pulmonary arterial hypertension (PAH) results from occlusion or vasoconstriction of pulmonary vessels, leading to progressive right ventricular failure. Dasatinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myelogenous leukemia, has been associated with PAH. In contrast, the BCR-ABL1 TKI imatinib has demonstrated anti-vasoproliferative properties and has been investigated as a potential treatment for PAH. Here we describe studies evaluating the effects of dasatinib and imatinib on cardiovascular and pulmonary functions to understand the reported differential consequences of the two TKIs in a clinical setting.. The direct effects of dasatinib and imatinib were explored in vivo to investigate possible mechanisms of dasatinib-induced PAH. In addition, effects of dasatinib and imatinib on PAH-related mediators were evaluated in vitro.. In rats, both TKIs increased plasma nitric oxide (NO), did not induce PAH-related structural or molecular changes in PA or lungs, and did not alter hemodynamic lung function compared with positive controls. Similarly, in the pulmonary artery endothelial cells and smooth muscle cells co-culture model, imatinib and dasatinib increased NO and decreased endothelin-1 protein and mRNA.. The results of these studies indicated that dasatinib did not induce physiological changes or molecular signatures consistent with PAH when compared to positive controls. Instead, dasatinib induced changes consistent with imatinib. Both dasatinib and imatinib induced biochemical and structural changes consistent with a protective effect for PAH. These data suggest that other factors of unclear etiology contributed to the development of PAH in patients treated with dasatinib.

    Topics: Animals; Antineoplastic Agents; Dasatinib; Endothelin-1; Gene Expression; Hemodynamics; Hypertension, Pulmonary; Imatinib Mesylate; Lung; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Protein Kinase Inhibitors; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; RNA, Messenger

2017
Functional estimation of endothelin-1 receptor antagonism by bosentan, macitentan and ambrisentan in human pulmonary and radial arteries in vitro.
    European journal of pharmacology, 2017, Jun-05, Volume: 804

    Endothelin receptor antagonists are approved for pulmonary arterial hypertension. Development of selective ET. Human isolated pulmonary (i.d. 5.5mm) and human radial (i.d. 3.23mm) artery ring segments were mounted in organ baths for isometric force measurement. Single concentration-contraction curves to endothelin-1 were constructed in the absence or presence of bosentan (1-10µM), macitentan (0.03-0.3µM) or ambrisentan (0.1-1µM).. All 3 endothelin antagonists caused competitive rightward shifts in the endothelin-1 concentration-response curves in both arteries. The Clark plot and analysis gave the following pK. Noting the maximum plasma levels attained from recommended oral doses of each antagonist in volunteers, the pK

    Topics: Bosentan; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Phenylpropionates; Pulmonary Artery; Pyridazines; Pyrimidines; Radial Artery; Receptor, Endothelin A; Sulfonamides; Tissue Survival; Vasoconstriction

2017
Sildenafil improves the function of endothelial cells in patients suffering from congenital heart disease with pulmonary hypertension.
    Die Pharmazie, 2016, Oct-01, Volume: 71, Issue:10

    Aim of this study was to investigate the potential effects of sildenafil on the function of endothelial cells from patients with congenital heart disease with pulmonary hypertension (CHDPH). Patients who are diagnosed as CHD with PH (n=30) or without PH (n=30), and 30 healthy persons (control) were enrolled in this study. The 30 CHDPH cases were separated into two groups, one was given aspirin while the other received aspirin and sildenafil. An ELISA assay was used to detect the biological indexes for endothelial cells. Furthermore, 24 male New Zealand white rabbits were used to construct the CHDPH model. The signal pathway-related protein expression was analyzed using RT-PCR and western blotting. Compared to that in healthy people, levels for flowmediated dilatation (FDM), NO, and adiponectin (APN) were significantly decreased while endothelin (ET-1) was significantly increased in CHD patients, while their levels were drastically changed in CHDPH patients (P<0.01). Besides, no significant differences for expression levels including FDM, APN, NO, and ET-1 was observed in CHDPH patients receiving aspirin. But the levels for FDM, APN, NO, and ET-1 were significantly changed in CHDPH patients after treatment with sildenafil for 3 months (P<0.01). The mRNA and protein levels for JNK1/2, MAPK, and NF-κB were significantly increased in CHDPH rabbits compared to the control (P<0.01), but their levels were significantly suppressed by the sildenafil application compared to the CHDPH group (P<0.01). Taken together, our study suggested that sildenafil may play a protective role on endothelial function via suppressing the JNK and NF-κB signal pathways in CHDPH patients.

    Topics: Adiponectin; Animals; Aspirin; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Healthy Volunteers; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; NF-kappa B; Nitric Oxide; Platelet Aggregation Inhibitors; Rabbits; Signal Transduction; Sildenafil Citrate; Vasodilation; Vasodilator Agents

2016
Peroxisome Proliferator-Activated Receptor γ and microRNA 98 in Hypoxia-Induced Endothelin-1 Signaling.
    American journal of respiratory cell and molecular biology, 2016, Volume: 54, Issue:1

    Endothelin-1 (ET-1) plays a critical role in endothelial dysfunction and contributes to the pathogenesis of pulmonary hypertension (PH). We hypothesized that peroxisome proliferator-activated receptor γ (PPARγ) stimulates microRNAs that inhibit ET-1 and pulmonary artery endothelial cell (PAEC) proliferation. The objective of this study was to clarify molecular mechanisms by which PPARγ regulates ET-1 expression in vitro and in vivo. In PAECs isolated from patients with pulmonary arterial hypertension, microRNA (miR)-98 expression was reduced, and ET-1 protein levels and proliferation were increased. Similarly, hypoxia reduced miR-98 and increased ET-1 levels and PAEC proliferation in vitro. In vivo, hypoxia reduced miR-98 expression and increased ET-1 and proliferating cell nuclear antigen (PCNA) levels in mouse lung, derangements that were aggravated by treatment with the vascular endothelial growth factor receptor antagonist Sugen5416. Reporter assays confirmed that miR-98 binds directly to the ET-1 3'-untranslated region. Compared with littermate control mice, miR-98 levels were reduced and ET-1 and PCNA expression were increased in lungs from endothelial-targeted PPARγ knockout mice, whereas miR-98 levels were increased and ET-1 and PCNA expression was reduced in lungs from endothelial-targeted PPARγ-overexpression mice. Gain or loss of PPARγ function in PAECs in vitro confirmed that alterations in PPARγ were sufficient to regulate miR-98, ET-1, and PCNA expression. Finally, PPARγ activation with rosiglitazone regimens that attenuated hypoxia-induced PH in vivo and human PAEC proliferation in vitro restored miR-98 levels. The results of this study show that PPARγ regulates miR-98 to modulate ET-1 expression and PAEC proliferation. These results further clarify molecular mechanisms by which PPARγ participates in PH pathogenesis and therapy.

    Topics: 3' Untranslated Regions; Animals; Binding Sites; Cell Proliferation; Cells, Cultured; Endothelial Cells; Endothelin-1; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Hypoxia; Indoles; Male; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; PPAR gamma; Pulmonary Artery; Pyrroles; RNA Interference; Rosiglitazone; Signal Transduction; Thiazolidinediones; Transfection; Vascular Remodeling

2016
Echocardiographic findings and plasma endothelin-1 levels in obese patients with and without obstructive sleep apnea.
    Sleep & breathing = Schlaf & Atmung, 2016, Volume: 20, Issue:2

    Obstructive sleep apnea (OSA) and obesity are increasingly prevalent worldwide. Both promote endothelial dysfunction contributing to systemic and pulmonary hypertension over time. Endothelin-1 (ET-1) plays a pivotal role in the development of pulmonary hypertension (PH). The aim of the present study was to assess the association between plasma ET-1 and echocardiographic findings in obese individuals with and without OSA, as well as in non-obese patients with OSA.. Ninety-seven subjects (56 males) were enrolled in the study. All subjects underwent the following tests: venous endothelin-1 levels, pulmonary function testing, and arterial blood gas analysis. All patients except controls underwent transthoracic echocardiography and portable testing for sleep-disordered breathing.. Plasma ET-1 levels were significantly higher in obese patients, both with and without OSA (respectively, n = 30 (mean value, 268.06 ± 49.56 pg/ml) and n = 32 (mean value, 263.12 ± 65.26 pg/ml)), compared with non-obese patients with OSA or to healthy controls (respectively, n = 20 (mean value, 149.8 ± 23.09 pg/ml) and n = 15 (mean value, 152.3 ± 27.64 pg/ml); p < 0.0001). Pulmonary artery pressure (PAPs) in obese patients with OSA were significantly higher than in obese patients without OSA (p < 0.0001), while there was no statistical difference between PAPs of obese patients without OSA, compared with the group of non-obese OSA patients. Plasma ET-1 levels significantly correlated with systolic PAPs in obese patients both with and without OSA (respectively, n = 30, r = 0.385, p = 0.03567; n = 32, r = 0.3497, p = 0.0497).. Our study suggests that endothelin levels are more strongly associated with weight than the presence of sleep-disordered breathing, but pulmonary artery hypertension is associated with both weight and OSA.

    Topics: Adult; Comorbidity; Echocardiography, Doppler; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Obesity; Polysomnography; Pulmonary Wedge Pressure; Reference Values; Sleep Apnea, Obstructive; Statistics as Topic

2016
Endothelin-1 Predicts Hemodynamically Assessed Pulmonary Arterial Hypertension in HIV Infection.
    PloS one, 2016, Volume: 11, Issue:1

    HIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. ET-1 is a robust vasoconstrictor and key mediator of pulmonary vascular homeostasis. Higher levels of ET-1 predict disease severity and mortality in other forms of PAH, and endothelin receptor antagonists are central to treatment, including in HIV-associated PAH. The direct relationship between ET-1 and PAH in HIV-infected individuals is not well described.. We measured ET-1 and estimated pulmonary artery systolic pressure (PASP) with transthoracic echocardiography (TTE) in 106 HIV-infected individuals. Participants with a PASP ≥ 30 mmHg (n = 65) underwent right heart catheterization (RHC) to definitively diagnose PAH. We conducted multivariable analysis to identify factors associated with PAH.. Among 106 HIV-infected participants, 80% were male, the median age was 52 years and 77% were on antiretroviral therapy. ET-1 was significantly associated with higher values of PASP [14% per 0.1 pg/mL increase in ET-1, p = 0.05] and PASP ≥ 30 mmHg [PR (prevalence ratio) = 1.24, p = 0.012] on TTE after multivariable adjustment for PAH risk factors. Similarly, among the 65 individuals who underwent RHC, ET-1 was significantly associated with higher values of mean pulmonary artery pressure and PAH (34%, p = 0.003 and PR = 2.43, p = 0.032, respectively) in the multivariable analyses.. Higher levels of ET-1 are independently associated with HIV-associated PAH as hemodynamically assessed by RHC. Our findings suggest that excessive ET-1 production in the setting of HIV infection impairs pulmonary endothelial function and contributes to the development of PAH.

    Topics: Adult; Blood Pressure; Cardiac Catheterization; Echocardiography; Endothelin-1; Female; Hemodynamics; HIV Infections; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Artery; Systole

2016
Dual Endothelin Receptor Blockade Abrogates Right Ventricular Remodeling and Biventricular Fibrosis in Isolated Elevated Right Ventricular Afterload.
    PloS one, 2016, Volume: 11, Issue:1

    Pulmonary arterial hypertension is usually fatal due to right ventricular failure and is frequently associated with co-existing left ventricular dysfunction. Endothelin-1 is a powerful pro-fibrotic mediator and vasoconstrictor that is elevated in pulmonary arterial hypertension. Endothelin receptor blockers are commonly used as pulmonary vasodilators, however their effect on biventricular injury, remodeling and function, despite elevated isolated right ventricular afterload is unknown.. Elevated right ventricular afterload was induced by progressive pulmonary artery banding. Seven rabbits underwent pulmonary artery banding without macitentan; 13 received pulmonary artery banding + macitentan; and 5 did not undergo inflation of the pulmonary artery band (sham-operated controls).. Right and left ventricular collagen content was increased with pulmonary artery banding compared to sham-operated controls and ameliorated by macitentan. Right ventricular fibrosis signaling (connective tissue growth factor and endothelin-1 protein levels); extra-cellular matrix remodeling (matrix-metalloproteinases 2 and 9), apoptosis and apoptosis-related peptides (caspases 3 and 8) were increased with pulmonary artery banding compared with sham-operated controls and decreased with macitentan.. Isolated right ventricular afterload causes biventricular fibrosis, right ventricular apoptosis and extra cellular matrix remodeling, mediated by up-regulation of endothelin-1 and connective tissue growth factor signaling. These pathological changes are ameliorated by dual endothelin receptor blockade despite persistent elevated right ventricular afterload.

    Topics: Animals; Apoptosis; Disease Models, Animal; Echocardiography; Endothelin-1; Extracellular Matrix; Fibrosis; Gene Expression; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Pyrimidines; Rabbits; Receptors, Endothelin; RNA, Messenger; Signal Transduction; Sulfonamides; Ventricular Dysfunction, Right; Ventricular Remodeling

2016
CTRP9 Ameliorates Pulmonary Arterial Hypertension Through Attenuating Inflammation and Improving Endothelial Cell Survival and Function.
    Journal of cardiovascular pharmacology, 2016, Volume: 67, Issue:5

    Endothelial dysfunction and inflammation are believed to be 2 primary instigators of pulmonary arterial hypertension (PH). C1q/TNF-related protein 9 (CTRP9) plays important roles in anti-inflammation and improvement of epithelial function. However, the role of CTRP9 in the progression of PH remains still unclear. In this study, the role and mechanism of CTRP9 in the PH progression were explored. First, serum CTRP9 contents and CTRP9 mRNA expression in the pulmonary artery epithelial cells from patients with PH were detected. Our data on enzyme-linked immunosorbent assay and real-time quantitative Polymerase Chain Reaction showed that CTRP9 mRNA and protein content were markedly downregulated in the patients with PH. Then the pcDNA-CTRP9 expression vector or CTRP9 siRNA was transfected into the primary pulmonary artery epithelial cells from the patients with PH in vitro. CTRP9 overexpression significantly improved endothelial NOS protein expression and reduced the secretion of endothelin-1 (ET-1) and matrix metalloproteinase-2 (MMP-2), whereas knockdown of CTRP9 sharply reduced eNOS protein expression and promoted the secretion of ET-1 and MMP-2 in the cultured human epithelial cells. Moreover, the levels of phosphatidylinositol 3-kinase (PI3K) and pAkt were reduced in the epithelial cells and CTRP9 overexpression activated the PI3K/Akt pathway. CTRP9 could inhibit cell apoptosis and eNOS expression reduction in the cells pretreated with the PI3K/Akt inhibitor LY294002 and resist LY294002-induced ET-1 and MMP-2 secretion. Finally, to verify the role of CTRP9 in the progression of PH in vivo, the pcDNA-CTRP9 expression vector or CTRP9 siRNA was intravenously injected into rats with PH. Pulmonary arterial pressures of the rats were notably reduced by the pcDNA-CTRP9 injection and elevated by the CTRP9 siRNA injection. In conclusion, CTRP9 ameliorated PH by attenuating inflammation and improving endothelial cell survival and function.

    Topics: Adiponectin; Adult; Animals; Apoptosis; Chromones; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Female; Glycoproteins; Humans; Hypertension, Pulmonary; Male; Matrix Metalloproteinase 2; Morpholines; Phosphatidylinositol 3-Kinases; Pulmonary Artery; Rats; Real-Time Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

2016
Endothelial actions of atrial natriuretic peptide prevent pulmonary hypertension in mice.
    Basic research in cardiology, 2016, Volume: 111, Issue:2

    The cardiac hormone atrial natriuretic peptide (ANP) regulates systemic and pulmonary arterial blood pressure by activation of its cyclic GMP-producing guanylyl cyclase-A (GC-A) receptor. In the lung, these hypotensive effects were mainly attributed to smooth muscle-mediated vasodilatation. It is unknown whether pulmonary endothelial cells participate in the homeostatic actions of ANP. Therefore, we analyzed GC-A/cGMP signalling in lung endothelial cells and the cause and functional impact of lung endothelial GC-A dysfunction. Western blot and cGMP determinations showed that cultured human and murine pulmonary endothelial cells exhibit prominent GC-A expression and activity which were markedly blunted by hypoxia, a condition known to trigger pulmonary hypertension (PH). To elucidate the consequences of impaired endothelial ANP signalling, we studied mice with genetic endothelial cell-restricted ablation of the GC-A receptor (EC GC-A KO). Notably, EC GC-A KO mice exhibit PH already under resting, normoxic conditions, with enhanced muscularization of small arteries and perivascular infiltration of inflammatory cells. These alterations were aggravated on exposure of mice to chronic hypoxia. Lung endothelial GC-A dysfunction was associated with enhanced expression of angiotensin converting enzyme (ACE) and increased pulmonary levels of Angiotensin II. Angiotensin II/AT1-blockade with losartan reversed pulmonary vascular remodelling and perivascular inflammation of EC GC-A KO mice, and prevented their increment by chronic hypoxia. This experimental study indicates that endothelial effects of ANP are critical to prevent pulmonary vascular remodelling and PH. Chronic endothelial ANP/GC-A dysfunction, e.g. provoked by hypoxia, is associated with activation of the ACE-angiotensin pathway in the lung and PH.

    Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Endothelial Cells; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Lung; Mice; Mice, Knockout; Peptidyl-Dipeptidase A; Receptors, Atrial Natriuretic Factor

2016
Cardiac volume overload and pulmonary hypertension in long-term follow-up of patients with a transjugular intrahepatic portosystemic shunt.
    Alimentary pharmacology & therapeutics, 2016, Volume: 43, Issue:9

    Transjugular intrahepatic portosystemic shunt (TIPSS) cause haemodynamic changes in patients with cirrhosis, yet little is known about long-term cardiopulmonary outcomes.. To evaluate the long-term cardiopulmonary outcome after TIPSS.. We evaluated cardiopulmonary parameters including echocardiography during long-term follow-up after TIPSS. Results at 1-5 years after TIPSS were compared to those of cirrhotic controls. Pulmonary hypertension (PH) diagnoses rates were included. Endothelin 1, thromboxane B2 and serotonin were measured.. We found significant differences 1-5 years after TIPSS compared to pre-implantation values: median left atrial diameter (LAD) increased from 37 mm [interquartile range (IQR): 33-43] to 40 mm (IQR: 37-47, P = 0.001), left ventricular end-diastolic diameter (LV-EDD) increased from 45 mm (range: 41-49) to 48 mm (IQR: 45-52, P < 0.001), pulmonary artery systolic pressure (PASP) increased from 25 mmHg (IQR: 22-33) to 30 mmHg (IQR: 25-36, P = 0.038). Comparing results 1-5 years post-implantation to the comparison cohort revealed significantly higher (P < 0.05) LAD, LV-EDD and PASP values in TIPSS patients. PH prevalence was higher in the shunt group (4.43%) compared to controls (0.91%, P = 0.150). Thromboxane B2 levels correlated with PASP in the TIPSS cohort (P = 0.033). There was no transhepatic gradient observed for the vasoactive substances analysed.. TIPSS placement is accompanied by long-term cardiovascular changes, including cardiac volume overload, and is associated with an increased rate of pulmonary hypertension. The need for regular cardiac follow-up after TIPSS requires further evaluation.

    Topics: Adult; Cardiac Volume; Endothelin-1; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Liver Cirrhosis; Male; Middle Aged; Portasystemic Shunt, Transjugular Intrahepatic; Serotonin; Thromboxane B2

2016
Clinical and prognostic value of endothelin-1 and big endothelin-1 expression in children with pulmonary hypertension.
    Heart (British Cardiac Society), 2016, 07-01, Volume: 102, Issue:13

    Pulmonary arterial hypertension is known to be associated with increased expression of endothelin (ET)-1 and its precursor big ET-1. Therefore, we hypothesised that in children with pulmonary hypertension (PH) altered levels of ET-1 and big ET-1 may have clinical and prognostic impact.. Sixty-six children with different forms of PH (mean age 10.4±9.7 years) were included. Blood samples were taken from the pulmonary artery and a systemic artery. Levels of ET-1/big ET-1 were measured via ELISA method and compared with clinical and haemodynamic data. To assess prognostic relevance, Kaplan-Meier survival analysis was conducted with definition of end point as the composite of mortality, lung transplantation, use of intravenous prostanoids and Potts shunt creation.. ET-1 levels ranged between 0.09 and 11.64 (mean 1.48±2.34) fmol/mL, and big ET-1 levels between 0.05 and 2.92 (mean 0.84±0.58) fmol/mL. No significant relationships were found between ET-1/big ET-1 levels and functional class as well as haemodynamic indices of PH severity. Mean follow-up after catheterisation was 63.2±44.1 months. While 31 of the 66 (47%) patients with PH reached a predefined end point, there was no significant relation between levels of ET-1/big ET-1 and patient outcome.. Although children with PH had alterations in ET-1/big ET-1 expression, which may reflect changes in net release or lung clearance, levels of ET-1/big ET-1 showed no correlation with clinical and haemodynamic parameters, and were not able to predict outcome.

    Topics: Adolescent; Biomarkers; Blood Specimen Collection; Child; Child, Preschool; Endothelin-1; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Kaplan-Meier Estimate; Male; Prognosis; Retrospective Studies

2016
Modafinil improves monocrotaline-induced pulmonary hypertension rat model.
    Pediatric research, 2016, Volume: 80, Issue:1

    Pulmonary arterial hypertension (PAH) progressively leads to increases in pulmonary vasoconstriction. Modafinil plays a role in vasorelaxation and blocking KCa3.1 channel with a result of elevating intracellular cyclic adenosine monophosphate (cAMP) levels. The purpose of this study is to evaluate the effects on modafinil in monocrotaline (MCT)-induced PAH rat.. The rats were separated into three groups: the control group, the monocrotaline (M) group (MCT 60 mg/kg), and the modafinil (MD) group (MCT 60 mg/kg + modafinil).. Reduced right ventricular pressure (RVP) was observed in the MD group. Right ventricular hypertrophy was improved in the MD group. Reduced number of intra-acinar pulmonary arteries and medial wall thickness were noted in the MD group. After the administration of modafinil, protein expressions of endothelin-1 (ET-1), endothelin receptor A (ERA) and KCa3.1 channel were significantly reduced. Modafinil suppressed pulmonary artery smooth muscle cell (PASMC) proliferation via cAMP and KCa3.1 channel. Additionally, we confirmed protein expressions such as Bcl-2-associated X, vascular endothelial growth factor, tumor necrosis factor-α, and interleukin-6 were reduced in the MD group.. Modafinil improved PAH by vasorelaxation and a decrease in medial thickening via ET-1, ERA, and KCa3.1 down regulation. This is a meaningful study of a modafinil in PAH model.

    Topics: Animals; Benzhydryl Compounds; Body Weight; Cyclic AMP; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Heart Ventricles; Humans; Hypertension, Pulmonary; Intermediate-Conductance Calcium-Activated Potassium Channels; Male; Modafinil; Monocrotaline; Myocytes, Smooth Muscle; Pressure; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Vasoconstriction

2016
Biomarkers of hypoxia, endothelial and circulatory dysfunction among climbers in Nepal with AMS and HAPE: a prospective case-control study.
    Journal of travel medicine, 2016, Volume: 23, Issue:3

    The mechanisms underlying acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE) are not fully understood. We hypothesized that regulators of endothelial function, circulatory homeostasis, hypoxia and cell stress contribute to the pathobiology of AMS and HAPE.. We conducted a prospective case-control study of climbers developing altitude illness who were evacuated to the CIWEC clinic in Kathmandu, compared to healthy acclimatized climbers. ELISA was used to measure plasma biomarkers of the above pathways.. Of the 175 participants, there were 71 cases of HAPE, 54 cases of AMS and 50 acclimatized controls (ACs). Markers of endothelial function were associated with HAPE: circulating levels of endothelin-1 (ET-1) were significantly elevated and levels of sKDR (soluble kinase domain receptor) were significantly decreased in cases of HAPE compared to AC or AMS. ET-1 levels were associated with disease severity as indicated by oxygen saturation. Angiopoietin-like 4 (Angptl4) and resistin, a marker of cell stress, were associated with AMS and HAPE irrespective of severity. Corin and angiotensin converting enzyme, regulators of volume homeostasis, were significantly decreased in HAPE compared to AC.. Our findings indicate that regulators of endothelial function, vascular tone and cell stress are altered in altitude illness and may mechanistically contribute to the pathobiology of HAPE.

    Topics: Acclimatization; Acute Disease; Adult; Altitude Sickness; Biomarkers; Case-Control Studies; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Mountaineering; Nepal; Peptidyl-Dipeptidase A; Prospective Studies; Shock; Travel

2016
ASIC1-mediated calcium entry stimulates NFATc3 nuclear translocation via PICK1 coupling in pulmonary arterial smooth muscle cells.
    American journal of physiology. Lung cellular and molecular physiology, 2016, 07-01, Volume: 311, Issue:1

    The development of chronic hypoxia (CH)-induced pulmonary hypertension is associated with increased pulmonary arterial smooth muscle cell (PASMC) Ca(2+) influx through acid-sensing ion channel-1 (ASIC1) and activation of the Ca(2+)/calcineurin-dependent transcription factor known as nuclear factor of activated T-cells isoform c3 (NFATc3). Whether Ca(2+) influx through ASIC1 contributes to NFATc3 activation in the pulmonary vasculature is unknown. Furthermore, both ASIC1 and calcineurin have been shown to interact with the scaffolding protein known as protein interacting with C kinase-1 (PICK1). In the present study, we tested the hypothesis that ASIC1 contributes to NFATc3 nuclear translocation in PASMC in a PICK1-dependent manner. Using both ASIC1 knockout (ASIC1(-/-)) mice and pharmacological inhibition of ASIC1, we demonstrate that ASIC1 contributes to CH-induced (1 wk at 380 mmHg) and endothelin-1 (ET-1)-induced (10(-7) M) Ca(2+) responses and NFATc3 nuclear import in PASMC. The interaction between ASIC1/PICK1/calcineurin was shown using a Duolink in situ Proximity Ligation Assay. Inhibition of PICK1 by using FSC231 abolished ET-1-induced and ionomycin-induced NFATc3 nuclear import, but it did not alter ET-1-mediated Ca(2+) responses, suggesting that PICK1 acts downstream of Ca(2+) influx. The key findings of the present work are that 1) Ca(2+) influx through ASIC1 mediates CH- and ET-1-induced NFATc3 nuclear import and 2) the scaffolding protein PICK1 is necessary for NFATc3 nuclear import. Together, these data provide an essential link between CH-induced ASIC1-mediated Ca(2+) influx and activation of the NFATc3 transcription factor. Identification of this ASIC1/PICK1/NFATc3 signaling complex increases our understanding of the mechanisms contributing to the vascular remodeling and increased vascular contractility that are associated with CH-induced pulmonary hypertension.

    Topics: Acid Sensing Ion Channels; Active Transport, Cell Nucleus; Animals; Calcium Signaling; Carrier Proteins; Cell Cycle Proteins; Cell Hypoxia; Cells, Cultured; Endothelin-1; Female; Hypertension, Pulmonary; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NFATC Transcription Factors; Nuclear Proteins; Pulmonary Artery

2016
Vascular endothelial-cadherin downregulation as a feature of endothelial transdifferentiation in monocrotaline-induced pulmonary hypertension.
    American journal of physiology. Lung cellular and molecular physiology, 2016, 08-01, Volume: 311, Issue:2

    Increased pulmonary vascular resistance in pulmonary hypertension (PH) is caused by vasoconstriction and obstruction of small pulmonary arteries by proliferating vascular cells. In analogy to cancer, subsets of proliferating cells may be derived from endothelial cells transitioning into a mesenchymal phenotype. To understand phenotypic shifts transpiring within endothelial cells in PH, we injected rats with alkaloid monocrotaline to induce PH and measured lung tissue levels of endothelial-specific protein and critical differentiation marker vascular endothelial (VE)-cadherin. VE-cadherin expression by immonoblotting declined significantly 24 h and 15 days postinjection to rebound to baseline at 30 days. There was a concomitant increase in transcriptional repressors Snail and Slug, along with a reduction in VE-cadherin mRNA. Mesenchymal markers α-smooth muscle actin and vimentin were upregulated by immunohistochemistry and immunoblotting, and α-smooth muscle actin was colocalized with endothelial marker platelet endothelial cell adhesion molecule-1 by confocal microscopy. Apoptosis was limited in this model, especially in the 24-h time point. In addition, monocrotaline resulted in activation of protein kinase B/Akt, endothelial nitric oxide synthase (eNOS), nuclear factor (NF)-κB, and increased lung tissue nitrotyrosine staining. To understand the etiological relationship between nitrosative stress and VE-cadherin suppression, we incubated cultured rat lung endothelial cells with endothelin-1, a vasoconstrictor and pro-proliferative agent in pulmonary arterial hypertension. This resulted in activation of eNOS, NF-κB, and Akt, in addition to induction of Snail, downregulation of VE-cadherin, and synthesis of vimentin. These effects were blocked by eNOS inhibitor N(ω)-nitro-l-arginine methyl ester. We propose that transcriptional repression of VE-cadherin by nitrosative stress is involved in endothelial-mesenchymal transdifferentiation in experimental PH.

    Topics: Animals; Antigens, CD; Apoptosis; Cadherins; Cell Transdifferentiation; Cells, Cultured; Down-Regulation; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Enzyme Activation; Gene Silencing; Hypertension, Pulmonary; Lung; Monocrotaline; Nitric Oxide Synthase Type III; Rats, Wistar; Transcription, Genetic

2016
Intratracheal instillation of ethyl pyruvate nanoparticles prevents the development of shunt-flow-induced pulmonary arterial hypertension in a rat model.
    International journal of nanomedicine, 2016, Volume: 11

    To investigate whether inhalation of ethyl pyruvate (EP) encapsulated with poly(ethylene glycol)-block-lactide/glycolide copolymer nanoparticles (EP-NPs) can prevent the development of shunt-flow-induced hyperkinetic pulmonary arterial hypertension (PAH) in a rat model.. Rats were separated into five groups: blank (ie, no treatment after shunt flow), normal control (ie, no shunt flow or treatment), EP-NP instillation, EP-only instillation, and vehicle. The animals received intratracheal instillation of EP-NPs or other treatments immediately after a shunt flow, and treatment continued weekly until the end of the experiment. Hemodynamic data were recorded, pulmonary arterial remodeling was assessed, and levels of inflammatory mediators and ET1 expression in the lung and serum were analyzed. In addition, retention of EP in the lungs of rats in the EP-NP and EP-only groups was measured using high-performance liquid chromatography.. After 12 weeks, hemodynamic abnormalities and pulmonary arterial remodeling were improved in the EP-NP instillation group, compared with the blank, EP-only, and vehicle groups (P<0.05). In addition, the EP-NP group showed significantly decreased levels of HMGB1, IL-6, TNFα, reactive oxygen species, and ET1 in the lung during PAH development (P<0.05). Furthermore, EP-NP instillation was associated with reduced serum levels of inflammatory factors and ET1. High-performance liquid-chromatography measurement indicated that EP retention was greater in the lungs of the EP-NP group than in the EP-only group.. EP-NP instillation attenuated inflammation and prevented pulmonary arterial remodeling during the development of PAH induced by shunt flow. In the future, EP-NP delivery into the lung might provide a novel approach for preventing PAH.

    Topics: Animals; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Interleukin-6; Lung; Male; Nanoparticles; Polyesters; Polyethylene Glycols; Protective Agents; Pulmonary Artery; Pyruvates; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Vascular Remodeling

2016
Association of Elevated Plasma Endothelin-1 Levels With Pulmonary Hypertension, Mortality, and Heart Failure in African American Individuals: The Jackson Heart Study.
    JAMA cardiology, 2016, 07-01, Volume: 1, Issue:4

    Despite pathophysiological links between endothelin-1 and pulmonary vascular remodeling, to our knowledge, the association between plasma endothelin-1 levels and pulmonary hypertension has not been studied in the general population. Also, whether endothelin-1 can predict future heart failure and mortality, outcomes that are associated with pulmonary hypertension, in a population cohort is unclear.. To determine whether elevated plasma endothelin-1 levels are associated with pulmonary hypertension, mortality, and heart failure.. Data from the Jackson Heart Study, a longitudinal, prospective observational cohort study of heart disease in African American individuals from Jackson, Mississippi, were analyzed. The community population sample was limited to participants with detectable tricuspid regurgitation on echocardiography. The study participants included self-identified African American individuals with plasma endothelin-1 levels and tricuspid regurgitation on echocardiogram (n = 3223) at the time of first examination (2000-2004). The analysis of the data began on April 14, 2014, and was completed on February 23, 2016.. Log-transformed plasma endothelin-1 level.. Cross-sectional analysis: presence of pulmonary hypertension (defined as an elevated pulmonary artery systolic pressure >40 mm Hg on echocardiogram). Longitudinal outcomes were all-cause mortality (median follow-up, 7.75 years) and heart failure admissions (median follow-up, 5.32 years).. Of the 3223 participants enrolled in the study, 1051 were men (32.6%). Mean (SD) endothelin-1 levels were 1.36 (0.64) pg/mL; 217 of 3223 cohort members (6.7%) had pulmonary hypertension. After adjusting for potential confounders, log-transformed endothelin-1 levels were associated with increased odds of pulmonary hypertension (adjusted odds ratio per log increment in endothelin-1, 1.66; 95% CI, 1.16-2.37). Log-transformed endothelin-1 levels were associated with mortality (adjusted hazard ratio per log increment in endothelin-1, 1.69; 95% CI, 1.27-2.25; median follow-up, 7.75 years) and heart failure (adjusted hazard ratio per log increment in endothelin-1, 1.57, 95% CI, 1.05-2.37; median follow-up, 5.32 years) in the study cohort. Phenotyping by pulmonary hypertension and endothelin-1 level showed mortality decreasing in order from subgroup with pulmonary hypertension and high endothelin-1 (high endothelin-1: ≥1.7 pg/mL; upper quartile); pulmonary hypertension and low endothelin-1 <1.7 pg/mL; lower 3 quartiles); no pulmonary hypertension and high endothelin-1; and no pulmonary hypertension and low endothelin-1 (log-rank χ2 = 77.16; P < .01 ).. Elevated plasma endothelin-1 levels, especially associated with an elevated pulmonary artery systolic pressure on echocardiogram, may identify an at-risk population that could be evaluated for targeted prevention and management strategies in future studies.

    Topics: Adult; Aged; Biomarkers; Black or African American; Cross-Sectional Studies; Endothelin-1; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Mississippi; Prospective Studies

2016
The role of circulating thrombospondin-1 in patients with precapillary pulmonary hypertension.
    Respiratory research, 2016, 07-30, Volume: 17, Issue:1

    The vasoconstrictive protein TSP-1 is released from endothelial cells upon increased shear stress and hypoxia. Both conditions are prevalent in pulmonary hypertension (PH). TSP-1 damages the local microcirculation by disrupting pathways, which are essential for specific medical therapeutics. Furthermore, TSP-1 induces excessive fibrosis and smooth muscle proliferation - a common finding in advanced PH - via TGF-ß and might promote disease progression. The prognostic impact of circulating TSP-1, influence on hemodynamic parameters and interaction with other biomarkers in patients with PH is incompletely understood. This study examines prospectively circulating TSP-1 in association with hemodynamic parameters, clinical variables and mortality.. Circulating TSP-1 was measured prospectively in 93 patients with precapillary PH undergoing right heart catheterization and in 19 subjects without PH. TSP-1 levels were determined by ELISA and examined in the context of hemodynamic variables. For evaluation of survival, patients were monitored for adverse events on a 3-monthly basis and contacted at the end of the study after 5 years. In addition, levels of big-endothelin and humoral cofactors of TSP-1 release were measured.. Patients with PH had significantly increased TSP-1 levels compared to controls without PH (1114 ± 136 ng/mL vs. 82.1 ± 15.8 ng/mL, p < 0.05). Levels were correlated with mean pulmonary artery pressure (PAPm, r = -0.58, p < 0.001) and pulmonary vascular resistance (PVR, r = 0.33, p = 0.002). Survivors had lower TSP-levels as non-survivors and all cause mortality associated with TSP-1 plasma levels above 2051 ng/mL (p = 0.0002, HR 1.49).. High plasma levels of TSP-1 are associated with increased PAPm, increased PVR and decreased survival. Due to its interaction with therapeutic pathways, studies are warranted to clarify the impact of TSP-1 on of specific medications for PH.

    Topics: Adult; Aged; Arterial Pressure; Biomarkers; Cardiac Catheterization; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Pulmonary Artery; Risk Factors; Thrombospondin 1; Time Factors; Up-Regulation; Vascular Resistance

2016
Role of dynorphin in hypoxic pulmonary hypertension.
    European journal of pharmacology, 2016, Nov-15, Volume: 791

    Previously study showed κ-opioid receptor stimulation with exogenous κ-opioid receptor agonist elicited a protective effect against hypoxic pulmonary hypertension (HPH). However, the effect of endogenous κ-opioid receptor agonist dynorphin A on HPH remains unclear. This study was to determine the role of dynorphin in HPH. Hypoxia for 2 weeks induced HPH. Compared with the HPH group, the HPH + nor-BNI (a selective κ-opioid receptor antagonist) group showed a significant increase in mean pulmonary arterial pressure (mPAP). Exogenous treatment with dynorphin A 1-13 significantly decreased mPAP in HPH rat. In addition, we evaluated the effect of exogenous κ-opioid receptor agonist U50,488H on mPAP. The anti-HPH effect of dynorphin A was less than that of U50,488H. Meanwhile, level of dynorphin A in serum and lung was increased during hypoxia for 2 weeks, while it decreased after hypoxia for 4 weeks. In addition, both the level of ET-1 and AngII were increased during hypoxia. Dynorphin A 1-13 and U50,488H time-dependently relaxed pulmonary artery from both normal and HPH rats. The relaxation of dynorphin A was less than that of U50,488H. Dynorphin A 1-13 inhibited the proliferation of pulmonary artery smooth muscle cells (PASMCs) during hypoxia, which was blocked by nor-BNI. κ-opioid receptor expression increased in PASMCs in both normoxia exposed to dynorphin A 1-13 and during hypoxia. Hypoxia-induced increase was enhanced by dynorphin A 1-13 and abolished by nor-BNI. In conclusion, endogenous dynorphin A released in the early stage of hypoxia plays a protective effect against HPH via stimulation of κ-opioid receptor.

    Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Angiotensin II; Animals; Blood Pressure; Cell Hypoxia; Cell Proliferation; Dynorphins; Endothelin-1; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Lung; Male; Myocytes, Smooth Muscle; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

2016
Activation of the nicotinamide N-methyltransferase (NNMT)-1-methylnicotinamide (MNA) pathway in pulmonary hypertension.
    Respiratory research, 2016, 08-31, Volume: 17, Issue:1

    Pulmonary arterial hypertension (PAH) is associated with inflammatory response but it is unknown whether it is associated with alterations in NNMT activity and MNA plasma concentration. Here we examined changes in NNMT-MNA pathway in PAH in rats and humans.. PAH in rats was induced by a single subcutaneous injection of MCT (60 mg/kg). Changes in NNMT activity in the lungs and liver (assessed as the rate of conversion of nicotinamide (NA) to MNA), changes in plasma concentration of MNA and its metabolites (analyzed by LC/MS) were analyzed in relation to PAH progression. PAH was characterized by right ventricular hypertrophy (gross morphology), cardiac dysfunction (by MRI), lung histopathology, lung ultrastructure, and ET-1 concentration in plasma. NO-dependent and PGI2-dependent function in isolated lungs was analyzed. In naive patients with idiopathic pulmonary hypertension (IPAH) characterized by hemodynamic and biochemical parameters MNA and its metabolites in plasma were also measured.. MCT-injected rats developed hypertrophy and functional impairment of the right ventricle, hypertrophy of the pulmonary arteries, endothelial ultrastructural defects and a progressive increase in ET-1 plasma concentration-findings all consistent with PAH development. In isolated lung, NO-dependent regulation of hypoxic pulmonary vasoconstriction was impaired, while PGI2 production (6-keto-PGF1α) was increased. NNMT activity increased progressively in the liver and in the lungs following MCT injection, and NNMT response was associated with an increase in MNA and 6-keto-PGF1α concentration in plasma. In IPAH patients plasma concentration of MNA was elevated as compared with healthy controls.. Progression of pulmonary hypertension is associated with the activation of the NNMT-MNA pathway in rats and humans. Given the vasoprotective activity of exogenous MNA, which was previously ascribed to PGI2 release, the activation of the endogenous NNMT-MNA pathway may play a compensatory role in PAH.

    Topics: 6-Ketoprostaglandin F1 alpha; Adult; Animals; Case-Control Studies; Disease Models, Animal; Disease Progression; Endothelin-1; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Liver; Lung; Male; Middle Aged; Monocrotaline; Niacinamide; Nicotinamide N-Methyltransferase; Nitric Oxide; Rats, Wistar; Signal Transduction; Time Factors; Ventricular Dysfunction, Right; Ventricular Function, Right

2016
Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways.
    Scientific reports, 2016, 09-01, Volume: 6

    Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCT-induced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined. Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factor (PDGF)-BB stimulated PASMCs migration, which were associated with cell-cycle arrest at G0/G1 phase. Liraglutide may have both preventive and therapeutic effects on MCT-induced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling.

    Topics: Animals; Becaplermin; Cell Cycle; Cell Movement; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Endothelin-1; Flow Cytometry; Guanylate Cyclase; Hemodynamics; Hypertension, Pulmonary; Liraglutide; Male; Monocrotaline; Nitric Oxide Synthase Type III; Proto-Oncogene Proteins c-sis; Rats; Rats, Wistar; rho-Associated Kinases

2016
[K198N polymorphism in the EDN1 gene in patients with pulmonary arterial hypertension].
    Medicina clinica, 2015, Apr-20, Volume: 144, Issue:8

    In pulmonary arterial hypertension (PAH) an association with a polymorphism in the endothelin gene (EDN1) has been described. The main objective of this study was to analyze the polymorphism K198N in the gene EDN1 in patients with PAH, correlating the results with clinical and hemodynamic parameters.. We compared 41 patients diagnosed with idiopathic and associated PAH of group i with 50 healthy controls. Polymerase chain reaction and direct sequencing were used to analyze the polymorphism K198N. We compared the genotype distribution and searched for a correlation with clinical, hemodynamic and therapeutic response.. Genotype GG was present in 42% of patients in this study and 65% of controls. The GT+TT genotypes appeared in 58% of patients and in 35% of controls. Statistically significant differences between patients and controls (P=.032) were detected, with a relative risk in carriers of having the T allele of 2.51 (95% CI 1.07 to 5.86). The analysis by PolyPhen software defined K198N change as pathogenic. No significant differences in the response to treatment at medium term were found.. The genotype analysis of the EDN1 gene polymorphism shows statistically significant differences in patients with PAH compared to healthy individuals. Individuals carrying at least one T allele exhibit a higher relative significant risk to develop HAP.

    Topics: Adult; Case-Control Studies; Endothelin-1; Female; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; Hypertension, Pulmonary; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Sequence Analysis, DNA

2015
Pulmonary arterial hypertension associated with impaired lysosomal endothelin-1 degradation.
    Cardiology in the young, 2015, Volume: 25, Issue:4

    We report on a boy with severe pulmonary arterial hypertension associated with mucolipidosis, a rare lysosomal storage disorder. During diagnostic catheterisation, we found increased endothelin-1 levels, but normal big endothelin-1-levels (the precursor form of endothelin-1), which suggests impaired degradation of endothelin-1 rather than increased synthesis. As endothelin-1 degradation takes place in the lysosome, it appears likely that lysosomal dysfunction caused by the underlying disease contributes to the development of pulmonary arterial hypertension in this patient.

    Topics: Catheterization; Child; Echocardiography; Endothelin-1; Humans; Hypertension, Pulmonary; Lysosomal Storage Diseases; Lysosomes; Male; Mucolipidoses; Pulmonary Artery; Turkey

2015
Kelussia odoratissima Mozzaf - a promising medicinal herb to prevent pulmonary hypertension in broiler chickens reared at high altitude.
    Journal of ethnopharmacology, 2015, Jan-15, Volume: 159

    Kelussia odoratissima Mozzaf, formerly Apium odoratissima, is a plant locally called "Karafs", found in central Zagros region of Iran. Leaves and stems of the plant are traditionally used in the treatment of hypertension and inflammation. Lowering blood pressure effects of Kelussia odoratissima Mozzaf (wild celery) was evaluated in preventing pulmonary hypertension syndrome (PHS) in broiler chickens reared at high altitude (2,100 m).. A total number of 208 day-old male broilers (Ross 308) were randomly assigned to four treatments including different levels of Kelussia odoratissima Mozzaf (0%, 0.25%, 0.5%, and 0.75%) in a 42-day trial.. Body weight gain and feed:gain responses significantly (P<0.05) improved when Kelussia odoratissima Mozzaf was included in broiler diets at 0.75% in the growing stage and throughout the trial. Over-expression of inducible nitric oxide (NO) synthase in the heart was observed in chickens fed Kelussia odoratissima Mozzaf. Birds received Kelussia odoratissima Mozzaf at 0.5% and 0.75% had significantly (P<0.05) higher circulatory concentrations of NO though significantly (P<0.05) lower serum malondialdehyde concentration, hematocrit and heterophil to lymphocyte ratio when compared to the birds fed the control diet. Feeding Kelussia odoratissima Mozzaf at 0.5% and 0.75% prevented from right ventricular hypertrophy and led to a significant decline in mortality from PHS.. It can be concluded that Kelussia odoratissima Mozzaf is a promising medicinal herb to prevent PHS in broiler chickens by improving blood pressure and antioxidant responses.

    Topics: Altitude; Animals; Apiaceae; Chickens; Diet; Eating; Endothelin-1; Gene Expression; Heart Ventricles; Hypertension, Pulmonary; Male; Nitric Oxide Synthase Type II; Phytotherapy; Plant Leaves; Plant Shoots; Plants, Medicinal; Superoxide Dismutase; Superoxide Dismutase-1; Weight Gain

2015
The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension.
    The Journal of biological chemistry, 2015, Jan-23, Volume: 290, Issue:4

    Pulmonary hypertension (PH) is a complex disorder, spanning several known vascular cell types. Recently, we identified the microRNA-130/301 (miR-130/301) family as a regulator of multiple pro-proliferative pathways in PH, but the true breadth of influence of the miR-130/301 family across cell types in PH may be even more extensive. Here, we employed targeted network theory to identify additional pathogenic pathways regulated by miR-130/301, including those involving vasomotor tone. Guided by these predictions, we demonstrated, via gain- and loss-of-function experimentation in vitro and in vivo, that miR-130/301-specific control of the peroxisome proliferator-activated receptor γ regulates a panel of vasoactive factors communicating between diseased pulmonary vascular endothelial and smooth muscle cells. Of these, the vasoconstrictive factor endothelin-1 serves as an integral point of communication between the miR-130/301-peroxisome proliferator-activated receptor γ axis in endothelial cells and contractile function in smooth muscle cells. Thus, resulting from an in silico analysis of the architecture of the PH disease gene network coupled with molecular experimentation in vivo, these findings clarify the expanded role of the miR-130/301 family in the global regulation of PH. They further emphasize the importance of molecular cross-talk among the diverse cellular populations involved in PH.

    Topics: Algorithms; Animals; Cells, Cultured; Endothelin-1; Endothelins; Gene Expression Regulation; HEK293 Cells; Humans; Hypertension, Pulmonary; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oligonucleotides; PPAR gamma; Pulmonary Artery; Signal Transduction; Systems Biology; Vasoconstriction

2015
No redistribution of lung blood flow by inhaled nitric oxide in endotoxemic piglets pretreated with an endothelin receptor antagonist.
    Journal of applied physiology (Bethesda, Md. : 1985), 2015, Mar-15, Volume: 118, Issue:6

    Inhaled nitric oxide (INO) improves ventilation-perfusion matching and alleviates pulmonary hypertension in patients with acute respiratory distress syndrome. However, outcome has not yet been shown to improve, and nonresponse is common. A better understanding of the mechanisms by which INO acts may guide in improving treatment with INO in patients with severe respiratory failure. We hypothesized that INO may act not only by vasodilation in ventilated lung regions, but also by causing vasoconstriction via endothelin (ET-1) in atelectatic, nonventilated lung regions. This was studied in 30 anesthetized, mechanically ventilated piglets. The fall in oxygenation and rise in pulmonary artery pressure during a sepsislike condition (infusion of endotoxin) were blunted by INO 40 ppm. Endotoxin infusion increased serum ET-1, and INO almost doubled the ratio between mRNA expression of endothelin receptor A (mediating vasoconstriction) and B (mediating vasodilation and clearance of ET-1) (ET-A/ET-B) in atelectatic lung regions. INO caused a shift in blood flow away from atelectatic lung regions in the endotoxemic piglets, but not during ET receptor antagonism. We conclude that INO in short-term experiments, in addition to causing selective pulmonary vasodilation in ventilated lung regions, increases the ET-A/ET-B mRNA expression ratio in lung tissue. This might augment the vasoconstriction in atelectatic lung regions, enhancing the redistribution of pulmonary blood flow to ventilated lung regions which are reached by INO. Such vasoconstriction may be an important additional factor explaining the effect of INO.

    Topics: Administration, Inhalation; Animals; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Endotoxins; Hypertension, Pulmonary; Lung; Lung Injury; Nitric Oxide; Pulmonary Circulation; Receptors, Endothelin; Respiration; Respiration, Artificial; Respiratory Distress Syndrome; RNA, Messenger; Swine; Vasoconstriction

2015
Takayasu arteritis-associated pulmonary hypertension.
    The Journal of rheumatology, 2015, Volume: 42, Issue:3

    To investigate the probable pathogenesis, clinical features, diagnosis, and therapy of patients with pulmonary hypertension (PH) in Takayasu arteritis (TA).. A total of 48 patients with TA who had PH, 20 patients with TA who had pulmonary arterial involvement (PA) without PH, and 30 patients with idiopathic pulmonary arterial hypertension (IPAH) were enrolled in the study from 2009 to 2013.. Among the 48 patients with TA who had PH, 36 (75.0%) had PA, and left heart disease (LHD) was present in 12 (25.0%). Serum levels of big endothelin 1 (ET-1) were independently correlated with pulmonary arterial systolic pressure (r = 0.33, p = 0.04). Compared to patients with IPAH, patients with PH because of PA who underwent right heart catheterization had lower average cardiac indexes (2.0 ± 0.5 vs 3.0 ± 1.2 l/min/m(2), p = 0.05), and they all developed favorable responses to acute vasodilator testing (100%) in comparison to 10 of the patients with IPAH (33.3%). During a mean followup of 36.0 ± 13.2 months (12.0-65.0 mos), of the patients with PH associated with PA, 3 died of heart failure. Six patients who underwent pulmonary artery revascularization were found to have good prognoses after followup for a mean duration of 6.2 ± 1.9 months. Additionally, 12 patients with PH with LHD were followed for 38.4 ± 15.6 months (12.0-60.0 mos), and 1 patient died of heart failure during the followup period.. Patients with TA are at increased risk for PH. Early screening of patients with TA with unexplained symptoms related to PH should be applied. PH-specific therapies or revascularization may be effective treatments in the early stages of patients with PA, PH, and severe pulmonary artery stenosis.

    Topics: Adolescent; Adult; Cardiac Catheterization; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prognosis; Takayasu Arteritis; Treatment Outcome; Young Adult

2015
Pathophysiology of infantile pulmonary arterial hypertension induced by monocrotaline.
    Pediatric cardiology, 2015, Volume: 36, Issue:5

    Pediatric pulmonary arterial hypertension (PAH) presents certain specific features. In this specific age group, experimental models to study the pathophysiology of PAH are lacking. To characterize hemodynamic, morphometric, and histological progression as well as the expression of neurohumoral factors and regulators of cardiac transcription in an infantile model of PAH induced by monocrotaline (MCT), eight-day-old Wistar rats were randomly injected with MCT (30 mg/kg, sc, n = 95) or equal volume of saline solution (n = 92). Animals were instrumented for biventricular hemodynamic recording 7, 14, and 21 days after MCT, whereas samples were collected at 1, 3, 7, 14, and 21 days after MCT. Different time point postinjections were defined for further analysis. Hearts and lungs were collected for morphometric characterization, assessment of right- and left-ventricle (RV and LV) cardiomyocyte diameter and collagen type-I and type-III ratio, RV collagen volume fraction, and pulmonary vessels wall thickness. mRNA quantification was undertaken for brain natriuretic peptide (BNP), endothelin-1 (ET-1), and for cardiac transcription regulators (HOP and Islet1). Animals treated with MCT at the 8th day of life presented RV hypertrophy since day 14 after MCT injection. There were no differences on the RV collagen volume fraction or collagen type-I and type-III ratio. Pulmonary vascular remodelling and PAH were present on day 21, which were accompanied by an increased expression of BNP, ET-1, HOP, and Islet1. The infantile model of MCT-induced PAH can be useful for the study of its pathophysiology and to test new therapeutic targets in pediatric age group.

    Topics: Animals; Animals, Newborn; Collagen Type I; Collagen Type III; Disease Models, Animal; Endothelin-1; Female; Heart; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Male; Monocrotaline; Myocytes, Cardiac; Natriuretic Peptide, Brain; Pyrrolizidine Alkaloids; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Transcription Factors

2015
Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension.
    American journal of physiology. Lung cellular and molecular physiology, 2015, Apr-01, Volume: 308, Issue:7

    This study examines how heme biosynthesis modulation with δ-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension.

    Topics: Aminolevulinic Acid; Animals; Endothelin-1; Ferrochelatase; Heme; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Mice, Inbred C57BL; MicroRNAs; Mitochondria; Pulmonary Artery; Superoxide Dismutase; Superoxides

2015
CT-proET1 predicts pulmonary hemodynamics in Scleroderma-associated pulmonary hypertension.
    Clinical research in cardiology : official journal of the German Cardiac Society, 2015, Volume: 104, Issue:6

    Topics: Aged; Endothelin-1; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Peptide Fragments; Pilot Projects; Prognosis; Scleroderma, Systemic

2015
Ginsenoside Rb1 attenuates agonist-induced contractile response via inhibition of store-operated calcium entry in pulmonary arteries of normal and pulmonary hypertensive rats.
    Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 2015, Volume: 35, Issue:4

    Pulmonary hypertension (PH) is characterized by sustained vasoconstriction, enhanced vasoreactivity and vascular remodeling, which leads to right heart failure and death. Despite several treatments are available, many forms of PH are still incurable. Ginsenoside Rb1, a principle active ingredient of Panax ginseng, exhibits multiple pharmacological effects on cardiovascular system, and suppresses monocrotaline (MCT)-induced right heart hypertrophy. However, its effect on the pulmonary vascular functions related to PH is unknown.. We examined the vasorelaxing effects of ginsenoside Rb1 on endothelin-1 (ET-1) induced contraction of pulmonary arteries (PAs) and store-operated Ca(2+) entry (SOCE) in pulmonary arterial smooth muscle cells (PASMCs) from chronic hypoxia (CH) and MCT-induced PH.. Ginsenoside Rb1 elicited concentration-dependent relaxation of ET-1-induced PA contraction. The vasorelaxing effect was unaffected by nifedipine, but abolished by the SOCE blocker Gd(3+). Ginsenoside Rb1 suppressed cyclopiazonic acid (CPA)-induced PA contraction, and CPA-activated cation entry and Ca(2+) transient in PASMCs. ET-1 and CPA-induced contraction, and CPA-activated cation entry and Ca(2+) transients were enhanced in PA and PASMCs of CH and MCT-treated rats; the enhanced responses were abolished by ginsenoside Rb1.. Ginsenoside Rb1 attenuates ET-1-induced contractile response via inhibition of SOCE, and it can effectively antagonize the enhanced pulmonary vasoreactivity in PH.

    Topics: Animals; Calcium; Calcium Channels; Cell Hypoxia; Cells, Cultured; Disease Models, Animal; Endothelin-1; Gadolinium; Ginsenosides; Hypertension, Pulmonary; Indoles; Male; Monocrotaline; Muscle Contraction; Myocytes, Smooth Muscle; Nifedipine; Panax; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum

2015
Beneficial Effects of Renal Denervation on Pulmonary Vascular Remodeling in Experimental Pulmonary Artery Hypertension.
    Revista espanola de cardiologia (English ed.), 2015, Volume: 68, Issue:7

    Activation of both the sympathetic nervous system and the renin-angiotensin-aldosterone system is closely associated with pulmonary arterial hypertension. We hypothesized that renal denervation decreases renin-angiotensin-aldosterone activity and inhibits the progression of pulmonary arterial hypertension.. Twenty-two beagles were randomized into 3 groups. The dogs' pulmonary dynamics were measured before and 8 weeks after injection of 0.1mL/kg dimethylformamide (control dogs) or 2mg/kg dehydromonocrotaline (pulmonary arterial hypertension and pulmonary arterial hypertension + renal denervation dogs). Eight weeks after injection, neurohormone levels and pulmonary tissue morphology were measured.. Levels of plasma angiotensin II and endothelin-1 were significantly increased after 8 weeks in the pulmonary arterial hypertension dogs and were higher in the lung tissues of these dogs than in those of the control and renal denervation dogs (mean [standard deviation] angiotensin II: 65 [9.8] vs 38 [6.7], 46 [8.1]; endothelin-1: 96 [10.3] vs 54 [6.2], 67 [9.4]; P < .01). Dehydromonocrotaline increased the mean pulmonary arterial pressure (16 [3.4] mmHg vs 33 [7.3] mmHg; P < .01), and renal denervation prevented this increase. Pulmonary smooth muscle cell proliferation was higher in the pulmonary arterial hypertension dogs than in the control and pulmonary arterial hypertension + renal denervation dogs.. Renal denervation attenuates pulmonary vascular remodeling and decreases pulmonary arterial pressure in experimental pulmonary arterial hypertension. The effect of renal denervation may contribute to decreased neurohormone levels.

    Topics: Angiotensin II; Animals; Collagen; Dimethylformamide; Dinoprostone; Dogs; Echocardiography; Electrocardiography; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Kidney; Lung; Male; Monocrotaline; Neurotransmitter Agents; Random Allocation; Renal Artery; Renin-Angiotensin System; Sympathectomy; Vascular Remodeling

2015
IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: Role of epigenetic regulation.
    Vascular pharmacology, 2015, Volume: 73

    Pulmonary hypertension is a fatal disease characterized by a progressive increase in pulmonary artery pressure accompanied by pulmonary vascular remodeling and increased vasomotor tone. Although some biological pathways have been identified in neonatal hypoxia-induced pulmonary hypertension (PH), little is known regarding the role of growth factors in the pathogenesis of PH in neonates. In this study, using a model of hypoxia-induced PH in neonatal mice, we demonstrate that the growth factor insulin-like growth factor-1 (IGF-1), a potent activator of the AKT signaling pathway, is involved in neonatal PH. After exposure to hypoxia, IGF-1 signaling is activated in pulmonary endothelial and smooth muscle cells in vitro, and the IGF-1 downstream signal pAKT(S473) is upregulated in lungs of neonatal mice. We found that IGF-1 regulates ET-1 expression in pulmonary endothelial cells and that IGF-1 expression is regulated by histone deacetylases (HDACs). In addition, there is a differential cytosine methylation site in the IGF-1 promoter region in response to neonatal hypoxia. Moreover, inhibition of HDACs with apicidin decreases neonatal hypoxia-induced global DNA methylation levels in lungs and specific cytosine methylation levels around the pulmonary IGF-1 promoter region. Finally, HDAC inhibition with apicidin reduces chronic hypoxia-induced activation of IGF-1/pAKT signaling in lungs and attenuates right ventricular hypertrophy and pulmonary vascular remodeling. Taken together, we conclude that IGF-1, which is epigenetically regulated, is involved in the pathogenesis of pulmonary hypertension in neonatal mice. This study implicates a novel HDAC/IGF-1 epigenetic pathway in the regulation of hypoxia-induced PH and warrants further study of the role of IGF-1 in neonatal pulmonary hypertensive disease.

    Topics: Animals; Animals, Newborn; Arterial Pressure; Cells, Cultured; Disease Models, Animal; DNA Methylation; Endothelin-1; Epigenesis, Genetic; Gene Expression Regulation; Histone Deacetylase Inhibitors; Histone Deacetylases; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Insulin-Like Growth Factor I; Mice, Inbred C57BL; Phosphorylation; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt; Pulmonary Artery; RNA Interference; Signal Transduction; Time Factors; Transfection; Vascular Remodeling

2015
The Effect of Umbilical Cord Blood Derived Mesenchymal Stem Cells in Monocrotaline-induced Pulmonary Artery Hypertension Rats.
    Journal of Korean medical science, 2015, Volume: 30, Issue:5

    Pulmonary arterial hypertension (PAH) causes right ventricular failure due to a gradual increase in pulmonary vascular resistance. The purposes of this study were to confirm the engraftment of human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) placed in the correct place in the lung and research on changes of hemodynamics, pulmonary pathology, immunomodulation and several gene expressions in monocrotaline (MCT)-induced PAH rat models after hUCB-MSCs transfusion. The rats were grouped as follows: the control (C) group; the M group (MCT 60 mg/kg); the U group (hUCB-MSCs transfusion). They received transfusions via the external jugular vein a week after MCT injection. The mean right ventricular pressure (RVP) was significantly reduced in the U group after the 2 week. The indicators of RV hypertrophy were significantly reduced in the U group at week 4. Reduced medial wall thickness in the pulmonary arteriole was noted in the U group at week 4. Reduced number of intra-acinar muscular pulmonary arteries was observed in the U group after 2 week. Protein expressions such as endothelin (ET)-1, endothelin receptor A (ERA), endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 significantly decreased at week 4. The decreased levels of ERA, eNOS and MMP-2 immunoreactivity were noted by immnohistochemical staining. After hUCB-MSCs were administered, there were the improvement of RVH and mean RVP. Reductions in several protein expressions and immunomodulation were also detected. It is suggested that hUCB-MSCs may be a promising therapeutic option for PAH.

    Topics: Animals; Cytokines; Disease Models, Animal; Endothelin-1; Fetal Blood; Gene Expression Regulation; Hemodynamics; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Immunohistochemistry; Lung; Male; Matrix Metalloproteinase 2; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Monocrotaline; Nitric Oxide Synthase Type III; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

2015
The effects of mycophenolate mofetil on cytokines and their receptors in pulmonary arterial hypertension in rats.
    Scandinavian journal of rheumatology, 2015, Volume: 44, Issue:5

    To analyse the effects of mycophenolate mofetil (MMF) on pulmonary artery pressure (PAP) and the expression of cytokines and their receptors in a rat model of pulmonary arterial hypertension (PAH).. Thirty-eight healthy male inbred Sprague-Dawley rats were divided randomly into four groups: a control group, a monocrotaline (MCT) group, an MMF20 group (MCT+20 mg/kg/day MMF), and an MMF40 group (MCT+40 mg/kg/day MMF). Systolic PAP (SPAP), the right ventricular hypertrophy index (RVI), and the levels of expression of cytokines and their receptors were measured and analysed.. SPAP, RVI, levels of expression of basic fibroblast growth factor (bFGF) in serum and lung homogenates, alveolar arterial wall thickness, and the number of muscular arteries in the MMF20 and MMF40 groups were decreased in comparison with the MCT group.. MMF inhibits the formation of vascular muscle and decreases SPAP and RVI by inhibition of the expression of bFGF, endothelin-1 (ET-1), and their receptors, resulting in the inhibition of smooth muscle proliferation and amelioration of PAH.

    Topics: Animals; Blood Pressure; Cell Proliferation; Cytokines; Disease Models, Animal; Endothelin-1; Fibroblast Growth Factor 2; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Muscle, Smooth, Vascular; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Cytokine; Receptors, Fibroblast Growth Factor

2015
Plasma Levels of Acylated Ghrelin in Children with Pulmonary Hypertension Associated with Congenital Heart Disease.
    Pediatric cardiology, 2015, Volume: 36, Issue:7

    This study aims to estimate plasma levels of acylated ghrelin in children with pulmonary hypertension (PH) associated with congenital heart disease (CHD) and to correlate the levels of acylated ghrelin with endothelin-1 (ET-1), nitric oxide (NO), and clinical hemodynamic parameters. We investigated the plasma concentration of acylated ghrelin, ET-1, NO, and the hemodynamic parameters in 20 children with CHD, 20 children with PH-CHD, and 20 normal children. Plasma-acylated ghrelin and NO levels were significantly higher in CHD group than in control subjects (P < 0.001). Moreover, plasma-acylated ghrelin, ET-1, and NO levels were significantly elevated in PH-CHD group compared with the CHD group (P < 0.05). In PH-CHD children, plasma-acylated ghrelin levels correlated positively with pulmonary artery systolic pressure (PASP; r = 0.740, P < 0.001), pulmonary artery diastolic pressure (PADP; r = 0.613, P = 0.004), right ventricular systolic pressure (RVSP; r = 0.642, P = 0.002), mean pulmonary arterial hypertension (mPAP; r = 0.685, P = 0.001), right ventricle diameter (RVD; r = 0.473, P = 0.035), pulmonary artery trunk diameter (PAD; r = 0.613, P = 0.004), NO (r = 0.463, P = 0.04), and ET-1 (r = 0.524, P = 0.018). Plasma-acylated ghrelin levels were elevated both in CHD and in PH-CHD. Increased acylated ghrelin levels correlated positively with ET-1, NO, PASP, PADP, RVSP, mPAP, RVD, and PAD. Acylated ghrelin may be a new biomarker of PH-CHD.

    Topics: Biomarkers; Cardiac Catheterization; Case-Control Studies; Child, Preschool; Echocardiography; Endothelin-1; Female; Ghrelin; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Male; Nitric Oxide; Pulmonary Artery

2015
Salvia Miltiorrhiza Bge.f.alba Ameliorates the Progression of Monocrotaline-Induced Pulmonary Hypertension by Protecting Endothelial Injury in Rats.
    The Tohoku journal of experimental medicine, 2015, Volume: 236, Issue:2

    Pulmonary hypertension (PH) is a life-threatening disease that is characterized by elevated pulmonary blood pressure, abnormally thickened pulmonary arteries, and right ventricular hypertrophy. Monocrotaline (MCT) has been used to generate an experimental model of PH in rats, with PH initiated from injuries of lung vascular endothelium. Salvia Miltiorrhiza Bge.f.alba is a widely used traditional herb in China, known to exert protective effects on vascular endothelial cell injury in animal experiments. However, the role of Salvia Miltiorrhiza Bge.f.alba in PH remains unclear. Thus, we investigated the effects of the aqueous extract of Salvia Miltiorrhiza Bge.f.alba (AESM) on MCT-induced PH and explored the pertinent mechanism. PH was induced in rats by a single subcutaneous injection of MCT (60 mg/kg body weight). Low or high dose (4.6 g/kg or 14 g/kg body weight) of AESM was then administered orally for 21 days to PH rats. Hemodynamic study showed that AESM reduced mean pulmonary artery pressure and improved right ventricle function. Lung pathological analysis revealed that AESM reduced wall thickness and lumen stenosis of pulmonary vessels. Also AESM ameliorated right ventricular hypertrophy. Measurement of biochemical parameters indicated that AESM decreased endothelin-1 and thromboxane A2 in plasma and increased nitrogen monoxide and prostacyclin in the plasma and reduced the increase of transforming growth factor β1 in lung tissue. Our results suggest that AESM may ameliorate the progression of MCT-induced PH in rats, at least in part by its protective effect on endothelial injury. Therefore, Salvia Miltiorrhiza Bge.f.alba could be useful in the treatment of PH.

    Topics: Animals; Endothelin-1; Endothelium, Vascular; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; Nitric Oxide; Plant Extracts; Poisons; Prostaglandins I; Rats; Rats, Sprague-Dawley; Salvia miltiorrhiza; Thromboxane A2; Transforming Growth Factor beta1; Ventricular Function, Right

2015
[Beneficial effects of renal denervation on pulmonary vascular remodeling in experimental pulmonary artery hypertension].
    Zhonghua yi xue za zhi, 2015, Apr-14, Volume: 95, Issue:14

    To explore the effects of renal sympathetic denervation (RSD) on pulmonary vascular remodeling in a model of pulmonary arterial hypertension (PAH).. According to the random number table, 24 beagles were randomized into control, PAH and PAH+RSD groups (n=8 each). The levels of neurohormone, echocardiogram and dynamics parameters were measured. Then 0.1 ml/kg dimethylformamide (control group) or 2 mg/kg dehydromonocrotaline (PAH and PAH+RSD groups) were injected. The PAH+RSD group underwent RSD after injection. At week 8 post-injection, the neurohormone levels, echocardiogram, dynamics parameters and pulmonary tissue morphology were observed.. The values of right ventricular systolic pressure (RVSP) and pulmonary arterial systolic pressure (PASP) in PAH and PAH+RSD groups were both significantly higher than those in control group ((42.8±8.7), (30.8±6.8) vs (23.2±5.7) mmHg (1 mmHg=0.133 kPa) and (45.1±11.2), (32.6±7.9) vs (24.7±7.1) mmHg). Meanwhile, the values of RVSP and PASP in PAH group were higher than those in PAH+RSD group (all P<0.01). The levels of serum angiotensin II (Ang II) and endothelin-1 significantly increased after 8 weeks in PAH dogs ((228±41) vs (113±34) pg/ml and (135±15) vs (77±7) pg/ml, all P<0.01). And Ang II and endothelin-1 were higher in lung tissues of PAH group ((65±10) and (96±10) pg/ml) than in those of control group ((38±7) and (54±6) pg/ml) and PAH+RSD group ((46±8) and (67±9) pg/ml) (all P<0.01). Pulmonary tissues had marked collagen hyperplasia and lamellar corpuscles of type 2 alveolar cells were damaged more severely in PAH dogs than in PAH+RSD dogs.. RSD suppresses pulmonary vascular remodeling and decreases pulmonary arterial pressure in experimental PAH. And the effect of RSD on PAH may contribute to decreased neurohormone levels.

    Topics: Angiotensin II; Animals; Blood Pressure; Denervation; Dogs; Echocardiography; Endothelin-1; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Kidney; Lung; Monocrotaline; Pulmonary Artery; Sympathectomy; Vascular Remodeling

2015
Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis.
    The European respiratory journal, 2015, Volume: 46, Issue:4

    Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor β1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form.

    Topics: Animals; Bleomycin; Chymases; Disease Models, Animal; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Hemodynamics; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Immunohistochemistry; Lung; Mast Cells; Matrix Metalloproteinase 2; Mesocricetus; Pulmonary Artery; Pulmonary Fibrosis; Radioimmunoassay; Random Allocation; Transforming Growth Factor beta1

2015
4,4'-Methylenedianiline Alters Serotonergic Transport in a Novel, Sex-Specific Model of Pulmonary Arterial Hypertension in Rats.
    Toxicological sciences : an official journal of the Society of Toxicology, 2015, Volume: 147, Issue:1

    Pulmonary arterial hypertension (PAH) is a cardiovascular disorder characterized by elevated pulmonary artery pressure as a result of arterial wall thickening. Patients are 3-4 times more likely to be women than men. This gender discrepancy demonstrates a need for an animal model with similar sex differences. 4,4'-Methylenedianiline (DAPM) is an aromatic amine used industrially in the synthesis of polyurethanes. Chronic, intermittent treatment of male and female rats with DAPM resulted in medial hyperplasia of pulmonary arterioles, exclusively in females, coupled to increases in pulmonary arterial pressures. Significant increases in plasma levels of endothelin-1 (ET-1) and serotonin, but decreases in nitrite [Formula: see text], were observed in females treated with DAPM. A decrease was observed in the serum ratio of the estrogen metabolites 2-hydroxyestradiol (2-OHE1)/16α-hydroxyestrogen (16α-OHE1). In females, ET-1,[Formula: see text] , and 2-OHE1/16α-OHE1 were significantly correlated with peak pressure gradient, an indirect measure of pulmonary arterial pressure. Expression of the serotonin transport protein (SERT) was significantly higher in the arteries of DAPM-treated females. In vitro, DAPM induced human pulmonary vascular smooth muscle cell proliferation and serotonin uptake, both of which were inhibited by treatment with the estrogen receptor antagonist ICI 182,780 or the selective serotonin reuptake inhibitor fluoxetine. DAPM also induced the release of serotonin from human pulmonary endothelial cells in culture, which is blocked by ICI 182,780. Taken together, this suggests that DAPM-mediated dysregulation of serotonin transport is estrogen-receptor dependent. Thus, DAPM-induced PAH pathology may be a new tool to clarify the sex selectivity of PAH disease pathogenesis.

    Topics: Aniline Compounds; Animals; Endocrine Disruptors; Endothelin-1; Epithelial Cells; Estrogens; Female; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Muscle, Smooth, Vascular; Nitric Oxide; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; RNA-Binding Proteins; Serotonin; Sex Characteristics

2015
Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.
    American journal of respiratory and critical care medicine, 2015, Dec-01, Volume: 192, Issue:11

    Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases.. To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs).. A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Single-nucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort.. Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months.. ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.

    Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelin-1; Exercise Test; Exercise Tolerance; Female; Follow-Up Studies; Genome-Wide Association Study; Humans; Hypertension, Pulmonary; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Retrospective Studies; Treatment Outcome

2015
Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension.
    Biochemical and biophysical research communications, 2015, Sep-25, Volume: 465, Issue:3

    Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAH. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH.

    Topics: Animals; Biomarkers; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Mice; Mice, Transgenic; Pulmonary Artery

2015
[The changes of vascular active substances in pulmonary embolism rats and a comparative study of anticoagulant drugs].
    Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 2015, Volume: 31, Issue:2

    To establish the rat model of acute pulmonary embolism, and study the changes of vascular active substances in pulmonary embolism rats, and investigate the interventive effect of anticoagulant drugs on vascular active substances.. One hundred and twenty-eight rats were randomly divided into four groups: control group, model group, low-molecular-weight heparin and warfarin treated group and rivaroxaban-treated group (n = 32 in each group). The method of autologous thrombosis was used to establish the animal model of acute pulmonary embolism. The animals were treated with saline or different anticoagulant drugs. The physiological and biochemical parameters were detected at different time points after embolization. The rats were killed after embolism of 24 h, 3 d, 5 d or 1 week respectively and the pathologic samples of lung tissues were collected to analyze the pulmonary pathological changes in different groups.. Rats in embolization group after blood clots injection showed shortness of breath, oral cyanosis; quicken heart rates and other symptoms. All embolization groups had pulmonary hypertension, the levels of type B natriuretic peptide (BNP) were increased significantly. The ratio of endothelin-1 (ET-1)/NO and thromboxane (TXB2) and prostacyclin (6-k-PGFla) were abnormal. After treated with effective anticoagulant drugs, the levels of BNP, ET-1, NO, TXB2 and 6-k-PGF1a were tended to the normal levels in the control group. The pulmonary hypertensions were gradually decreased. The efficacy of rivaroxaban on pulmonary embolism was the same as that of the low molecular weight heparin or warfarin.. Anticoagulation therapy can effectively improve endothelial function after pulmonary embolism, reduce pulmonary hypertension, and revise the increased BNP levels to normal levels. The efficacy of rivaroxaban is not inferior to that of low molecular weight heparin and warfarin.

    Topics: Animals; Anticoagulants; Disease Models, Animal; Endothelin-1; Heparin, Low-Molecular-Weight; Hypertension, Pulmonary; Lung; Morpholines; Pulmonary Embolism; Rats; Rivaroxaban; Thiophenes; Warfarin

2015
MR-proADM Predicts Exercise Capacity and Survival Superior to Other Biomarkers in PH.
    Lung, 2015, Volume: 193, Issue:6

    Besides the established biomarker NT-proBNP, the new cardiovascular biomarkers MR-proANP, MR-proADM, Copeptin, and CT-proET-1 are promising to evaluate hemodynamics, exercise parameters, and prognosis in patients with pulmonary hypertension (PH).. 125 consecutive patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) were prospectively enrolled at five German PH centers. Blood samples were taken during right heart catheterization. The primary study endpoint was the correlation between biomarkers and hemodynamic and exercise parameters. As secondary endpoint, prediction of 1-year mortality was evaluated.. MR-proADM showed the strongest correlations with 6MWD and VO2peak, whereas NT-proBNP showed the strongest correlations with PVR, PAPm, and CI. In multivariate analysis, only MR-proADM was independently associated with exercise variables, whereas only NT-proBNP independently predicted hemodynamic parameters. All biomarkers were associated with 1-year survival, with MR-proADM showing the highest C index of 0.78. In multivariate analysis, MR-proADM predicted survival independent of age, 6-MWD, CI, RAP, and NT-proBNP. The cut-off of 1.08 nmol/l provided a sensitivity of 83 % and specificity of 66 %.. Different biomarkers reflect distinctive disease aspects in PH. NT-proBNP best predicts hemodynamic impairment while MR-proADM strongly correlates with exercise capacity. Additionally, MR-proADM represents a promising new marker to evaluate prognosis in patients with PAH and CTEPH. Multi-marker strategies should further be evaluated.

    Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Chronic Disease; Endothelin-1; Exercise Tolerance; Female; Germany; Glycopeptides; Heart Atria; Humans; Hypertension, Pulmonary; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Prospective Studies; Protein Precursors; Pulmonary Embolism; Pulmonary Wedge Pressure; Vascular Resistance

2015
Peroxisome proliferator-activated receptor-α-mediated transcription of miR-301a and miR-454 and their host gene SKA2 regulates endothelin-1 and PAI-1 expression in sickle cell disease.
    Bioscience reports, 2015, Oct-12, Volume: 35, Issue:6

    Endothelin-1 (ET-1) and plasminogen activator inhibitor-1 (PAI-1) play important roles in pulmonary hypertension (PH) in sickle cell disease (SCD). Our previous studies show higher levels of placenta growth factor (PlGF) in SCD correlate with increased plasma levels of ET-1, PAI-1, and other physiological markers of PH. PlGF-mediated ET-1 and PAI-1 expression occurs via activation of hypoxia-inducible factor-1α (HIF-1α). However, relatively little is understood regarding post-transcriptional regulation of PlGF-mediated expression of ET-1 and PAI-1. Herein, we show PlGF treatment of endothelial cells reduced levels of miR-301a and miR-454 from basal levels. In addition, both miRNAs targeted the 3'-UTRs of ET-1 and PAI-1 mRNAs. These results were corroborated in the mouse model of SCD [Berkeley sickle mice (BK-SS)] and in SCD subjects. Plasma levels of miR-454 in SCD subjects were significantly lower compared with unaffected controls, which correlated with higher plasma levels of both ET-1 and PAI-1. Moreover, lung tissues from BK-SS mice showed significantly reduced levels of pre-miR-301a and concomitantly higher levels of ET-1 and PAI-1. Furthermore, we show that miR-301a/miR-454 located in the spindle and kinetochore-associated protein-2 (SKA2) transcription unit was co-transcriptionally regulated by both HIF-1α and peroxisome proliferator-activated receptor-α (PPAR-α) as demonstrated by SKA2 promoter mutational analysis and ChIP. Finally we show that fenofibrate, a PPAR-α agonist, increased the expression of miR-301a/miR-454 and SKA2 in human microvascular endothelial cell line (HMEC) cells; the former were responsible for reduced expression of ET-1 and PAI-1. Our studies provide a potential therapeutic approach whereby fenofibrate-induced miR-301a/miR-454 expression can ameliorate PH and lung fibrosis by reduction in ET-1 and PAI-1 levels in SCD.

    Topics: Anemia, Sickle Cell; Animals; Cell Line; Chromosomal Proteins, Non-Histone; Endothelin-1; Fenofibrate; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; MicroRNAs; Placenta Growth Factor; Plasminogen Activator Inhibitor 1; PPAR alpha; Pregnancy Proteins; Promoter Regions, Genetic

2015
Correlation between congenital heart disease complicated with pulmonary artery hypertension and circulating endothelial cells as well as endothelin-1.
    International journal of clinical and experimental pathology, 2015, Volume: 8, Issue:9

    To investigate changes in the level of circulating endothelial cells (CECs) and endothelin-1 (ET-1) in peripheral venous blood of the patients with congenital heart disease (CHD) complicated with pulmonary artery hypertension (PAH), and research on their effects in the onset and progress of CHD complicated with PAH.. A case-control study including 30 cases of healthy controls, 15 cases of left-to-right shunt CHD without PAH, 26 cases of CHD complicated with mild PAH, and 17 cases of CHD complicated with moderate-severe PAH was performed. We used flow cytometry to measure the percentage of CECs accounting for nucleated cells in whole blood, and enzyme linked immunosorbent assay (ELISA) to measure the level of ET-1 in serum. The differences of above-mentioned biomarkers between different groups were compared.. (1) The level of CECs and ET-1in the group of moderate-severe PAH was significantly higher than those in the group of mild PAH and the group of CHD without PAH. Significantly difference was also observed between the level of CECs and ET-1 in the group of mild PAH and those in the group of CHD without PAH and the control group. Meanwhile, the level of CECs and ET-1 in the group of large shunt was significantly higher than those in the group few shunt and few-medium shunt. (2) Strong positive correlations were observed between pulmonary artery systolic pressure and percentage of CECs as well as ET-1 production. Mean pulmonary artery pressure also positively correlated with percentage of CECs as well as ET-1 production. (3) Arterial partial pressure of oxygen as well as arterial oxygen saturation negatively correlated with the level of CECs, whereas the volume of left-to-right shunt positively correlated with the level of ET-1. (4) The level of CECs and ET-1 were positively correlated as well in CHD patients.. CHD complicated with PAH is associated with increased CEC counts and ET-1 production. This study suggests that CECs and ET-1 could be used as clinical biomarkers to define medical strategies for control of PAH.

    Topics: Adolescent; Adult; Aged; Arterial Pressure; Biomarkers; Case-Control Studies; Cell Count; Child; Child, Preschool; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Linear Models; Male; Middle Aged; Oxygen; Partial Pressure; Pulmonary Artery; Pulmonary Circulation; Severity of Illness Index; Up-Regulation; Young Adult

2015
Toward Precision Medicine in Pulmonary Arterial Hypertension.
    American journal of respiratory and critical care medicine, 2015, Dec-01, Volume: 192, Issue:11

    Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Polymorphism, Single Nucleotide

2015
The synergistic therapeutic effect of hepatocyte growth factor and granulocyte colony-stimulating factor on pulmonary hypertension in rats.
    Heart and vessels, 2014, Volume: 29, Issue:4

    Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary arterial pressure and vascular resistance. Despite advances in therapy for PAH, its treatment and prognosis remain poor. We aimed to investigate whether the transplantation of bone marrow mesenchymal stem cells (MSCs) overexpressing hepatocyte growth factor (HGF), alone or in combination with granulocyte colony-stimulating factor (G-CSF), attenuates the development of experimental monocrotaline (MCT)-induced PAH. Three weeks after MCT administration, rats were divided into the following groups: (1) untreated (PAH); (2) HGF treated; (3) MSCs administered; (4) HGF-MSCs treated; and (5) HGF-MSCs plus G-CSF treated. After 3 weeks, hemodynamic changes, histomorphology, and angiogenesis were evaluated. To elucidate the molecular mechanisms of vascular remodeling and angiogenesis, serum levels of transforming growth factor (TGF)-β and endothelin-1 (ET-1) were measured, and the gene and protein expression levels of vascular cell adhesion molecule-1 (VCAM-1) and matrix metalloproteinase-9 (MMP-9) were determined. Compared with the PAH, MSC, and G-CSF groups, the HGF and HGF+G-CSF groups exhibited significantly reduced right ventricular hypertrophy and mean pulmonary arterial pressure (P < 0.05). Histologically, vessel muscularization or thickening and collagen deposition were also significantly decreased (P < 0.05). The number of vessels in the HGF+G-CSF group was higher than that in the other groups (P < 0.05). The TGF-β and ET-1 concentrations in the plasma of pulmonary hypertensive rats were markedly lower in the HGF and HGF+G-CSF groups (P < 0.05). Furthermore, HGF induced the expression of VCAM-1, and HGF treatment together with G-CSF synergistically stimulated MMP-9 expression. Transplanted HGF-MSCs combined with G-CSF potentially offer synergistic therapeutic benefit for the treatment of PAH.

    Topics: Animals; Arterial Pressure; Cells, Cultured; Disease Models, Animal; Endothelin-1; Genetic Therapy; Granulocyte Colony-Stimulating Factor; Hepatocyte Growth Factor; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Matrix Metalloproteinase 9; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Neovascularization, Physiologic; Pulmonary Artery; Rats, Sprague-Dawley; Recovery of Function; Time Factors; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1; Vascular Remodeling

2014
Improvement of plasma endothelin-1 and nitric oxide in patients with systemic sclerosis by bosentan therapy.
    Rheumatology international, 2014, Volume: 34, Issue:2

    The aim of this study was to evaluate the effects of bosentan on plasma endothelin-1 (ET-1) and nitric oxide (NO) as pulmonary hypertension (PH)-associated biochemical markers in patients with systemic sclerosis (SSc). Twenty-four SSc patients receiving bosentan for 24 weeks were registered in this prospective observational study. Ten patients were complicated with clinically suspected PH. Plasma levels of ET-1 and NO were assessed at baseline and after 24 weeks of treatment in SSc patients and in 15 healthy controls. Plasma levels of ET-1 and NO at baseline were significantly higher in SSc patients than in healthy controls (p < 0.000), and they were also significantly higher in SSc patients with PH than in those without PH (p < 0.01). Plasma ET-1 levels were significantly decreased after 24 weeks of bosentan therapy (p < 0.0001), and ET-1 levels of SSc patients with PH decreased to a level comparable to that in patients without PH. In the 10 SSc patients with PH, changes in plasma ET-1 levels during the 24 weeks of the study were significantly larger in the 5 patients whose functional class (FC) improved than in the 5 patients whose FC was unchanged (p < 0.05). Plasma NO levels were also slightly decreased in SSc patients after 24 weeks of bosentan therapy. Plasma ET-1 levels could reflect the presence and severity of PH in SSc patients. Additionally, changes in plasma ET-1 levels may indicate the response to bosentan therapy in SSc patients with PH.

    Topics: Aged; Antihypertensive Agents; Biomarkers; Bosentan; Endothelin-1; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Prospective Studies; Scleroderma, Systemic; Severity of Illness Index; Sulfonamides; Time Factors; Treatment Outcome

2014
Endothelial Krüppel-like factor 4 modulates pulmonary arterial hypertension.
    American journal of respiratory cell and molecular biology, 2014, Volume: 50, Issue:3

    Krüppel-like factor 4 (KLF4) is a transcription factor expressed in the vascular endothelium, where it promotes anti-inflammatory and anticoagulant states, and increases endothelial nitric oxide synthase expression. We examined the role of endothelial KLF4 in pulmonary arterial (PA) hypertension (PAH). Mice with endothelial KLF4 knockdown were exposed to hypoxia for 3 weeks, followed by measurement of right ventricular and PA pressures, pulmonary vascular muscularization, and right ventricular hypertrophy. The effect of KLF4 on target gene expression was assessed in lungs from these mice, verified in vitro by small interfering RNA (siRNA) knockdown of KLF4, and further studied at the promoter level with cotransfection experiments. KLF4 expression was measured in lung tissue from patients with PAH and normal control subjects. We found that, after hypoxia, right ventricular and PA pressures were significantly higher in KLF4 knockdown animals than controls. Knockdown animals also had more severe pulmonary vascular muscularization and right ventricular hypertrophy. KLF4 knockdown resulted in increased pulmonary expression of endothelin-1 and decreased expression of endothelial nitric oxide synthase, endothelin receptor subtype B, and prostacyclin synthase. Concordant findings were observed in vitro, both with siRNA knockdown of KLF4 and promoter activity assays. Finally, KLF4 expression was reduced in lungs from patients with PAH. In conclusion, endothelial KLF4 regulates the transcription of genes involved in key pathways implicated in PAH, and its loss exacerbates pulmonary hypertension in response to chronic hypoxia in mice. These results introduce a novel transcriptional modulator of PAH, with the potential of becoming a new therapeutic target.

    Topics: Animals; Arterial Pressure; Case-Control Studies; Cells, Cultured; Cytochrome P-450 Enzyme System; Disease Models, Animal; Endothelial Cells; Endothelin-1; Familial Primary Pulmonary Hypertension; Human Umbilical Vein Endothelial Cells; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Intramolecular Oxidoreductases; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Pulmonary Artery; Receptor, Endothelin B; RNA Interference; Time Factors; Transfection; Ventricular Function, Right; Ventricular Pressure

2014
Combination of sildenafil and bosentan for pulmonary hypertension in a human ex vivo model.
    Cardiovascular drugs and therapy, 2014, Volume: 28, Issue:1

    Both sildenafil and bosentan have been used clinically to treat pulmonary arterial hypertension. As these substances target different pathways to modulate vasoconstriction, we investigated the combined effects of both drug classes in isolated human pulmonary vessels.. Segments of pulmonary arteries (PA) and veins (PV) were harvested from 51 patients undergoing lobectomy. Contractile force was determined isometrically in an organ bath. Vessels were constricted with norepinephrine (NE) to determine effects of sildenafil. They were constricted with ET-1 to assess effects of bosentan, and with NE and ET-1 to evaluate the combination of both substances.. Sildenafil (1E-5 M) significantly reduced maximum constriction by NE of both PA (13.0 ± 11.1 vs. 34.9 ± 7.6% relative to KCl induced constriction; n = 6; p < 0.001) and PV (81.2 ± 34.2 vs 121.6 ± 20.8%; n = 6; p < 0.01) but did not affect basal tones. Bosentan (1E-5 M) significantly reduced maximum constriction of PV (56.6 ± 21.5 vs. 172.1 ± 30.0%; n = 6; p < 0.01) by ET-1 and led to a small but insignificant decrease of basal tone (p = 0.07). Bosentan almost completely abolished constriction of PA (1.0 ± 0.9 vs. 74.7 ± 25.7 %; n = 6; p < 0.001) by ET-1, but did not affect basal tone. Bosentan (1E-7 M) significantly attenuated combined ET-1/NE dose-response curves in PA (93.1 ± 47.4 vs. 125.3 ± 41.0%; n = 12; p < 0.001) whereas the effect of sildenafil (1E-5 M) was less pronounced (103.6 ± 20.2%; p < 0.05). Simultaneous administration of both substances showed a significantly greater reduction of maximum constriction in PA compared to individual administration (64.6 ± 26.3 %; p < 0.001).. Sildenafil only at its highest concentration was effective in suppressing NE induced pulmonary vessel contraction. Bosentan was able to completely suppress ET-1 induced contraction of PA and strongly attenuated contraction of PV. The present data suggest a benefit of sildenafil/bosentan combination therapy as they affect different pathways and may allow lower dosages.

    Topics: Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Norepinephrine; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasoconstriction

2014
Evidence for the involvement of type I interferon in pulmonary arterial hypertension.
    Circulation research, 2014, Feb-14, Volume: 114, Issue:4

    Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognized at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted.. To explore the role of type I IFN in PAH.. Cells were cultured using standard approaches. Cytokines were measured by ELISA. Gene and protein expression were measured using reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knockout (IFNAR1(-/-)) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II, and III IFN levels were elevated in serum of patients with systemic sclerosis associated PAH. Serum interferon γ inducible protein 10 (IP10; CXCL10) and endothelin 1 were raised and strongly correlated together. IP10 correlated positively with pulmonary hemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1(-/-) mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum endothelin 1 levels.. These data indicate that type I IFN, via an action of IFNAR1, mediates PAH.

    Topics: Animals; Cells, Cultured; Chemokine CXCL10; Disease Models, Animal; Endothelial Cells; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Interferon-alpha; Interferon-beta; Interferon-gamma; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Culture Techniques; Receptor, Interferon alpha-beta; Scleroderma, Systemic; Signal Transduction

2014
Inhibition of vascular endothelial growth factor receptor under hypoxia causes severe, human-like pulmonary arterial hypertension in mice: potential roles of interleukin-6 and endothelin.
    Life sciences, 2014, Nov-24, Volume: 118, Issue:2

    Severe pulmonary arterial hypertension (PAH) is an incurable disease whose exact mechanisms remain unknown. However, growing evidence highlights the role of inflammation and endothelin (ET) signaling. The lack of reliable models makes it difficult to investigate the pathophysiology of this disease. Our aim was therefore to develop a mouse model of severe PAH closely mimicking the human condition to explore the role of interleukin-6 (IL-6), and ET signaling in advanced PAH progression.. Young male SV129 mice received vascular endothelial growth factor receptor inhibitor (SU5416) three times a week and were exposed to hypoxia (10% O2) for three weeks. Molecular analysis and histological assessment were examined using real-time PCR, Western blot and immunostaining, respectively.. The developed murine model presented important characteristics of severe PAH in human: concentric neointimal wall thickening, plexogenic lesions, recruitment of macrophages, and distal arteriolar wall muscularization. We detected an increase of IL-6 production and a stronger macrophage recruitment in adventitia of remodeled arterioles developing plexogenic lesions. Moreover, ET-1 and ET receptor A were up-regulated in lung lysates and media of remodeled arterioles. Recombinant IL-6 stimulated the proliferation and regulated endothelial cells in increasing ET-1 and decreasing ET receptor B.. These data describe a murine model, which displays the most important features of human severe PAH. We assume that inflammation, particularly IL-6 regulating ET signaling, plays a crucial role in forming plexogenic lesions. This model is thus reliable and might be used for a better understanding of severe PAH progression and treatment.

    Topics: Animals; Biomarkers; Body Weight; Cell Hypoxia; Cell Line; Disease Models, Animal; Endothelial Cells; Endothelin-1; Heart Rate; Humans; Hypertension, Pulmonary; Indoles; Inflammation; Interleukin-6; Lung; Male; Mice; Pulmonary Artery; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Up-Regulation

2014
Ethyl pyruvate ameliorates monocrotaline-induced pulmonary arterial hypertension in rats.
    Journal of cardiovascular pharmacology, 2014, Volume: 64, Issue:1

    Ethyl pyruvate (EP) is an anti-inflammatory and anti-oxidant agent associated with many diseases. In this study, we evaluated whether EP could attenuate monocrotaline-induced pulmonary arterial hypertension (PAH).. A PAH model was established by subcutaneously injecting a single dose of monocrotaline (60 mg/kg). And then a daily intraperitoneal injection of EP (50 mg/kg) was administered on day 1 to day 28 (preventive EP treatment) or day 15 to day 28 (therapeutic EP treatment). Hemodynamic changes were measured by catheterization, and the right ventricle hypertrophy index, the medial wall thickness, and the medial wall areas were also calculated. Enzyme-linked immunosorbent assay and immunohistochemical analysis were used to determine the serum levels and expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and endothelin-1 (ET-1) in the lung tissue.. Both preventive and therapeutic EP treatment significantly ameliorated hemodynamic changes and vascular remodeling indicators (all P < 0.05). The serum levels and expression of TNF-α, IL-6, and ET-1 in the lung tissue were also significantly decreased (all P < 0.05).. EP ameliorates monocrotaline-induced PAH and reverses pulmonary vascular remolding in rats by inhibiting the release of TNF-α and IL-6 and reducing the expression of ET-1.

    Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Drug Administration Schedule; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Hypertension, Pulmonary; Injections, Intraperitoneal; Interleukin-6; Male; Monocrotaline; Pyruvates; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

2014
Palosuran treatment effective as bosentan in the treatment model of pulmonary arterial hypertension.
    Inflammation, 2014, Volume: 37, Issue:4

    Pulmonary arterial hypertension (PAH) is a progressive and fatal disorder that any valuable advance in the management of diseases has crucial importance. The present study aimed to compare the Endothelin1 (ET1) inhibitor bosentan which is regarded as standard therapy with different dose regimens of palosuran which is urotensin-II (UII) inhibitor and explore the discrepancy for mean pulmonary arterial pressure (mPAP), UII, ET1 levels, and pulmonary vascular pathology. Seventy rats were randomly divided into seven groups of ten animals each: group 1 (control group) received the vehicle subcutaneously, instead of monocrotaline (MCT) and vehicle; group 2 (MCT group) received subcutaneous MCT and vehicle; and group 3 (MCT + palosuran 30 mg) received subcutaneous MCT and palosuran. Other groups consist of group 4 (MCT + palosuran 100 mg), group 5 (MCT + bosentan 30 mg), group 6 (MCT + bosentan 100 mg), and group 7 (combination therapy). Serum ET1, UII, mPAP levels, and pulmonary arteriolar pathology of different diameter vessels of all groups have been measured and recorded. The ET1 and UII levels of untreated rats (group 2) were significantly higher than the other groups (p < 0.05). Moreover, mPAP levels of group 2 were significantly higher than the other groups (p = 0.001). Finally, 50-125-μm diameter of arteriole wall thickness was found to be significantly thicker in monocrotaline group compared to groups 4 and 6 (p < 0.001). Statistical differences of wall thickness/diameter ratios of arteries and arterioles larger than 125 was found to be significant between group 5, group 6, and the control group (p < 0.001). UII inhibitor is at least as effective as standard therapy bosentan. Findings of this study consolidate that palosuran could be a new future promising therapeutic option in PAH.

    Topics: Animals; Arterial Pressure; Bosentan; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Pulmonary Artery; Quinolines; Rats; Rats, Wistar; Sulfonamides; Urea; Urotensins

2014
Pulmonary hypertension in patients with advanced heart failure is associated with increased levels of interleukin-6.
    Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals, 2014, Volume: 19, Issue:5

    Inflammatory, endothelial and neurohormonal biomarkers are involved in heart failure (HF) and pulmonary hypertension (PH) pathogenesis.. To study these biomarkers in PH due to advanced HF.. Thirty adults with HF were included. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP), endothelin-1 and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were measured in peripheral vein and pulmonary artery during right heart catheterisation.. IL-6, TNF-α, hsCRP and NT-proBNP correlated with pulmonary pressures independent of ventricular function, HF etiology and vascular bed. IL-6 was independent predictor of systolic pulmonary artery pressure (sPAP).. Inflammatory biomarkers correlate to PH severity. IL-6 predicts sPAP in advanced HF.

    Topics: Aged; Biomarkers; C-Reactive Protein; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Interleukin-6; Linear Models; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Artery; Tumor Necrosis Factor-alpha

2014
Endothelial nitric oxide synthase-enhancing G-protein coupled receptor antagonist inhibits pulmonary artery hypertension by endothelin-1-dependent and endothelin-1-independent pathways in a monocrotaline model.
    The Kaohsiung journal of medical sciences, 2014, Volume: 30, Issue:6

    This study investigates whether endothelin-1 (ET-1) mediates monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) and right ventricular hypertrophy (RVH), and if so, whether the G-protein coupled receptor antagonist KMUP-1 (7-{2-[4-(2-chlorobenzene)piperazinyl]ethyl}-1,3-dimethylxanthine) inhibits ET-1-mediated PA constriction and the aforementioned pathological changes. In a chronic rat model, intraperitoneal MCT (60 mg/kg) induced PAH and increased PA medial wall thickening and RV/left ventricle + septum weight ratio on Day 21 after MCT injection. Treatment with sublingual KMUP-1 (2.5 mg/kg/day) for 21 days prevented these changes and restored vascular endothelial nitric oxide synthase (eNOS) immunohistochemical staining of lung tissues. Western blotting analysis demonstrated that KMUP-1 enhanced eNOS, soluble guanylate cyclase, and protein kinase G levels, and reduced ET-1 expression and inactivated Rho kinase II (ROCKII) in MCT-treated lung tissue over long-term administration. In MCT-treated rats, KMUP-1 decreased plasma ET-1 on Day 21. KMUP-1 (3.6 mg/kg) maximally appeared at 0.25 hours in the plasma and declined to basal levels within 24 hours after sublingual administration. In isolated PA of MCT-treated rats, compared with control and pretreatment with l-NG-nitroarginine methyl ester (100 μM), KMUP-1 (0.1-100 μM) inhibited ET-1 (0.01 μM)-induced vasoconstriction. Endothelium-denuded PA sustained higher contractility in the presence of KMUP-1. In a 24-hour culture of smooth muscle cells (i.e., PA smooth muscle cells or PASMCs), KMUP-1 (0.1-10 μM) inhibited RhoA- and ET-1-induced RhoA activation. KMUP-1 prevented MCT-induced PAH, PA wall thickening, and RVH by enhancing eNOS and suppressing ET-1/ROCKII expression. In vitro, KMUP-1 inhibited ET-1-induced PA constriction and ET-1-dependent/independent RhoA activation of PASMCs. In summary, KMUP-1 attenuates ET-1-induced/ET-1-mediated PA constriction, and could thus aid in the treatment of PAH caused by MCT.

    Topics: Animals; Blood Pressure; Body Weight; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Endothelin-1; Guanylate Cyclase; Heart Rate; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; In Vitro Techniques; Male; Monocrotaline; Nitric Oxide Synthase Type III; Piperazines; Piperidines; Pulmonary Artery; Purines; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Sildenafil Citrate; Soluble Guanylyl Cyclase; Sulfonamides; Vasoconstriction; Xanthines

2014
Differentially expressed plasma microRNAs and the potential regulatory function of Let-7b in chronic thromboembolic pulmonary hypertension.
    PloS one, 2014, Volume: 9, Issue:6

    Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease characterized by misguided thrombolysis and remodeling of pulmonary arteries. MicroRNAs are small non-coding RNAs involved in multiple cell processes and functions. During CTEPH, circulating microRNA profile endued with characteristics of diseased cells could be identified as a biomarker, and might help in recognition of pathogenesis. Thus, in this study, we compared the differentially expressed microRNAs in plasma of CTEPH patients and healthy controls and investigated their potential functions. Microarray was used to identify microRNA expression profile and qRT-PCR for validation. The targets of differentially expressed microRNAs were identified in silico, and the Gene Ontology database and Kyoto Encyclopedia of Genes and Genomes pathway database were used for functional investigation of target gene profile. Targets of let-7b were validated by fluorescence reporter assay. Protein expression of target genes was determined by ELISA or western blotting. Cell migration was evaluated by wound healing assay. The results showed that 1) thirty five microRNAs were differentially expressed in CTEPH patients, among which, a signature of 17 microRNAs, which was shown to be related to the disease pathogenesis by in silico analysis, gave diagnostic efficacy of both sensitivity and specificity >0.9. 2) Let-7b, one of the down-regulated anti-oncogenic microRNAs in the signature, was validated to decrease to about 0.25 fold in CTEPH patients. 3) ET-1 and TGFBR1 were direct targets of let-7b. Altering let-7b level influenced ET-1 and TGFBR1 expression in pulmonary arterial endothelial cells (PAECs) as well as the migration of PAECs and pulmonary arterial smooth muscle cells (PASMCs). These results suggested that CTEPH patients had aberrant microRNA signature which might provide some clue for pathogenesis study and biomarker screening. Reduced let-7b might be involved in the pathogenesis of CTEPH by affecting ET-1 expression and the function of PAECs and PASMCs.

    Topics: Adult; Case-Control Studies; Cell Movement; Cells, Cultured; Chronic Disease; Endothelial Cells; Endothelin-1; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Male; MicroRNAs; Middle Aged; Myocytes, Smooth Muscle; Protein Binding; Protein Serine-Threonine Kinases; Pulmonary Artery; Pulmonary Embolism; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Signal Transduction; Transcriptome

2014
HMGB1 promotes the development of pulmonary arterial hypertension in rats.
    PloS one, 2014, Volume: 9, Issue:7

    Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. However, the molecular and cellular mechanisms driving inflammation have not been fully elucidated.. To elucidate the roles of high mobility group box 1 protein (HMGB1), a ubiquitous DNA-binding protein with extracellular pro-inflammatory activity, in a rat model of PAH.. Male Sprague-Dawley rats were administered monocrotaline (MCT). Concentrations of HMGB1 in bronchoalveolar lavage fluid (BALF) and serum, and localization of HMGB1 in the lung were examined over time. The protective effects of anti-HMGB1 neutralizing antibody against MCT-induced PAH were tested.. HMGB1 levels in BALF were elevated 1 week after MCT injection, and this elevation preceded increases of other pro-inflammatory cytokines, such as TNF-α, and the development of PAH. In contrast, serum HMGB1 levels were elevated 4 weeks after MCT injection, at which time the rats began to die. Immunohistochemical analyses indicated that HMGB1 was translocated to the extranuclear space in periarterial infiltrating cells, alveolar macrophages, and bronchial epithelial cells of MCT-injected rats. Anti-HMGB1 neutralizing antibody protected rats against MCT-induced lung inflammation, thickening of the pulmonary artery wall, and elevation of right ventricular systolic pressure, and significantly improved the survival of the MCT-induced PAH rats.. Our results identify extracellular HMGB1 as a promoting factor for MCT-induced PAH. The blockade of HMGB1 activity improved survival of MCT-induced PAH rats, and thus might be a promising therapy for the treatment of PAH.

    Topics: Animals; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Disease Models, Animal; DNA-Binding Proteins; Endothelin-1; Hemodynamics; HMGB1 Protein; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Inflammation; Interleukin-1beta; Male; Monocrotaline; Pulmonary Artery; Random Allocation; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Vascular Resistance; Ventricular Dysfunction, Right

2014
Glycyrrhizin, inhibitor of high mobility group box-1, attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling in rats.
    Respiratory research, 2014, Nov-25, Volume: 15

    High mobility group box-1 (HMGB1), a proinflammatory cytokine, plays a pivotal role in tissue remodeling and angiogenesis, both of which are crucial for the pathogenesis of pulmonary arterial hypertension. In this study, we explored the relationship between HMGB1 and pulmonary hypertension and whether glycyrrhizin, an inhibitor of HMGB1, attenuates disease progression in an animal model of pulmonary hypertension induced by monocrotaline sodium (MCT).. After inducing pulmonary hypertension through a single subcutaneous injection of MCT (60 mg/kg) to Sprague-Dawley rats, we administered daily intraperitoneal injections of either glycyrrhizin (GLY, 50 mg/kg), an inhibitor of HMGB1, or saline (control) for either 4 or 6 weeks.. Expression levels of HMGB1 in serum increased from the second week after MCT injection and remained elevated throughout the experiment periods. Lung tissue levels of HMGB1 assessed by immunohistochemical staining at 4 weeks after MCT injection also increased. Chronic inhibition of HMGB1 by GLY treatment reduced the MCT-induced increase in right ventricular (RV) systolic pressure, RV hypertrophy (ratio of RV to [left ventricle + septum]), and pulmonary inflammation. MCT-induced muscularization of the pulmonary artery was also attenuated in the GLY-treated group. As assessed 6 weeks after MCT injection, the GLY-treated group exhibited increased survival (90% [18 of 20]) when compared with the control group (60% [12 of 20]; p =0.0027).. Glycyrrhizin, an inhibitor of HMGB1, attenuates pulmonary hypertension progression and pulmonary vascular remodeling in the MCT-induced pulmonary hypertension rat model. Further studies are needed to confirm the potential of HMGB1 as a novel therapeutic target for pulmonary hypertension.

    Topics: Animals; Antihypertensive Agents; Arterial Pressure; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Glycyrrhizic Acid; HMGB1 Protein; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Muscle, Smooth, Vascular; Pneumonia; Pulmonary Artery; Rats, Sprague-Dawley; Time Factors; Vascular Remodeling; Ventricular Dysfunction, Right; Ventricular Function, Right

2014
Relationship between endothelin-1 levels and pulmonary arterial hypertension in HIV-infected patients.
    AIDS (London, England), 2014, Nov-28, Volume: 28, Issue:18

    Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with average survival of less than 3 years if left untreated. It is most common in patients infected with HIV. Although the pathogenesis in this population is not fully understood, it is thought that HIV infection, through the immune response and release of different inflammatory mediators such as endothelin-1, may contribute directly to endothelial damage. Our objective was to quantify endothelin-1 levels in HIV-infected patients and determine whether or not there is an association between this marker and PAH.. A case-control study in patients attending an infectious diseases clinic.. The sample was composed of 79 patients divided into three groups: 23 HIV patients with PAH (HIV+/PAH+), 45 HIV patients without PAH (HIV+/PAH-) and a control group of 11 healthy individuals. The ratio between the HIV+/PAH- and HIV+/PAH+ groups was 2 : 1. Patients were matched by age, sex, risk group and viral load; the control group by age and sex. All patients had blood taken for endothelin-1 plasma quantification.. We found lower endothelin-1 levels in the controls than in the HIV+/PAH- group [0.71 pg/ml (interquartile range, IQR 0.54-0.94) vs. 1.13 pg/ml (IQR 0.87-1.38); P = 0.005] and the HIV+/PAH+ cohort [1.16 pg/ml (IQR 0.86-2.37); P = 0.003]. Patients with severe PAH had higher endothelin-1 levels [2.94 pg/ml (IQR 1.81-6.33)] than patients with mild and moderate PAH.. Plasma endothelin-1 levels are higher in HIV patients with PAH than in the HIV-noninfected population and levels increase with the severity of the PAH.

    Topics: Adult; Biomarkers; Case-Control Studies; Endothelin-1; Female; HIV Infections; Humans; Hypertension, Pulmonary; Male; Middle Aged

2014
Epigenetics of hypoxic pulmonary arterial hypertension following intrauterine growth retardation rat: epigenetics in PAH following IUGR.
    Respiratory research, 2013, Feb-14, Volume: 14

    Accumulating evidence reveals that intrauterine growth retardation (IUGR) can cause varying degrees of pulmonary arterial hypertension (PAH) later in life. Moreover, epigenetics plays an important role in the fetal origin of adult disease. The goal of this study was to investigate the role of epigenetics in the development of PAH following IUGR.. The IUGR rats were established by maternal undernutrition during pregnancy. Pulmonary vascular endothelial cells (PVEC) were isolated from the rat lungs by magnetic-activated cell sorting (MACS). We investigated epigenetic regulation of the endothelin-1 (ET-1) gene in PVEC of 1-day and 6-week IUGR rats, and response of IUGR rats to hypoxia.. The maternal nutrient restriction increased the histone acetylation and hypoxia inducible factor-1α (HIF-1α) binding levels in the ET-1 gene promoter of PVEC in IUGR newborn rats, and continued up to 6 weeks after birth. These epigenetic changes could result in an IUGR rat being highly sensitive to hypoxia later in life, causing more significant PAH or pulmonary vascular remodeling.. These findings suggest that epigenetics is closely associated with the development of hypoxic PAH following IUGR, further providing a new insight for improved prevention and treatment of IUGR-related PAH.

    Topics: Acetylation; Actins; Age Factors; Animals; Animals, Newborn; Binding Sites; Blood Pressure; Cell Separation; Disease Models, Animal; Endothelial Cells; Endothelin-1; Epigenesis, Genetic; Familial Primary Pulmonary Hypertension; Female; Fetal Growth Retardation; Flow Cytometry; Histones; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lung; Pregnancy; Promoter Regions, Genetic; Pulmonary Artery; Rats; Rats, Sprague-Dawley

2013
[Association between pulmonary vascular remodeling and expression of hypoxia-inducible factor-1α, endothelin-1 and inducible nitric oxide synthase in pulmonary vessels in neonatal rats with hypoxic pulmonary hypertension].
    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 2013, Volume: 15, Issue:2

    To investigate the association between pulmonary vascular remodeling and expression of hypoxia-inducible factor-1α (HIF-1α), endothelin-1 (ET-1) and inducible nitric oxide synthase (iNOS) in pulmonary vessels in neonatal rats with hypoxic pulmonary hypertension (HPH).. A neonatal rat model of HPH was established as an HPH group, and normal neonatal rats were enrolled as a control group. The mean pulmonary arterial pressure (mPAP) was measured. The percentage of medial thickness to outer diameter of the small pulmonary arteries (MT%) and the percentage of medial cross-section area to total cross-section area of the pulmonary small arteries (MA%) were measured as the indicators for pulmonary vascular remodeling. The immunohistochemical reaction intensities for HIF-1α, ET-1 and iNOS and their mRNA expression in lung tissues of neonatal rats were measured. Correlation analysis was performed to determine the relationship between pulmonary vascular remodeling and mRNA expression of HIF-1α, ET-1 and iNOS.. The mPAP of the HPH group kept increasing on days 3, 5, 7, 10, 14, and 21 of hypoxia, with a significant difference compared with the control group (P<0.05). The HPH group had significantly higher MT% and MA% than the control group from day 7 of hypoxia (P<0.05). HIF-1α protein expression increased significantly on days 3, 5, 7 and 10 days of hypoxia, and HIF-1α mRNA expression increased significantly on days 3, 5 and 7 days of hypoxia in the HPH group compared with the control group (P<0.05). ET-1 protein expression increased significantly on days 3, 5 and 7 days of hypoxia and ET-1 mRNA expression increased significantly on day 3 of hypoxia in the HPH group compared with the control group (P<0.05). Both iNOS protein and mRNA expression were significantly higher on days 3, 5 and 7 days of hypoxia than the control group (P<0.05). Both MT% and MA% were positively correlated with HIF-1α mRNA expression (r=0.835 and 0.850 respectively; P<0.05).. Pulmonary vascular remodeling is developed on day 7 of hypoxia in neonatal rats. HIF-1α, ET-1 and iNOS are all involved in the occurrence and development of HPH in neonatal rats.

    Topics: Animals; Animals, Newborn; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Nitric Oxide Synthase Type II; Pulmonary Artery; Rats; Rats, Wistar

2013
NFAT is required for spontaneous pulmonary hypertension in superoxide dismutase 1 knockout mice.
    American journal of physiology. Lung cellular and molecular physiology, 2013, May-01, Volume: 304, Issue:9

    Elevated reactive oxygen species are implicated in pulmonary hypertension (PH). Superoxide dismutase (SOD) limits superoxide bioavailability, and decreased SOD activity is associated with PH. A decrease in SOD activity is expected to increase superoxide and reduce hydrogen peroxide levels. Such an imbalance of superoxide/hydrogen peroxide has been implicated as a mediator of nuclear factor of activated T cells (NFAT) activation in epidermal cells. We have shown that NFATc3 is required for chronic hypoxia-induced PH. However, it is unknown whether NFATc3 is activated in the pulmonary circulation in a mouse model of decreased SOD1 activity and whether this leads to PH. Therefore, we hypothesized that an elevated pulmonary arterial superoxide/hydrogen peroxide ratio activates NFATc3, leading to PH. We found that SOD1 knockout (KO) mice have elevated pulmonary arterial wall superoxide and decreased hydrogen peroxide levels compared with wild-type (WT) littermates. Right ventricular systolic pressure (RVSP) was elevated in SOD1 KO and was associated with pulmonary arterial remodeling. Vasoreactivity to endothelin-1 was also greater in SOD1 KO vs. WT mice. NFAT activity and NFATc3 nuclear localization were increased in pulmonary arteries from SOD1 KO vs. WT mice. Administration of A-285222 (selective NFAT inhibitor) decreased RVSP, arterial wall thickness, vasoreactivity, and NFAT activity in SOD1 KO mice to WT levels. The SOD mimetic, tempol, also reduced NFAT activity, NFATc3 nuclear localization, and RVSP to WT levels. These findings suggest that an elevated superoxide/hydrogen peroxide ratio activates NFAT in pulmonary arteries, which induces vascular remodeling and increases vascular reactivity leading to PH.

    Topics: Animals; Cyclic N-Oxides; Endothelin-1; Female; Hydrogen Peroxide; Hypertension, Pulmonary; Hypoxia; Male; Mice; Mice, Knockout; NFATC Transcription Factors; Pulmonary Artery; Pyrazoles; Spin Labels; Superoxide Dismutase; Superoxide Dismutase-1; Superoxides

2013
Transfection of human hepatocyte growth factor gene inhibits advancing pulmonary arterial hypertension induced by shunt flow in a rabbit model.
    Transplantation proceedings, 2013, Volume: 45, Issue:2

    We investigated gene transfer with human hepatocyte growth factor (HGF) to suppress pulmonary arterial hypertension (PAH) produced by an arteriovenous shunt in a rabbit model. The rabbit model of advanced PAH was used to show that HGF targets pulmonary arteriolar endothelial cells and inhibits disease progression. In the PAH rabbit model transfected with the HGF gene, hemodynamic abnormalities and right ventricular hypertrophy were prevented, as confirmed by invasive measurements and electrocardiographic examinations. In addition to augmented expression of HGF, an increased number of pulmonary arterioles were detected by immunohistochemical analysis. Western Blot and real-time reverse transcriptase-polymerase chain reaction indicated increased protein and mRNA levels of HGF and endothelial nitricoxide synthase (eNOS) in lungs after HGF transfection. Notably, exogenous HGF reduced lung expression of endothelin-1 (ET-1), which was critically involved in PAH-related pathologic changes. Our results suggested that HGF transfection suppresses PAH induced by shunt flow through enhanced expression of HGF with subsequent regulation of the concentrations of eNOS and ET-1 secreted by endothelial cells thereby promoting angiogenesis in injured lung tissue.

    Topics: Animals; Arterioles; Arteriovenous Shunt, Surgical; Blotting, Western; Carotid Artery, Common; Disease Models, Animal; Disease Progression; Electrocardiography; Endothelial Cells; Endothelin-1; Familial Primary Pulmonary Hypertension; Genetic Therapy; Hemodynamics; Hepatocyte Growth Factor; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Immunohistochemistry; Jugular Veins; Lung; Male; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Rabbits; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Transfection

2013
Effects of cyclic intermittent hypoxia on ET-1 responsiveness and endothelial dysfunction of pulmonary arteries in rats.
    PloS one, 2013, Volume: 8, Issue:3

    Obstructive sleep apnoea (OSA) is a risk factor for cardiovascular disorders and in some cases is complication of pulmonary hypertension. We simulated OSA by exposing rats to cyclic intermittent hypoxia (CIH) to investigate its effect on pulmonary vascular endothelial dysfunction. Sprague-Dawley Rats were exposed to CIH (FiO2 9% for 1 min, repeated every 2 min for 8 h/day, 7 days/wk for 3 wk), and the pulmonary arteries of normoxia and CIH treated rats were analyzed for expression of endothelin-1 (ET-1) and ET receptors by histological, immunohistochemical, RT-PCR and Western Blot analyses, as well as for contractility in response to ET-1. In the pulmonary arteries, ET-1 expression was increased, and ET-1 more potently elicited constriction of the pulmonary artery in CIH rats than in normoxic rats. Exposure to CIH induced marked endothelial cell damage associated with a functional decrease of endothelium-dependent vasodilatation in the pulmonary artery. Compared with normoxic rats, ETA receptor expression was increased in smooth muscle cells of the CIH rats, while the expression of ETB receptors was decreased in endothelial cells. These results demonstrated endothelium-dependent vasodilation was impaired and the vasoconstrictor responsiveness increased by CIH. The increased responsiveness to ET-1 induced by intermittent hypoxia in pulmonary arteries of rats was due to increased expression of ETA receptors predominantly, meanwhile, decreased expression of ETB receptors in the endothelium may also participate in it.

    Topics: Animals; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Hypertension, Pulmonary; Hypoxia; Male; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Sleep Apnea, Obstructive; Vasoconstriction; Vasodilation

2013
Ghrelin and its relation with N-terminal brain natriuretic peptide, endothelin-1 and nitric oxide in patients with idiopathic pulmonary hypertension.
    Cardiology, 2013, Volume: 124, Issue:4

    To investigate ghrelin levels in patients with idiopathic pulmonary arterial hypertension (IPAH) and the association of ghrelin with N-terminal brain natriuretic peptide (N-BNP), endothelin-1 (ET-1) and nitric oxide (NO).. Plasma ghrelin, N-BNP, ET-1 and NO were measured, and echocardiography was performed in 20 IPAH patients and in 20 control subjects matched for age, sex and body mass index.. Plasma ghrelin and NT-proBNP levels were significantly higher in IPAH patients compared with values in control subjects (p < 0.05). In IPAH patients, ghrelin levels correlated positively with N-BNP (r = 0.616, p = 0.004), NO (r = 0.464, p = 0.039), right ventricle diameter (RVD; r = 0.485, p = 0.030) and pulmonary arterial systolic pressure (PASP; r = 0.591, p = 0.006). N-BNP levels correlated positively with RVD (r = 0.551, p = 0.012) and ET-1 (r = 0.451, p = 0.046).. Plasma ghrelin levels were elevated in IPAH. Increased ghrelin levels correlated positively with N-BNP, PASP, RVD and NO, and N-BNP levels correlated positively with RVD and ET-1. Pulmonary vascular pathology is a complex imbalance of opposing forces. Ghrelin may not only provide a novel prognostic biomarker for IPAH but also be a potential new therapeutic strategy.

    Topics: Adult; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Familial Primary Pulmonary Hypertension; Female; Ghrelin; Humans; Hypertension, Pulmonary; Male; Natriuretic Peptide, Brain; Nitric Oxide; Peptide Fragments; Prognosis

2013
Effects of ambrisentan in a patient affected by combined pulmonary fibrosis and emphysema and by severe pulmonary hypertension: clinical, functional, and biomolecular findings.
    Clinical drug investigation, 2013, Volume: 33, Issue:6

    Combined pulmonary fibrosis and emphysema (CPFE) is a computed tomography (CT)-defined syndrome of combined pulmonary fibrosis and emphysema, characterized by subnormal spirometry, impairment of gas exchange, and high prevalence of pulmonary hypertension. Although endothelin-1 (ET-1) plays an important role in the development of lung fibrosis as well as in pulmonary hypertension, no ET-1-targeted therapy is currently recommended. Here we report a case of CPFE successfully treated with ambrisentan, an endothelin-A receptor antagonist, and also discuss the biologic mechanisms underlying the observed therapeutic effects. A 79-year-old man with chronic obstructive pulmonary disease (COPD) was referred to our respiratory unit as an outpatient for dyspnea. Clinical, radiologic, and laboratory findings suggested a diagnosis of chronic hypoxemic, type 1 respiratory failure, due to combined pulmonary fibrosis and emphysema, complicated by severe, precapillary pulmonary hypertension. Pharmacologic treatment with ambrisentan induced an initial improvement in clinical symptoms that proved to be very relevant 9 months later. In order to investigate the biologic mechanisms underlying the clinical effects of ambrisentan, we performed an "in vitro" study on primary cultures of fibrotic human lung fibroblasts, as well as on human umbilical vein endothelial cells, incubated for 24 and 48 h with ET-1, in the absence or presence of an overnight treatment with ambrisentan. ET-1 significantly increased cell proliferation and mitogen-activated protein kinase activation (P < 0.01). These effects were significantly (P < 0.01) inhibited by ambrisentan in both cell cultures. In conclusion, we hypothesize that the clinical benefits induced by ambrisentan in this patient with CPFE can be attributed to its vasodilator and anti-proliferative actions, exerted on pulmonary the vascular bed and lung fibroblasts.

    Topics: Aged; Emphysema; Endothelin A Receptor Antagonists; Endothelin-1; Human Umbilical Vein Endothelial Cells; Humans; Hypertension, Pulmonary; Male; Phenylpropionates; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Pyridazines; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome

2013
Oestrogen and the sexual dimorphism of pulmonary arterial hypertension: a translational challenge.
    The European respiratory journal, 2013, Volume: 41, Issue:5

    Topics: Animals; Endothelin-1; Epoprostenol; Estradiol; Female; Hypertension, Pulmonary; Nitric Oxide

2013
Erythrocytosis and pulmonary hypertension in a mouse model of human HIF2A gain of function mutation.
    The Journal of biological chemistry, 2013, Jun-14, Volume: 288, Issue:24

    The central pathway for oxygen-dependent control of red cell mass is the prolyl hydroxylase domain protein (PHD):hypoxia inducible factor (HIF) pathway. PHD site specifically prolyl hydroxylates the transcription factor HIF-α, thereby targeting the latter for degradation. Under hypoxia, this modification is attenuated, allowing stabilized HIF-α to activate target genes, including that for erythropoietin (EPO). Studies employing genetically modified mice point to Hif-2α, one of two main Hif-α isoforms, as being the critical regulator of Epo in the adult mouse. More recently, erythrocytosis patients with heterozygous point mutations in the HIF2A gene have been identified; whether these mutations were polymorphisms unrelated to the phenotype could not be ruled out. In the present report, we characterize a mouse line bearing a G536W missense mutation in the Hif2a gene that corresponds to the first such human mutation identified (G537W). We obtained mice bearing both heterozygous and homozygous mutations at this locus. We find that these mice display, in a mutation dose-dependent manner, erythrocytosis and pulmonary hypertension with a high degree of penetrance. These findings firmly establish missense mutations in HIF-2α as a cause of erythrocytosis, highlight the importance of this HIF-α isoform in erythropoiesis, and point to physiologic consequences of HIF-2α dysregulation.

    Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Blood Gas Analysis; Cells, Cultured; Disease Models, Animal; Endothelin-1; Erythropoiesis; Erythropoietin; Gene Expression; Gene Knock-In Techniques; Genetic Association Studies; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Kidney; Lung; Mice; Mice, Inbred C57BL; Mutagenesis; Mutation, Missense; Polycythemia; Proto-Oncogene Proteins c-sis; Respiratory Rate; RNA, Messenger; Up-Regulation; Vascular Endothelial Growth Factor A

2013
Complexities of oestradiol pharmacology in pulmonary arterial hypertension.
    The European respiratory journal, 2013, Volume: 41, Issue:6

    Topics: Animals; Endothelin-1; Epoprostenol; Estradiol; Female; Hypertension, Pulmonary; Nitric Oxide

2013
Complexities of oestradiol pharmacology in pulmonary arterial hypertension.
    The European respiratory journal, 2013, Volume: 41, Issue:6

    Topics: Animals; Endothelin-1; Epoprostenol; Estradiol; Female; Hypertension, Pulmonary; Nitric Oxide

2013
Adverse biventricular remodeling in isolated right ventricular hypertension is mediated by increased transforming growth factor-β1 signaling and is abrogated by angiotensin receptor blockade.
    American journal of respiratory cell and molecular biology, 2013, Volume: 49, Issue:6

    The pressure-loaded right ventricle (RV) adversely affects left ventricular (LV) function. We recently found that these ventricular-ventricular interactions lead to LV myocardial fibrosis through transforming growth factor-β1 (TGF-β1) signaling. We investigated the mechanisms mediating biventricular fibrosis in RV afterload and their potential modification by angiotensin receptor blockade. An adjustable pulmonary artery band (PAB) was placed in rabbits. In sham-operated control rabbits, the band was left uninflated (n = 6). In the RV afterload group, the PAB was sequentially inflated to generate systemic RV pressure at 28 days (n = 8). In a third group, the PAB was inflated to systemic levels, and the angiotensin receptor blocker losartan was added (n = 6). Five weeks after surgery, the animals were killed for assessments of biventricular hypertrophy, fibrosis, apoptosis, and the components of their signaling pathways. PAB animals developed biventricular hypertrophy, fibrosis, and apoptosis, versus sham rabbits, in which these conditions were decreased with losartan. RV and LV TGF-β1, connective tissue growth factor (CTGF) (CCN2), endothelin-1 (ET-1), endothelin receptor B, and matrix metalloproteinase 2/9 mRNA levels were increased in PAB animals versus sham animals, and decreased with losartan. Given the marked biventricular CTGF up-regulation in PAB and down-regulation with losartan, we investigated CTGF signaling. RV and LV Smad 2/3/4 protein levels and LV RhoA mRNA levels were increased with PAB and reduced with losartan. In conclusion, isolated RV afterload induces biventricular fibrosis and apoptosis, which are reduced by angiotensin receptor blockade. Adverse ventricular-ventricular interactions induced by isolated RV afterload appear to be mediated through TGF-β1-CTGF and ET-1 pathways.

    Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Apoptosis; Connective Tissue Growth Factor; Endothelin-1; Familial Primary Pulmonary Hypertension; Fibrosis; Hypertension; Hypertension, Pulmonary; Losartan; Male; Matrix Metalloproteinase 2; Rabbits; Receptor, Endothelin B; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta1; Ventricular Dysfunction, Right; Ventricular Remodeling

2013
An exploratory panel of biomarkers for risk prediction in pulmonary hypertension: emerging role of CT-proET-1.
    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 2013, Volume: 32, Issue:12

    Pulmonary arterial hypertension (PAH) is a rare, deadly condition. Although risk stratification is extremely important for assessment of prognosis and to guide therapy, there is lack of evidence concerning the role of novel biomarkers. In a pivotal study, we sought to comparatively investigate the predictive power of several new biomarkers in PAH.. Patients with prevalent PAH were enrolled in the study protocol, which included clinical, functional and echocardiographic assessment. Blood samples were collected at baseline for determination of NT-proBNP, CT-proET-1, MR-proANP, MR-proADM, copeptin and troponin I. Patients were clinically followed-up up to 12 months for first occurrence of hospital admission due to PAH-related clinical worsening, heart/lung transplantation or all-cause mortality.. Among the 28 included patients the pre-specified end-point occurred in 8 (29% event rate). There were higher baseline levels of CT-proET-1, copeptin, MR-proANP, NT-proBNP and troponin I in patients who reached the composite end-point. They also had larger right atria. In multivariate Cox regression, CT-proET-1 was the only biomarker associated with increased hazard of reaching the primary composite end-point (hazard ratio per tertile increase = 10.1; 95% CI 2.0 to 50.6).. CT-proET-1 provided prognostic information independent of other biomarkers. Importantly, we have provided the first evidence that CT-proET-1 may be superior to commonly used biomarkers.

    Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Cohort Studies; Echocardiography; Endothelin-1; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Glycopeptides; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Prospective Studies; Regression Analysis; Risk Factors; Troponin I

2013
The interaction of endothelin-1 and TGF-β1 mediates vascular cell remodeling.
    PloS one, 2013, Volume: 8, Issue:8

    Pulmonary arterial hypertension is characterized by increased thickness of pulmonary vessel walls due to both increased proliferation of pulmonary arterial smooth muscle cell (PASMC) and deposition of extracellular matrix. In patients suffering from pulmonary arterial hypertension, endothelin-1 (ET-1) synthesis is up-regulated and may increase PASMC activity and vessel wall remodeling through transforming growth factor beta-1 (TGF-β1) and connective tissue growth factor.. To assess the signaling pathway leading to ET-1 induced proliferation and extracellular matrix deposition by human PASMC.. PASMC were serum starved for 24 hours before stimulation with either ET-1 and/or TGF-β1. ET-1 was inhibited by Bosentan, ERK1/2 mitogen activated protein kinase (MAPK) was inhibited by U0126 and p38 MAPK was inhibited by SB203580.. ET-1 increased PASMC proliferation when combined with serum. This effect involved the mitogen activated protein kinases (MAPK) ERK1/2 MAPK and was abrogated by Bosentan which caused a G1- arrest through activation of p27((Kip)). Regarding the contribution of extracellular matrix deposition in vessel wall remodeling, TGF-β1 increased the deposition of collagen type-I and fibronectin, which was further increased when ET-1 was added mainly through ERK1/2 MAPK. In contrast, collagen type-IV was not affected by ET-1. Bosentan dose-dependently reduced the stimulatory effect of ET-1 on collagen type-I and fibronectin, but had no effect on TGF-β1.. ET-1 alone does not induce PASMC proliferation and extracellular matrix deposition. However, ET-1 significantly up-regulates serum induced proliferation and TGF-β1 induced extracellular matrix deposition, specifically of collagen type-I and fibronectin. The synergistic effects of ET-1 on serum and TGF-β1 involve ERK1/2 MAPK and may thus present a novel mode of action in the pathogenesis of pulmonary arterial hypertension.

    Topics: Cell Line; Cell Proliferation; Collagen Type I; Endothelial Cells; Endothelin-1; Enzyme Inhibitors; Extracellular Matrix; Fibronectins; Humans; Hypertension, Pulmonary; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Transforming Growth Factor beta1

2013
[Correlation between serum marker variations and pulmonary hypertension secondary to chronic obstructive pulmonary disease].
    Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 2013, Volume: 33, Issue:10

    To examine the correlation of the changes in the serum markers (C-reactive protein, endothelin-1, interleukin-6, and brain natriuretic peptide) with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension secondary to COPD.. A total of 174 COPD patients with acute exacerbation, admitted between February 2011 and February, 2013, were enrolled in this study, with 43 volunteers with normal pulmonary functions as controls. Pulmonary arterial pressure was determined by Doppler echocardiograph, and the severities (mild, moderate and severe) of PH secondary to COPD was evaluated. The levels of serum markers were determined using ELISA kits.. The levels of serum markers in patients with COPD was significantly elevated compared with those of the control subjects (P<0.05), and further increased in patients with pulmonary hypertension secondary to COPD (P<0.05). A positive correlation was found between these serum markers and pulmonary artery pressure in COPD patients with mild and moderate pulmonary hypertension. In patients with severe pulmonary hypertension, only the serum level of brain natriuretic peptide continued to increase with pulmonary artery pressure (P<0.05), and the other markers did not further increase.. Early and combined examination of these serum markers in patients with COPD can help to identify pulmonary hypertension in early stage and estimate the severity of pulmonary hypertension. Hemodynamic monitoring of the changes of these serum markers can be of important clinical value in the treatment of pulmonary hypertension secondary to COPD and in evaluation of the prognosis of COPD.

    Topics: Aged; Biomarkers; Blood Pressure; C-Reactive Protein; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Interleukin-6; Male; Natriuretic Peptide, Brain; Pulmonary Disease, Chronic Obstructive

2013
Hypoxia mediates mutual repression between microRNA-27a and PPARγ in the pulmonary vasculature.
    PloS one, 2013, Volume: 8, Issue:11

    Pulmonary hypertension (PH) is a serious disorder that causes significant morbidity and mortality. The pathogenesis of PH involves complex derangements in multiple pathways including reductions in peroxisome proliferator-activated receptor gamma (PPARγ). Hypoxia, a common PH stimulus, reduces PPARγ in experimental models. In contrast, activating PPARγ attenuates hypoxia-induced PH and endothelin 1 (ET-1) expression. To further explore mechanisms of hypoxia-induced PH and reductions in PPARγ, we examined the effects of hypoxia on selected microRNA (miRNA or miR) levels that might reduce PPARγ expression leading to increased ET-1 expression and PH. Our results demonstrate that exposure to hypoxia (10% O2) for 3-weeks increased levels of miR-27a and ET-1 in the lungs of C57BL/6 mice and reduced PPARγ levels. Hypoxia-induced increases in miR-27a were attenuated in mice treated with the PPARγ ligand, rosiglitazone (RSG, 10 mg/kg/d) by gavage for the final 10 d of exposure. In parallel studies, human pulmonary artery endothelial cells (HPAECs) were exposed to control (21% O2) or hypoxic (1% O2) conditions for 72 h. Hypoxia increased HPAEC proliferation, miR-27a and ET-1 expression, and reduced PPARγ expression. These alterations were attenuated by treatment with RSG (10 µM) during the last 24 h of hypoxia exposure. Overexpression of miR-27a or PPARγ knockdown increased HPAEC proliferation and ET-1 expression and decreased PPARγ levels, whereas these effects were reversed by miR-27a inhibition. Further, compared to lungs from littermate control mice, miR-27a levels were upregulated in lungs from endothelial-targeted PPARγ knockout (ePPARγ KO) mice. Knockdown of either SP1 or EGR1 was sufficient to significantly attenuate miR-27a expression in HPAECs. Collectively, these studies provide novel evidence that miR-27a and PPARγ mediate mutually repressive actions in hypoxic pulmonary vasculature and that targeting PPARγ may represent a novel therapeutic approach in PH to attenuate proliferative mediators that stimulate proliferation of pulmonary vascular cells.

    Topics: Animals; Base Pairing; Base Sequence; Cell Proliferation; Disease Models, Animal; Early Growth Response Protein 1; Endothelial Cells; Endothelin-1; Gene Expression; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Hypertension, Pulmonary; Hypoxia; Lung; Mice; MicroRNAs; Models, Biological; PPAR gamma; Pulmonary Artery; RNA Interference; Sp1 Transcription Factor

2013
Over, and underexpression of endothelin 1 and TGF-beta family ligands and receptors in lung tissue of broilers with pulmonary hypertension.
    BioMed research international, 2013, Volume: 2013

    Transforming growth factor beta (TGF β ) is a family of genes that play a key role in mediating tissue remodeling in various forms of acute and chronic lung disease. In order to assess their role on pulmonary hypertension in broilers, we determined mRNA expression of genes of the TGF β family and endothelin 1 in lung samples from 4-week-old chickens raised either under normal or cold temperature conditions. Both in control and cold-treated groups of broilers, endothelin 1 mRNA expression levels in lungs from ascitic chickens were higher than levels from healthy birds (P < 0.05), whereas levels in animals with cardiac failure were intermediate. Conversely, TGF β 2 and TGF β 3 gene expression in lungs were higher in healthy animals than in ascitic animals in both groups (P < 0.05). TGF β 1, T β RI, and T β RII mRNA gene expression among healthy, ascitic, and chickens with cardiac failure showed no differences (P > 0.05). BAMBI mRNA gene expression was lowest in birds with ascites only in the control group as compared with the values from healthy birds (P < 0.05).

    Topics: Animals; Chickens; Endothelin-1; Gene Expression Regulation; Hypertension, Pulmonary; Ligands; Lung; Male; Poultry Diseases; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta

2013
Supplemental arginine administered in ovo or in the feed reduces the susceptibility of broilers to pulmonary hypertension syndrome.
    British poultry science, 2013, Volume: 54, Issue:5

    1. Two experiments were conducted to determine if in ovo and in-feed arginine (ARG) supplementation is effective in the prevention of pulmonary hypertension syndrome (PHS) in broiler chickens reared at high altitude. 2. In Experiment I, a total of 300 fertile eggs were divided into two equal groups. On d 5 of incubation, one group was injected with 0.5 ml of ARG (20 mg/ml) and the other remained untreated and served as controls. After hatching, male chicks (64 chickens per treatment) were selected and given a commercial maize-soyabean meal diet up to 48 d of age. 3. In Experiment II, a total of 128 male broiler chickens (Ross 308) were randomly assigned to two treatments, a control group that were fed on a basal diet that met ARG requirements and the second was fed on the basal diet supplemented with 1.5 g ARG per kg of diet. 4. Cumulative mortality from ascites was recorded in both experiments. Results from Experiment I indicated that in ovo injection of ARG significantly decreased ascites mortality of broilers (18.8 vs. 43.8%). Results from Experiment II showed a similar effect so that ascites mortality in the group that were given Arg supplement was significantly lower than the control (28.1 vs. 43.8%).

    Topics: Animals; Arginine; Ascites; Body Weight; Chi-Square Distribution; Chickens; Dietary Supplements; Endothelin-1; Hypertension, Pulmonary; Male; Nitric Oxide; Ovum; Poultry Diseases; Random Allocation; Thyroid Hormones

2013
A cell permeable peptide targeting the intracellular loop 2 of endothelin B receptor reduces pulmonary hypertension in a hypoxic rat model.
    PloS one, 2013, Volume: 8, Issue:11

    Cell permeable peptides (CPP) aid cellular uptake of targeted cargo across the hydrophobic plasma membrane. CPP-mediated cargo delivery of receptor signaling motifs provides an opportunity to regulate specific receptor initiated signaling cascades. Both endothelin-1 receptors, ETA and ETB, have been targets of antagonist therapies for individuals with pulmonary arterial hypertension (PAH). These therapies have had success but have been accompanied by adverse reactions. Also, unlike the CPP which target specific signaling cascades, the antagonists target the entire function of the receptor. Using the CPP strategy of biased antagonism of the ETB receptor's intracellular loop 2 (ICB2), we demonstrate blunting of hypoxic pulmonary hypertension (HPH) in the rat, including indices of pulmonary arterial pressure, right ventricular hypertrophy and pulmonary vascular remodeling. Further, ex vivo analysis of the pulmonary artery treated with the IC2B peptide upon injection manifests marked reductions in Akt and ERK activation. Both kinases have been intimately related to cell proliferation and vascular contraction, the hallmarks of PAH. These observations in sum illustrate an involvement of the ETB receptor in HPH and furthermore provide a basis for a novel, CPP-based, strategy in the treatment of PAH, ultimately able to target not only ET-1, but also other factors involved in the development of PAH.

    Topics: Animals; Cell-Penetrating Peptides; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Hypertension, Pulmonary; Hypoxia; Intracellular Space; Male; Molecular Targeted Therapy; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Signal Transduction

2013
Relationship between baseline ET-1 plasma levels and outcome in patients with idiopathic pulmonary hypertension treated with bosentan.
    International journal of cardiology, 2013, Jul-15, Volume: 167, Issue:1

    To address if baseline endothelin-1 (ET-1) plasma levels might predict clinical worsening (CW) in patients with idiopathic pulmonary hypertension (IPAH) treated with bosentan.. Forty-four consecutive patients with IPAH (WHO classes II-III) were included in this study. After an initial assessment (clinical status, pulmonary hemodynamics, samples for adrenomedullin (ADM), ET-1 and brain natriuretic peptide (BNP) plasma levels), patients were treated with bosentan and followed-up for CW.. We observed CW in 24 patients. Actuarial rates of freedom from CW were 74% at 1 year, 56% at 2 years, and 43% at 3 years. Patients with CW had a worse WHO functional class (II/III; no-CW 14/6 vs CW 5/19, p=0.002), six-minute walk-test distance (no-CW 439+94 m vs CW 385+82 m, p=0.04), mean pulmonary artery pressure (no-CW 47.4+10.6mm Hg vs CW 56+12.6mm Hg, p=0.02) and pulmonary vascular resistance (PVR no-CW 12.5+4.8 WU vs CW 16.4+6.3 WU, p=0.03) than the no-CW group. Moreover ET-1 (no-CW 14.1+4.2 pg/ml vs CW 21.3+6.3 pg/ml, p=0.0001), ADM (no-CW 14.9+7 pg/ml vs CW 21.5+10.4 pg/ml p=0.002) and BNP (no-CW 82.8+35.3 pg/ml vs CW 115.4+39.6 pg/ml, p=0.007) plasma levels were significantly higher in the CW group than in the no-CW group. The multivariate Cox proportional hazards model identified WHO class III (RR 4.6, 95%CI 14.6-1.45), ET-1 plasma levels (RR 1.1, 95%CI 2.05-1.01) and PVR (RR 1.2, 95%CI 1.3-1.03) as independent risk factors for CW.. These data confirm the high rate of CW in patients with IPAH treated with bosentan and document the impact of the endothelin system on CW of these patients.

    Topics: Adult; Aged; Antihypertensive Agents; Biomarkers; Bosentan; Endothelin-1; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies; Sulfonamides; Treatment Outcome

2013
Oestradiol ameliorates monocrotaline pulmonary hypertension via NO, prostacyclin and endothelin-1 pathways.
    The European respiratory journal, 2013, Volume: 41, Issue:5

    Pulmonary hypertension continues to be a serious clinical problem with high mortality. As oestrogen is a potential vasodilator of the pulmonary circulation, this study examined the mechanisms by which 17β-oestradiol improves monocrotaline (MCT)-induced pulmonary hypertension. Female Sprague-Dawley rats underwent bilateral ovariectomy or sham operations. The rats received MCT (50 mg·kg(-1)) and were treated with 17β-oestradiol (1 mg·kg(-1) per day) for either 5 weeks or only from week 4 to week 5. Plasma 17β-oestradiol concentrations were decreased in sham-operated, MCT-treated rats when compared with sham-operated rats (17.7 ± 4.7 versus 50.3 ± 15.4 pg·mL(-1); p=0.029). The 17β-oestradiol anabolic enzyme cytochrome P450 (CYP)-19 was decreased by MCT treatment, while the catabolic enzymes CYP-1A1 and -1B1 were increased. Ovariectomised and MCT-treated rats had more severe pulmonary hypertension. 17β-oestradiol suppressed pulmonary arterial smooth muscle cell proliferation and macrophage infiltration, and enhanced apoptosis by increasing nitric oxide (NO) and prostacyclin (prostaglandin (PG)I2) levels and reducing endothelin (ET)-1 levels. Phosphoinositide-3-kinase (PI3K) and Akt phosphorylations were markedly increased, but were inhibited by 17β-oestradiol treatment in rats with pulmonary hypertension. Oestrogen deficiency may aggravate development of pulmonary hypertension. 17β-oestradiol improved pulmonary hypertension via activation of the PI3K/Akt pathway to regulate NO, PGI2 and ET-1 expression.

    Topics: Animals; Aromatase; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Endothelin-1; Epoprostenol; Estradiol; Female; Hemodynamics; Hypertension, Pulmonary; Monocrotaline; Nitric Oxide; Phosphatidylinositol 3-Kinases; Rats; Rats, Sprague-Dawley; Signal Transduction

2013
Iptakalim ameliorates monocrotaline-induced pulmonary arterial hypertension in rats.
    Journal of cardiovascular pharmacology and therapeutics, 2013, Volume: 18, Issue:1

    We sought to investigate the experimental therapeutic effects and mechanisms of iptakalim, a new adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) opener, on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and right heart ventricle remodeling in rats.. Rats were injected with a single dose (50 mg/kg, ip) of MCT and given iptakalim (1, 3, and 9 mg/kg·per d, orally [po]) or saline for 28 days. The hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis.. Treatment with iptakalim at daily oral doses of 1, 3, and 9 mg/kg from the day of MCT injection attenuated the high right ventricle systolic pressure (RVSP) and the increased weight ratio of right ventricle (RV) to left ventricle (LV) plus septum (S) (RV/(LV+S)), decreased heart rate (HR) and decreased mean arterial pressure (MAP), inhibited the RV myocardial tissue cell apoptosis, and the RV myocardial cell B-type natriuretic peptide (BNP) protein expression. Iptakalim also decreased the serum levels of nitric oxide (NO), endothelin 1 (ET-1), BNP, and the levels of NO, ET-1, and tumor necrosis factor-alpha (TNF-α) in the lung tissue.. These results indicate that iptakalim prevents MCT-induced PAH and RV remodeling and its mechanisms are related to inhibiting the pathological increases in NO, ET-1, BNP, and TNF-α, and Iptakalim may be a promising candidate for the treatment of PAH.

    Topics: Animals; Endothelin-1; Familial Primary Pulmonary Hypertension; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; KATP Channels; Lung; Male; Monocrotaline; Natriuretic Peptide, Brain; Nitric Oxide; Propylamines; Rats; Rats, Wistar

2013
Urotensin inhibition with palosuran could be a promising alternative in pulmonary arterial hypertension.
    Inflammation, 2013, Volume: 36, Issue:2

    Pulmonary arterial hypertension (PAH) is a progressive and a life-threatening disease with its high morbidity and mortality ratios. On searching for new shining targets in pathogenesis, we noticed, in our previous studies, urotensin-II (UII) in systemic sclerosis with potent angiogenic and pro-fibrotic features. Owing to the mimicking properties of UII with endothelin-1 (ET1), we attempted to investigate the effect of palosuran in a PAH rat model. Thirty rats were randomly divided into three groups, with each group comprising 10 rats: group 1 (control group) received the vehicle subcutaneously, instead of monocrotaline (MCT) and vehicle; group 2 (MCT group) received subcutaneous MCT and vehicle; and group 3 (MCT + palosuran group) received subcutaneous MCT and palosuran. Serum UII, ET1, transforming growth factor-β1 (TGF-β1) levels, pulmonary arteriolar pathology of different diameter vessels, and cardiac indices were evaluated. The ET1, TGF-β1, and UII levels were significantly diminished in the treatment group, similar to the controls (p < 0.001). Right ventricular hypertrophy index and mean pulmonary arterial pressure scores were also significantly reduced in the treatment group (p = 0.001). Finally, in the 50-125-μm diameter arterioles, in contrast to Groups 3 and 1, there was a statistically significant thickness (p < 0.01) in the arteriolar walls of rats in Group 2. The treatment effect on arteries of more than 125-μm diameters was found to be valuable but not significant. Owing to its healing effect on hemodynamic, histological, and biochemical parameters of MCT-induced PAH, palosuran as an antagonist of UII might be an optional treatment alternative for PAH.

    Topics: Animals; Arterial Pressure; Arterioles; Endothelin-1; Familial Primary Pulmonary Hypertension; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Pulmonary Artery; Quinolines; Rats; Rats, Wistar; Transforming Growth Factor beta1; Urea; Urotensins

2013
A possible role for systemic hypoxia in the reactive component of pulmonary hypertension in heart failure.
    Journal of cardiac failure, 2013, Volume: 19, Issue:1

    The mechanisms underlying the reactive component of pulmonary hypertension (PH) in heart failure (HF) are unclear. We examined whether resting systemic oxygen levels are related to pulmonary hemodynamics in HF.. Thirty-nine HF patients underwent right heart catheterization. Subsequently, patients were classified as having: 1) no PH (n = 12); 2) passive PH (n = 10); or 3) reactive PH (n = 17). Blood was drawn from the radial and pulmonary arteries for the determination of PaO(2), SaO(2), PvO(2), SvO(2), and vasoactive neurohormones. PaO(2) and PvO(2) were lower in reactive PH versus no PH and passive PH patients (65.3 ± 8.6 vs 78.3 ± 11.4 mm Hg and 74.5 ± 14.0 mm Hg; 29.2 ± 4.1 vs 36.2 ± 2.8 mm Hg and 33.4 ± 2.3 mm Hg; P < .05). SaO(2) and SvO(2) were lower in reactive PH versus no PH patients (93 ± 3% vs 96 ± 3%; 51 ± 11% vs 68 ± 4%; P < .05), but not different versus passive PH patients. The transpulmonary pressure gradient (TPG) was inversely related to PaO(2), PvO(2), SaO(2), and SvO(2) in the reactive PH patients only (r ≤ -0.557; P < .05). Similarly, plasma endothelin-1 correlated with PaO(2), PvO(2), SvO(2) (r ≤ -0.495), and TPG (r = 0.662; P < .05) in reactive PH patients only.. Systemic hypoxia may play a role in the reactive component of PH in HF, potentially via a hypoxia-induced increase in endothelial release of the vasoconstrictor endothelin-1.

    Topics: Adult; Aged; Blood Gas Analysis; Cardiac Catheterization; Cardiac Output, Low; Cohort Studies; Disease Progression; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Multivariate Analysis; Neurotransmitter Agents; Oxygen; Prognosis; Prospective Studies; Regression Analysis; Risk Assessment; Severity of Illness Index; Survival Rate; Vascular Resistance

2013
Deletion of Fn14 receptor protects from right heart fibrosis and dysfunction.
    Basic research in cardiology, 2013, Volume: 108, Issue:2

    Pulmonary arterial hypertension (PAH) is a fatal disease for which no cure is yet available. The leading cause of death in PAH is right ventricular (RV) failure. Previously, the TNF receptor superfamily member fibroblast growth factor-inducible molecule 14 (Fn14) has been associated with different fibrotic diseases. However, so far there is no study demonstrating a causal role for endogenous Fn14 signaling in RV or LV heart disease. The purpose of this study was to determine whether global ablation of Fn14 prevents RV fibrosis and remodeling improving heart function. Here, we provide evidence for a causative role of Fn14 in pulmonary artery banding (PAB)-induced RV fibrosis and dysfunction in mice. Fn14 expression was increased in the RV after PAB. Mice lacking Fn14 (Fn14(-/-)) displayed substantially reduced RV fibrosis and dysfunction following PAB compared to wild-type littermates. Cell culture experiments demonstrated that activation of Fn14 induces collagen expression via RhoA-dependent nuclear translocation of myocardin-related transcription factor-A (MRTF-A)/MAL. Furthermore, activation of Fn14 in vitro caused fibroblast proliferation and myofibroblast differentiation, which corresponds to suppression of PAB-induced RV fibrosis in Fn14(-/-) mice. Moreover, our findings suggest that Fn14 expression is regulated by endothelin-1 (ET-1) in cardiac fibroblasts. We conclude that Fn14 is an endogenous key regulator in cardiac fibrosis and suggest this receptor as potential new target for therapeutic interventions in heart failure.

    Topics: Animals; Apoptosis Regulatory Proteins; Blotting, Western; Cell Differentiation; Cell Proliferation; Collagen; Cytokine TWEAK; Endothelin-1; Familial Primary Pulmonary Hypertension; Fibrosis; Fluorescent Antibody Technique; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Immunohistochemistry; Membrane Proteins; Mice; Mice, Knockout; Myocardium; Myofibroblasts; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Tumor Necrosis Factor; Signal Transduction; Trans-Activators; Transcription Factors; Tumor Necrosis Factors; TWEAK Receptor; Up-Regulation; Ventricular Dysfunction, Right

2013
Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α.
    Cell metabolism, 2013, Feb-05, Volume: 17, Issue:2

    Iron regulatory proteins (Irps) 1 and 2 posttranscriptionally control the expression of transcripts that contain iron-responsive element (IRE) sequences, including ferritin, ferroportin, transferrin receptor, and hypoxia-inducible factor 2α (HIF2α). We report here that mice with targeted deletion of Irp1 developed pulmonary hypertension and polycythemia that was exacerbated by a low-iron diet. Hematocrits increased to 65% in iron-starved mice, and many polycythemic mice died of abdominal hemorrhages. Irp1 deletion enhanced HIF2α protein expression in kidneys of Irp1(-/-) mice, which led to increased erythropoietin (EPO) expression, polycythemia, and concomitant tissue iron deficiency. Increased HIF2α expression in pulmonary endothelial cells induced high expression of endothelin-1, likely contributing to the pulmonary hypertension of Irp1(-/-) mice. Our results reveal why anemia is an early physiological consequence of iron deficiency, highlight the physiological significance of Irp1 in regulating erythropoiesis and iron distribution, and provide important insights into the molecular pathogenesis of pulmonary hypertension.

    Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Diet; Endothelial Cells; Endothelin-1; Erythropoietin; Gastrointestinal Hemorrhage; Gene Deletion; Hematopoiesis, Extramedullary; Hypertension, Pulmonary; Iron; Iron Regulatory Protein 1; Iron Regulatory Protein 2; Longevity; Mice; Models, Biological; Nerve Degeneration; Organ Specificity; Polycythemia; Protein Biosynthesis; Transcriptional Activation

2013
[Hypoxic pulmonary hypertension and novel ATP-sensitive potassium channel opener: the new hope on the horizon].
    Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 2012, Volume: 28, Issue:6

    Hypoxic pulmonary hypertension (HPH) is a syndrome characterized by the increase of pulmonary vascular tone and the structural remodeling of peripheral pulmonary arteries. The aim of specific therapies for hypoxic pulmonary hypertension is to reduce pulmonary vascular resistance, reverse pulmonary vascular remodeling, and thereby improving right ventricular function. Iptakalim, a lipophilic para-amino compound with a low molecular weight, has been demonstrated to be a new selective ATP-sensitive potassium (K(ATP)) channel opener via pharmacological, electrophysiological, biochemical studies, and receptor binding tests. In hypoxia-induced animal models, iptakalim decreases the elevated mean pressure in pulmonary arteries, and attenuates remodeling in the right ventricle, pulmonary arteries and airways. Furthermore, iptakalim has selective antihypertensive effects, selective vasorelaxation effects on smaller arteries, and protective effects on endothelial cells, but no effects on the central nervous, respiratory, digestive or endocrine systems at therapeutic dose. Our previous studies demonstrated that iptakalim inhibited the effects of endothelin-1, reduced the intracellular calcium concentration and inhibited the proliferation of pulmonary artery smooth muscle cells. Since iptakalim has been shown safe and effective in both experimental animal models and phase I clinical trials, it can be a potential candidate of HPH in the future.

    Topics: Animals; Antihypertensive Agents; Calcium; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Hypoxia; KATP Channels; Myocytes, Smooth Muscle; Propylamines; Pulmonary Artery

2012
Analysis of endothelin-1 and endothelin-1 receptor A gene polymorphisms in patients with pulmonary arterial hypertension.
    Internal and emergency medicine, 2012, Volume: 7, Issue:5

    This study analyses the frequency and the potential role of two polymorphisms, the +134del/insA, located in the gene encoding for Endothelin-1 (EDN1), and the His323His in the gene encoding for Endothelin receptor type A (EDNRA) in a cohort of 98 consecutive patients with pulmonary arterial hypertension from two different Cardiology Units (Mid-South of Italy), and in 100 healthy Caucasian subjects randomly recruited from the same area. Cardiac anatomy and function were analysed by non invasive diagnostic imaging techniques (Echocardiography standard m-mode, 2D, colour-Doppler) and by invasive studies (cardiac catheterization). Molecular screening of the region of interest was performed by automated sequencing. At univariate analysis, patients with the His323His TT genotype show a lower cardiac index (2 ± 0.6 vs. 2.3 ± 0.6; p = 0.05) and a higher indexed pulmonary vascular resistance (18.8 ± 9.6 vs. 14.2 ± 6.9; p = 0.01) at cardiac catheterization. A logistic multivariate model shows idiopathic disease (p = 0.01; OR = 3.8; CI = 1.3-11) and indexed pulmonary vascular resistances (p = 0.01; OR = 1.1; CI = 1-1.2) as independent predictors of TT genotype. Our findings may suggest a potential link between specific genotypes in the EDNRA gene and susceptibility for PAH.

    Topics: Adult; Aged; Endothelin-1; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Italy; Male; Middle Aged; Molecular Sequence Data; Polymorphism, Genetic; Receptor, Endothelin A

2012
Endothelin-1, the unfolded protein response, and persistent inflammation: role of pulmonary artery smooth muscle cells.
    American journal of respiratory cell and molecular biology, 2012, Volume: 46, Issue:1

    Endothelin-1 is a potent vasoactive peptide that occurs in chronically high levels in humans with pulmonary hypertension and in animal models of the disease. Recently, the unfolded protein response was implicated in a variety of diseases, including pulmonary hypertension. In addition, evidence is increasing for pathological, persistent inflammation in the pathobiology of this disease. We investigated whether endothelin-1 might engage the unfolded protein response and thus link inflammation and the production of hyaluronic acid by pulmonary artery smooth muscle cells. Using immunoblot, real-time PCR, immunofluorescence, and luciferase assays, we found that endothelin-1 induces both a transcriptional and posttranslational activation of the three major arms of the unfolded protein response. The pharmacologic blockade of endothelin A receptors, but not endothelin B receptors, attenuated the observed release, as did a pharmacologic blockade of extracellular signal-regulated kinases 1 and 2 (ERK-1/2) signaling. Using short hairpin RNA and ELISA, we observed that the release by pulmonary artery smooth muscle cells of inflammatory modulators, including hyaluronic acid, is associated with endothelin-1-induced ERK-1/2 phosphorylation and the unfolded protein response. Furthermore, the synthesis of hyaluronic acid induced by endothelin-1 is permissive for persistent THP-1 monocyte binding. These results suggest that endothelin-1, in part because it induces the unfolded protein response in pulmonary artery smooth muscle cells, triggers proinflammatory processes that likely contribute to vascular remodeling in pulmonary hypertension.

    Topics: Activating Transcription Factor 6; Animals; Arteritis; Cytokines; DNA-Binding Proteins; Endothelin A Receptor Antagonists; Endothelin-1; Hyaluronic Acid; Hypertension, Pulmonary; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Monocytes; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Pulmonary Artery; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Regulatory Factor X Transcription Factors; Signal Transduction; Transcription Factors; Unfolded Protein Response

2012
Effects of everolimus in combination with sildenafil in monocrotaline-induced pulmonary hypertension in rats.
    Cardiovascular toxicology, 2012, Volume: 12, Issue:1

    In our study, we investigated the efficacy of everolimus in combination with sildenafil on hemodynamic and morphological parameters in rats with monocrotaline-induced pulmonary hypertension (PH). Right ventricular pressure (RVP), right ventricular hypertrophy, and the response to vasoconstrictor and vasodilator agents in pulmonary arteries as evaluated by myography and histopathological changes were compared among the groups. RVP and right ventricle/body weight ratios were increased in non-treated monocrotaline groups versus the controls; these increased ratios were decreased in the treated groups and were similar to control values. The contractile responses to endothelin-1 in the pulmonary arteries were decreased in the non-treated monocrotaline groups versus the control. In the treatment groups, contractile responses were similar to those in the controls. Responses to acetylcholine and sodium nitroprusside relaxation were decreased in non-treated monocrotaline groups but were improved significantly in the everolimus groups. Upon histopathological examination, the vascular hypertrophy and cardiac hypertrophy observed in monocrotaline groups were improved by the sildenafil and everolimus treatment. In particular, these improvements became remarkable, including the inflammatory changes, in the everolimus treatment groups. In the light of these results, sildenafil and everolimus in combination were more effective than sildenafil treatment alone in reversing the remodelling process without any cardiovascular toxic effects in the monocrotaline-induced PH model.

    Topics: Acetylcholine; Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin-1; Everolimus; Female; Hypertension, Pulmonary; Monocrotaline; Nitroprusside; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sirolimus; Sulfones; Vasoconstrictor Agents; Vasodilator Agents; Ventricular Dysfunction, Right; Ventricular Remodeling

2012
TASK1 (K(2P)3.1) K(+) channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation.
    British journal of pharmacology, 2012, Volume: 165, Issue:5

    TASK1 (K(2P)3.1) two-pore-domain K(+) channels contribute substantially to the resting membrane potential in human pulmonary artery smooth muscle cells (hPASMC), modulating vascular tone and diameter. The endothelin-1 (ET-1) pathway mediates vasoconstriction and is an established target of pulmonary arterial hypertension (PAH) therapy. ET-1-mediated inhibition of TASK1 currents in hPASMC is implicated in the pathophysiology of PAH. This study was designed to elucidate molecular mechanisms underlying inhibition of TASK1 channels by ET-1.. Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record TASK1 currents from hPASMC and Xenopus oocytes.. ET-1 inhibited TASK1-mediated I(KN) currents in hPASMC, an effect attenuated by Rho kinase inhibition with Y-27632. In Xenopus oocytes, TASK1 current reduction by ET-1 was mediated by endothelin receptors ET(A) (IC(50) = 0.08 nM) and ET(B) (IC(50) = 0.23 nM) via Rho kinase signalling. TASK1 channels contain two putative Rho kinase phosphorylation sites, Ser(336) and Ser(393) . Mutation of Ser(393) rendered TASK1 channels insensitive to ET(A) - or ET(B)-mediated current inhibition. In contrast, removal of Ser(336) selectively attenuated ET(A) -dependent TASK1 regulation without affecting the ET(B) pathway.. ET-1 regulated vascular TASK1 currents through ET(A) and ET(B) receptors mediated by downstream activation of Rho kinase and direct channel phosphorylation. The Rho kinase pathway in PASMC may provide a more specific therapeutic target in pulmonary arterial hypertension treatment.

    Topics: Animals; Cells, Cultured; Endothelin-1; Female; GTP Phosphohydrolases; Humans; Hypertension, Pulmonary; Membrane Potentials; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Nerve Tissue Proteins; Phosphorylation; Potassium Channels, Tandem Pore Domain; Pulmonary Artery; Receptor, Endothelin A; Receptor, Endothelin B; rho-Associated Kinases; Signal Transduction; Vasoconstriction; Xenopus laevis

2012
Lysophosphatidic acid signaling protects pulmonary vasculature from hypoxia-induced remodeling.
    Arteriosclerosis, thrombosis, and vascular biology, 2012, Volume: 32, Issue:1

    Lysophosphatidic acid (LPA) is a bioactive lipid molecule produced by the plasma lysophospholipase D enzyme autotaxin that is present at ≥100 nmol/L in plasma. Local administration of LPA promotes systemic arterial remodeling in rodents. To determine whether LPA contributes to remodeling of the pulmonary vasculature, we examined responses in mice with alterations in LPA signaling and metabolism.. Enpp2(+/-) mice, which are heterozygous for the autotaxin-encoding gene and which have reduced expression of autotaxin/lysophospholipase D and approximately half normal plasma LPA, were hyperresponsive to hypoxia-induced vasoconstriction and remodeling, as evidenced by the development of higher right ventricular (RV) systolic pressure, greater decline in peak flow velocity across the pulmonary valve, and a higher percentage of muscularized arterioles. Mice lacking LPA(1) and LPA(2), 2 LPA receptors abundantly expressed in the vasculature, also had enhanced hypoxia-induced pulmonary remodeling. With age, Lpar1(-/-)2(-/-) mice spontaneously developed elevated RV systolic pressure and RV hypertrophy that was not observed in Lpar1(-/-) mice or Lpar2(-/-) mice. Expression of endothelin-1, a potent vasoconstrictor, was elevated in lungs of Lpar1(-/-)2(-/-) mice, and expression of endothelin(B) receptor, which promotes vasodilation and clears endothelin, was reduced in Enpp2(+/-) and Lpar1(-/-)2(-/-) mice.. Our findings indicate that LPA may negatively regulate pulmonary vascular pressure through LPA(1) and LPA(2) receptors and that in the absence of LPA signaling, upregulation in the endothelin system favors remodeling.

    Topics: Animals; Blood Pressure; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Lysophospholipids; Mice; Mice, Inbred BALB C; Mice, Knockout; Phosphoric Diester Hydrolases; Pulmonary Artery; Receptors, Lysophosphatidic Acid; Signal Transduction

2012
Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension.
    The European respiratory journal, 2012, Volume: 40, Issue:4

    Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by proximal pulmonary vascular obstruction by thrombo-fibrotic material, the origin of which has not been elucidated. Enhanced inflammation could contribute to persistent obstruction by impairing pulmonary vascular cell function in CTEPH. We investigated C-reactive protein (CRP) effects on pulmonary vascular cell function in vitro. Primary cultures of proximal pulmonary endothelial cells (ECs) and smooth muscle cells (SMCs) from CTEPH and nonthromboembolic pulmonary hypertension (PH) patients were established. Recombinant CRP effects on mitogenic activity, adhesion capacity, endothelin-1 and von Willebrand factor (vWF) secretion and intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule-1 expression were investigated in ECs and/or SMCs. Expression of the CRP receptor, lectin-like oxidised low-density lipoprotein receptor (LOX)-1, was evaluated in proximal pulmonary arterial tissue and cells by Western blotting and immunofluorescence. CRP increased CTEPH-SMC proliferation by 250%. CRP increased adhesion capacity, endothelin-1 and vWF secretion by CTEPH-ECs by 37%, 129% and 694%, respectively. CRP-induced adhesion of CTEPH-ECs to monocytes was mediated by ICAM-1. CRP had no effect on cells from nonthromboembolic PH patients, probably because of overexpression of LOX-1 in CTEPH. Local expression of CRP was detected in ECs and SMCs within pulmonary arterial tissue. CRP may contribute to persistent obstruction of proximal pulmonary arteries in CTEPH by promoting vascular remodelling, endothelial dysfunction and in situ thrombosis.

    Topics: Adult; Aged; C-Reactive Protein; Case-Control Studies; Cell Adhesion; Cell Proliferation; Cells, Cultured; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension, Pulmonary; Inflammation; Intercellular Adhesion Molecule-1; Male; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulmonary Artery; Receptors, Immunologic; Scavenger Receptors, Class E; Thromboembolism; von Willebrand Factor

2012
Effects of autologous bone marrow mononuclear cells implantation in canine model of pulmonary hypertension.
    Circulation journal : official journal of the Japanese Circulation Society, 2012, Volume: 76, Issue:4

    We investigated the safety and feasibility of intratracheal administration of autologous bone marrow-derived mononuclear cells (ABM-MNCs) and observed the effects in a canine model of pulmonary hypertension (PH).. The PH model was induced by intravenous injection of 3mg/kg dehydromonocrotaline (DMCT) via the right atrium. Two weeks after DMCT administration, the animals received 4 different treatments (n=10 in each group): (I) negative control group; (II): ABM-MNCs group; (III) PH group; (IV) PH+ABM-MNCs group. Six weeks after injection of cells (10⁷), the hemodynamic data were significantly improved in group IV compared with group III (P<0.05). The ratio of right ventricular weight to left ventricular plus septal weight was significantly decreased in group IV compared with group III (P<0.05). The mRNA levels of vascular endothelial growth factor, preproendothelin-1, interleukin-6 and tumor necrosis factor-α were significantly improved in group IV compared with group III (P<0.05). The immunofluorescence result showed that 6 weeks after administration ABM-MNCs could differentiate into pulmonary vascular endothelial cells.. Six weeks after intratracheal administration, ABM-MNCs significantly improved the impairment caused by DMCT in a canine model of PH (ie, decreased pulmonary arteriolar narrowing, alveolar septum thickening and right ventricular hypertrophy, enhanced angiogenesis) and this provides a firm foundation for a clinical trial.

    Topics: Animals; Bone Marrow Transplantation; Cell Differentiation; Cell Separation; Cell Tracking; Disease Models, Animal; Dogs; Endothelial Cells; Endothelin-1; Flow Cytometry; Fluorescent Antibody Technique; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Interleukin-6; Monocrotaline; Neovascularization, Physiologic; Pulmonary Artery; RNA, Messenger; Stem Cell Transplantation; Time Factors; Transplantation, Autologous; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Ventricular Function, Right

2012
Ambrisentan and tadalafil synergistically relax endothelin-induced contraction of rat pulmonary arteries.
    Hypertension (Dallas, Tex. : 1979), 2012, Volume: 59, Issue:3

    Endothelin receptor antagonists and phosphodiesterase type 5 inhibitors are used to treat pulmonary arterial hypertension. We tested the hypothesis that a selective endothelin type A receptor antagonist (ambrisentan) and a phosphodiesterase type 5 inhibitor (tadalafil) may act synergistically to relax endothelin-constricted pulmonary arteries. Rat isolated intrapulmonary arterial rings contracted with 8 nmol/L endothelin-1 were relaxed by 10 nmol/L ambrisentan and 30 nmol/L tadalafil alone by 26±3% and 21±1%, respectively, whereas both drugs in combination acted synergistically to relax arterial rings by 83±6%. The nonselective endothelin type A and B receptor antagonists bosentan (100 nmol/L) and macitentan (30 nmol/L) alone relaxed endothelin-contracted rings by 30±5% and 24±3%, respectively. Combinations of 30 nmol/L tadalafil with 100 nmol/L bosentan or 30 nmol/L macitentan relaxed endothelin-contracted rings by 53±5% or 46±7%, respectively; these values are similar to the calculated sums of the individual effects of these compounds. Denudation of endothelium from pulmonary arterial rings abolished the vasodilator response to 30 nmol/L tadalafil and the synergistic vasorelaxant effect of tadalafil with ambrisentan. In the presence of 1 μmol/L BQ-788, a selective endothelin type B receptor antagonist, the vasorelaxant effects of 10 nmol/L ambrisentan and 30 nmol/L tadalafil were additive but not synergistic. These data can be interpreted to suggest that ambrisentan and tadalafil synergistically inhibit endothelin-1-induced constriction of rat intrapulmonary arteries and that endothelin type B receptors in endothelium are necessary to enable a synergistic vasorelaxant effect of the drug combination.

    Topics: Animals; Blotting, Western; Carbolines; Disease Models, Animal; Drug Synergism; Endothelin-1; Hypertension, Pulmonary; Male; Phenylpropionates; Pulmonary Artery; Pyridazines; Rats; Rats, Sprague-Dawley; Tadalafil; Vasoconstriction; Vasodilator Agents

2012
Involvement of matrix metalloproteinase-2 in medial hypertrophy of pulmonary arterioles in broiler chickens with pulmonary arterial hypertension.
    Veterinary journal (London, England : 1997), 2012, Volume: 193, Issue:2

    Medial hypertrophy of pulmonary arterioles during pulmonary arterial hypertension (PAH) in humans is associated with enhanced proliferation of smooth muscle cells (SMCs). Elevated matrix metalloproteinase (MMP)-2 has been found in pulmonary artery SMCs (PA-SMCs) in humans with idiopathic PAH, leading to the hypothesis that MMP-2 contributes to the proliferation and migration of vascular SMCs in the pathogenesis of PAH. Rapidly growing meat-type (broiler) chickens provide a model of spontaneous PAH. The present study was conducted to determine whether MMP-2 is involved in the medial hypertrophy of pulmonary arterioles in this model. Cultured PA-SMCs from normal birds were used to evaluate the effect of MMPs on cell proliferation. Gelatin zymography showed that endothelin (ET)-1-induced proliferation of PA-SMCs was concomitant with increased pro- and active MMP-2 production. Reverse transcription PCR demonstrated upregulation of MMP-2 mRNA. However, PA-SMC proliferation was inhibited by the MMP inhibitors doxycycline and cis-9-octadecenoyl-N-hydroxylamide. In vivo experiments revealed a significant increase of MMP-2 expression in hypertrophied pulmonary arterioles of PAH broiler chickens, which was positively correlated with wall thickness and medial hypertrophy. MMP-2 may contribute to medial hypertrophy in pulmonary arterioles during PAH in broiler chickens by enhancing the proliferation of vascular SMCs.

    Topics: Animals; Arterioles; Chickens; Doxycycline; Electrophoresis, Polyacrylamide Gel; Endothelin-1; Familial Primary Pulmonary Hypertension; Gene Expression Regulation, Enzymologic; Hydroxamic Acids; Hypertension, Pulmonary; Hypertrophy; Lung; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Myocytes, Smooth Muscle; Poultry Diseases; Pulmonary Artery; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium Chloride

2012
Kinase-dependent activation of voltage-gated Ca2+ channels by ET-1 in pulmonary arterial myocytes during chronic hypoxia.
    American journal of physiology. Lung cellular and molecular physiology, 2012, May-15, Volume: 302, Issue:10

    Exposure to chronic hypoxia (CH) causes pulmonary hypertension. The vasoconstrictor endothelin-1 (ET-1) is thought to play a role in the development of hypoxic pulmonary hypertension. In pulmonary arterial smooth muscle cells (PASMCs) from chronically hypoxic rats, ET-1 signaling is altered, with the ET-1-induced change in intracellular calcium concentration (Δ[Ca(2+)](i)) occurring through activation of voltage-dependent Ca(2+) channels (VDCC) even though ET-1-induced depolarization via inhibition of K(+) channels is lost. The mechanism underlying this response is unclear. We hypothesized that activation of VDCCs by ET-1 following CH might be mediated by protein kinase C (PKC) and/or Rho kinase, both of which have been shown to phosphorylate and activate VDCCs. To test this hypothesis, we examined the effects of PKC and Rho kinase inhibitors on the ET-1-induced Δ[Ca(2+)](i) in PASMCs from rats exposed to CH (10% O(2), 3 wk) using the Ca(2+)-sensitive dye fura 2-AM and fluorescent microscopy techniques. We found that staurosporine and GF109203X, inhibitors of PKC, and Y-27632 and HA 1077, Rho kinase inhibitors, reduced the ET-1-induced Δ[Ca(2+)](i) by >70%. Inhibition of tyrosine kinases (TKs) with genistein or tyrphostin A23, or combined inhibition of PKC, TKs, and Rho kinase, reduced the Δ[Ca(2+)](i) to a similar extent as inhibition of either PKC or Rho kinase alone. The ability of PKC or Rho kinase to activate VDCCs in our cells was verified using phorbol 12-myristate 13-acetate and GTP-γ-S. These results suggest that following CH, the ET-1-induced Δ[Ca(2+)](i) in PASMCs occurs via Ca(2+) influx through VDCCs mediated primarily by PKC, TKs, and Rho kinase.

    Topics: Animals; Calcium; Calcium Channels; Calcium Signaling; Chronic Disease; Endothelin-1; Fluorescent Dyes; Fura-2; Gene Expression; Hypertension, Pulmonary; Hypoxia; Ion Channel Gating; Male; Microscopy, Fluorescence; Muscle Cells; Muscle, Smooth, Vascular; Protein Kinase C; Protein Kinase Inhibitors; Rats; Rats, Wistar; rho-Associated Kinases

2012
The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease.
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2012, Volume: 26, Issue:6

    Development of pulmonary hypertension is a common and deadly complication of interstitial lung disease. Little is known regarding the cellular and molecular mechanisms that lead to pulmonary hypertension in patients with interstitial lung disease, and effective treatment options are lacking. The purpose of this study was to examine the adenosine 2B receptor (A(2B)R) as a regulator of vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. To accomplish this, cellular and molecular changes in vascular remodeling were monitored in mice exposed to bleomycin in conjunction with genetic removal of the A(2B)R or treatment with the A(2B)R antagonist GS-6201. Results demonstrated that GS-6201 treatment or genetic removal of the A(2B)R attenuated vascular remodeling and hypertension in our model. Furthermore, direct A(2B)R activation on vascular cells promoted interleukin-6 and endothelin-1 release. These studies identify a novel mechanism of disease progression to pulmonary hypertension and support the development of A(2B)R antagonists for the treatment of pulmonary hypertension secondary to interstitial lung disease.

    Topics: Adenosine-5'-(N-ethylcarboxamide); Animals; Bleomycin; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Interleukin-6; Lung Diseases, Interstitial; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Purinergic P1 Receptor Agonists; Purines; Pyrazoles; Receptor, Adenosine A2B

2012
Docosahexaenoic acid monoacylglyceride decreases endothelin-1 induced Ca(2+) sensitivity and proliferation in human pulmonary arteries.
    American journal of hypertension, 2012, Volume: 25, Issue:7

    Pulmonary artery vasoconstriction and vascular remodeling contribute to a sustained elevation of pulmonary vascular resistance and pressure in patients with pulmonary arterial hypertension (PH), an often fatal hemodynamic disease. The effect of docosahexaenoic acid monoacylglyceride (MAG-DHA) and the role of the 17 kDa protein kinase C-potentiated inhibitor protein (CPI-17) were determined on vasoconstriction and smooth muscle cell proliferation of human pulmonary arteries (HPA).. HPA were obtained from 16 patients undergoing lung resection for carcinoma. The mechanical tension and Ca(2+) sensitivity were measured on arterial rings treated with endothelin-1 (ET-1) in the absence or presence of MAG-DHA. The effect of MAG-DHA on the level of proliferation of smooth muscle cells isolated from HPA was evaluated in order to determine the role of CPI-17 protein.. MAG-DHA treatment decreased the reactivity and Ca(2+) sensitivity induced by ET-1 in HPA. MAG-DHA treatment also decreased the expression of vascular endothelial growth factor (VEGF) induced by ET-1. Moreover, both VEGF inhibitor and MAG-DHA treatments reduced Ca(2+) hypersensitivity induced by ET-1, which was associated to a reduction in CPI-17 and myosin-binding subunit of the myosin light chain phosphatase (MYPT-1) phosphorylation levels. Proliferation of ET-1-stimulated HPA smooth muscle cells (PASMc) was also decreased following CPI-17 small interfering RNA transfection and MAG-DHA treatments. Western blot analyses revealed that MAG-DHA treatment resulted in decreased phosphorylation levels of CPI-17 and extracellular signal-regulated kinases (ERK) in PASMc treated with ET-1.. We have demonstrated that VEGF interacts with CPI-17 signaling pathway resulting in an increase in Ca(2+) sensitivity and proliferation of PASMc, whereas MAG-DHA treatment reversed these effects.

    Topics: Calcium; Cell Proliferation; Endothelin-1; Humans; Hypertension, Pulmonary; Intracellular Signaling Peptides and Proteins; Monoglycerides; Muscle Proteins; Muscle, Smooth, Vascular; Phosphoprotein Phosphatases; Pulmonary Artery; Vascular Endothelial Growth Factor A; Vasoconstriction

2012
Beneficial effects of γ-aminobutyric acid on right ventricular pressure and pulmonary vascular remodeling in experimental pulmonary hypertension.
    Life sciences, 2012, Oct-15, Volume: 91, Issue:13-14

    It has been reported that activation of the sympathetic nervous system and increase in plasma norepinephrine (NE) levels are observed in patients with pulmonary hypertension (PH). γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system and suppresses peripheral sympathetic neurotransmission. This study investigated whether chronic treatment with GABA prevents the development of monocrotaline (MCT)-induced PH. To elucidate the relationship between the development of PH and sympathetic nerve activity, hemodynamic parameters, cardiac functions, and plasma NE concentrations as well as cardiac endothelin-1 (ET-1) contents of MCT-induced PH rats were evaluated with or without GABA treatment.. Rats were injected with MCT (60 mg/kg) or saline subcutaneously and these rats were randomly divided into GABA (500 mg/kg/day for 4 weeks)- or vehicle-treated groups, respectively.. MCT-treated rats had higher right ventricular systolic pressures, right ventricle-to-left ventricle plus septum weight ratios, pulmonary arterial medial thickening, and plasma NE levels than those of saline-injected rats. MCT-induced alternations were significantly attenuated by treatment with GABA. In MCT-induced PH rats with or without GABA treatment, plasma NE levels were positively correlated with right ventricular systolic pressure. Right ventricular endothelin-1 (ET-1) contents were increased by MCT injection, but these increments were not affected by treatment with GABA.. These results suggest that plasma NE levels play an important role in the development of MCT-induced PH in rats and that GABA exerts a preventive effect against MCT-induced PH by suppressing the sympathetic nervous system but not the cardiac ET-1 system.

    Topics: Animals; Blood Pressure; Disease Models, Animal; Endothelin-1; gamma-Aminobutyric Acid; Heart Ventricles; Hypertension, Pulmonary; Male; Monocrotaline; Norepinephrine; Pulmonary Artery; Random Allocation; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System; Ventricular Pressure

2012
[The endothelin-1 and von Willebrand factor in the development of lung hypertension in children with chronic bronchopulmonary pathology].
    Klinicheskaia laboratornaia diagnostika, 2012, Issue:1

    The assessment of the indicators of functional state of endothelium (endothelin-1 level and von Willebrand factor activity) was implemented in healthy children and patients with bronchopulmonary pathology with normal and high pressure in pulmonary artery It is established that pulmonary hypertension in children with chronic bronchopulmonary pathology is associated with the endothelium dysfunction (increase of endothelin-1 concentration and activity of von Willebrand factor). The direct dependence of evidence of the pulmonary hypertension from the level of endothelin-1 and activity of von Willebrand factor is proved. The increase of the level of endothelin-1 and the activity of von Willebrand factor is a risk factor of the development of pulmonary hypertension in children with chronic bronchopulmonary pathology.

    Topics: Adolescent; Bronchial Diseases; Child; Child, Preschool; Chronic Disease; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension, Pulmonary; Male; Risk Factors; von Willebrand Factor

2012
Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension.
    Circulation, 2012, Aug-21, Volume: 126, Issue:8

    Pulmonary arterial hypertension (PAH) is characterized, in part, by decreased endothelial nitric oxide (NO(·)) production and elevated levels of endothelin-1. Endothelin-1 is known to stimulate endothelial nitric oxide synthase (eNOS) via the endothelin-B receptor (ET(B)), suggesting that this signaling pathway is perturbed in PAH. Endothelin-1 also stimulates adrenal aldosterone synthesis; in systemic blood vessels, hyperaldosteronism induces vascular dysfunction by increasing endothelial reactive oxygen species generation and decreasing NO(·) levels. We hypothesized that aldosterone modulates PAH by disrupting ET(B)-eNOS signaling through a mechanism involving increased pulmonary endothelial oxidant stress.. In rats with PAH, elevated endothelin-1 levels were associated with elevated aldosterone levels in plasma and lung tissue and decreased lung NO(·) metabolites in the absence of left-sided heart failure. In human pulmonary artery endothelial cells, endothelin-1 increased aldosterone levels via peroxisome proliferator-activated receptor gamma coactivator-1α/steroidogenesis factor-1-dependent upregulation of aldosterone synthase. Aldosterone also increased reactive oxygen species production, which oxidatively modified cysteinyl thiols in the eNOS-activating region of ET(B) to decrease endothelin-1-stimulated eNOS activity. Substitution of ET(B)-Cys405 with alanine improved ET(B)-dependent NO(·) synthesis under conditions of oxidant stress, confirming that Cys405 is a redox-sensitive thiol that is necessary for ET(B)-eNOS signaling. In human pulmonary artery endothelial cells, mineralocorticoid receptor antagonism with spironolactone decreased aldosterone-mediated reactive oxygen species generation and restored ET(B)-dependent NO(·) production. Spironolactone or eplerenone prevented or reversed pulmonary vascular remodeling and improved cardiopulmonary hemodynamics in 2 animal models of PAH in vivo.. Our findings demonstrate that aldosterone modulates an ET(B) cysteinyl thiol redox switch to decrease pulmonary endothelium-derived NO(·) and promote PAH.

    Topics: Aldosterone; Animals; Cells, Cultured; Cysteine; Disease Models, Animal; Endothelial Cells; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Male; Mineralocorticoid Receptor Antagonists; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidation-Reduction; Oxidative Stress; Pulmonary Artery; Pulmonary Wedge Pressure; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Spironolactone; Sulfhydryl Compounds

2012
Biventricular structural and functional responses to aortic constriction in a rabbit model of chronic right ventricular pressure overload.
    The Journal of thoracic and cardiovascular surgery, 2012, Volume: 144, Issue:6

    Chronic right ventricular (RV) pressure overload results in pathologic RV hypertrophy and diminished RV function. Although aortic constriction has been shown to improve systolic function in acute RV failure, its effect on RV responses to chronic pressure overload is unknown.. Adjustable vascular banding devices were placed on the main pulmonary artery and descending aorta. In 5 animals (sham group), neither band was inflated. In 9 animals (PAB group), only the pulmonary arterial band was inflated, with adjustments on a weekly basis to generate systemic or suprasystemic RV pressure at 28 days. In 9 animals, both pulmonary arterial and aortic devices were inflated (PAB + AO group), the pulmonary arterial band as for the PAB group and the aortic band adjusted to increase proximal systolic blood pressure by approximately 20 mm Hg. Effects on the functional performance were assessed 5 weeks after surgery by conductance catheters, followed by histologic and molecular assessment.. Contractile performance was significantly improved in the PAB + AO group versus the PAB group for both ventricles. Relative to sham-operated animals, both banding groups showed significant differences in myocardial histologic and molecular responses. Relative to the PAB group, the PAB + AO group showed significantly decreased RV cardiomyocyte diameter, decreased RV collagen content, and reduced RV expression of endothelin receptor type B, matrix metalloproteinase 9, and transforming growth factor β genes.. Aortic constriction in an experimental model of chronic RV pressure overload not only resulted in improved biventricular systolic function but also improved myocardial remodeling. These data suggest that chronically increased left ventricular afterload leads to a more physiologically hypertrophic response in the pressure-overloaded RV.

    Topics: Animals; Aorta; Arterial Pressure; Chronic Disease; Collagen; Collagenases; Connective Tissue Growth Factor; Constriction; Disease Models, Animal; Endothelin-1; Familial Primary Pulmonary Hypertension; Heart Failure; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Myocardial Contraction; Myocardium; Pulmonary Artery; Rabbits; Receptors, Endothelin; Recovery of Function; Time Factors; Transforming Growth Factor beta; Ventricular Function, Left; Ventricular Function, Right; Ventricular Pressure; Ventricular Remodeling

2012
[Pathophysiological characteristics of rat pulmonary hypertension and cor pulmonale induced by monocrotaline].
    Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 2012, Volume: 28, Issue:3

    To explore the mechanism of pulmonary hypertension and Cor Pulmonale rat models induced by monocrotaline (MCT).. Twenty Wistar male rats were randomly divided into normal control group and model group (n= 10), which received a single intraperitoneal injection of MCT solution (50 mg/kg , the first day) or dissolvant, respectively. On day 28 after MCT administration, the hemodynamic parameters were assessed; levels of tumour necrosis factor-alpha (TNF-alpha), nitric oxide (NO), endothelin-1 (ET-1), B-type natriuretic peptide(BNP) in pulmonary tissue or blood were measured using radio immunoassay or nitrate reductase method.. 28 days after MCT injection, compared with control group, right ventricle systolic pressure (RVSP) increased and heart rate(HR), mean arterial pressure (MAP) decreased; Levels of TNF-alpha, NO, ET-1 in pulmonary tissue or blood increased significantly in MCT group.. The potential mechanism of MCI- induced pulmonary hypertension and Cor Pulmonale rat models associates with increasing TNF-alpha, NO, ET-1 levels in vivo, which results from inflammatory injury of lung tissue and blood vessels induced by MCT.

    Topics: Animals; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Nitric Oxide; Pulmonary Heart Disease; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

2012
Plasma endothelin-1 and vascular endothelial growth factor levels and their relationship to hemodynamics in idiopathic pulmonary fibrosis.
    Respiration; international review of thoracic diseases, 2012, Volume: 84, Issue:4

    Pulmonary hypertension (PH) is associated with a poor prognosis in idiopathic pulmonary fibrosis (IPF). Endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) are important in both fibrosis and vascular remodeling.. We sought to determine the relationship between ET-1 and VEGF levels and hemodynamics in patients with IPF. We hypothesized that higher levels of ET-1 and VEGF would be associated with higher pulmonary artery pressures (PAP) and pulmonary vascular resistance (PVR) in patients with IPF.. We performed a cross-sectional analysis of 52 adults with IPF enrolled in a prospective cohort with available clinical data, platelet-free plasma, and hemodynamics. ET-1 and VEGF levels were measured via immunoassay. The associations of ET-1 and VEGF with PAP and PVR were examined using generalized additive models adjusted for age, gender, race/ethnicity, and forced vital capacity (% predicted).. Sixteen of 52 (30.8%) had PH (mean PAP ≥25 mm Hg). After multivariable adjustment, higher ET-1 levels were significantly associated with higher systolic (p = 0.01), diastolic (p = 0.02), and mean (p = 0.01) PAP and possibly higher PVR (p = 0.09). There were no significant associations between VEGF levels and hemodynamics.. Higher levels of ET-1 were associated with higher PAP and possibly higher PVR in participants with IPF. In a subgroup of patients, ET-1 may be a contributor to pulmonary vascular disease burden in IPF.

    Topics: Aged; Arterial Pressure; Cross-Sectional Studies; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Male; Middle Aged; Prospective Studies; Pulmonary Artery; Vascular Endothelial Growth Factor A; Vascular Resistance

2012
Pulmonary hypertension: have we learned enough yet?
    Internal and emergency medicine, 2012, Volume: 7, Issue:5

    Topics: Endothelin-1; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Polymorphism, Genetic; Receptor, Endothelin A

2012
Viral Toll Like Receptor activation of pulmonary vascular smooth muscle cells results in endothelin-1 generation; relevance to pathogenesis of pulmonary arterial hypertension.
    Biochemical and biophysical research communications, 2012, Oct-05, Volume: 426, Issue:4

    Pulmonary arterial hypertension (PAH) is a rare but fatal condition in which raised pulmonary vascular resistance leads to right heart failure and death. Endothelin-1 is a potent endogenous vasoconstrictor, which is considered to be central to many of the events that lead to PAH, and is an important therapeutic target in the treatment of the condition. In many cases of PAH, the aetiology is unknown but inflammation is increasingly thought to play an important role and viruses have been implicated in the development of disease. The Toll Like Receptors (TLRs) play a key role in innate immune responses by initiating specific anti-bacterial and anti-viral defences in recognition of signature molecular motifs on the surface of invading pathogens. In this study, we set out to examine the expression of bacterial and viral TLRs in human pulmonary artery smooth muscle cells and to establish whether their activation could be relevant to PAH. We found that the viral TLR3 and bacterial TLRs 4 and 6 were most abundantly expressed in human pulmonary artery smooth muscle cells. Using specific TLR ligands, we found that activation of TLRs 3 and 4 resulted in IL-8 release by human pulmonary artery smooth muscle cells but that only TLR3 stimulation resulted in IP10 and endothelin-1 release. These data suggest that human pulmonary artery smooth muscle cells express significant levels of viral TLR3 and respond to its activation by releasing endothelin-1. This may have importance in understanding the association between viruses and the development of PAH.

    Topics: Cells, Cultured; Chemokines; Cytokines; Endothelin-1; Familial Primary Pulmonary Hypertension; Gene Expression; Humans; Hypertension, Pulmonary; Interleukin-8; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Poly I-C; Receptors, Cytokine; Toll-Like Receptor 3; Tumor Necrosis Factor-alpha

2012
Bosentan reduces pulmonary artery pressure in high altitude residents.
    High altitude medicine & biology, 2012, Volume: 13, Issue:3

    Endothelin-1 (ET-1) plays a critical role in the regulation of pulmonary vascular tone. The aim of this study was to investigate the role of ET-1 in the pathogenesis of high altitude pulmonary arterial hypertension (HAPH).. Pulmonary artery pressure (PAP) was measured by echocardiography in permanent residents of the Kyrgyz Republic (3200-4000 m above sea level) both before and 3 h after a single oral dose of ET receptor antagonist, bosentan (125 mg). Plasma ET-1 levels were measured by ELISA assay. Genomic DNA was extracted from peripheral blood samples and the frequency of -3a and -4a alleles of the ET-1 gene determined by PCR.. Plasma ET-1 in HAPH highlanders was significantly higher than in healthy subjects (7.05±2.35 vs. 4.65±1.65 pg/ml, p<0.002). After the treatment with 125 mg bosentan, systolic PAP decreased from 46±1.9 to 37±2.2 mm Hg (p<0.01), and pulmonary artery acceleration time (PAAT) increased from 0.086±0.001 to 0.098±0.001 sec (p<0.001). The frequency of the -4a allele was significantly higher in HAPH patients compared to healthy highlanders (0.43 vs. 0.3, χ(2)=4.3, p=0.03).. Increased ET-1 levels play an important role in development of HAPH.

    Topics: Adult; Aged; Altitude; Antihypertensive Agents; Bosentan; Case-Control Studies; Echocardiography; Endothelin-1; Female; Gene Frequency; Genotype; Humans; Hypertension, Pulmonary; Male; Middle Aged; Polymorphism, Genetic; Pulmonary Artery; Sulfonamides

2012
Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells.
    PloS one, 2012, Volume: 7, Issue:10

    Two endothelin receptor antagonists (ERAs), bosentan and ambrisentan, are currently approved for the treatment of pulmonary arterial hypertension (PAH), a devastating disease involving an activated endothelin system and aberrant contraction and proliferation of pulmonary arterial smooth muscle cells (PASMC). The novel ERA macitentan has recently concluded testing in a Phase III morbidity/mortality clinical trial in PAH patients. Since the association and dissociation rates of G protein-coupled receptor antagonists can influence their pharmacological activity in vivo, we used human PASMC to characterize inhibitory potency and receptor inhibition kinetics of macitentan, ambrisentan and bosentan using calcium release and inositol-1-phosphate (IP(1)) assays. In calcium release assays macitentan, ambrisentan and bosentan were highly potent ERAs with K(b) values of 0.14 nM, 0.12 nM and 1.1 nM, respectively. Macitentan, but not ambrisentan and bosentan, displayed slow apparent receptor association kinetics as evidenced by increased antagonistic potency upon prolongation of antagonist pre-incubation times. In compound washout experiments, macitentan displayed a significantly lower receptor dissociation rate and longer receptor occupancy half-life (ROt(1/2)) compared to bosentan and ambrisentan (ROt(1/2):17 minutes versus 70 seconds and 40 seconds, respectively). Because of its lower dissociation rate macitentan behaved as an insurmountable antagonist in calcium release and IP(1) assays, and unlike bosentan and ambrisentan it blocked endothelin receptor activation across a wide range of endothelin-1 (ET-1) concentrations. However, prolongation of the ET-1 stimulation time beyond ROt(1/2) rendered macitentan a surmountable antagonist, revealing its competitive binding mode. Bosentan and ambrisentan behaved as surmountable antagonists irrespective of the assay duration and they lacked inhibitory activity at high ET-1 concentrations. Thus, macitentan is a competitive ERA with significantly slower receptor dissociation kinetics than the currently approved ERAs. Slow dissociation caused insurmountable antagonism in functional PASMC-based assays and this could contribute to an enhanced pharmacological activity of macitentan in ET-1-dependent pathologies.

    Topics: Animals; Bosentan; Calcium; CHO Cells; Clinical Trials, Phase III as Topic; Cricetinae; Endothelin Receptor Antagonists; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Inositol Phosphates; Myocytes, Smooth Muscle; Phenylpropionates; Pulmonary Artery; Pyridazines; Pyrimidines; Receptors, Endothelin; Sulfonamides

2012
[Pathophysiology of pulmonary hypertension: advances and prospects].
    Revue des maladies respiratoires, 2012, Volume: 29, Issue:8

    Topics: Endothelin-1; Endothelium, Vascular; Fibroblast Growth Factors; Humans; Hypertension, Pulmonary; Immunoglobulin G; Leptin; Myofibroblasts; Nitric Oxide; Platelet-Derived Growth Factor; Prognosis; Prostaglandins I; Protein Kinase Inhibitors; Serotonin; Serotonin Receptor Agonists; T-Lymphocytes

2012
Cardiomyocyte-specific overexpression of HEXIM1 prevents right ventricular hypertrophy in hypoxia-induced pulmonary hypertension in mice.
    PloS one, 2012, Volume: 7, Issue:12

    Right ventricular hypertrophy (RVH) and right ventricular (RV) contractile dysfunction are major determinants of prognosis in pulmonary arterial hypertension (PAH) and PAH remains a severe disease. Recently, direct interruption of left ventricular hypertrophy has been suggested to decrease the risk of left-sided heart failure. Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) is a negative regulator of positive transcription elongation factor b (P-TEFb), which activates RNA polymerase II (RNAPII)-dependent transcription and whose activation is strongly associated with left ventricular hypertrophy. We hypothesized that during the progression of PAH, increased P-TEFb activity might also play a role in RVH, and that HEXIM1 might have a preventive role against such process. We revealed that, in the mouse heart, HEXIM1 is highly expressed in the early postnatal period and its expression is gradually decreased, and that prostaglandin I(2), a therapeutic drug for PAH, increases HEXIM1 levels in cardiomyocytes. These results suggest that HEXIM1 might possess negative effect on cardiomyocyte growth and take part in cardiomyocyte regulation in RV. Using adenovirus-mediated gene delivery to cultured rat cardiomyocytes, we revealed that overexpression of HEXIM1 prevents endothelin-1-induced phosphorylation of RNAPII, cardiomyocyte hypertrophy, and mRNA expression of hypertrophic genes, whereas a HEXIM1 mutant lacking central basic region, which diminishes P-TEFb-suppressing activity, could not. Moreover, we created cardiomyocyte-specific HEXIM1 transgenic mice and revealed that HEXIM1 ameliorates RVH and prevents RV dilatation in hypoxia-induced PAH model. Taken together, these findings indicate that cardiomyocyte-specific overexpression of HEXIM1 inhibits progression to RVH under chronic hypoxia, most possibly via inhibition of P-TEFb-mediated enlargement of cardiomyocytes. We conclude that P-TEFb/HEXIM1-dependent transcriptional regulation may play a pathophysiological role in RVH and be a novel therapeutic target for mitigating RVH in PAH.

    Topics: Animals; Disease Progression; Endothelin-1; Gene Expression; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Mice; Mice, Transgenic; Myocytes, Cardiac; Organ Specificity; Positive Transcriptional Elongation Factor B; Rats; RNA-Binding Proteins; Transcription Factors

2012
[Adenosine receptors agonists mitigated PAH of rats induced by chronic hypoxia through reduction of renin activity/angiotensin II levels and increase of inducible nitric oxide synthase-nitric oxide levels].
    Zhonghua er ke za zhi = Chinese journal of pediatrics, 2012, Volume: 50, Issue:10

    Recent studies showed that adenosine played important roles in vasodilation. This study aimed to investigate the effects of adenosine, its A1 and A2b receptor agonists on pulmonary artery hypertension (PAH) induced by chronic hypoxia in rats by continuously subcutaneous administration with an osmotic pump for 14 days, and to see if rennin angiotensin system and inducible nitric oxygen synthase (iNOS)/nitric oxide (NO) mediate the effects.. Fifty-six male SD rats were randomly assigned to seven groups. Each group included eight rats. They were normoxic group, hypoxic group, adenosine-treated group [adenosine was administered at a dose of 150 µg(kg·min) under the hypoxic condition], adenosine A1 receptor agonist CPA-treated group [CPA was administered at a dose of 20 µg/(kg·min) under the hypoxic condition], CPA plus selective adenosine A1 antagonist DPCPX-treated group [CPA and DPCPX were administered simultaneously under the hypoxic condition, the dose of CPA was the same as the above, and the dose of DPCPX was 25 µg/(kg·min)], adenosine A2b receptor agonist NECA-treated group [NECA was administered at a dose of 30 µg/(kg·min) under the hypoxic condition], NECA plus selective adenosine A2b receptor antagonist MRS-treated group[ NECA and MRS1754 were administered simultaneously under the hypoxic condition, the dose of NECA was the same as the above, and the dose of MRS1754 was 50 µg/(kg·min)]. Osmotic pumps containing adenosine or selective adenosine A1 receptor agonist (CPA), or nonselective but potent adenosine A2b receptor agonist (NECA) were placed subcutaneously 7 days after hypoxia and continuously administered the agents for 14 days.Mean pulmonary artery pressure (mPAP) was detected after administration of the agents. Then blood samples were taken from heart for measurement of renin activity, angiotensin II (AngII) and endothelin-1 (ET-1) concentration by radioimmunoassay, NO by measuring nitrate. Small pulmonary arteries were prepared for immunoreactivity staining of proliferating cell nuclear antigen (PCNA) and iNOS.. (1) Chronic hypoxia induced PAH [mPAP: (31.38 ± 3.42) mm Hg]. Adenosine or CPA or NECA administered for 14 days by subcutaneous route attenuated the mPAP [(21.17 ± 3.56) mm Hg, (22.88 ± 2.95) mm Hg, (19.81 ± 2.39) mm Hg, respectively], which showed significant difference when compared with hypoxia group (P < 0.05 respectively). (2) Plasma rennin activity and AngII level in hypoxia group [(2.51 ± 0.25) ng/(ml·h), (83.01 ± 9.38) pg/ml] were significantly higher than that in normoxic group (P < 0.05, respectively).(3) Adenosine treatment decreased the rennin activity and AngII level when compared with hypoxic group(P < 0.05, respectively);CPA and NECA attenuated respectively the rennin activity and AngII level of rats induced by chronic hypoxia (P < 0.05, respectively). (4) Adenosine administration for 14 days attenuated the wall thickness induced by chronic hypoxia (P < 0.05). CPA showed no effect on wall thickness, but NECA significantly attenuated the wall thickness (P < 0.05). (5) The number of iNOS staining positive cells in small pulmonary artery was higher in hypoxia group than in that in normoxic rats (23.75 ± 7.91 vs. 8.00 ± 2.20, P < 0.05). Adenosine or CPA, or NECA administration increased respectively the iNOS expression in rats treated with chronic hypoxia. Chronic hypoxia caused significant decrease of nitric oxide level. Adenosine treatment increased the nitric oxide level in rats treated with chronic hypoxia. CPA and NECA also increased respectively the nitric oxide level in rats treated with chronic hypoxia. Chronic hypoxia caused significant increase of ET-1 level. The ET-1 level in rats treated with adenosine, CPA or NCEA respectively were lower than that in chronic hypoxia rats (P < 0.05). (6) Adenosine treatment partially attenuated the number of PCNA-positively stained cells. NECA treatment also attenuated the PCNA expression, but CPA showed no effect.. Adenosine and its agonists CPA, NECA administered continually by subcutaneous route attenuate mPAP of rats induced by chronic hypoxia. CPA attenuates mPAP through reduction of RA/AngII activity and balance of NO/ET-1 level. NECA attenuates mPAP by inhibiting PCNA expression and proliferation of mooth muscle of pulmonary artery.

    Topics: Adenosine; Angiotensin II; Animals; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Proliferating Cell Nuclear Antigen; Pulmonary Artery; Purinergic P1 Receptor Agonists; Random Allocation; Rats; Rats, Sprague-Dawley; Renin

2012
[Effect of hypoxia-inducible factor-1α, endothelin-1 and inducible nitric oxide synthase in the pathogenesis of hypoxia-induced pulmonary hypertension of the neonatal rats].
    Zhonghua er ke za zhi = Chinese journal of pediatrics, 2012, Volume: 50, Issue:12

    To study the effect of hypoxia-inducible factor-1α (HIF-1α) in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH) of the neonatal rats through the study on the expression level of HIF-1α and its regulation factors: endothelin-1 (ET-1) and inducible nitric oxide synthase (iNOS) in blood serum and lung tissue.. To make an HPH model of neonatal rats, 120 newborn Wistar rats were divided at random into two groups: HPH group and the regular oxygen controlled group with the same birthday. The rats of the two groups were put in the condition of hypoxia for 3, 5, 7, 10, 14, 21 days and then 10 rats of HPH group and control group were picked up, their mean pulmonary arterial pressure (mPAP), serum HIF-1α, and iNOS, and ET-1 content were tested, and finally their lung tissue was taken after they were sacrificed and the expression level of the gene mRNA of HIF-1α, iNOS and ET-1.. (1) The rats experienced hypoxia for 3, 5, 7, 10, 14 or 21 days had an increasing mPAP: [8.47 ± 1.45, 10.04 ± 1.69, 10.89 ± 2.97, 16.96 ± 1.97, 13.01 ± 1.93, 21.04 ± 2.13 (mm Hg)], which had a significant differences compared with control groups [5.11 ± 1.06, 8.12 ± 1.11, 8.77 ± 0.92, 12.23 ± 1.78, 8.89 ± 0.89, 11.09 ± 1.64 (mm Hg)] (P < 0.05). (2) The rats in hypoxia group had a higher serum HIF-1α [0.83 ± 0.07, 0.84 ± 0.17, 0.97 ± 0.13, 1.10 ± 0.30, 0.92 ± 0.19 (pg/nmol)] than the control group [0.26 ± 0.20, 0.37 ± 0.16, 0.44 ± 0.18, 0.41 ± 0.23, 0.66 ± 0.18 (pg/nmol)] as they experienced hypoxia for 3, 5, 7, 10, and 14 days (P < 0.05); HIF-1α mRNA expression in lung tissue (1.301 ± 0.47, 1.032 ± 0.47, 1.453 ± 0.76) was also significantly higher than that of the control group (0.231 ± 0.26, 0.425 ± 0.59, 0.692 ± 0.13) (P < 0.05); serum ET-1 levels [51.50 ± 3.19, 44.1 ± 10.81, 56.85 ± 9.10, 52.91 ± 9.59, 51.16 ± 8.87, 50.21 ± 10.41 (pg/nmol)] were clearly higher than that of the control group [9.04 ± 2.85, 21.70 ± 8.78, 19.63 ± 9.66, 18.30 ± 7.32, 19.69 ± 5.92, 16.88 ± 6.14 (pg/nmol)] (P < 0.01); ET-1 mRNA expression in lung tissue (0.037 ± 0.018) was significantly increased after 3-day hypoxia as compared with control group (0.006 ± 0.004) (P < 0.05). Serum content of iNOS (5.62 ± 0.79) µmol/L was significantly higher than the control group (1.63 ± 0.67) µmol/L (P < 0.05) after a 3-day hypoxia, but there was no significant difference after a hypoxia for 5, 7 or 10 days, compared with the control group (P > 0.05), and the content of serum iNOS after hypoxia for 14 or 21 days (4.56 ± 0.96, 5.86 ± 1.76) µmol/L was lower than that of the control group (10.35 ± 1.99, 8.44 ± 2.76) µmol/L (P < 0.05). iNOS mRNA expression in lung tissue (0.035 ± 0.024, 0.332 ± 0.198, 0.527 ± 0.098) significantly increased after hypoxia for 3, 5 or 7 days as compared with the control group (0.005 ± 0.0001, 0.008 ± 0.002, 0.040 ± 0.012) (P < 0.05).. As an initial factor, low oxygen made HIF-1α, ET-1 and iNOS expression raised in the pathogenesis of HPH of the neonatal rats and causedn a imbalance of ET-1 and NO. HIF-1α, ET-1 and iNOS altogether contributed to the occurrence and development of HPH in neonatal rats.

    Topics: Animals; Animals, Newborn; Arterial Pressure; Disease Models, Animal; Endothelin-1; Female; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lung; Male; Nitric Oxide Synthase Type II; Pulmonary Artery; Random Allocation; Rats; Rats, Wistar; RNA, Messenger

2012
[Relationship between serum uric acid levels and patient conditions and prognosis in idiopathic pulmonary arterial hypertension].
    Zhonghua yi xue za zhi, 2012, Dec-11, Volume: 92, Issue:46

    To explore the relationship between serum uric acid levels and patient conditions and prognosis in idiopathic pulmonary arterial hypertension (IPAH).. A total of 76 IPAH patients confirmed by right heart catheterization were enrolled consecutively and followed up until the endpoint of all-cause death. Their baseline data were recorded and analyzed by Spearman's rank test and independent t-test. And the follow-up outcomes were analyzed with Kaplan-Meier plots.. There were 27 males and 49 females with a mean age of 29.7 ± 9.7 years. They were classified into World Health Organization functional class (WHO-FC)II (n = 28), class III (n = 45) and class IV (n = 3). Their baseline mean pulmonary artery pressure was (65 ± 16) mm Hg, pulmonary vascular resistance (1677 ± 669) dyn×s(-1)×cm(-5), pulmonary capillary wedge pressure (9.6 ± 5.0) mm Hg, mean right atrial pressure (9.8 ± 6.1) mm Hg, cardiac index (2.07 ± 0.57) L ×min(-1)× m(-2) and serum uric acid (391 ± 103) µmol/L. The correlation analysis indicated that the serum level of uric acid correlated positively with right ventricular diameter (r = 0.28, P = 0.018) and negatively with CI (r = -0.34, P = 0.003). Independent t-test results indicated that the patients with a higher level of uric acid were apt to have a worse WHO-FC, and the higher level uric acid group (serum uric acid > 416.5 µmol/L) had a relative higher level of WHO-FC, NT-proBNP and endothelin-1. A lower level of CI denoted more severe conditions and prognosis. Survival analysis indicated that the serum level of uric acid could strongly predict survival in IPAH patients with over time and those with a high level of uric acid had a worse prognosis.. The serum level of uric acid correlates significantly with patient conditions and prognosis in IPAH. And a higher serum level of uric acid predicts worse conditions and prognosis.

    Topics: Adult; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Natriuretic Peptide, Brain; Prognosis; Uric Acid; Young Adult

2012
Attenuation of pulmonary hypertension secondary to left ventricular dysfunction in the rat by Rho-kinase inhibitor fasudil.
    Pediatric pulmonology, 2011, Volume: 46, Issue:1

    Pulmonary hypertension (PH) in left ventricular dysfunction is attributable not only to backward failure of the left ventricle, but also to increased pulmonary vascular resistance (PVR) in some patients. Recently, Rho-kinase has been known as a potent growth stimulator and mediator of vasoconstriction, and Rho-kinase inhibitors could ameliorate PVR, little is known about the role of Rho-kinase in left ventricular dysfunction-induced PH. We utilized the ascending aortic-banded rat and assessed the effect of Rho-kinase inhibitor fasudil on the development of PH secondary to left ventricular dysfunction. Subsequently, in rats subjected to aortic banding for 6 weeks, there were increases in mean pulmonary arterial pressure, pulmonary arteriolar medial thickness, active RhoA, Rho-kinase II, Rho-kinase activity, endothelial nitric oxide synthase (eNOS) and endothelin-1(ET-1) concomitant with decreased levels in NO and cGMP in the lung. Treatment with fasudil at a dose of 30 mg/kg/day from days 1 to 28 or from days 29 to 42 decreased the mean pulmonary arterial pressure by 57% and 56%, right ventricular hypertrophy by 31% and 30%, pulmonary arteriolar medial thickness by 50% and 50%, and pulmonary expression of Rho-kinase II by 41% and 28%, respectively, as well as augmented pulmonary expression of eNOS by 16% and 31% and NO by 50% and 76%, respectively, when compared with the vehicle controls. In conclusion, these results suggest that inhibition of Rho-kinase may provide therapeutic potential for preventing and attenuating the development of PH in left ventricular dysfunction. Further translational study in human is needed to substantiate the findings.

    Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Arterioles; Cyclic GMP; Endothelin-1; Hypertension, Pulmonary; Lung; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Protein Kinase Inhibitors; Pulmonary Artery; Rats; Rats, Wistar; rho-Associated Kinases; Treatment Outcome; Ventricular Dysfunction, Left

2011
B-type natriuretic peptide, vascular endothelial growth factor, endothelin-1, and nitric oxide synthase in chronic mountain sickness.
    American journal of physiology. Heart and circulatory physiology, 2011, Volume: 300, Issue:4

    The pathogenesis of chronic mountain sickness (CMS) may involve vasoactive peptides. The aim of this study was to investigate associations between CMS and levels of B-type natriuretic peptide (BNP), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and endothelial nitric oxide synthase (eNOS). A total of 24 patients with CMS and 50 control subjects residing at 4,300 m participated in this study. Mean pulmonary arterial pressure (mPAP) was measured by echocardiography. Serum BNP, VEGF, ET-1, and eNOS were measured. Receiver operator characteristic curves to assess the balance of sensitivity and specificity for CMS were constructed. As a result, patients with CMS had significantly greater mPAP compared with controls and had lower arterial O(2) saturation (Sa(O(2))). Both BNP and ET-1 correlated positively with mPAP and negatively with Sa(O(2)), whereas serum VEGF levels were inversely correlated with Sa(O(2)); eNOS correlated negatively with mPAP and positively with Sa(O(2)). Median concentrations of BNP were greater in patients with CMS compared with those without CMS: 369 pg/ml [interquartile range (IQR) = 336-431] vs. 243 pg/ml (IQR = 216-279); P < 0.001. Similarly, concentrations of VEGF [543 pg/ml (IQR = 446-546) vs. 243 pg/ml (IQR = 216-279); P < 0.001] and ET-1 [14.7 pg/ml (IQR = 12.5-17.9) vs. 11.1 pg/ml (IQR = 8.7-13.9); P = 0.05] were higher in those with CMS compared with those without, whereas eNOS levels were lower in those with CMS [8.90 pg/ml (IQR 7.59-10.8) vs. 11.2 pg/ml (9.13-13.1); P < 0.001]. The areas under the receiver operator characteristic curves for diagnosis of CMS were 0.91, 0.93, 0.77, and 0.74 for BNP, VEGF, ET-1, and eNOS, respectively. In age- and biomarker-adjusted logistic regression, BNP and VEGF were positively predictive of CMS, whereas eNOS was inversely predictive. In conclusion, severe chronic hypoxemia and consequent pulmonary hypertension in patients with CMS may stimulate release of natriuretic peptides and angiogenic cytokines. These vasoactive peptides may play an important role in the pathogenesis and clinical expression of CMS and may indicate potential prognostic factors in CMS that could serve as targets for therapeutic trials or clinical decision making.

    Topics: Adult; Altitude Sickness; Blood Pressure; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Nitric Oxide Synthase Type III; Oxygen; Pulmonary Artery; ROC Curve; Sensitivity and Specificity; Ultrasonography; Vascular Endothelial Growth Factors

2011
[Role of hypoxia-inducible factor-1α endothelin-1 and inducible nitric oxide synthase in the pathogenesis of hypoxia-induced pulmonary hypertension of the newborn].
    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 2011, Volume: 13, Issue:1

    To investigate the roles of hypoxia-inducible factor-1α (HIF-1α), endothelin-1 (ET-1) and inducible nitric oxide synthase (iNOS) in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH) of the newborn.. Seventy-five term hospitalized neonates with HPH (mild 29 cases, moderate 25 cases, severe 21 cases) and 22 term hospitalized neonates without HPH (control group) were enrolled between June 2006 and November 2009. Serum levels of HIF-1α, iNOS and ET-1 were measured using ELASA 1, 3 and 7 days after birth.. Serum concentrations of HIF-1α and ET-1 in the mild, moderate and severe HPH groups were significantly higher than those in the control group (P<0.01) 1 day after birth, and were related to the severity of HPH. The serum iNOS concentrations in the moderate and severe HPH groups were also significantly higher than those in the control group (P<0.01). By 3 days after birth, serum ET-1 concentration in the moderate HPH group and serum concentrations of HIF-1α, ET-1 and iNOS in the severe HPH group reminded significantly higher than those in the control group (P<0.05). At 7 days after birth, serum ET-1 concentration in the severe HPH group still remained higher than that in the control group (P<0.05).. Serum levels of HIF-1α, ET-1 and iNOS increase in neonates with HPH, resulting in an imbalance of ET-1 and NO. This may be of importance in the pathogenesis of neonatal HPH.

    Topics: Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Infant, Newborn; Male; Nitric Oxide Synthase Type II

2011
Role of the gap junctions in the contractile response to agonists in pulmonary artery from two rat models of pulmonary hypertension.
    Respiratory research, 2011, Mar-17, Volume: 12

    Pulmonary hypertension (PH) is characterized by arterial vascular remodelling and alteration in vascular reactivity. Since gap junctions are formed with proteins named connexins (Cx) and contribute to vasoreactivity, we investigated both expression and role of Cx in the pulmonary arterial vasoreactivity in two rat models of PH.. Intrapulmonary arteries (IPA) were isolated from normoxic rats (N), rats exposed to chronic hypoxia (CH) or treated with monocrotaline (MCT). RT-PCR, Western Blot and immunofluorescent labelling were used to study the Cx expression. The role of Cx in arterial reactivity was assessed by using isometric contraction and specific gap junction blockers. Contractile responses were induced by agonists already known to be involved in PH, namely serotonin, endothelin-1 and phenylephrine.. Cx 37, 40 and 43 were expressed in all rat models and Cx43 was increased in CH rats. In IPA from N rats only, the contraction to serotonin was decreased after treatment with 37-43Gap27, a specific Cx-mimetic peptide blocker of Cx 37 and 43. The contraction to endothelin-1 was unchanged after incubation with 40Gap27 (a specific blocker of Cx 40) or 37-43Gap27 in N, CH and MCT rats. In contrast, the contraction to phenylephrine was decreased by 40Gap27 or 37-43Gap27 in CH and MCT rats. Moreover, the contractile sensitivity to high potassium solutions was increased in CH rats and this hypersensitivity was reversed following 37-43Gap27 incubation.. Altogether, Cx 37, 40 and 43 are differently expressed and involved in the vasoreactivity to various stimuli in IPA from different rat models. These data may help to understand alterations of pulmonary arterial reactivity observed in PH and to improve the development of innovative therapies according to PH aetiology.

    Topics: Analysis of Variance; Animals; Blood Pressure; Blotting, Western; Connexin 43; Connexins; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Fluorescent Antibody Technique; Gap Junction alpha-4 Protein; Gap Junction alpha-5 Protein; Gap Junctions; Hypertension, Pulmonary; Hypoxia; Male; Monocrotaline; Muscle, Smooth, Vascular; Phenylephrine; Pulmonary Artery; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Serotonin; Vasoconstriction; Vasoconstrictor Agents

2011
[Serum levels of HIF-1α, ET-1 and Ca(2+) in neonates with hypoxic pulmonary hypertension].
    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 2011, Volume: 13, Issue:3

    To study the changes and significance of serum hypoxia-inducible factor-1α (HIF-1α), endothelin-1 (ET-1) and calcium (Ca(2+)) levels in neonates with hypoxic pulmonary hypertension (HPH).. Seventy-five neonates with HPH (29 mild, 25 moderate and 21 severe) and 22 hospitalized neonates with non-HPH (control group) were enrolled. Pulmonary artery systolic blood pressure (PASP) was measured by bedside echocardiography within 24 hrs after birth. Serum levels of HIF-1α and ET-1 were measured using ELASA. Serum Ca2+ concentrations were measured with ion selective electrode.. Serum levels of HIF-1α and ET-1 in the HPH group increased significantly compared with those in the control group (P<0.01), and were positively related with PASP (Rhif-1α=0.75, P<0.01; Ret-1=0.56,P<0.05). Serum Ca2+ levels in neonates with severe HPH were significantly lower than those in the control group (P<0.05). There were no correlation between serum Ca2+ levels and PASP.. Serum HIF-1α and ET-1 levels are positively related with PASP in neonates with HPH, suggesting that serum HIF-1α and ET-1 may be involved in the occurrence of neonatal HPH. Serum Ca2+ levels are reduced in severe neonates with HPH, suggesting that serum Ca2+ may play a role in the occurrence of severe HPH.

    Topics: Blood Pressure; Calcium; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Infant, Newborn; Male; Pulmonary Artery

2011
Activation of endothelin-1 receptor signaling pathways is associated with neointima formation, neoangiogenesis and irreversible pulmonary artery hypertension in patients with congenital heart disease.
    Circulation journal : official journal of the Japanese Circulation Society, 2011, Volume: 75, Issue:6

    It is unclear why some patients, who undergo complete repair or palliative surgery for congenital heart disease (CHD), still develop irreversible pulmonary artery hypertension (PAH). There is no consensus to preoperationally assess the reversible and irreversible pulmonary vasculopathy seen in PAH.. The peri-operative pulmonary hemodynamic data of 16 CHD patients (reversible PAH, n = 6; irreversible PAH, n = 10) were analyzed. The lung biopsies were also performed during surgery for defining histopathological characteristics as well as immunohistochemical expression of endothelin-1 (ET-1), endothelin-1 receptors (ETR), and its downstream signaling markers in the small pulmonary arteries and arterioles. Neointimal formation and neoangiogenesis was characterized by increased intimal layer immunoreactivity for α-SMA, Factor VIII, CD34, and VEGF. Neointimal formation was found in 90% of patients and neoangiogenesis was found in 80% of patients with irreversible PAH. Neither was present in the reversible PAH group and the control group. Expression of ET-1 and ETR in the neointimal layer of the pulmonary arterioles was upregulated in irreversible PAH, and immunoreactivity of phospho-Akt, phospho-ERK1/2, and phospho-mTOR was also increased in irreversible PAH.. Increased expression of ET-1, ETR, and activation of signaling pathways were observed in the pulmonary arteries and arterioles of irreversible PAH patients associated with CHD. Activation of these pathways might in turn lead to neointimal formation and neoangiogenesis and thus might contribute to irreversible pulmonary vascular abnormalities.

    Topics: Actins; Adolescent; Adult; Antigens, CD34; Biopsy; Cell Proliferation; China; Endothelin-1; Factor VIII; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Immunohistochemistry; Male; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neovascularization, Pathologic; Phosphorylation; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Receptor, Endothelin A; Receptor, Endothelin B; Retrospective Studies; Signal Transduction; TOR Serine-Threonine Kinases; Tunica Intima; Up-Regulation; Vascular Endothelial Growth Factor A; Young Adult

2011
Bosentan attenuates right ventricular hypertrophy and fibrosis in normobaric hypoxia model of pulmonary hypertension.
    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 2011, Volume: 30, Issue:7

    Maladaptive right ventricular (RV) hypertrophic responses lead to RV dysfunction and failure in patients with pulmonary arterial hypertension, but the mechanisms responsible for these changes are not well understood. The objective of this study was to evaluate the effect of treatment with bosentan on RV hypertrophy (RVH), fibrosis and expression of protein kinase C (PKC) isoforms in the RV of rats exposed to chronic hypoxia.. Adult Sprague-Dawley rats were housed in normoxia or hypoxia (FIO(2) = 10%) and administered vehicle or 100 mg/kg/day bosentan. After 3 weeks, echocardiographic and hemodynamic assessment was performed. PKC, procollagen-1 and collagen expression levels were assessed using immunoblot or colorimetric assay.. RV systolic pressure (RVSP) and RVH were higher in hypoxic compared with normoxic animals (RVSP: 72 ± 4 vs 25 ± 2 mm Hg, p < 0.05; RVH: 1.2 ± 0.06 vs 0.5 ± 0.03 mg/g body weight, p < 0.05). Bosentan had no effect on RVSP or mass in normoxic animals, but did attenuate RVH in hypoxic animals (hypoxic/vehicle: 1.2 ± 0.06; hypoxic/bosentan: 1.0 ± 0.05 mg/g body weight; p < 0.05). Hypoxia increased RV procollagen-1, and total collagen expression, effects that were attenuated by bosentan treatment. Hypoxia increased RV total and cytosolic PKC-δ protein expression, but had no effect on PKC-α or -ε isoforms. Administration with bosentan did not affect total PKC-δ protein expression. However, animals treated with bosentan had an increase in membranous PKC-δ when exposed to hypoxia.. Bosentan inhibits RVH and RV collagen expression in rats exposed to chronic hypoxia, possibly via alteration of PKC-δ activity.

    Topics: Animals; Antihypertensive Agents; Bosentan; Collagen; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Fibrosis; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Myocardium; Protein Isoforms; Protein Kinase C; Rats; Rats, Sprague-Dawley; Signal Transduction; Sulfonamides; Ventricular Dysfunction, Right

2011
Efficacy of aminaftone in a rat model of monocrotaline-induced pulmonary hypertension.
    European journal of pharmacology, 2011, Sep-30, Volume: 667, Issue:1-3

    Pulmonary hypertension is characterized by increased vascular resistances, that could lead to right heart failure and death. Endothelin-1 (ET-1) is a peptide with strong vasoconstrictive and pro-fibrotic properties and is one of the main mediators of pulmonary hypertension. Aminaftone, a synthetic molecule derivative of 4-amynobenzoic acid, down-regulates ET-1 production in vitro by interfering with the transcription of the pre-pro-ET-1 gene. The aim of this study was to test whether the inhibition of ET-1 production by aminaftone attenuates the effects of pulmonary hypertension. Pulmonary hypertension was induced through s.c. injection of 60 mg/kg monocrotaline. The rats were randomly assigned to the following experimental groups: Control; Monocrotaline; Aminaftone 30 mg/kg/day; Aminaftone 150 mg/kg/day. After 5 weeks, mortality was significantly lower in the animals treated with aminaftone at both doses compared to monocrotaline alone. Aminaftone reduced plasma concentration of ET-1 and seemed to reduce right heart hypertrophy and the wall thickness of the pulmonary arteries at the highest dose. Aminaftone may represent a novel treatment strategy of pulmonary hypertension.

    Topics: 4-Aminobenzoic Acid; Animals; Body Weight; Cardiomegaly; Disease Models, Animal; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; para-Aminobenzoates; Pulmonary Artery; Rats; Rats, Wistar; Survival Analysis

2011
Exogenous ghrelin improves blood flow distribution in pulmonary hypertension-assessed using synchrotron radiation microangiography.
    Pflugers Archiv : European journal of physiology, 2011, Volume: 462, Issue:3

    Ghrelin has cardioprotective properties and, recently, has been shown to improve endothelial function and reduce endothelin-1 (ET-1)-mediated vasoconstriction in peripheral vascular disease. Recently, we reported that ghrelin attenuates pulmonary hypertension (PH) caused by chronic hypoxia (CH), which we hypothesized in this study may be via suppression of the ET-1 pathway. We also aimed to determine whether ghrelin's ability to prevent alterations of the ET-1 pathway also prevented adverse changes in pulmonary blood flow distribution associated with PH. Sprague-Dawley rats were exposed to CH (10% O(2) for 2 weeks) with daily subcutaneous injections of ghrelin (150 μg/kg) or saline. Utilizing synchrotron radiation microangiography, we assessed pulmonary vessel branching structure, which is indicative of blood flow distribution, and dynamic changes in vascular responsiveness to (1) ET-1 (1 nmol/kg), (2) the ET-1(A) receptor antagonist, BQ-123 (1 mg/kg), and (3) ACh (3.0 μg kg⁻¹ min⁻¹). CH impaired blood flow distribution throughout the lung. However, this vessel "rarefaction" was attenuated in ghrelin-treated CH-rats. Moreover, ghrelin (1) reduced the magnitude of endothelial dysfunction, (2) prevented an increase in ET-1-mediated vasoconstriction, and (3) reduced pulmonary vascular remodeling and right ventricular hypertrophy-all adverse consequences associated with CH. These results highlight the beneficial effects of ghrelin for maintaining optimal lung perfusion in the face of a hypoxic insult. Further research is now required to establish whether ghrelin is also an effective therapy for restoring normal pulmonary hemodynamics in patients that already have established PH.

    Topics: Acetylcholine; Angiography; Animals; Antihypertensive Agents; Endothelin-1; Ghrelin; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Synchrotrons; Vasoconstriction; Vasodilator Agents

2011
Role for PKCβ in enhanced endothelin-1-induced pulmonary vasoconstrictor reactivity following intermittent hypoxia.
    American journal of physiology. Lung cellular and molecular physiology, 2011, Volume: 301, Issue:5

    Intermittent hypoxia (IH) resulting from sleep apnea causes both systemic and pulmonary hypertension. Enhanced endothelin-1 (ET-1)-induced vasoconstrictor reactivity is thought to play a central role in the systemic hypertensive response to IH. However, whether IH similarly increases pulmonary vasoreactivity and the signaling mechanisms involved are unknown. The objective of the present study was to test the hypothesis that IH augments ET-1-induced pulmonary vasoconstrictor reactivity through a PKCβ-dependent signaling pathway. Responses to ET-1 were assessed in endothelium-disrupted, pressurized pulmonary arteries (∼150 μm inner diameter) from eucapnic-IH [(E-IH) 3 min cycles, 5% O(2)-5% CO(2)/air flush, 7 h/day; 4 wk] and sham (air-cycled) rats. Arteries were loaded with fura-2 AM to monitor vascular smooth muscle (VSM) intracellular Ca(2+) concentration ([Ca(2+)](i)). E-IH increased vasoconstrictor reactivity without altering Ca(2+) responses, suggestive of myofilament Ca(2+) sensitization. Consistent with our hypothesis, inhibitors of both PKCα/β (myr-PKC) and PKCβ (LY-333-531) selectively decreased vasoconstriction to ET-1 in arteries from E-IH rats and normalized responses between groups, whereas Rho kinase (fasudil) and PKCδ (rottlerin) inhibition were without effect. Although E-IH did not alter arterial PKCα/β mRNA or protein expression, E-IH increased basal PKCβI/II membrane localization and caused ET-1-induced translocation of these isoforms away from the membrane fraction. We conclude that E-IH augments pulmonary vasoconstrictor reactivity to ET-1 through a novel PKCβ-dependent mechanism that is independent of altered PKC expression. These findings provide new insights into signaling mechanisms that contribute to vasoconstriction in the hypertensive pulmonary circulation.

    Topics: Animals; Blood Gas Analysis; Blotting, Western; Calcium; Endothelin-1; Fura-2; Gene Expression Regulation; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Muscle, Smooth, Vascular; Protein Kinase C; Protein Kinase C beta; Protein Kinase C-alpha; Protein Kinase Inhibitors; Pulmonary Artery; Rats; Rats, Wistar; rho-Associated Kinases; RNA, Messenger; Signal Transduction; Vasoconstriction; Vasoconstrictor Agents

2011
Portopulmonary hypertension and serum endothelin levels in hospitalized patients with cirrhosis.
    Hepatobiliary & pancreatic diseases international : HBPD INT, 2011, Volume: 10, Issue:4

    Cirrhosis is associated with several extrahepatic manifestations including portopulmonary hypertension (PPHT). Recent data suggest that endothelins (ETs) are related to the pathophysiology of PPHT. The study aimed to measure serum ET levels in hospitalized cirrhotic patients and to determine their association with PPHT and patient outcome.. Fifty-seven cirrhotic patients [43 males; median age 58 (28-87) years] underwent Doppler echocardiography. Patients with systolic pulmonary arterial pressure ≥40 mmHg and pulmonary acceleration time <100 ms were deemed to have PPHT. ET-1, 2, and 3 serum levels were measured with an ELISA assay. All-cause mortality was recorded over a median period of 24 months.. Nine out of 57 patients (15.8%) had PPHT. Among various clinical variables, only autoimmune hepatitis was associated with PPHT (OR=11.5; 95% CI, 1.58-83.4; P=0.01). ET-1 levels [9.1 (1.6-20.7) vs 2.5 (1.4-9.2) pg/mL, P=0.02] and the ET-1/ET-3 ratio [4.73 (0.9-22.4) vs 1.6 (0.3-10.7), P=0.02] were significantly higher in patients with PPHT than in those without. ET-2 and ET-3 levels did not differ between the two groups. There was no difference in survival between the two groups, although ET-1 levels were associated with an adverse outcome in Cox regression analysis (HR=1.11; 95% CI, 1.02-1.22; P=0.02 per unit increase in ET-1).. Our data suggest that ET-1 and the ET-1/ET-3 ratio are elevated in patients with PPHT and that ET-1 is associated with a poor outcome irrespective of PPHT.

    Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Chi-Square Distribution; Echocardiography, Doppler, Color; Echocardiography, Doppler, Pulsed; Endothelin-1; Endothelin-2; Endothelin-3; Endothelins; Enzyme-Linked Immunosorbent Assay; Female; Greece; Hospitalization; Humans; Hypertension, Portal; Hypertension, Pulmonary; Kaplan-Meier Estimate; Liver Cirrhosis; Logistic Models; Male; Middle Aged; Prognosis; Proportional Hazards Models; Risk Assessment; Risk Factors; Time Factors

2011
YC-1 attenuates hypoxia-induced pulmonary arterial hypertension in mice.
    Pulmonary pharmacology & therapeutics, 2011, Volume: 24, Issue:6

    Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance and elevation of pulmonary arterial pressure, leading to right ventricular failure and eventual death. Currently, no curative therapy for PAH is available, and the overall prognosis is very poor. Recently, direct activators of soluble guanylyl cyclase (sGC) have been tested as a novel therapeutic modality in experimental models of pulmonary arterial hypertension (PAH).. In this study, we used in vitro and in vivo models to evaluate the therapeutic potential of 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), a dual functioning chemical, as a direct activator of guanylyl cyclase and an inhibitor of hypoxia-inducible factor-1.. We analyzed the effects of YC-1 on cell proliferation and the levels of p21 and p53 in human pulmonary artery smooth muscle cells (HPASMCs) under hypoxia. We also determined the effects of YC-1 on expression of endothelin-1 (ET-1) and phosphorylation status of endothelial nitric oxide synthase (eNOS) at Ser(1179) in human pulmonary artery endothelial cells (HPAECs) under hypoxia. In mice, hypoxic PAH was induced by exposure to normobaric hypoxic conditions for 28 days. To assess preventive or therapeutic effects, randomized mice were subjected to once daily i.p. injections of YC-1 for the entire hypoxic period (5 mg/kg) or for the last seven days of a 28-day hypoxic period (5 and 10 mg/kg). On day 28, we measured the right ventricular systolic pressure (RVSP) and determined the degrees of right ventricular hypertrophy (RVH) and vascular remodeling.. In HPASMCs, YC-1 inhibited hypoxia-induced proliferation and induction of p53 and p21 in a concentration-dependent manner. Also, YC-1 suppressed the hypoxia-induced expression of ET-1 mRNA and dephosphorylation of eNOS at Ser(1179) in HPAECs. In the preventive in vivo model, a daily dose of 5 mg/kg YC-1 significantly prevented the elevation of RVSP, development of RVH, and pulmonary vascular remodeling, which were caused by hypoxic exposure. In the therapeutic model, YC-1 at daily doses of 5 and 10 mg/kg alleviated RVH and pulmonary vascular remodeling but did not prevent the elevation of RVSP.. Our results indicate that YC-1 prevents the development of hypoxia-induced PAH in a preventive model and alleviates RVH and pulmonary vascular remodeling in a therapeutic model. Therefore, these data imply that YC-1 has therapeutic potential for use in a single or combination therapy for PAH.

    Topics: Animals; Cell Proliferation; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21; Endothelin-1; Enzyme Activators; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Hypoxia; Indazoles; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Nitric Oxide Synthase Type III; Pulmonary Artery; Tumor Suppressor Protein p53

2011
[The relationship between inflammatory mediators and pulmonary hypertension in patients with chronic obstructive pulmonary disease].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2011, Volume: 34, Issue:12

    The levels of C-reactive protein (CRP), tumor necrosis factor (TNF)-α, brain natriuretic peptide (BNP) and endothelin-1 (ET-1) were investigated to analyze the systemic inflammation in chronic obstructive pulmonary disease (COPD) patients with and without pulmonary hypertension.. From January 2006 to December 2010, 89 patients with COPD were enrolled in our hospital. There were 67 males and 22 females, with a mean age of (70 ± 7) and a mean FEV(1) of (47 ± 13)%. Pulmonary pressure was assessed by Doppler echocardiography. The levels of plasma BNP, TNF-α and ET-1 were measured by enzyme-linked immunosorbent assay kits. High-sensitivity plasma CRP level was assessed by chemiluminescent immunoassay.. Forty-two patients were classified as COPD with pulmonary hypertension group and 47 patients as COPD without pulmonary hypertension group. The level of CRP [51.4 mg/L (20.1 - 92.0) mg/L], ET-1 [5.9 ng/L (3.7 - 10.4) ng/L] and BNP [303.2 ng/L (112.5 - 824.7) ng/L] in patients with pulmonary hypertension were significantly higher than in that in patients without hypertension, CRP [26.7 mg/L (11.5 - 62.9) mg/L], ET-1 [2.1 ng/L (1.3 - 4.7) ng/L] and BNP [143.7 ng/L (85.5 - 306.7) ng/L]. The level of TNF-α showed no difference between the 2 groups [8.5 ng/L (4.8 - 13.7) ng/L and 6.7 ng/L (3.2 - 10.3) ng/L], respectively. Multivariate analysis showed that PaO₂ (P < 0.05), CRP (P < 0.05) and BNP (P < 0.05) could predict pulmonary hypertension independently.. The level of CRP, ET-1 and BNP were related to pulmonary hypertension in COPD patients, suggesting that systemic inflammation play a role in the pathogenesis of pulmonary hypertension in COPD.

    Topics: Aged; C-Reactive Protein; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Inflammation; Inflammation Mediators; Male; Middle Aged; Natriuretic Peptide, Brain; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

2011
Protective effects of vasonatrin peptide against hypobaric hypoxia-induced pulmonary hypertension in rats.
    Clinical and experimental pharmacology & physiology, 2010, Volume: 37, Issue:1

    1. The aim of the present study was to investigate the in vivo effects of vasonatrin peptide (VNP) on hypoxia-induced pulmonary hypertension (HPH). 2. The HPH model was developed by subjecting rats to hypobaric hypoxia. The HPH rats were then treated with either VNP (50 microg/kg per day, i.p.) or saline (0.5 mL, i.p.) every day for 7 days. Haemodynamic indices, right ventricular hypertrophy (RVH) and remodelling of the pulmonary arteries were evaluated. In addition, plasma levels of atrial natriuretic peptide (ANP), endothelin (ET)-1 and angiotensin II (AngII) were determined, as was natriuretic peptide receptor-C (NPR-C) mRNA expression in the right ventricle. 3. Hypobaric hypoxia induced severe HPH compared with the normoxic control group. Treatment of HPH rats with VNP for 1 week significantly reduced mean pulmonary arterial pressure, pulmonary vascular resistance, RVH and muscularization of the pulmonary arteries, although pulmonary blood flow was increased in this group. In addition, significantly lower levels of plasma ET-1 and AngII and cardiac NPR-C mRNA expression were observed in VNP-treated compared with saline-treated HPH rats, whereas higher plasma concentrations of ANP were found in the former group. Acute intravenous administration of 50 microg/kg VNP significantly ameliorated pulmonary haemodynamics in HPH rats. 4. Taken together, the date indicate that VNP has certain preventative and therapeutic effects against HPH.

    Topics: Angiotensin II; Animals; Antihypertensive Agents; Atmospheric Pressure; Atrial Natriuretic Factor; Disease Models, Animal; Endothelin-1; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor

2010
Endothelial ET(B) limits vascular remodelling and development of pulmonary hypertension during hypoxia.
    Journal of vascular research, 2010, Volume: 47, Issue:1

    We hypothesised that the potential protective effects of endothelial ET(B) are important in limiting pulmonary vascular muscularisation, vasoconstriction and the development of pulmonary arterial hypertension in response to hypoxia.. EC-specific ET(B) knockout mice (EC ET(B)(-/-)) and control mice (ET(B)(f/f)) were subjected to hypobaric hypoxic (10% FiO2) or normoxic conditions for 14 days before assessment of right ventricular pressure and pulmonary vascular morphology and function.. During normoxia, no difference in right ventricular pressure was detected between EC ET(B)(-/-) (23.7 +/- 1.7 mm Hg) and ET(B)(f/f) mice (20.2 +/- 1.5 mm Hg). Hypoxia induced an exaggerated increase in right ventricular pressure in EC ET(B)(-/-) mice (34.4 +/- 1.2 mm Hg vs. 24.6 +/- 1.4 mm Hg), accompanied by an increase in right ventricular mass. No effect was observed in ET(B)(f/f) mice. Endothelin-1 constricted pulmonary arteries from both groups, although maximum response was similar irrespective of inspired oxygen or genotype. Hypoxia increased the percentage of muscularised vessels in both groups of mice, but the percentage increase was significantly greater in EC ET(B)(-/-) mice.. The potential protective effects of endothelial ET(B) are important in limiting pulmonary vascular muscularisation and the development of pulmonary arterial hypertension in response to hypoxia.

    Topics: Animals; Blood Pressure; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Pulmonary Artery; Receptor, Endothelin B; Vasoconstriction; Ventricular Pressure

2010
Urotensin-II contributes to pulmonary vasoconstriction in a perinatal model of persistent pulmonary hypertension of the newborn secondary to meconium aspiration syndrome.
    Pediatric research, 2010, Volume: 67, Issue:2

    Meconium aspiration syndrome (MAS) disrupts perinatal decreases in pulmonary vascular resistance (PVR) and is the commonest cause of neonatal pulmonary hypertension. The contribution of the potent vasoactive agent urotensin-II (U-II), in the pathophysiology of this condition, is unknown. In a new perinatal model of MAS, we combined measurement of circulating U-II levels with U-II receptor blockade studies. Nineteen anesthetized lambs were instrumented then randomly allocated to the following groups: 1) control (n = 5), 2) control plus specific U-II receptor blockade with palosuran (n = 5), 3) tracheal instillation of meconium (n = 5), 4) meconium instillation plus palosuran (n = 4). Hemodynamics, PVR, and plasma U-II were measured for 6 h after delivery. After birth in controls, U-II increased (p < 0.05), and PVR fell (p = 0.01) and this fall was prevented by U-II receptor blockade. By contrast, meconium lambs displayed a greater rise in U-II levels (p < 0.05 versus control) with an increase in PVR (p < 0.005) that was attenuated by U-II receptor blockade (p < 0.001). These findings suggest that U-II normally acts as a pulmonary vasodilator after birth, but in the presence of MAS, it assumes a vasoconstrictor role. U-II receptor blockade also improves pulmonary hemodynamics in this model.

    Topics: Animals; Animals, Newborn; Blood Pressure; Cardiac Output; Disease Models, Animal; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Meconium Aspiration Syndrome; Oxygen; Pulmonary Artery; Quinolines; Receptors, G-Protein-Coupled; Sheep; Time Factors; Up-Regulation; Urea; Urotensins; Vascular Resistance; Vasoconstriction; Vasodilation

2010
Differential expression of vasoactive mediators in microparticle-challenged lungs of chickens that differ in susceptibility to pulmonary arterial hypertension.
    American journal of physiology. Regulatory, integrative and comparative physiology, 2010, Volume: 298, Issue:1

    Pulmonary hypertension syndrome (PHS; ascites) in fast growing meat-type chickens (broilers) is characterized by the onset of idiopathic pulmonary arterial hypertension (IPAH) leading to right-sided congestive heart failure and terminal ascites. Intravenous microparticle (MP) injection is a tool used by poultry geneticists to screen for the broilers that are resistant (RES) or susceptible (SUS) to IPAH in a breeding population. MPs occlude pulmonary arterioles and initiate focal inflammation, causing local tissues and responding leukocytes to release vasoactive mediators such as serotonin (5-HT), endothelin-1 (ET-1), and nitric oxide (NO). RT-PCR was used to examine the differences between RES and SUS broilers in terms of gene expression of ET-1, ET receptor types A and B (ET(A) and ET(B)), the serotonin transporter (SERT), serotonin receptors (5-HT(1A), 5-HT(2A), 5-HT(1B), 5-HT(2B)), endothelial NO synthase (eNOS), and inducible NOS (iNOS) in the lungs of these broilers before (0 h) and after (2, 6, 12, 24, and 48 h) MP injection. In SUS broilers MP injection elicited higher (P < 0.05) pulmonary expression of 5-HT(1A), 5-HT(2B), and ET-1, which promote vasoconstriction and proliferation of pulmonary arterial smooth muscle cells (PASMC). In RES broilers the MP injection elicited higher expression of eNOS, iNOS, and ET(B), which promote vasodilation and inhibit PASMC proliferation. These observations support the hypothesis that the resistance of broiler chickens to IPAH may be due to the higher expression of vasoactive mediators that favor enhanced vasodilation and attenuated vasoconstriction during MP injection challenges to the pulmonary vasculature.

    Topics: Animals; Chickens; Disease Susceptibility; Endothelin-1; Hypertension, Pulmonary; Injections, Intravenous; Lung; Male; Mass Screening; Microspheres; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Poultry Diseases; Pulmonary Artery; Receptors, Endothelin; Receptors, Serotonin; Serotonin; Vasoconstriction; Vasodilation

2010
Placenta growth factor in sickle cell disease: association with hemolysis and inflammation.
    Blood, 2010, Mar-11, Volume: 115, Issue:10

    Placenta growth factor (PlGF) is released by immature erythrocytes and is elevated in sickle cell disease (SCD). Previous data generated in vitro suggest that PlGF may play a role in the pathophysiology of SCD-associated pulmonary hypertension (PHT) by inducing the release of the vasoconstrictor, endothelin-1. In this cross-sectional study of 74 patients with SCD, we confirm that PlGF is significantly elevated in SCD compared with healthy control subjects. We found significantly higher levels of PlGF in SCD patients with PHT but observed no association of PlGF with the frequency of acute pain episodes or history of acute chest syndrome. The observed correlation between PlGF and various measures of red cell destruction suggests that hemolysis, and the resultant erythropoietic response, results in the up-regulation of PlGF. Although relatively specific, PlGF, as well as N-terminal pro-brain natriuretic peptide and soluble vascular cell adhesion molecule, has low predictive accuracy for the presence of PHT. Prospective studies are required to conclusively define the contribution of PlGF to the pathogenesis of PHT and other hemolytic complications in SCD.

    Topics: Adult; Anemia, Sickle Cell; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Female; Hemolysis; Humans; Hypertension, Pulmonary; Inflammation; Male; Middle Aged; Placenta Growth Factor; Predictive Value of Tests; Pregnancy Proteins; Prognosis; Young Adult

2010
Effect of carbon dioxide on pulmonary vascular tone at various pulmonary arterial pressure levels induced by endothelin-1.
    Lung, 2010, Volume: 188, Issue:3

    There have been contradictory reports suggesting that CO(2) may constrict, dilate, or have no effect on pulmonary vessels. Permissive hypercapnia has become a widely adopted ventilatory technique used to avoid ventilator-induced lung injury, particularly in patients with acute respiratory distress syndrome (ARDS). On the other hand, respiratory alkalosis produced by mechanically induced hyperventilation is the mainstay of treatment for newborn infants with persistent pulmonary hypertension. It is important to clarify the vasomotor effect of CO(2) on pulmonary circulation in order to better evaluate the strategies of mechanical ventilation in intensive care. In the present study, pulmonary vascular responses to CO(2) were observed in isolated rat lungs (n = 32) under different levels of pulmonary arterial pressure (PAP) induced by various doses of endothelin-1 (ET-1). The purposes of this study were to investigate (1) the vasodilatory effect of 5% CO(2) in either N(2) (hypoxic-hypercapnia) or air (normoxic-hypercapnia) at different PAP levels induced by various doses of endothelin-1, and (2) the role of nitric oxide (NO) in mediating the pulmonary vascular response to hypercapnia, hypoxia, and ET-1. The results indicated that (1) CO(2) produces pulmonary vasodilatation at high PAP under ET-1 and hypoxic vasoconstriction; (2) the vasodilatory effect of CO(2) at different pressure levels varies in accordance with the levels of PAP, the dilatory effect tends to be more evident at higher PAP; and (3) endogenous NO attenuates ET-1 and hypoxic pulmonary vasoconstriction but does not augment the CO(2)-induced vasodilatation.

    Topics: Animals; Blood Pressure; Carbon Dioxide; Endothelin B Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; In Vitro Techniques; Male; Nitric Oxide; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Vasodilation

2010
High levels of placenta growth factor in sickle cell disease promote pulmonary hypertension.
    Blood, 2010, Jul-08, Volume: 116, Issue:1

    Pulmonary hypertension is associated with reduced nitric oxide bioavailability and early mortality in sickle cell disease (SCD). We previously demonstrated that placenta growth factor (PlGF), an angiogenic factor produced by erythroid cells, induces hypoxia-independent expression of the pulmonary vasoconstrictor endothelin-1 in pulmonary endothelial cells. Using a lentivirus vector, we simulated erythroid expression of PlGF in normal mice up to the levels seen in sickle mice. Consequently, endothelin-1 production increased, right ventricle pressures increased, and right ventricle hypertrophy and pulmonary changes occurred in the mice within 8 weeks. These findings were corroborated in 123 patients with SCD, in whom plasma PlGF levels were significantly associated with anemia, endothelin-1, and tricuspid regurgitant velocity; the latter is reflective of peak pulmonary artery pressure. These results illuminate a novel mechanistic pathway linking hemolysis and erythroid hyperplasia to increased PlGF, endothelin-1, and pulmonary hypertension in SCD, and suggest that strategies that block PlGF signaling may be therapeutically beneficial.

    Topics: Adult; Anemia, Sickle Cell; Animals; Cell Line; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Humans; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myocardium; Placenta Growth Factor; Pregnancy Proteins

2010
HLA-B35 upregulates endothelin-1 and downregulates endothelial nitric oxide synthase via endoplasmic reticulum stress response in endothelial cells.
    Journal of immunology (Baltimore, Md. : 1950), 2010, May-01, Volume: 184, Issue:9

    The presence of the HLA-B35 allele has emerged as an important risk factor for the development of isolated pulmonary hypertension in patients with scleroderma, however the mechanisms underlying this association have not been fully elucidated. The goal of our study was to determine the molecular mechanisms that mediate the biological effects of HLA-B35 in endothelial cells (ECs). Our data demonstrate that HLA-B35 expression at physiological levels via adenoviral vector resulted in significantly increased endothelin-1 (ET-1) and a significantly decreased endothelial NO synthase (eNOS), mRNA, and protein levels. Furthermore, HLA-B35 greatly upregulated expression of chaperones, including heat shock proteins (HSPs) HSP70 (HSPA1A and HSPA1B) and HSP40 (DNAJB1 and DNAJB9), suggesting that HLA-B35 induces the endoplasmic reticulum (ER) stress and unfolded protein response in ECs. Examination of selected mediators of the unfolded protein response, including H chain binding protein (BiP; GRP78), C/Ebp homologous protein (CHOP; GADD153), endoplasmic reticulum oxidase, and protein disulfide isomerase has revealed a consistent increase of BiP expression levels. Accordingly, thapsigargin, a known ER stress inducer, stimulated ET-1 mRNA and protein levels in ECs. This study suggests that HLA-B35 could contribute to EC dysfunction via ER stress-mediated induction of ET-1 in patients with pulmonary hypertension.

    Topics: Cell Line; Cells, Cultured; Down-Regulation; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endothelin-1; Endothelium, Vascular; HLA-B35 Antigen; Humans; Hypertension, Pulmonary; Nitric Oxide Synthase Type III; Stress, Physiological; Up-Regulation

2010
Congenital diaphragmatic hernia: endothelin-1, pulmonary hypertension, and disease severity.
    American journal of respiratory and critical care medicine, 2010, Aug-15, Volume: 182, Issue:4

    Endothelin-1 (ET1) is dysregulated in pulmonary hypertension (PH). It may be important in the pathobiology of congenital diaphragmatic hernia (CDH).. We hypothesized that ET1 levels in the first month would be higher in infants with CDH who subsequently expired or were discharged on oxygen (poor outcome). We further hypothesized that ET1 levels would be associated with concurrent severity of PH.. We sampled plasma at 24 to 48 hours, and 1, 2, and 4 weeks of age in 40 prospectively enrolled newborns with CDH. We performed echocardiograms to estimate pulmonary artery pressure at less than 48 hours of age and weekly to 4 weeks. PH was classified in relationship to systemic blood pressure (SBP): less than 2/3 SBP, 2/3 SBP-systemic is related to pressure, or systemic-to-suprasystemic pressure.. ET1 levels at 1 and 2 weeks were higher in infants with poor outcome compared with infants discharged on room air (median and interquartile range: 27.2 [22.6, 33.7] vs. 19.1 [16.1, 29.5] pg/ml, P = 0.03; and 24.9 [17.6, 39.5] vs. 17.4 [13.7, 21.8] pg/ml, P = 0.01 at 1 and 2 weeks, respectively). Severity of PH was significantly associated with increasing ET1 levels at 2 weeks (16.1 [13.7, 21.8], 21.0 [17.4, 31.1], and 23.6 [21.9, 39.5] pg/ml for increasing PH class, P = 0.03). Increasing severity of PH was also associated with poor outcome at that time (P = 0.001).. Infants with CDH and poor outcome have higher plasma ET1 levels and severity of PH than infants discharged on room air. Severity of PH is associated with ET1 levels.

    Topics: Biomarkers; Cohort Studies; Echocardiography; Endothelin-1; Female; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Prospective Studies; ROC Curve; Severity of Illness Index; Survival Analysis

2010
Effects of electro-acupuncture on endothelium-derived endothelin-1 and endothelial nitric oxide synthase of rats with hypoxia-induced pulmonary hypertension.
    Experimental biology and medicine (Maywood, N.J.), 2010, Volume: 235, Issue:5

    Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure (PAP), pulmonary vascular remodeling and right ventricular hypertrophy, which are mainly due to endothelial dysfunction. Electro-acupuncture has shown beneficial effects on cardiovascular homeostasis, but little evidence has been obtained on pulmonary effects. The goal of the present study was to investigate whether electro-acupuncture on bladder-13 and -15 points can protect against chronic hypoxia-induced PH by regulating endothelium-derived endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS). Male Wistar rats were exposed to hypoxia to induce PH. Hemodynamic analysis revealed that mean PAP was similar under normoxic conditions. Chronic hypoxia increased mean PAP to 37 +/- 3 mmHg, and electro-acupuncture attenuated it to 29 +/- 3 mmHg. Absolute right ventricular weight was ameliorated by electro-acupuncture from 0.288 +/- 0.048 g to 0.228 +/- 0.029 g under hypoxic conditions. Hypoxia-induced right ventricular hypertrophy index decreased from 0.477 +/- 0.069 to 0.378 +/- 0.053 with electro-acupuncture treatment. Histological examination revealed that hypoxic rats showed increased medial pulmonary artery wall thickness as well as muscularization. However, these alternations by chronic hypoxia were attenuated by electro-acupuncture. There was no difference in eNOS or ET-1 between groups under normoxic conditions. Electro-acupuncture treatment significantly improved the circulating eNOS concentration (365.36 +/- 31.51 pg/mL) compared with only hypoxia exposure (247.60 +/- 30.64 pg/mL). In lung homogenate, levels of eNOS under hypoxia increased from 684.96 +/- 117.90 to 869.86 +/- 197.61 pg/mg by electro-acupuncture treatment. Levels of ET-1 changed oppositely to eNOS in response to electro-acupuncture (ET-1 in plasma, 29.44 +/- 2.09 versus 20.70 +/- 2.37 pg/mL; ET-1 in lung homogenate, 120.51 +/- 3.03 versus 110.60 +/- 4.04 pg/mg). In conclusion, these results indicated that treatment with electro-acupuncture can protect against hypoxia-induced PH, possibly by regulating the balance of endothelium-derived vasoconstrictors and vasodilators.

    Topics: Animals; Electroacupuncture; Endothelin-1; Endothelium; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Lung; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Tissue Extracts

2010
Plasma cytokines and portopulmonary hypertension in patients with cirrhosis waiting for orthotopic liver transplantation.
    Angiology, 2010, Volume: 61, Issue:8

    Portopulmonary hypertension (PPHTN) is a rare complication in patients with portal hypertension. A role of endothelin 1 (ET-1) and other cytokines was demonstrated in primary pulmonary hypertension but not in PPHTN. We evaluated the possible role of ET-1, interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNF-α) in the pathogenesis of PPHTN. Plasmatic concentrations of ET-1, IL-6, IL-1β, and TNF-α were measured in patients with pulmonary systolic arterial pressure (PAPs) >30 mm Hg and in patients with cirrhosis. In all, Six out of 11 patients with PAPs >30 mm Hg had PPHTN on right heart catheterization. The remaining 10 patients had an hyperdynamic circulation (HC). In PPHTN patients, ET-1 and IL-6 were significantly higher compared with HC and patients with cirrhosis. Endothelin 1 and IL-6 could be implicated in the pathogenesis of PPHTN. On the basis of these results, ET-1 receptor antagonists or anti-IL-6 could have a rationale in the treatment of PPHTN.

    Topics: Cardiac Catheterization; Cytokines; Echocardiography, Doppler, Color; Endothelin-1; Humans; Hypertension, Portal; Hypertension, Pulmonary; Interleukin-1beta; Interleukin-6; Liver Cirrhosis; Liver Transplantation; Middle Aged; Tumor Necrosis Factor-alpha

2010
Inhibition of endothelin-1 and hypoxia-induced pulmonary pressor responses in the rat by a novel selective endothelin-A receptor antagonist, di-n-butylaminocarbamyl-L-leucyl-D-tryptophanyl-D-4-chloro-Phe.
    Journal of cardiovascular pharmacology, 2010, Volume: 56, Issue:3

    Pulmonary hypertension is a kind of disease associated with a very high rate of mortality, and there are not many effective drugs for the treatment. Today, endothelin (ET)-1 receptor antagonists were proved to be effective in the treatment of pulmonary hypertension. Aiming at developing new endothelin-A receptor (ETA) antagonist for treatment of pulmonary hypertension, di-n-butylaminocarbamyl-L-leucyl-D-tryptophanyl-D-4-chloro-Phe, named GF063, was synthesized at base of selective ETA receptor antagonist BQ485 and selected for the further pharmacological characterization. The preliminary pharmacodynamics of GF063 was evaluated by radioligand receptor binding assay and test of antivasoconstriction effects in vitro and in vivo. The integrative pharmacodynamics was evaluated in hypoxia-induced rat pulmonary hypertension. In vitro, GF063 bound to ETA receptor with 100,000-fold higher affinity than to ETB receptor. GF063 concentration dependently inhibited contraction of isolated rat aortic ring induced by ET-1 and shifted the cumulative concentration-contraction response curve to right with no change in the maximal response. In vivo, GF063 inhibited the increase of mean systemic arterial pressure induced by ET-1 in anesthetized rat. In hypoxia-induced rat pulmonary hypertension model, pretreatment with GF063 (40 mg/kg, s.c.) significantly decreased pulmonary artery pressure and right ventricular hypertrophy, also significantly inhibited the increase of ET-1 level in lung, improved hemodynamics, and alleviated the wall thickness of pulmonary vessels. This study indicated that GF063, as a selective ETA receptor antagonist, could inhibit vasoconstriction effects in vivo and in vitro, could prevent pulmonary hypertension induced by hypoxia, and may have great potential to be developed as a new drug of antipulmonary hypertension.

    Topics: Animals; Aorta, Thoracic; Blood Pressure; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Lung; Male; Oligopeptides; Pulmonary Artery; Rats; Rats, Wistar; Vasoconstriction

2010
Rosiglitazone attenuates hypoxia-induced pulmonary arterial hypertension in rats.
    Respirology (Carlton, Vic.), 2010, Volume: 15, Issue:4

    Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) is decreased in the lungs of patients with pulmonary hypertension, and PPARgamma ligands have been associated with the release of vasoactive substances from vascular endothelial cells and prevention of vascular remodelling. We hypothesized that PPARgamma may play a critical role in the development of pulmonary hypertension induced by chronic hypoxia.. Male adult Sprague-Dawley rats were exposed to normoxia, normoxia and rosiglitazone (8 mg/kg orally, 5 days/week), hypoxia (12% inspired O(2) fraction), or hypoxia and rosiglitazone for 4 weeks. On the last day of the fourth week, pulmonary arterial pressure was measured and morphological changes in pulmonary vessels were assessed. The expression of PPARgamma, endothelin (ET)-1 and vascular endothelial growth factor (VEGF) was also analysed.. Rosiglitazone inhibited the development of pulmonary hypertension, and pulmonary vascular remodelling induced by chronic hypoxia. PPARgamma expression was decreased and expression of ET-1 and VEGF was increased in lung tissues of the hypoxia group. Rosiglitazone treatment prevented the hypoxia-induced reduction in PPARgamma expression, and restored ET-1 and VEGF expression almost to the levels of the normoxia group.. Rosiglitazone inhibited the development of pulmonary hypertension induced by chronic hypoxia, perhaps by reversing the changes in PPARgamma, ET-1 and VEGF expression induced by hypoxia. These findings indicate that rosiglitazone may be beneficial in the treatment of chronic hypoxic pulmonary hypertension.

    Topics: Animals; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; PPAR gamma; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Rosiglitazone; Thiazolidinediones; Vascular Endothelial Growth Factors

2010
BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension.
    American journal of physiology. Lung cellular and molecular physiology, 2010, Volume: 299, Issue:3

    Macrophage derived-endothelin-1 (ET-1) has been suggested to contribute to a number of chronic lung diseases. Whether the ET-1 cascade from non-vascular sources (inflammatory cells) also contributes to pulmonary artery hypertension (PAH) and in particular to heritable PAH (HPAH) with known bone morphogenetic protein type 2 receptor (BMPR2) mutations is not known. We tested this notion using bone marrow-derived macrophages (BMDM; precursors of tissue macrophages) isolated from ROSA26rtTAXTetO(7)-tet-BMPR2(R899X) mice (model of PAH with universal expression of a mutated BMPR2 gene) with and without activation by LPS and in human lung tissue from HPAH with BMPR2 mutations and idiopathic PAH (IPAH). At baseline ET(A) and ET(B) receptors and endothelin converting enzyme (ECE) gene expression was reduced in BMPR2 mutant BMDM compared with controls. In control BMDM, LPS resulted in increased ppET-1 gene expression and ET-1 in culture media, whereas ET(A) and ET(B) receptor and ECE gene expression was decreased. These findings were more severe in BMPR2 mutant BMDM. Antagonism of the ET(B) receptor resulted in increased ET-1 in the media, suggesting that decreased ET-1 uptake by the ET(B) receptor contributes to the elevation. While ET-1 expression was demonstrated in lung macrophages from controls and IPAH and HPAH patients, ET(A) and ET(B) expression was decreased in the HPAH, but not IPAH, patients compared with controls. We conclude that reduced expression of macrophage ET-1 receptors in HPAH increases lung ET-1 and may contribute to the pathogenesis and maintenance of HPAH. This is the first description of protein expression that distinguishes HPAH from IPAH in patients.

    Topics: Adolescent; Adult; Aged; Animals; Aspartic Acid Endopeptidases; Bone Morphogenetic Protein Receptors, Type II; Endothelin-1; Endothelin-Converting Enzymes; Female; Gene Expression; Humans; Hypertension, Pulmonary; Macrophages; Macrophages, Alveolar; Male; Metalloendopeptidases; Mice; Mice, Mutant Strains; Microscopy, Confocal; Middle Aged; Mutation; Receptor, Endothelin A; Receptor, Endothelin B; Tissue Distribution; Young Adult

2010
Bone morphogenic protein-9 stimulates endothelin-1 release from human pulmonary microvascular endothelial cells: a potential mechanism for elevated ET-1 levels in pulmonary arterial hypertension.
    Microvascular research, 2010, Volume: 80, Issue:3

    Abnormalities of signalling for the transforming growth factor beta (TGFβ) family of peptides, including bone morphogenic proteins (BMP), have been described in heritable pulmonary arterial hypertension (PAH). TGFβ can modulate synthesis of the vasoconstrictor and mitogen, endothelin-1 (ET-1), a mediator that contributes to the pathogenesis of PAH. BMP-9 is a circulating peptide recently recognized to affect endothelial function. The stimuli for increased microvascular endothelial production of ET-1 in PAH are unknown. We therefore studied the effects of BMP-9 on ET-1 production by human lung blood microvascular endothelial cells (HMVEC-LBl) in vitro. In vitro, BMP-9 increased ET-1 production by HMVEC-LBl. The effect was identical to TGFβ-1, but BMP-9 and TGFβ-1 combined further increased ET-1 levels by 29%. As compared to TGFβ-1, BMP-9 induced more potent and rapid phosphorylation of Smad 1/5, the downstream signalling molecules of the activin-like kinase 1 (ALK-1) receptor. Moreover, as has been previously shown for endothelial cells of other origin, BMP-9 also induced Smad 2 phosphorylation in HMVEC-LBl. In conclusion, BMP-9 stimulates ET-1 production by HMVEC-LBl in vitro. BMP-9 signals via several Smad pathways. These studies provide novel mechanisms for the potentiation of PAH.

    Topics: Cells, Cultured; Endothelial Cells; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Familial Primary Pulmonary Hypertension; Growth Differentiation Factor 2; Humans; Hypertension, Pulmonary; Lung; Microvessels; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Receptor, Endothelin B; Signal Transduction; Smad1 Protein; Smad2 Protein; Smad5 Protein; Time Factors; Transforming Growth Factor beta1; Up-Regulation

2010
Determination of endothelin-1 in rats using a high-performance liquid chromatography coupled to electrospray tandem mass spectrometry.
    Talanta, 2010, Jul-15, Volume: 82, Issue:2

    A sensitive and specific liquid chromatography tandem mass spectrometry method with electrospray ionization for the determination of endothelin-1 in rat plasma and lung effluents has been developed and validated. Detection was achieved by an Applied Biosystems MDS Sciex API 2000 triple quadrupole mass spectrometer coupled to an Agilent 1100 LC system. The limit of detection and the limit of the quantification of ET-1 in matrix buffer was estimated at 40 pM and 1 nM, respectively. The precision and accuracy for both intra- and inter-day determination of the analyte ranged from 2.5% to 14.7% and from 104.2% to 113.3%, respectively. No significant relative matrix effect was observed. Stability of ET-1 established in a bench-top, autosampler, long-term storage stability as well as freeze/thaw cycles shown no significant degradation products in the samples. The results of the method validation indicated that this method is applicable for the determination of the ET-1 concentration in an effluent from the isolated lung preparation as well as in vivo in plasma samples to evaluate ET-1 as a potential biomarker of the progression of pulmonary endothelial dysfunction and pulmonary hypertension in rats induced by a monocrotaline injection.

    Topics: Animals; Chromatography, High Pressure Liquid; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Limit of Detection; Molecular Structure; Rats; Tandem Mass Spectrometry

2010
Protective effects of a dual endothelin converting enzyme/neutral endopeptidase inhibitor on the development of pulmonary hypertension secondary to cardiac dysfunction in the rat.
    Pediatric pulmonology, 2010, Volume: 45, Issue:11

    Endothelium-derived nitric oxide (NO) and endothelin (ET)-1 interact to regulate the vascular tone in pulmonary hypertension (PH). We investigated the protective effects of an orally active, dual endothelin converting enzyme (ECE)/neutral endopeptidase (NEP) inhibitor/CGS 26393 on pulmonary vascular remodeling and pulmonary expressions of ET-1 and endothelial nitric oxide synthase (eNOS) during the development of PH secondary to cardiac dysfunction. Significant increases in the mean pulmonary arterial pressure, pulmonary arteriolar medial thickness, and pulmonary expression of ET-1 were seen in rats subjected to aortic banding for 4 weeks, compared with sham-operated rats. Treatment with CGS 26393 (30 mg/kg, twice daily, p.o.) began on 1 day after aortic banding. CGS 26393 treated rats had lower mean pulmonary arterial pressure (15 ± 1 mmHg, mean ± SEM, P < 0.05) compared to vehicle-treated rats (37 ± 1 mmHg). It also normalized pulmonary arteriolar medial thickness and reduced the levels of pulmonary ET-1 and big ET-1 by 55% (P < 0.05) and 28% (P < 0.01), respectively, when compared with vehicle-treated animals. Meanwhile, the expressions of eNOS mRNA and eNOS protein and cGMP levels in the lung of CGS 26393-treated rats were increased by 62% (P < 0.05), 100% (P < 0.05), and 32% (P < 0.01), respectively, compared to the vehicle-treated rats. These results suggest that CGS 26393 could offer preventive effects on the development of PH by ameliorating pulmonary remodeling, decreasing ET-1 production, and up-regulating eNOS and cGMP in aorta-banded rats. However, the molecular mechanisms by which treatment with CGS 26393 results in altered expressions of eNOS and cGMP awaits further investigation.

    Topics: Animals; Aspartic Acid Endopeptidases; Blood Pressure; Endothelin-1; Endothelin-Converting Enzymes; Hypertension, Pulmonary; Lung; Metalloendopeptidases; Neprilysin; Nitric Oxide Synthase Type III; Organophosphonates; Protease Inhibitors; Pulmonary Artery; Rats; Rats, Wistar; Tetrazoles; Up-Regulation

2010
[Some special characteristics of vascular reactivity in heart failure].
    Kardiologiia, 2010, Volume: 50, Issue:7

    We determined parameters of elasticity of peripheral arteries in patients with heart failure (HF) including those with pulmonary arterial hypertension. We also investigated pulmonary artery responses to vasoconstricting factors in vitro. Reactivity of the aorta and carotid artery was studied on the model of experimental HF. Lowering of elasticity of small arteries progressed with worsening of HF functional class and increase of pulmonary arterial hypertension. In the genesis of pulmonary hypertension definite role played elevated constrictor response of pulmonary artery to endothelin 1 at the background of dysfunction of endothelial ETB receptors. Endothelial dependent reactivity of the aorta and carotid artery was impaired and their constrictor effect augmented.

    Topics: Comorbidity; Disease Progression; Elasticity; Endothelin B Receptor Antagonists; Endothelin-1; Endpoint Determination; Heart Failure; Humans; Hypertension, Pulmonary; Pulmonary Artery; Receptor, Endothelin B; Vascular Resistance; Vasoconstrictor Agents

2010
Sildenafil added to sitaxsentan in overcirculation-induced pulmonary arterial hypertension.
    American journal of physiology. Heart and circulatory physiology, 2010, Volume: 299, Issue:4

    Experimental left-to-right shunt-induced pulmonary arterial hypertension (PAH) can be partially prevented by the endothelin-A receptor blocker sitaxsentan or by the phosphodiesterase-5 inhibitor sildenafil. We hypothesized that the combined administration of these drugs would completely prevent shunt-induced PAH, arguing in favor of a major role of endothelial dysfunction in the initiation of the disease. Twenty-four 3-wk-old piglets were randomized to a sham operation or to placebo, sitaxsentan therapy, or sitaxsentan combined with sildenafil after the anastomosis of the left subclavian artery to the pulmonary arterial trunk. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry and quantitative real-time PCR for endothelin-1, angiopoietin-1, and bone morphogenetic protein receptor (BMPR) signaling molecules. Three months of left-to-right shunting induced an increase in pulmonary vascular resistance (PVR) and medial thickness, an overexpression of endothelin-1, and angiopoietin-1 and decreased expressions of BMPR-2 and BMPR-1A. Sitaxsentan partially prevented a shunt-induced increase in PVR, medial thickness, and associated biological disturbances. Sildenafil combined with sitaxsentan normalized PVR, medial thickness, and the expression of endothelin-1. However, the expression of angiopoietin-1 remained increased, and the expressions of BMPR-1A and BMPR-2 were incompletely returned to normal. The coupling of right ventricular end-systolic to arterial elastances was maintained in all circumstances. Sitaxsentan combined with sildenafil prevents shunt-induced PAH more effectively than sitaxsentan alone, suggesting a major role for the targeted signaling pathways in the initiation of the disease. Sitaxsentan alone or combined with sildenafil did not affect right ventricular function.

    Topics: Angiopoietin-1; Animals; Bone Morphogenetic Protein Receptors, Type II; Disease Models, Animal; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Isoxazoles; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Pulmonary Circulation; Purines; Sildenafil Citrate; Subclavian Artery; Sulfones; Thiophenes; Treatment Outcome

2010
Endothelin-mediated gut microcirculatory dysfunction during porcine endotoxaemia.
    British journal of anaesthesia, 2010, Volume: 105, Issue:5

    The potent vasoconstrictor endothelin-1 has been implicated in the pathogenesis of the microcirculatory dysfunction seen in sepsis. The mixed endothelin receptor antagonist tezosentan and the selective endothelin A-receptor antagonist TBC3711 were used to investigate the importance of the different endothelin receptors in modulating splanchnic regional blood flow and microvascular blood flow in endotoxaemia.. Eighteen anaesthetized pigs were i.v. infused with endotoxin (Escherichia coli lipopolysaccharide, serotype 0111:b4) for 300 min. After 120 min, six animals received tezosentan and six animals received TBC3711. Six animals served as endotoxin-treated controls. Laser Doppler flowmetry was used to measure microcirculatory blood flow in the liver and ileum. Superior mesenteric artery flow (SMA(FI)) and portal vein flow (PV(FI)) were measured with ultrasonic flow probes, and air tonometry was used to measure Pco₂ in the ileal mucosa.. TBC3711 did not improve splanchnic regional blood flow or splanchnic microvascular blood flow compared with endotoxin-treated controls. Tezosentan increased PV(FI) (P<0.05), but SMA(FI) was not improved compared with the other groups. In the tezosentan group, microvascular blood flow in the ileal mucosa (MCQ(muc)) improved and mucosal-arterial Pco₂ gap decreased (P<0.05 for both) compared with endotoxin-treated controls and the TBC3711 group.. Tezosentan improved MCQ(muc) without any concomitant increase in SMA(FI), implying a direct positive effect on the microcirculation. TBC3711 was not effective in improving regional splanchnic blood flow or splanchnic microvascular blood flow. Dual endothelin receptor antagonism was necessary to improve MCQ(muc), indicating a role for the endothelin B-receptor in mediating the microcirculatory failure in the ileal mucosa.

    Topics: Animals; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endotoxemia; Female; Hypertension, Pulmonary; Ileum; Intestinal Mucosa; Isoxazoles; Microcirculation; Pyridines; Receptor, Endothelin A; Receptor, Endothelin B; Splanchnic Circulation; Sulfones; Sus scrofa; Tetrazoles; Vasodilator Agents

2010
Endothelin A receptor blockade improves regression of flow-induced pulmonary vasculopathy in piglets.
    The Journal of thoracic and cardiovascular surgery, 2010, Volume: 140, Issue:3

    In patients with chronic thromboembolic pulmonary hypertension, high flow in unobstructed lung regions may induce small-vessel damage responsible for persistent pulmonary hypertension after pulmonary thromboendarterectomy. In piglets, closure of an experimental aortopulmonary shunt reverses the flow-induced vascular lesions and diminishes the elevated levels of messenger RNA (mRNA) expression for endothelin-1 and endothelin receptor A (ETA). We wanted to study the effect of the ETA antagonist TBC 3711 on reversal of flow-induced pulmonary vascular lesions.. Twenty piglets were studied. In 15 piglets, pulmonary vasculopathy was induced by creating an aortopulmonary shunt. After 5 weeks of shunting, some animals were studied (n = 5); others underwent shunt closure for 1 week with (n = 5) or without (n = 5) TBC3711 treatment. Anti-ETA treatment started 1 week before and ended 1 week after the shunt closure. The controls were sham-operated animals (n = 5).. High blood flow led to medial hypertrophy of the distal pulmonary arteries (54.9% +/- 1.3% vs 35.3% +/- 0.9%; P < .0001) by stimulating smooth muscle cell proliferation (proliferating cell nuclear antigen) and increased the expression of endothelin-1, ETA or endothelin receptor type A or endothelin receptor A, angiopoietin 1, and Tie2 (real-time polymerase chain reaction). One week after shunt closure, gene expression levels were normal and smooth muscle cells showed increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) without proliferation. However, pulmonary artery wall thickness returned to control values only in the group given TBC3711 (33.2% +/- 8% with and 50.3% +/- 1.3% without; P < .05).. Anti-ETA therapy accelerated the reversal of flow-induced pulmonary arterial disease after flow correction. In patients with chronic thromboembolic pulmonary hypertension and severe distal pulmonary vasculopathy, anti-ETA agents may prove useful for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy.

    Topics: Angiopoietin-1; Animals; Animals, Newborn; Antihypertensive Agents; Aorta; Apoptosis; Cell Proliferation; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Hemodynamics; Hypertension, Pulmonary; Hypertrophy; Isoxazoles; Muscle, Smooth, Vascular; Pulmonary Artery; Pulmonary Circulation; Pulmonary Embolism; Receptor, Endothelin A; Receptor, TIE-2; RNA, Messenger; Sulfones; Swine; Time Factors

2010
Rescue treatment with a Rho-kinase inhibitor normalizes right ventricular function and reverses remodeling in juvenile rats with chronic pulmonary hypertension.
    American journal of physiology. Heart and circulatory physiology, 2010, Volume: 299, Issue:6

    Chronic pulmonary hypertension in infancy and childhood is characterized by a fixed and progressive increase in pulmonary arterial pressure and resistance, pulmonary arterial remodeling, and right ventricular hypertrophy and systolic dysfunction. These abnormalities are replicated in neonatal rats chronically exposed to hypoxia from birth in which increased activity of Rho-kinase (ROCK) is critical to injury, as evidenced by preventive effects of ROCK inhibitors. Our objective in the present study was to examine the reversing effects of a late or rescue approach to treatment with a ROCK inhibitor on the pulmonary and cardiac manifestations of established chronic hypoxic pulmonary hypertension. Rat pups were exposed to air or hypoxia (13% O(2)) from postnatal day 1 and were treated with Y-27632 (15 mg/kg) or saline vehicle by twice daily subcutaneous injection commencing on day 14, for up to 7 days. Treatment with Y-27632 significantly attenuated right ventricular hypertrophy, reversed arterial wall remodeling, and completely normalized right ventricular systolic function in hypoxia-exposed animals. Reversal of arterial wall remodeling was accompanied by increased apoptosis and attenuated content of endothelin (ET)-1 and ET(A) receptors. Treatment of primary cultured juvenile rat pulmonary artery smooth muscle cells with Y-27632 attenuated serum-stimulated ROCK activity and proliferation and increased apoptosis. Smooth muscle apoptosis was also induced by short interfering RNA-mediated knockdown of ROCK-II, but not of ROCK-I. We conclude that sustained rescue treatment with a ROCK inhibitor reversed both the hemodynamic and structural abnormalities of chronic hypoxic pulmonary hypertension in juvenile rats and normalized right ventricular systolic function. Attenuated expression and activity of ET-1 and its A-type receptor on pulmonary arterial smooth muscle was a likely contributor to the stimulatory effects of ROCK inhibition on apoptosis. In addition, our data suggest that ROCK-II may be dominant in enhancing survival of pulmonary arterial smooth muscle.

    Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Age Factors; Aging; Amides; Animals; Apoptosis; Cell Proliferation; Cells, Cultured; Chronic Disease; Disease Models, Animal; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Injections, Subcutaneous; Muscle, Smooth, Vascular; Myocardium; Protein Kinase Inhibitors; Pulmonary Artery; Pyridines; Rats; Receptor, Endothelin A; rho-Associated Kinases; RNA Interference; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Remodeling

2010
Plasma C-reactive protein and endothelin-1 level in patients with chronic obstructive pulmonary disease and pulmonary hypertension.
    Journal of Korean medical science, 2010, Volume: 25, Issue:10

    Pulmonary hypertension is a frequent complication of chronic obstructive pulmonary disease (COPD) and associated with a worse survival and increased risk of hospitalization for exacerbation of COPD. However, little information exists regarding the potential role of systemic inflammation in pulmonary hypertension of COPD. The purpose of the present study was to investigate the degree of C-reactive protein (CRP) and endothelin-1 (ET-1) levels in COPD patient with and without pulmonary hypertension. The levels of CRP and ET-1 were investigated in 58 COPD patient with pulmonary hypertension and 50 patients without pulmonary hypertension. Pulmonary hypertension was defined as a systolic pulmonary artery pressure (Ppa) ≥35 mmHg assessed by Doppler echocardiography. Plasma CRP and ET-1 levels were significantly higher in patients with pulmonary hypertension than in patients without hypertension. There were significant positive correlations between the plasma ET-1 level and CRP level in the whole study groups. For COPD patients, systolic Ppa correlated significantly with plasma CRP levels and plasma ET-1 levels. These findings support a possibility that CRP and ET-1 correlate to pulmonary hypertension in COPD patients.

    Topics: Aged; Blood Pressure; C-Reactive Protein; Echocardiography, Doppler; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive

2010
Short and long term anti-inflammatory effects of bosentan therapy in patients with pulmonary arterial hypertension: relation to clinical and hemodynamic responses.
    Expert opinion on therapeutic targets, 2010, Volume: 14, Issue:12

    We sought to investigate the short- and long- term effects of bosentan therapy on endothelial, inflammatory and fibrotic markers in patients with pulmonary arterial hypertension (PAH) and the relation to clinical and hemodynamic responses.. We studied 16 patients with moderate-severe idiopathic PAH, in WHO functional class II-IV, despite conventional treatment. Patients received additional treatment with bosentan, 62.5 mg twice daily for 1 month, followed by 125 mg twice daily for 11 months. Study endpoints included 6-min walking distance (6MWD), mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and plasma levels of intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), IL-6 and brain natriuretic peptide (BNP). Patients were assessed at baseline, 2 months and 12 months after initiation of bosentan.. At 2 months there was an improvement in 6MWD (p < 0.001) and functional class (p < 0.001) and a marked fall in PVR (p < 0.001), ICAM-1 (p < 0.001), IL-6 (p < 0.001)and BNP (p = 0.001). At 12 months, 6MWD was further improved (p < 0.001), PVR remained significantly improved (p < 0.001), mPAP was significantly decreased (p < 0.001) and ICAM-1, IL-6 and BNP remained significantly lower (p < 0.001). Significant correlations were found between changes in ICAM-1 and cardiac index (r = 0.59, p = 0.01), IL-6 and PVR (r = 0.51, p = 0.04), BNP and 6MWD (r = -0.53, p = 0.03) and BNP and PAP (r = 0.51, p = 0.04) between 2- and 12-months treatment.. In patients with moderate-severe PAH, the addition of bosentan to therapy, exerts favorable anti-inflammatory effects, which are associated with clinical and hemodynamic improvement.

    Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Biomarkers, Pharmacological; Bosentan; Endothelin-1; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Middle Aged; Sulfonamides; Time Factors; Treatment Outcome; Vascular Resistance; Young Adult

2010
Scleroderma renal crisis accompanied by new-onset pulmonary arterial hypertension: an acute systemic endothelial injury? Case report and literature.
    Inflammation & allergy drug targets, 2010, Volume: 9, Issue:4

    Systemic Sclerosis (SSc) is a multisystem connective tissue disease characterized by fibrosis of the skin and internal organs and extensive vasculopathy. We report a case of a 41 year-old white woman with a 10 year-history of limited scleroderma, who developed the rare combination of Scleroderma Renal Crisis (SRC) and Systemic Sclerosis related Pulmonary Arterial Hypertension (SScPAH) in the same time. Although the patient received the proposed antihypertensive treatment, the renal function did not recover, and she initiated on renal replacement therapy. SRC and SScPAH are two aspects of SSc vasculopathy characterized by endothelial dysfunction mediated by endothelin-1 and other vasoactive hormones. Further new studies with therapies directed towards the underlying mechanisms of SRC (i.e. endothelin-receptor antagonists), which are proven helpful in SScPAH, should take place to establish new therapeutic options and improve prognosis of these patients, for which our therapeutic armamentarium is currently poor.

    Topics: Acute Kidney Injury; Adult; Endothelin-1; Endothelium, Vascular; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Renal Replacement Therapy; Scleroderma, Systemic

2010
Going to altitude? Bring your vitamins!
    The Journal of physiology, 2010, Dec-01, Volume: 588, Issue:Pt 23

    Topics: Altitude Sickness; Ascorbic Acid; Endothelin-1; Humans; Hypertension, Pulmonary; Nitric Oxide; Oxidative Stress; Vitamin E

2010
Bosentan - a previously unrecognised cause of facial telangiectasia.
    Annals of the Academy of Medicine, Singapore, 2010, Volume: 39, Issue:11

    Topics: Aged; Antihypertensive Agents; Bosentan; Endothelin-1; Face; Female; Humans; Hypertension, Pulmonary; Sulfonamides; Telangiectasis

2010
Plasma endothelin-1 and nitrate levels in Down's syndrome with complete atrioventricular septal defect-associated pulmonary hypertension: a comparison with non-Down's syndrome children.
    European journal of pediatrics, 2009, Volume: 168, Issue:5

    Children with Down's syndrome (DS)-associated complete atrioventricular septal defect (AVSD) have rapid and aggressive development of pulmonary vascular disease when compared with non-Down's syndrome (ND) children. We aimed to evaluate the role of plasma endothelin-1 (ET-1) and nitrate levels in DS children with complete AVSD-associated pulmonary hypertension (PH) and compare this to ND patients. The study included 20 patients (11 males, nine females) who had complete AVSD associated with PH. Comparisons were made between DS patients (n=12) aged 4 to 8 months (median 5 months) and ND patients (n=8) aged 4 to 12 months (median 7 months). Blood samples were drawn from the inferior vena cava, pulmonary artery, pulmonary vein, and aorta. The plasma ET-1 concentrations of the two groups were compared to the peripheral venous and arterial ET-1 levels, and pulmonary vein nitrate was compared to the peripheral arterial nitrate levels of ten healthy infants. The mean pulmonary artery (PA) pressure and pulmonary vascular resistance (Rp) were significantly higher in the DS group than ND patients, and the pulmonary blood flow (Qp) in ND patients was higher than DS patients. There were no differences between the two study groups in regard to plasma ET-1 and nitrate levels obtained from matched sampling sites. The plasma ET-1 and nitrate levels were significantly higher in both study groups compared to the control subjects. The plasma ET-1 and nitrate levels in DS patients with PH were not different when compared to those of ND patients.

    Topics: Child; Child, Preschool; Down Syndrome; Endothelin-1; Female; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Male; Nitrates

2009
Potential biomarkers for detecting pulmonary arterial hypertension in patients with systemic sclerosis.
    Rheumatology international, 2009, Volume: 29, Issue:9

    Pulmonary arterial hypertension (PAH) is the major complication of systemic sclerosis (SSc) and the main cause of morbi-mortality. It is important to find predictors for this vascular problem. The objective of this study was to determine the serum levels of different biomarkers in patients with SSc and secondary PAH and to compare them with those of healthy control subjects to define their potential role as predictors of PAH. Cross-section study in which 20 patients with SSc were included. PAH was diagnosed by echocardiogram. The optical densities of endoglin (Eng), endothelin-1 (ET-1), platelet-derived growth factor (PDGF), tumoral necrosis factor alpha (TNF-alpha), Transforming growth factor beta 2 (TGF-beta2) and Interleukin 8 (IL-8) were measured in 20 patients with SSc and 20 healthy controls matched by sex. The differences found between the group of patients with PAH and the control group were (mean or median and range): ET-1 (0.20; 0.10-0.35 vs. 0.16; 0.10-0.24; P = 0.0276), IL-8 (195.7; 45.5-504 vs. 118.9; 23-299.5; P = 0.0364), TNF-alpha (0.70; 0.50-0.96 vs. 0.48; 0.38-0.65; P = 1 x 10(-8)) and Eng (0.95; 0.57-1.72 vs. 0.75; 0.57-0.89; P = 0.0028). A correlation was found between the progression of the disease and the development of Raynaud's phenomenon (Rho: 0.67 and P = 0.0011), ET-1 and Eng (Rho: 0.53 and P = 0.0196), and between IL-8 and Eng (Rho: 0.68 and P = 0.0019). In conclusions, the elevation of the serum levels of Eng and ET-1 could represent a useful tool as PAH biomarkers. Nevertheless, the diagnostic value of these markers needs to be determined by prospective studies.

    Topics: Adult; Age of Onset; Aged; Antigens, CD; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Echocardiography; Endoglin; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Receptors, Cell Surface; Scleroderma, Systemic

2009
Elevated levels of activin A in clinical and experimental pulmonary hypertension.
    Journal of applied physiology (Bethesda, Md. : 1985), 2009, Volume: 106, Issue:4

    Activin A, a member of the transforming growth factor (TGF)-beta superfamily, is involved in regulation of tissue remodeling and inflammation. Herein, we wanted to explore a role for activin A in pulmonary hypertension (PH). Circulating levels of activin A and its binding protein follistatin were measured in patients with PH (n = 47) and control subjects (n = 14). To investigate synthesis and localization of pulmonary activin A, we utilized an experimental model of hypoxia-induced PH. In mouse lungs, we also explored signaling pathways that can be activated by activin A, such as phosphorylation of Smads, which are mediators of TGF-beta signaling. Possible pathophysiological mechanisms initiated by activin A were explored by exposing pulmonary arterial smooth muscle cells in culture to this cytokine. Elevated levels of activin A and follistatin were found in patients with PH, and activin A levels were significantly related to mortality. Immunohistochemistry of lung autopsies from PH patients and lungs with experimental PH localized activin A primarily to alveolar macrophages and bronchial epithelial cells. Mice with PH exhibited increased pulmonary levels of mRNA for activin A and follistatin in the lungs, and also elevated pulmonary levels of phosphorylated Smad2. Finally, we found that activin A increased proliferation and induced gene expression of endothelin-1 and plasminogen activator inhibitor-1 in pulmonary artery smooth muscle cells, mediators that could contribute to vascular remodeling. Our findings in both clinical and experimental studies suggest a role for activin A in the development of various types of PH.

    Topics: Activins; Adult; Animals; Blood Pressure; Blotting, Western; Cell Proliferation; Cytokines; Endothelial Cells; Endothelin-1; Female; Follistatin; Humans; Hypertension, Pulmonary; Immunoenzyme Techniques; Male; Mice; Mice, Inbred C57BL; Middle Aged; Myocytes, Smooth Muscle; Phosphorylation; Pulmonary Artery; RNA; Smad2 Protein; Up-Regulation

2009
Anakinra and its rapidly expanding role in management of nonarthritic systemic disorders.
    The Journal of rheumatology, 2009, Volume: 36, Issue:2

    Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Coronary Circulation; Diabetes Mellitus; Endothelin-1; Humans; Hyperalgesia; Hypertension, Pulmonary; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Myocardial Infarction; Pneumonia; Receptors, Tumor Necrosis Factor; Syndrome

2009
Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension.
    Basic research in cardiology, 2009, Volume: 104, Issue:5

    Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocrine activation and intrinsic myocardial dysfunction have been described in the left ventricle (LV). In order to establish the timing of LV dysfunction development in PH and to clarify underlying molecular changes, Wistar rats were studied 4 and 6 weeks after subcutaneous injection of monocrotaline (MCT) 60 mg/kg (MCT-4, n = 11; MCT-6, n = 11) or vehicle (Ctrl-4, n = 11; Ctrl-6, n = 11). Acute single beat stepwise increases of systolic pressure were performed from baseline to isovolumetric (LVPiso). This hemodynamic stress was used to detect early changes in LV performance. Neurohumoral activation was evaluated by measuring angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1) LV mRNA levels. Cardiomyocyte apoptosis was evaluated by TUNEL assay. Extracellular matrix composition was evaluated by tenascin-C mRNA levels and interstitial collagen content. Myosin heavy chain (MHC) composition of the LV was studied by protein quantification. MCT treatment increased RV pressures and RV/LV weight ratio, without changing LV end-diastolic pressures or dimensions. Baseline LV dysfunction were present only in MCT-6 rats. Afterload elevations prolonged tau and upward-shifted end-diastolic pressure dimension relations in MCT-4 and even more in MCT-6. MHC-isoform switch, ACE upregulation and cardiomyocyte apoptosis were present in both MCT groups. Rats with severe PH develop LV dysfunction associated with ET-1 and tenascin-C overexpression. Diastolic dysfunction, however, could be elicited at earlier stages in response to hemodynamic stress, when only LV molecular changes, such as MHC isoform switch, ACE upregulation, and myocardial apoptosis were present.

    Topics: Animals; Apoptosis; Collagen; Diastole; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Male; Monocrotaline; Myocardial Contraction; Myocardium; Myosin Heavy Chains; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; RNA, Messenger; Systole; Tenascin; Time Factors; Ventricular Dysfunction, Left; Ventricular Pressure

2009
Transpulmonary plasma ET-1 and nitrite differences in high altitude pulmonary hypertension.
    High altitude medicine & biology, 2009,Spring, Volume: 10, Issue:1

    Berger, Marc M., Christoph Dehnert, Damian M. Bailey, Andrew M. Luks, Elmar Menold, Christian Castell, Guido Schendler, Vitalie Faoro, Heimo Mairbäurl, Peter Bärtsch, and Eric R. Swenson. Transpulmonary plasma ET-1 and nitrite differences in high altitude pulmonary hypertension. High Alt. Med. Biol. 10:17-24, 2009.- Thirty-four mountaineers were studied at low (110 m) and high altitude (4559 m) to evaluate if increased pulmonary artery systolic pressure (PASP) at high altitude is associated with increased pulmonary endothelin-1 (ET-1) availability and alterations in nitrite metabolism across the lung. Blood samples were obtained using central venous and radial artery catheters for plasma ET-1 and nitrite. Pulmonary blood flow was measured by inert gas rebreathing to calculate transpulmonary exchange of plasma ET-1 and nitrite, and PASP was assessed by transthoracic Doppler echocardiography. After ascent to high altitude, PASP increased from 23 +/- 4 to 39 +/- 10 mmHg. Arterial and central venous plasma ET-1 increased, while plasma nitrite did not change significantly. At low altitude there was a transpulmonary loss of plasma ET-1, but a transpulmonary gain at high altitude. In contrast was a transpulmonary gain of plasma nitrite at low altitude and a transpulmonary loss at high altitude. PASP positively correlated with a transpulmonary gain of plasma ET-1 and negatively correlated with a transpulmonary loss of plasma nitrite. These results suggest that a transpulmonary gain of plasma ET- 1 is associated with higher PASP at high altitude. Transpulmonary loss of plasma nitrite indicates either less pulmonary nitric oxide (NO) production, which contributes to higher PASP, or increased NO bioavailability arising from nitrite reduction, which may oppose ET-1-mediated vasoconstriction.

    Topics: Adult; Altitude; Blood Gas Analysis; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Lung; Male; Mountaineering; Nitrites; Oxygen; Systole; Ultrasonography

2009
Bosentan increases serum IL-12 levels in systemic sclerosis patients with pulmonary arterial hypertension.
    Journal of dermatological science, 2009, Volume: 55, Issue:1

    Topics: Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Cytokines; Endothelin-1; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Interleukin-12; Male; Middle Aged; Receptors, Endothelin; Scleroderma, Systemic; Sulfonamides

2009
Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension.
    American journal of physiology. Heart and circulatory physiology, 2009, Volume: 296, Issue:6

    We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle (day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 microg*kg(-1)*day(-1) ip) or a similar volume of saline, resulting in four groups: sham (n = 11), sham-AP (n = 11), MCT (n = 16), and MCT-AP (n = 13). On day 25, right ventricular (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. When compared with sham, the MCT group presented a significant increase of RV mass (166 +/- 38%), diameter of cardiomyocyte (40 +/- 10%), myocardial fibrosis (95 +/- 20%), peak systolic pressure (99 +/- 22%), peak rate of ventricular pressure rise (dP/dt(max); 74 +/- 24%), peak rate of ventricular pressure decline (dP/dt(min); 73 +/- 19%), and time constant tau (55 +/- 16%). In these animals, RV expression of apelin (-73 +/- 10%) and its receptor APJ (-61 +/- 20%) was downregulated, whereas mRNA expression of type B natriuretic peptide (9,606 +/- 713%), angiotensinogen (191 +/- 147%), endothelin-1 (RV, 497 +/- 156%; and LV, 799 +/- 309%), plasmatic levels of apelin (104 +/- 48%), and angiotensin 1-7 (161 +/- 151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation.

    Topics: Angiotensin I; Animals; Antihypertensive Agents; Apelin; Apelin Receptors; Carrier Proteins; Endothelin-1; Gene Expression Profiling; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Intercellular Signaling Peptides and Proteins; Male; Monocrotaline; Myocardium; Peptide Fragments; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; RNA, Messenger; Ventricular Function, Right

2009
Preventive effects of raloxifene, a selective estrogen receptor modulator, on monocrotaline-induced pulmonary hypertension in intact and ovariectomized female rats.
    European journal of pharmacology, 2009, Jul-01, Volume: 614, Issue:1-3

    We investigated whether the chronic treatment with raloxifene, a selective estrogen receptor modulator, prevents the development of monocrotaline-induced pulmonary hypertension in ovary-intact and ovariectomized female rats. Four weeks after a single subcutaneous injection of monocrotaline (60 mg/kg), right ventricular systolic pressure, right ventricle-to-left ventricle plus septal weight ratio, pulmonary arterial medial thickening and endothelin-1 levels in right ventricular tissue increased significantly in both female rats, compared with saline-treated control rats. These monocrotaline-induced alterations were much greater in ovariectomized rats than the changes in intact females. Daily oral administration of raloxifene (10 mg/kg/day for 4 weeks) significantly attenuated the increase in right ventricular systolic pressure to the same levels in both groups of animals, but raloxifene suppressed the increases in right ventricle-to-left ventricle plus septal weight ratio and pulmonary arterial medial thickness more efficiently in ovariectomized females than the case with intact females. In addition, raloxifene completely suppressed the increase in right ventricular endothelin-1 levels in ovariectomized rats, but not in intact females. These data suggest that chronic treatment with raloxifene effectively prevents the development of monocrotaline-induced pulmonary hypertension in ovariectomized female rats than in intact females, at least in part, by suppressing right ventricular endothelin-1 overproduction.

    Topics: Animals; Blood Pressure; Body Weight; Endothelin-1; Female; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Monocrotaline; Organ Size; Ovariectomy; Pulmonary Artery; Raloxifene Hydrochloride; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Substrate Specificity; Time Factors; Ventricular Dysfunction, Right

2009
Pulmonary vascular dysfunction in end-stage cystic fibrosis: role of NF-kappaB and endothelin-1.
    The European respiratory journal, 2009, Volume: 34, Issue:6

    Pulmonary hypertension is rare in chronic respiratory diseases but has a strong impact on the prognosis and is partly underlined by factors other than hypoxaemia. The aim of the present study was to assess the potential role of endothelin-1 (ET-1) and nuclear factor (NF)-kappaB vasoconstrictive pathways in pulmonary hypertension. The effects of ET-1 receptors blockers (BQ 123 and 788) and of genistein were assessed on response to acetylcholine of pulmonary vascular rings from cystic fibrosis (CF) lung transplant recipients (n = 23). NF-kappaB and ET-1 receptor expression was immunodetected in pulmonary arteries and quantitated using Western blotting. ET-1 vascular content was quantitated using ELISA. In total, 14 out of 23 subjects exhibited strongly impaired pulmonary vasodilation (p<0.01 versus nine out of 23 subjects with a normal response) associated with an activation of ET-1 receptors A and NF-kappaB pathways. Genistein restored vasodilation in subjects with an abnormal response. Pulmonary vascular dysfunction is frequent in end-stage CF, involving the NF-kappaB pathway and that of ET-1 through ET-1 receptor A (ETAR). These data leave a conceptual place for ETAR blockers and isoflavones in the management of the devastating vascular complication of chronic obstructive respiratory diseases such as CF.

    Topics: Acetylcholine; Adult; Cystic Fibrosis; Dose-Response Relationship, Drug; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Genistein; Homeostasis; Humans; Hypertension, Pulmonary; Male; NF-kappa B; Vascular Diseases

2009
Regression of flow-induced pulmonary arterial vasculopathy after flow correction in piglets.
    The Journal of thoracic and cardiovascular surgery, 2009, Volume: 137, Issue:6

    Chronic thromboembolic pulmonary hypertension is due to partial obstruction of the pulmonary arterial bed and may resolve after pulmonary thromboendarterectomy. Persistent pulmonary hypertension, the main complication after pulmonary thromboendarterectomy, may reflect vessel alterations induced by high flow in unobstructed lung territories. The aim of this study was to determine whether correcting high flow led to reversal of the vasculopathy in piglets.. The effects of high pulmonary blood flow were investigated 5 weeks after creation of an aortopulmonary shunt (n = 10), and reversibility of vessel disease was evaluated at 1 week (n = 10) and 5 weeks after shunt closure (n = 10), compared to sham-operated animals (n = 10). Hemodynamic variables, pulmonary artery reactivity, and morphometry were recorded. We also investigated the endothelin, angiopoietin, and nitric oxide synthase pathways.. High flow increased medial thickness in distal pulmonary arteries (55.6% +/- 1.2% vs 35.9% +/- 0.8%; P < .0001) owing to an increase of smooth muscle cell proliferation (proliferating cell nuclear antigen labeling). The endothelium-dependent relaxation was altered (P < .05). This phenomenon was associated to an overexpression of endothelin-1, endothelin-A, angiopoietin 1, angiopoietin 2, and Tie-2 (P < .05). After 1 week of shunt closure, all overexpressed genes returned to control values, the proliferation of smooth muscle cells stopped, and smooth muscle cell apoptosis increased (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), preceding the normalization of the wall thickness hypertrophy and the pulmonary artery vasoreactivity observed at 5 weeks after shunt closure.. These results demonstrate that endothelin-1 and angiopoietin pathways are involved in vasculopathy development and may be important therapeutic targets for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy.

    Topics: Acetylcholine; Angiopoietin-1; Animals; Apoptosis; Cell Proliferation; Collagen; Cyclic Nucleotide Phosphodiesterases, Type 5; Endarterectomy; Endothelin-1; Hypertension, Pulmonary; Lung; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Pulmonary Artery; Pulmonary Circulation; Pulmonary Embolism; Receptor, TIE-2; Receptors, Endothelin; Tunica Media; Vasoconstriction; Vasodilation

2009
Clinical significance of plasma endothelin-1 level after bosentan administration in pulmonary arterial hypertension.
    Journal of cardiology, 2009, Volume: 53, Issue:3

    Endothelin (ET)-1 has been shown to play a significant pathogenic role in pulmonary arterial hypertension (PAH). However, the pathobiological significance of increased ET-1 concentration after administration of ET receptor antagonist in patients with PAH has not yet been fully examined.. In 16 PAH patients, plasma ET-1 concentration was measured at 0, 1, 3, 6, and 24h after a single 62.5mg dose of bosentan, a dual ET receptor antagonist, and the peak and 24-h change in ET-1 concentration from baseline were examined. The severity of PAH was evaluated by hemodynamic parameters, 6-min walk distance, New York Heart Association (NYHA) functional class, and brain natriuretic peptide (BNP).. Plasma ET-1 concentration significantly increased from 1.93+/-0.12 to 3.36+/-0.18 pg/ml after bosentan administration in PAH patients (p<0.01). The peak-to-baseline ratio of ET-1 concentration after bosentan administration showed a significant positive correlation with baseline ET-1 concentration (p<0.05). After 4-week bosentan administration, NYHA functional class improved in 7 patients but was not changed in 9 patients. The optimal cut-off point of % change of ET-1 concentration at 24h for discriminating the two groups was 30%. According to this cut-off point, patients were divided into the higher (n=7) and the lower (n=9) groups. NYHA functional class did not change in the lower group, but significantly improved (p<0.01) in the higher group after 4-week bosentan administration. In addition, plasma BNP levels significantly decreased from baseline in the higher group compared with those in the lower group after 12-week bosentan administration (-44+/-11% vs. 7+/-20%, p<0.05).. Although the population in this study is small and heterogeneous, measurement of plasma ET-1 concentration after bosentan administration might predict the responsiveness to bosentan treatment, and be useful in the determination of effective therapy in treatment of PAH patients.

    Topics: Adult; Antihypertensive Agents; Biomarkers; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Sulfonamides; Time Factors; Treatment Outcome; Young Adult

2009
Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: role of ETB-receptor expression levels.
    Pulmonary pharmacology & therapeutics, 2009, Volume: 22, Issue:4

    The endothelin (ET) system is activated in pulmonary arterial hypertension (PAH). The therapeutic value of pharmacological blockade of ET receptors has been demonstrated in various animal models and led to the current approval and continued development of these drugs for the therapy of human PAH. However, we currently incompletely comprehend what local modifications of this system occur as a consequence of PAH, particularly in small resistance arteries, and how this could affect the pharmacological response to ET receptor antagonists with various selectivities for the receptor subtypes. Therefore, the purposes of this study were to evaluate potential modifications of the pharmacology of the ET system in rat pulmonary resistance arteries from monocrotaline (MCT)-induced pulmonary arterial hypertension.. ET-1 levels were quantified by ELISA. PreproET-1, ETA and ETB receptor mRNA expressions were quantified in pulmonary resistance arteries using Q-PCR, while protein expression was evaluated by Western blots. Reactivity to ET-1 of isolated pulmonary resistance arteries was measured in the presence of ETA (A-147627), ETB (A-192621) and dual ETA/B (bosentan) receptor antagonists.. In rats with PAH, plasma ET-1 increased (p < 0.001) while pulmonary levels were reduced(p < 0.05). In PAH arteries, preproET-1 (p < 0.05) and ETB receptor (p < 0.001) gene expressions were reduced, as were ETB receptor protein levels (p < 0.05). ET-1 induced similar vasoconstrictions in both groups. In arteries from sham animals, neither bosentan nor the ETA or the ETB receptor antagonists modified the response. In arteries from PAH rats, however, bosentan and the ETA receptor antagonist potently reduced the maximal contraction, while bosentan also reduced sensitivity (p < 0.01).. The effectiveness of both selective ETA and dual ETA/B receptor antagonists is markedly increased in PAH. Down-regulation of pulmonary resistance arteries ETB receptor may contribute to this finding.

    Topics: Animals; Basilar Artery; Blotting, Western; Endothelin B Receptor Antagonists; Endothelin-1; Fluorescent Antibody Technique; Hypertension, Pulmonary; Male; Microscopy, Confocal; Monocrotaline; Poisons; Pulmonary Artery; Pulmonary Veins; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Vascular Resistance

2009
Time-dependent phenotypic and contractile changes of pulmonary artery in chronic hypoxia-induced pulmonary hypertension.
    Journal of pharmacological sciences, 2009, Volume: 110, Issue:2

    Phenotypic and contractile changes in pulmonary arterial smooth muscle cells (PASMCs) were examined in rats with pulmonary hypertension induced by hypoxia. Exposure to hypoxia induced pulmonary hypertension within 1-4 weeks. Staining with BrdU revealed that proliferative activities of PASMCs peaked at 1 week of hypoxic exposure, and then moderate proliferative activity was maintained for the next 2-4 weeks. The beta-actin/alpha-actin ratio also increased at 1-2 weeks of exposure to hypoxia. Absolute contractility of the pulmonary arterial ring continuously decreased during hypoxia, whereas the basal active tonus of the pulmonary artery increased at 1-3 weeks. Nicardipine, the ETA-receptor antagonis, CI-1034 and the rho-kinase inhibitor Y27632 partially inhibited the elevated active tonus. Endothelin-1 content in the pulmonary hypertensive lung was continuously increased during exposure to hypoxia. In conclusion, the hypoxia-induced proliferative activity of PASMCs comprised a transient phase followed by a sustained phase. The change in PASMCs from a contractile to a synthetic phenotype also correlated with proliferative activity, which subsequently decreased PASMC contractility. The continuous production of endothelin-1 upon hypoxic exposure might contribute to the increased basal tonus of the pulmonary arterial wall, which might subsequently increase pulmonic arterial pressure, resulting in accelerated pulmonary hypertension.

    Topics: Actins; Amides; Animals; Cell Proliferation; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Immunohistochemistry; Male; Muscle Contraction; Muscle, Smooth; Nicardipine; Phenotype; Pulmonary Artery; Pyridines; Rats; Rats, Sprague-Dawley; Thiazines; Time Factors

2009
Effects of pathological flow on pulmonary artery endothelial production of vasoactive mediators and growth factors.
    Journal of vascular research, 2009, Volume: 46, Issue:6

    Alterations in pulmonary blood flow are often associated with the initiation and progression of pulmonary vascular disease. However, the cellular mechanisms involved in mediating flow effects in the pulmonary circulation remain unclear. Depending on the disease condition, flow may be extremely low or high. We therefore examined effects of pathologically low and high flow on endothelial production of factors capable of affecting pulmonary vascular tone and structure as well as on potential underlying mechanisms.. Flow effects on pulmonary endothelial release of NO, PGF(1a), ET-1 and TxB(2), on expression of total and phosphorylated eNOS as well as Akt, and on VEGF were examined. Additionally, in a coculture system, effects of flow-exposed endothelial cells on smooth muscle (SM) proliferation and contractile protein were studied.. Compared to physiological flow, pathologically high and low flow attenuated endothelial release of NO and PGF(1a), and enhanced release of ET-1. Physiological flow activated the Akt/eNOS pathway, while pathological flow depressed it. Pathologically high flow altered VE-cadherin expression. Pathologically high flow on the endothelium upregulated alpha-SM-actin and SM-MHC without affecting SM proliferation.. Physiological flow leads to production of mediators which favor vasodilation. Pathological flow alters the balance of mediator production which favors vasoconstriction.

    Topics: Actins; Animals; Animals, Newborn; Antigens, CD; Cadherins; Cattle; Cell Proliferation; Cells, Cultured; Coculture Techniques; Endothelial Cells; Endothelial Growth Factors; Endothelin-1; Hypertension, Pulmonary; Mechanotransduction, Cellular; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Myosin Heavy Chains; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Prostaglandins F; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Pulsatile Flow; Stress, Mechanical; Thromboxane B2; Vascular Endothelial Growth Factor A; Vasoconstrictor Agents; Vasodilator Agents

2009
Endothelin-1 across the lung circulation in patients with pulmonary arterial hypertension and influence of epoprostenol infusion.
    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 2009, Volume: 28, Issue:8

    The endothelin-1 (ET-1) system plays a pathophysiologic role in patients with pulmonary arterial hypertension (PAH). Results from previous studies assessing the transpulmonary gradient of ET-1 have been inconsistent. The influence of an intravenous epoprostenol infusion on the transpulmonary ET-1 gradient is unknown.. In a prospective investigation, serum concentrations of ET-1 were measured in 39 consecutive patients (31 women; mean age, 20-77 years) with pulmonary hypertension (33 with PAH) and compared with 20 controls. The effect of intravenous epoprostenol administration on the transpulmonary gradient of ET-1 was analyzed in 13 patients with pulmonary hypertension. Blood samples were taken simultaneously from the pulmonary artery and radial artery.. The serum levels of ET-1 were significantly higher in the arterial (3.9 +/- 1.28 vs 2.53 +/- 0.24 pg/ml, p < 0.001) and mixed venous blood samples (3.9 +/- 1.21 vs 2.52 +/- 0.29 pg/ml, p < 0.001) in patients with pulmonary hypertension than in controls. The arterial/venous ratio of ET-1 in patients (1.0 +/- 0.1) and in the control group (1.0 +/- 0.05) was similar (p = 0.79). During intravenous epoprostenol infusion, there were no changes in the mean transpulmonary ET-1 gradient (0.98 +/- 0.07 vs 0.96 +/- 0.09, p = 0.52), despite significant hemodynamic changes.. The ET-1 radial artery/pulmonary artery ratio of unity indicates a balanced release and clearance of ET-1 across the lung circulation in controls and in patients with different forms of pulmonary hypertension. ET-1 levels across the pulmonary circulation did not change during epoprostenol infusion.

    Topics: Adult; Aged; Antihypertensive Agents; Endothelin-1; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Prospective Studies; Pulmonary Artery; Pulmonary Circulation; Radial Artery; Young Adult

2009
Update on endothelin-related diseases. Proceedings of a workshop, 27 March 2008, Geneva, Switzerland.
    European journal of clinical investigation, 2009, Volume: 39 Suppl 2

    Topics: Animals; Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Humans; Hypertension, Pulmonary; Renal Insufficiency

2009
Endothelin-1 impairs nitric oxide signaling in endothelial cells through a protein kinase Cdelta-dependent activation of STAT3 and decreased endothelial nitric oxide synthase expression.
    DNA and cell biology, 2009, Volume: 28, Issue:11

    In an ovine model of persistent pulmonary hypertension of the newborn (PPHN), endothelin-1 (ET-1) expression is increased, while endothelial nitric oxide synthase (eNOS) expression is decreased. However, the molecular mechanisms by which ET-1 attenuates eNOS expression in endothelial cells are not completely understood. Thus, the goal of this study was to determine if the overexpression of ET-1 decreases eNOS expression in pulmonary arterial endothelial cells isolated from fetal lambs. To increase the ET-1 expression, cells were transfected with a plasmid coding for Prepro-ET-1, a precursor of ET-1. After overexpression of Prepro-ET-1, ET-1 levels in the culture medium were significantly increased (control = 805.3 +/- 69.8; Prepro-ET-1 overexpression = 1351 +/- 127.9). eNOS promoter activity, protein levels, and NO generation were all significantly decreased by the overexpression of Prepro-ET-1. The decrease in transcription correlated with increased activity of protein kinase Cdelta (PKCdelta) and STAT3. Further, DNA binding activity of STAT3 was also increased by Prepro-ET-1 overexpression. The increase in STAT3 activity and decrease in eNOS promoter activity were inhibited by the overexpression of dominant negative mutants of PKCdelta or STAT3. Further, a 2 bp mutation in the STAT3 binding site in the eNOS promoter inhibited STAT3 binding and led to enhanced promoter activity in the presence of Prepro-ET-1 overexpression. In conclusion, ET-1 secretion is increased by Prepro-ET-1 overexpression. This results in activation of PKCdelta, which phosphorylates STAT3, increasing its binding to the eNOS promoter. This in turn decreases eNOS promoter activity, protein levels, and NO production. Thus, ET-1 can reduce eNOS expression and NO generation in fetal pulmonary artery endothelial cells through PKCdelta-mediated activation of STAT3.

    Topics: Animals; Cells, Cultured; Endothelial Cells; Endothelin-1; Hypertension, Pulmonary; Nitric Oxide Synthase Type III; Protein Kinase C-delta; Sheep; Sheep Diseases; Signal Transduction; STAT3 Transcription Factor

2009
[Endothelin-1 and brain natriuretic peptide in the development of pulmonary hypertension in interstitial lung diseases].
    Terapevticheskii arkhiv, 2009, Volume: 81, Issue:12

    To study the plasma concentration of brain natriuretic peptide (BNP) and endothelin-1 (ET-1) as markers of pulmonary hypertension (PH) developed in interstitial lung diseases (ILD).. Along with physical examination, 97 patients with ILD underwent measurements of the plasma concentrations of BNP and ET-1, 6-minute walk test, external respiration function test, echocardiography, by measuring pulmonary artery systolic pressure (P(syst)), and chest multispiral computed tomography, by estimating the mean diameter of the pulmonary artery trunk.. The plasma concentration of ET-1 proved to be significantly higher in the presence of active lung lesion (5.2 +/- 3.9 and 2.8 +/- 1.8 pg/ml; p = 0.0001). In patients with ILD, persistent PH was associated with the significantly elevated plasma concentrations of BNP (69.3 +/- 341.35 and 23.7 +/- 26.69 pg/ml; p = 0.018). The increase of plasma BNP concentrations correlated with the shorter distance covered during a 6-minute walk test and diminished functional vital capacity.. The increased plasma levels of ET-1 in ILD reflects the transient pulmonary artery pressure elevation associated with the activity of the pulmonary process while those of BNP are indicative of developed persistent PH.

    Topics: Biomarkers; Case-Control Studies; Data Interpretation, Statistical; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Middle Aged; Natriuretic Peptide, Brain; Severity of Illness Index

2009
Differential roles of endothelin-1 ETA and ETB receptors and vasoactive intestinal polypeptide in regulation of the airways and the pulmonary vasculature in isolated rat lung.
    Experimental physiology, 2008, Volume: 93, Issue:11

    The available treatment strategies against pulmonary hypertension include the administration of endothelin-1 (ET-1) receptor subtype blockers (ET(A) and ET(B) antagonists); vasoactive intestinal polypeptide (VIP) has recently been suggested as a potential new therapeutic agent. We set out to investigate the ability of these agents to protect against the vasoconstriction and impairment of lung function commonly observed in patients with pulmonary hypertension. An ET(A) blocker (BQ123), ET(B) blocker (BQ788), a combination of these selective blockers (ET(A) + ET(B) blockers) or VIP (V6130) was administered into the pulmonary circulation in four groups of perfused normal rat lungs. Pulmonary vascular resistance (PVR) and forced oscillatory lung input impedance (Z(L)) were measured in all groups under baseline conditions and at 1 min intervals following ET-1 administrations. The airway resistance, inertance, tissue damping and elastance were extracted from the Z(L) spectra. While VIP, ET(A) blocker and combined ET(A) and ET(B) blockers significantly prevented the pulmonary vasoconstriction induced by ET-1, ET(B) blockade enhanced the ET-1-induced increases in PVR. In contrast, the ET(A) and ET(B) blockers markedly elevated the ET-1-induced increases in airway resistance, while VIP blunted this constrictor response. Our results suggest that VIP potently acts against the airway and pulmonary vascular constriction mediated by endothelin-1, while the ET(A) and ET(B) blockers exert a differential effect between airway resistance and PVR.

    Topics: Airway Resistance; Animals; Antihypertensive Agents; Bronchoconstriction; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Lung; Lung Compliance; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Respiratory Mechanics; Vascular Resistance; Vasoactive Intestinal Peptide; Vasoconstriction

2008
[Effects of continuous adenosine infusion on pulmonary hypertension in chronically hypoxic rats].
    Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 2008, Volume: 28, Issue:6

    To observe the effects of continuous subcutaneous adenosine infusion on pulmonary hypertension in chronically hypoxic rats.. Twenty-four SD rats were randomized into normoxic group, hypoxic group and adenosine-treated hypoxic group. Hypoxic environment was simulated in a chamber filled with 10% oxygen and 90% nitrogen. After 7 days of hypoxia, adenosine were administered subcutaneously in the rats in adenosine-treated group at the rate of 100 microg kg(-1) min(-1) via an Alzet micro-osmotic pump for 14 days, while the pumps in the other two groups contained normal saline. After 21 days of hypoxia, pulmonary artery pressure and tail-cuff blood pressure were measured, with the plasma rennin activity (RA), angiotensin II (AngII), endothelin (ET)-1, and nitric oxide (NO) determined. Inducible nitric oxide synthase (iNOS) expression in the pulmonary artery of the rats was detected using immunohistochemical method.. The mean pulmonary artery pressure (mPAP) was significantly higher in the hypoxic group than that in the normoxic group (P<0.01) and in the adenosine-treated group (P<0.01). Plasma ET-1 was significantly higher but plasma NO significantly lower in the hypoxic group than in the normoxic group (P<0.01) and the adenosine-treated group (P<0.01). iNOS expression in the pulmonary artery was higher in the hypoxic group than in normoxic group (P<0.01), and adenosine significantly increased iNOS expression in comparison with the normoxic and hypoxic groups (P<0.01). Plasma RA and AngII in the hypoxic group were significantly higher than those in the normoxic group (P<0.01) and the adenosine-treated (P<0.01).. Adenosine administered by continuous subcutaneous infusion alleviates chronically hypoxia-induced pulmonary hypertension in rats, in which rennin angiotensin system, ET-1, and iNOS/NO play a role.

    Topics: Adenosine; Animals; Chronic Disease; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Infusions, Subcutaneous; Male; Nitric Oxide Synthase Type II; Random Allocation; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

2008
Pharmacological characterization of 3-azabicyclo[3,2,1] octane-1-yl-l-leucyl-d-tryptophanyl-d-4-Cl-phenylalanine: A novel ET(A) receptor-selective antagonist.
    Pulmonary pharmacology & therapeutics, 2008, Volume: 21, Issue:5

    Pulmonary hypertension is a kind of disease associated with a very high rate of mortality. There are not many effective drugs for the treatment of pulmonary hypertension. Treatment with ET-1 receptor antagonists was proved to be effective in the treatment of pulmonary hypertension. Aiming at developing new endothelin A receptor (ET(A)) antagonist for treatment of pulmonary hypertension, 242 peptide compounds were synthesized by structural optimization of a selective ET(A) receptor antagonist BQ-123. Among these, -azabicyclo[3,2,1]octane-1-yl-l-Leucyl-d-tryptophanyl-d-4-Cl-phenylalanine, named ETP-508, was selected for further harmacological characterization.. Radioligand binding assay was performed to study the binding affinity of ETP-508 for ET(A) and ET(B) receptors. The biological activity of ETP-508 was evaluated in isolated rat aortic ring experiment and in systemic arterial pressure experiment. In addition, hypotensive effect of ETP-508 was investigated on hypoxia-induced pulmonary hypertension.. ETP-508 binds to endothelin ET(A) receptor with >10,000-fold higher affinity than to endothelin B receptor in rat lung tissue preparation. ETP-508 inhibited endothelin-1 (ET-1)-induced contraction of isolated rat aortic ring and shifted the cumulative concentration-contraction response curve to ET-1 to right with no change in the maximal response. In vivo, ETP-508 inhibited the increased effect of ET-1 on mean systemic arterial pressure. Pre-treatment with ETP-508 by intravenous infusion significantly inhibited chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. ETP-508 also significantly inhibited the increase in lung ET-1 expression level, hemoglobin, red-cell count and red-cell hematocrit as induced by hypoxia. Furthermore, ETP-508 partially reversed pre-established pulmonary hypertension and right ventricle hypertrophy by chronic hypoxia.. These results indicated that ETP-508 is a novel highly selective ET(A) receptor antagonist and may have a great potential to be developed as a drug of anti-pulmonary hypertension.

    Topics: Animals; Aorta, Thoracic; Azabicyclo Compounds; Azepines; Blood Pressure; Chronic Disease; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Lung; Male; Molecular Structure; Oligopeptides; Peptides, Cyclic; Rats; Rats, Wistar; Time Factors; Vasoconstriction

2008
Statins suppress MMP2 secretion via inactivation of RhoA/ROCK pathway in pulmonary vascular smooth muscles cells.
    European journal of pharmacology, 2008, Sep-04, Volume: 591, Issue:1-3

    Recent studies have shown that statins ameliorate hypoxia-induced pulmonary hypertension in animal models. Yet, the underlying molecular mechanisms have not been completely understood. Here, we investigated the hypothesis that statins regulate vascular remodeling by modulation of matrix metalloproteinases (MMP) secretion in primary cultured pulmonary artery smooth muscle cells (PASMCs). Angiotensin II induced a concentration-dependent MMP2 secretion. A 2.75 fold increase was achieved by 100 nM angiotensin II stimulation for 24 h in primary cultured PASMCs (P<0.01 versus control), which was reversed by silencing Ras homolog gene family member A (RhoA) or inhibition of its downstream Rho-associated kinase (ROCK). There was no effect of angiotensin II on the expression of tissue inhibitors of matrix metalloproteinases (TIMPs). Pre-exposure of cells to simvastatin concentration-dependently blocked angiotensin II-stimulated MMP2 release. MMP2 release was reduced to1.34 fold increase in the presence of 10 microM simvastatin (P<0.01 versus angiotensin II-stimulated cells). We further revealed that simvastatin suppression of RhoA activation mediated its inhibitory effect on angiotensin II-triggered MMP2 release. Similarly, simvastatin suppressed endothelin-1-induced MMP2 release through RhoA/ROCK pathway. These results indicated a novel statins-regulation of RhoA/ROCK signaling against pulmonary vascular remodeling, and suggest that statins could prove useful in targeting this pathway in pulmonary hypertension and other disease conditions.

    Topics: Angiotensin II; Animals; Cells, Cultured; Dose-Response Relationship, Drug; Endothelin-1; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Matrix Metalloproteinase 2; Muscle, Smooth, Vascular; Pulmonary Artery; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Simvastatin

2008
[Long-term therapy with endothelin-1 antagonist for pulmonary hypertension secondary to systemic sclerosis].
    Harefuah, 2008, Volume: 147, Issue:4

    Pulmonary hypertension in systemic sclerosis appears in up to 35% of patients, is characterized by increased pulmonary artery resistance, and carries a poorer prognosis than in patients with other causes of pulmonary hypertension. The recommended therapy for stage III disease, based on clinical trials and by the Israeli Ministry of Health for 2006, includes bosentan (Tracleer), an endothelin-1 antagonist. This is a case report of a patient with severe pulmonary hypertension secondary to systemic sclerosis where therapy with prostacyclins was contraindicated due to the development of congestive heart failure and severe atherosclerosis. The patient responded well to bosentan monotherapy for 4 years until his death.

    Topics: Antihypertensive Agents; Bosentan; Endothelin-1; Fatal Outcome; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prognosis; Scleroderma, Systemic; Sulfonamides

2008
[Chronic theatment with an endothelin-converting enzyme inhibitor reduces the development of hypoxia-induced pulmonary hypertension in rat].
    Rossiiskii fiziologicheskii zhurnal imeni I.M. Sechenova, 2008, Volume: 94, Issue:7

    The aim of this study was to investigate how blocking functional endothelin-converting enzyme activity may offer a new approach to inhibition of changes in pulmonary vessels reactivity due to development of hypoxia-induced pulmonary arterial hypertension in rats. This data shows that treatment with endothelin-converting enzyme blocker PP36 significantly reduced pathological changes due to hypoxia-induced pulmonary hypertension. One of the reasons may be the increased production and role of nitric oxide in pulmonary artery tone.

    Topics: Animals; Aspartic Acid Endopeptidases; Blood Circulation; Deoxyuridine; Dipeptides; Endothelin-1; Endothelin-Converting Enzymes; Hypertension, Pulmonary; Hypoxia; Injections, Intravenous; Male; Metalloendopeptidases; Nitric Oxide Donors; Nitric Oxide Synthase; Propanolamines; Rats; Rats, Wistar; Succinates

2008
Venous endotelin-1 (ET-1) and brain natriuretic peptide (BNP) plasma levels during 6-month bosentan treatment for pulmonary arterial hypertension.
    Regulatory peptides, 2008, Nov-29, Volume: 151, Issue:1-3

    Bosentan, an endothelin (ET) ETA-ETB receptors antagonist, is an effective therapy for idiopathic pulmonary arterial hypertension (PAH) and for PAH related to connective tissue disease (CTD). The aim of this study was to evaluate the behaviour of ET-1 and brain natriuretic peptide (BNP) venous plasma levels during a 6-month dual ET-1 receptor blockade and the potential influence of baseline ET-1 venous plasma levels on the clinical efficacy of bosentan.. Twenty-five patients with PAH (idiopathic n=16, CTD n=9) in WHO functional class II-III were included in this study. After initial evaluation, patients' WHO class, 6-minute walking-test (6MWT), ET-1 and BNP venous plasma levels were assessed at baseline and after 6-month bosentan therapy. To evaluate whether the ET-1 levels could influence the clinical response to bosentan, data were analyzed for the whole population which was stratified according to high and low ET-1 plasma levels (on the basis of the baseline median value of ET-1 plasma: Gr.1<18.7 pg/ml, Gr.2>18.7 pg/ml).. Study population included patients with moderate-severe PAH. After 6-month of treatment we observed a significant increase in 6MWT distance (from 435+/-85) m to 467+/-77 m, p>0.001) and an improvement in WHO class (from 2.4+/-0.5 to 2+/-0.6 p>0.01), with a significant decrease in BNP (from 87+/-33 pg/ml to 67+/-41 pg/ml, p=0.006) and a trend towards lower ET-1 plasma levels (from 17.7+/-5 pg/ml to 16+/-6 pg/ml, p=ns). Improvement in effort tolerance (Delta distance) was not correlated to modification in ET-1 (DeltaET-1) and BNP (DeltaBNP) plasma levels, while we found a significant correlation between DeltaET-1 and DeltaBNP (r=0.63, p=0.0006). Analyzing the subpopulation, Gr.2 patients were older (Gr.1: 41+/-10 years vs Gr.2: 50+/-9 years, p=0.04), had less effort capacity (6MWT distance, Gr.1: 469+/-76 m, vs Gr.2: 398+/-82 m, p=0.03), and showed a trend towards higher BNP values (Gr.1: 82+/-41 pg/ml vs Gr.2: 92+/-23 pg/ml, p=0.051), but no significant differences in pulmonary hemodynamics. After the 6-month treatment both groups showed a significant improvement in 6MWT (Gr.1: +32+/-24 m, Gr.2: +32+/-21 m p=0.05) without differences between groups. WHO class had a trend towards lower class (Gr.1: -0.5+/-0.5, Gr.2: -0.3+/-0.4 p=0.15) in both groups. BNP plasma levels showed a significant decrease only in Gr.2 (Gr.1: -6+/-41 pg/ml, Gr.2: -34+/-19 pg/ml p=0.02); similarly ET-1 plasma levels showed a trend towards a decrease only in Gr.2 (Gr.1: 0.2+/-4.6 pg/ml, Gr.2: -3.8+/-6.6 pg/ml p=0.09).. Our data confirm that bosentan is an effective therapy for patients with PAH. Its clinical efficacy (effort tolerance and NYHA) seems to be independent from baseline venous ET1 plasma levels. Bosentan therapy seems to elicit different patterns in ET-1 and BNP plasma levels, with decrease of the peptides only in patients with higher activation of the systemic endothelin system. Further studies are warranted to explore the potential impact of baseline ET-1 levels on the long-term effects (clinical worsening) of bosentan therapy.

    Topics: Adult; Antihypertensive Agents; Bosentan; Endothelin A Receptor Antagonists; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Sulfonamides; Time Factors

2008
Exhaled and arterial levels of endothelin-1 are increased and correlate with pulmonary systolic pressure in COPD with pulmonary hypertension.
    BMC pulmonary medicine, 2008, Sep-26, Volume: 8

    Endothelin-1 (ET-1) and Nitric Oxide (NO) are crucial mediators for establishing pulmonary artery hypertension (PAH). We tested the hypothesis that their imbalance might also occur in COPD patients with PAH.. The aims of the study were to measure exhaled breath condensate (EBC) and circulating levels of ET-1, as well as exhaled NO (FENO) levels by, respectively, a specific enzyme immunoassay kit, and by chemiluminescence analysis in 3 groups of subjects: COPD with PAH (12), COPD only (36), and healthy individuals (15). In order to evaluate pulmonary-artery systolic pressure (PaPs), all COPD patients underwent Echo-Doppler assessment.. Significantly increased exhaled and circulating levels of ET-1 were found in COPD with PAH compared to both COPD (p < 0.0001) only, and healthy controls (p < 0.0001). In COPD with PAH, linear regression analysis showed good correlation between ET-1 in EBC and PaPs (r = 0.621; p = 0.031), and between arterial levels of ET-1 and PaPs (r = 0.648; p = 0.022), while arterial levels of ET-1 inversely correlated with FEV1%, (r = -0.59, p = 0.043), and PaPs negatively correlated to PaO2 (r = -0.618; p = 0.032). Significantly reduced levels of FENO were found in COPD associated with PAH, compared to COPD only (22.92 +/- 11.38 vs.35.07 +/- 17.53 ppb; p = 0.03). Thus, we observed an imbalanced output in the breath between ET-1 and NO, as expression of pulmonary endothelium and epithelium impairment, in COPD with PAH compared to COPD only. Whether this imbalance is an early cause or result of PAH due to COPD is still unknown and deserves further investigations.

    Topics: Aged; Biomarkers; Blood Gas Analysis; Blood Pressure; Breath Tests; Case-Control Studies; Endothelin-1; Exhalation; Female; Forced Expiratory Volume; Humans; Hypertension, Pulmonary; Linear Models; Male; Middle Aged; Nitric Oxide; Pulmonary Disease, Chronic Obstructive

2008
Rescue of pulmonary hypertension with an oral sulfonamide antibiotic sulfisoxazole by endothelin receptor antagonistic actions.
    Hypertension research : official journal of the Japanese Society of Hypertension, 2008, Volume: 31, Issue:9

    Pulmonary hypertension (PH) is a disease of unknown etiology that ultimately causes right ventricle heart failure with a lethal outcome. An increase in circulating endothelin (ET)-1 levels may contribute to disease progression. This study aimed to examine the possible effects of an orally active ET receptor antagonist, sulfisoxazole (SFX), for the rescue of PH, right ventricular hypertrophy, and eventual right ventricular failure. PH rats (single injection of monocrotaline [MCT]) were treated with an ET antagonist, SFX, an orally active sulfonamide antibody. Effects of SFX on PH rats were assessed in terms of survival rate, pulmonary artery blood pressure (PABP), autonomic nerve activity, and atrial natriuretic peptide (ANP) concentration in right ventricular myocytes and plasma. SFX did not change systemic blood pressure, however, it significantly suppressed the elevation of PABP. SFX maintained the derangement of autonomic nerve control, blunted an increase in ANP in myocytes and plasma, and significantly improved survival in right heart failure and/or related organs dysfunction in PH rats. The ET antagonistic action of the antimicrobial agent, SFX, was experimentally confirmed for treatment of PH in rats.

    Topics: Administration, Oral; Animals; Anti-Infective Agents; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; Electrocardiography; Endothelin Receptor Antagonists; Endothelin-1; Heart Rate; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Myocytes, Cardiac; Pulmonary Artery; Rats; Rats, Wistar; Receptors, Endothelin; Sulfisoxazole; Sympathetic Nervous System

2008
Successful treatment of sarcoidosis-associated pulmonary hypertension with bosentan.
    Respiration; international review of thoracic diseases, 2008, Volume: 75, Issue:2

    Sarcoidosis is a systemic granulomatous disease of unknown etiology, in which the lungs and intrathoracic lymph nodes are predominant sites of involvement. Pulmonary hypertension is a known complication of sarcoidosis. Treatment of sarcoidosis-associated pulmonary hypertension has traditionally focused on the initiation of systemic corticosteroids, but has had inconsistent results. We present a patient with sarcoidosis-associated pulmonary hypertension who achieved substantial clinical improvement with the dual endothelin receptor antagonist bosentan.

    Topics: Antihypertensive Agents; Bosentan; Endothelin-1; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Respiratory Function Tests; Sarcoidosis, Pulmonary; Sulfonamides

2008
Exogenous ghrelin attenuates the progression of chronic hypoxia-induced pulmonary hypertension in conscious rats.
    Endocrinology, 2008, Volume: 149, Issue:1

    Chronic exposure to hypoxia, a common adverse consequence of most pulmonary disorders, can lead to a sustained increase in pulmonary arterial pressure (PAP), right ventricular hypertrophy, and is, therefore, closely associated with heart failure and increased mortality. Ghrelin, originally identified as an endogenous GH secretagogue, has recently been shown to possess potent vasodilator properties, likely involving modulation of the vascular endothelium and its associated vasoactive peptides. In this study we hypothesized that ghrelin would impede the pathogenesis of pulmonary arterial hypertension during chronic hypoxia (CH). PAP was continuously measured using radiotelemetry, in conscious male Sprague Dawley rats, in normoxia and during 2-wk CH (10% O(2)). During this hypoxic period, rats received a daily sc injection of either saline or ghrelin (150 microg/kg). Subsequently, heart and lung samples were collected for morphological, histological, and molecular analyses. CH significantly elevated PAP in saline-treated rats, increased wall thickness of peripheral pulmonary arteries, and, consequently, induced right ventricular hypertrophy. In these rats, CH also led to the overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA within the lung. Exogenous ghrelin administration attenuated the CH-induced overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA. Consequently, ghrelin significantly attenuated the development of pulmonary arterial hypertension, pulmonary vascular remodeling, and right ventricular hypertrophy. These results demonstrate the therapeutic benefits of ghrelin for impeding the pathogenesis of pulmonary hypertension and right ventricular hypertrophy, particularly in subjects prone to CH (e.g. pulmonary disorders).

    Topics: Algorithms; Animals; Blood Glucose; Body Weight; Chronic Disease; Consciousness; Disease Progression; Drug Evaluation, Preclinical; Endothelin-1; Fatty Acids, Nonesterified; Ghrelin; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Male; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; RNA, Messenger

2008
Early increase in pulmonary vascular reactivity with overexpression of endothelin-1 and vascular endothelial growth factor in canine experimental heart failure.
    Experimental physiology, 2008, Volume: 93, Issue:3

    Heart failure is a cause of pulmonary vasoconstriction and remodelling, leading to pulmonary hypertension (PH) and decreased survival. The pathobiology of PH in heart failure remains incompletely understood. We investigated pulmonary vascular function and signalling molecules in early stage PH secondary to experimental heart failure. Eight beagle dogs with overpacing-induced heart failure underwent haemodynamic assessment and postmortem pulmonary arterial reactivity, morphometry and quantification of genes encoding for factors involved in vascular reactivity and remodelling: endothelin-1 (ET-1), ETA and ETB receptors, vascular endothelial growth factor (VEGF), VEGF receptors 1 and 2 (VEGFR1 and VEGFR2), endothelial nitric oxide synthase, angiopoietin-1, bone morphogenetic protein receptors (BMPR1A and BMPR2), serotonin transporter (5-HTT) and the 5-HT(2B) receptor. Overpacing was associated with a decrease in cardiac output and an increase in pulmonary vascular pressures. However, there were no changes in pulmonary vascular resistance or in arteriolar medial thickness. There were increased expressions of genes encoding for ET-1, ETB, VEGF and VEGFR2, while expression of the other genes analysed remained unchanged. In vitro, pulmonary arteries showed decreased relaxation and increased reactivity, while systemic mammary arteries were unaffected. Early PH in heart failure is characterized by altered vasoreactivity and increased ET-1/ETB and VEGF/VEGFR2 signalling.

    Topics: Animals; Blood Pressure; Cardiac Output; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Endothelin-1; Heart Failure; Hemodynamics; Hypertension, Pulmonary; Male; Polymerase Chain Reaction; Pulmonary Artery; Pulmonary Circulation; Receptor, Endothelin B; Time Factors; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vascular Resistance; Vasoconstriction; Vasodilation

2008
Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension.
    Annals of the rheumatic diseases, 2008, Volume: 67, Issue:8

    To study the expression of adhesion molecules in patients with systemic sclerosis (SSc) with and without pulmonary arterial hypertension (PAH) and the effects of therapy with the endothelin-1 (ET-1) receptor antagonist, bosentan.. In all, 35 patients with SSc and 25 healthy donors (HD) were selected for this study. Of 35 patients, 10 had isolated PAH assessed by Doppler echocardiography and treated with bosentan. Peripheral blood (PB) lymphocytes were isolated by density gradient centrifugation, and the expression of lymphocyte function-associated antigen-1 (LFA-1), very late antigen-4 (VLA-4) and L-selectin on CD3 T cells was assessed by double immunofluorescence and flow-cytometry. As endothelial activation markers, serum soluble P-selectin, platelet/endothelial cell adhesion molecule (PECAM)-1, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1 and von Willebrand factor (vWF) antigen were assessed by ELISA. In patients with SSc-PAH, T cell subsets and soluble endothelial markers were assessed at baseline and after 6 and 12 months of bosentan therapy.. In patients with SSc-PAH, serum soluble ICAM-1, VCAM-1, P-selectin and PECAM-1 levels were higher than in HD at baseline and fell to normal values after 12 months of bosentan therapy. CD3-LFA1 T cells were significantly higher in PAH-SSc at baseline than in HD or SSc and significantly decreased after therapy. CD3-L-selectin T cells were significantly lower in SSc-PAH at baseline than in HD or SSc and rose to normal levels after bosentan therapy.. This study confirms that endothelial activation occurs in SSc, and suggests that changes in the T cell/endothelium interplay take place in SSc-associated PAH. Bosentan seems to be able to hamper these changes and restore T cell functions in these patients.

    Topics: Adult; Aged; Analysis of Variance; Antibodies, Antinuclear; Antihypertensive Agents; Autoantibodies; Bosentan; Case-Control Studies; CD3 Complex; Cell Adhesion Molecules; Centromere; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Integrin alpha4beta1; L-Selectin; Lymphocyte Function-Associated Antigen-1; Male; Middle Aged; Scleroderma, Systemic; Sulfonamides; T-Lymphocytes

2008
Endotoxemic pulmonary hypertension is largely mediated by endothelin-induced venous constriction.
    Intensive care medicine, 2008, Volume: 34, Issue:5

    To analyze the effect of endothelin-1 on pulmonary arterial and venous contractile force in vitro and on up- and downstream pulmonary vascular resistance in vivo under sham and endotoxemic conditions in pigs.. In vitro: paired preparations of pulmonary arteries and veins were mounted in a myograph (n=13) for measurements of contractile responses to increasing concentrations of phenylephrine, endothelin-1, and sarafotoxin (endothelin receptor type B agonist). In vivo: 20 pigs were anesthetized, mechanically ventilated, and subjected to phenylephrine (reference substance), endothelin-1, sarafotoxin, endotoxin, and tezosentan (dual endothelin receptor antagonist). Hemodynamic and gas-exchange variables were monitored. Pulmonary capillary pressure, used for calculation of upstream and downstream vascular resistance, was assessed by the pulmonary vascular occlusion technique.. Pulmonary veins were more sensitive than arteries to endothelin-1 both in vitro and in vivo. This difference was more pronounced with sarafotoxin, where almost no arterial effects were noted. In vivo and in vitro exposure to phenylephrine resulted in selective arterial constriction. Endotoxin infusion resulted in pulmonary hypertension with a clear downstream dominance. The latter changes including the increase in capillary pressure were totally abolished by intervention with the dual endothelin receptor antagonist tezosentan.. The endothelin system is extensively involved in endotoxemic pulmonary venous hypertension, an effect possibly mediated by the endothelin B receptor.

    Topics: Animals; Ciprofloxacin; Endothelin-1; Female; Hypertension, Pulmonary; Lipopolysaccharides; Lung; Male; Pyridines; Respiratory Distress Syndrome; Sepsis; Swine; Tetrazoles; Vascular Resistance; Vasoconstriction; Vasodilator Agents

2008
Spontaneous short-term variations of circulating endothelin-1 in pulmonary hypertension.
    Translational research : the journal of laboratory and clinical medicine, 2008, Volume: 151, Issue:3

    Endothelin-1 (ET-1) is overexpressed in pulmonary arteries of pulmonary hypertension (PH) patients and contributes to the sustained vasoconstriction, remodeling process, and thrombosis of vessels that underlie development and progression of this disease. Increased circulating ET-1 correlates with markers of PH severity, and ET-1 is regarded as a potential diagnostic and prognostic biomarker in PH. Because the within-individual variability measured in PH patients and in healthy subjects contributes to determine the biomarker predictive value and must be taken into account to establish cutoff values, we determined the short-term variability of circulating ET-1 in controls and in PH patients.

    Topics: Adult; Analysis of Variance; Biomarkers; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Artery; Reference Values; Sensitivity and Specificity; Time Factors

2008
Inhalation of endothelin receptor blockers in pulmonary hypertension.
    American journal of physiology. Lung cellular and molecular physiology, 2008, Volume: 294, Issue:4

    Endothelin 1 (ET-1) is a potent pulmonary vasoconstrictor and mediator of lung diseases. Antagonism of the ET-1-mediated effects has become an important therapeutic approach. ET-1 (A and B) receptors are differentially distributed in the lung vasculature. Whereas the ET(A) receptors mainly mediate vasoconstriction, the endothelial ET(B) receptor seems to have vasodilative properties. We sought to determine if antagonism of ET receptors can be achieved by inhalation of specific blockers in a model of ET-1-mediated pulmonary hypertension.

    Topics: Administration, Inhalation; Antihypertensive Agents; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Artery; Pulmonary Edema; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

2008
Endothelin-1 and asymmetric dimethylarginine in children with left-to-right shunt after intracardiac repair.
    Clinical research in cardiology : official journal of the German Cardiac Society, 2008, Volume: 97, Issue:6

    Endothelin-1 (ET-1) is an endogenous vasoconstrictive peptide hormone and asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of nitric oxide synthase. We hypothesized that both could contribute to pulmonary hypertension in patients with left-to-right shunt after intracardiac repair.. We prospectively analyzed ET-1 and ADMA plasma levels in 31 patients (m = 16; f = 15) at an age of 0.6 [0.2-27] years (median [range]) with left-to-right shunt (ASD II: n = 12; VSD: n = 11; AVSD: n = 8) presenting with a Qp/Qs of 2.7 [1.4-6.3] and a pulmonary arterial mean pressure (PAP) of 23 [13-57] mmHg. Blood specimens were taken prior to cardiopulmonary bypass (CPB), after weaning from CPB and at 3, 6, 12 and 24 h after CPB.. 12/31 patients were found to have pulmonary hypertension prior to intracardiac repair and 11/12 patients showed persistent pulmonary hypertension during the first 24 h after CPB. Patients with pulmonary hypertension at 12 h after CPB showed significant higher plasma ET-1 compared with patients with normal PAP (1.4 [0-7.9] versus 0.5 [0-2.5] pg/ml; P = 0.048 (Mann-Whitney)). Plasma ADMA decreased from 1.3 [0.75-2.3] micromol/l before CPB to 0.7 [0.4-2.1] micromol/l at 12 h (P < 0.05). However patients with pulmonary hypertension did not show different ADMA plasma levels.. Increased plasma ET-1 but not inhibition of nitric oxide synthase by ADMA is associated with pulmonary hypertension after intracardiac repair.

    Topics: Adolescent; Adult; Arginine; Biomarkers; Cardiopulmonary Bypass; Child; Child, Preschool; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Infant; Male; Nitric Oxide Synthase; Pancreatitis-Associated Proteins; Postoperative Complications; Prospective Studies; Statistics, Nonparametric; Time Factors; Treatment Outcome; Young Adult

2008
Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells.
    Circulation, 2008, Apr-22, Volume: 117, Issue:16

    Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells (PASMCs) during hypoxia and may play a protective role in the response of the lung to hypoxia. Selective COX-2 inhibition may have detrimental pulmonary vascular consequences during hypoxia.. To investigate the role of COX-2 in the pulmonary vascular response to hypoxia, we subjected wild-type and COX-2-deficient mice to a model of chronic normobaric hypoxia. COX-2-null mice developed severe pulmonary hypertension with exaggerated elevation of right ventricular systolic pressure, significant right ventricular hypertrophy, and striking vascular remodeling after hypoxia. Pulmonary vascular remodeling in COX-2-deficient mice was characterized by PASMC hypertrophy but not increased proliferation. Furthermore, COX-2-deficient mice had significant upregulation of the endothelin-1 receptor (ET(A)) in the lung after hypoxia. Similarly, selective pharmacological inhibition of COX-2 in wild-type mice exacerbated hypoxia-induced pulmonary hypertension and resulted in PASMC hypertrophy and increased ET(A) receptor expression in pulmonary arterioles. The absence of COX-2 in vascular smooth muscle cells during hypoxia in vitro augmented traction forces and enhanced contractility of an extracellular matrix. Treatment of COX-2-deficient PASMCs with iloprost, a prostaglandin I(2) analog, and prostaglandin E(2) abrogated the potent contractile response to hypoxia and restored the wild-type phenotype.. Our findings reveal that hypoxia-induced pulmonary hypertension and vascular remodeling are exacerbated in the absence of COX-2 with enhanced ET(A) receptor expression and increased PASMC hypertrophy. COX-2-deficient PASMCs have a maladaptive response to hypoxia manifested by exaggerated contractility, which may be rescued by either COX-2-derived prostaglandin I(2) or prostaglandin E(2).

    Topics: Animals; Blood Pressure; Cells, Cultured; Chronic Disease; Collagen; Cyclooxygenase 2; Dinoprostone; Endothelin-1; Gels; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Iloprost; Mice; Mice, Mutant Strains; Muscle Contraction; Muscle, Smooth, Vascular; Pulmonary Artery; Receptor, Endothelin A; Traction; Vasoconstriction; Vasodilator Agents

2008
Perinatal profile of ventricular overload markers in congenital diaphragmatic hernia.
    Journal of pediatric surgery, 2008, Volume: 43, Issue:4

    In congenital diaphragmatic hernia (CDH), pulmonary hypertension increases right ventricle (RV) afterload, which could impair heart function and contribute to poor outcome for most affected infants. Nevertheless, the real significance of vascular pulmonary alterations in perinatal hemodynamics is largely unknown. It is defined that ventricular pressure overload induces increased myocardium gene expression of B-type natriuretic peptide (BNP) and components of the renin-angiotensinogen and endothelin (ET)-1 systems. Our aim was to evaluate perinatal myocardium expression of these genes associated with ventricular pressure overload in a nitrofen-induced CDH rat model.. In the nitrofen-induced CDH rat model, fetuses from dated pregnant Sprague-Dawley rats at 15.5, 17.5, 19.5 and 21.5 days postcoitum as well as newborn pups were assigned to 3 experimental groups: control, nitrofen (exposed to nitrofen, without CDH), and CDH (exposed to nitrofen, with CDH). Myocardial samples collected from the RV and left ventricle (LV) were processed for quantification of messenger RNA (mRNA) of BNP, angiotensinogen, and ET-1.. The perinatal expression of BNP, angiotensinogen, and ET-1 mRNA in the RV and LV of the control group revealed daily changes. During gestation, the expression of BNP and angiotensinogen mRNA underwent significant oscillation compared with control in both nitrofen-exposed fetuses, although we cannot identify significant differences between the nitrofen and CDH groups. After birth, we found a significant increasing expression of all studied genes only in the RV of CDH pups.. Perinatal myocardial quantification of BNP, angiotensinogen, and ET-1 mRNA levels suggests that both nitrofen-exposed and control pups revealed prenatal variations of expression of the studied genes. Moreover, CDH is associated with significant molecular alterations only in the RV after birth.

    Topics: Adaptation, Biological; Angiotensinogen; Animals; Base Sequence; Biomarkers; Endothelin-1; Gene Expression; Genetic Markers; Heart Ventricles; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Molecular Sequence Data; Myocardium; Natriuretic Peptide, Brain; Phenyl Ethers; Rats; Rats, Sprague-Dawley; RNA, Messenger

2008
[Relativity between change of right ventricular function and the serum concentration of ET-1 in patients with cor pulmonale in plain and plateau].
    Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 2007, Volume: 23, Issue:1

    Topics: Aged; Altitude; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Heart Disease; Ventricular Function, Right

2007
[Study on relativity of hypoxic pulmonary hypertension with levels of endothelin-1 and vascular endothelial growth factor in plasma of pulmonary artery and carotid artery].
    Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 2007, Volume: 23, Issue:4

    To study the effects of endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) on the mechanism of hypoxic pulmonary hypertension (HPH).. We studied 4 groups of age-controlled male rats, i.e., normal control for 2 weeks group (N2), normal control for 3 weeks group (N3), exposed to hypoxia for 2 weeks group (H2) and for 3 weeks group (H3). Chronic HPH rat models were established by chronic hypobaric hypoxia [(10.0% +/- 0.5% O2] for 2 and 3 weeks, respectively. The rats were anesthetized and fixed, and the levels of mean pulmonary artery pressure (mPAP) and carotid arterial pressure (CAP) were measured using catheters by a microcomputer via transducers. The weight ratio of right ventricle (RV) and left ventricle and septum (LV + S) [RV/ (LV+S)] were determined. The contents of ET-1 in plasma of pulmonary artery and carotid artery and in homogenates of lung and systemic arteries were determined by radioimmunoassay, and the contents of VEGF in serum of pulmonary artery and carotid artery were determined by ABC-ELISA.. HPH rat models were established successfully. Compared with control groups, the values of ET-1 were both enhanced in carotid artery and pulmonary artery plasma in model groups (P < 0.01). In the HPH groups, the level of pulmonary artery plasma ET-1 was significantly lower than that of carotid artery plasma, but just the reverse was ET-1 in control rats. The levels of ET-1 in homogenates of lungs from HPH models were significantly higher than those in homogenates of lungs from control groups (P < 0.01), and markedly higher than those in homogenates of systemic arteries from HPH rats (P < 0.01) SThe values of VEGF in serum of pulmonary artery from H3 group were significantly higher than those from control groups and H2 group (P < 0.01). In serum of carotid artery, the values of VEGF from the HPH models were higher than those from the control groups (P < 0.01).. ET-1 and VEGF play important roles in the pathogenesis of HPH. The result that ET-1 concentration around pulmonary arteries was significantly higher than that around systemic arteries may be one of the mechanisms accounting for the different reaction of them to hypoxia.

    Topics: Animals; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A

2007
Endothelin-1/endothelin-3 ratio: a potential prognostic factor of pulmonary arterial hypertension.
    Chest, 2007, Volume: 131, Issue:1

    Pulmonary arterial hypertension (PAH) is a rare condition characterized by elevated pulmonary artery pressure leading to right-heart failure and death. Endothelin (ET)-1 has been shown to play a significant pathogenic role in PAH. ET-3 has not yet been investigated in PAH.. ET-1 and ET-3 plasma concentrations were measured in 33 PAH patients prior to any specific PAH therapy and in 9 control subjects. In PAH patients, hemodynamic parameters measured by right-heart catheterization, 6-min walk distance (6MWD), New York Heart Association (NYHA) functional class, and time until lung transplantation or death were recorded.. In patients with PAH, levels of ET-1 were increased while those of ET-3 were decreased, as compared to control subjects (p < 0.005 for both comparisons). ET-1/ET-3 ratio varied little in control subjects, while it increased threefold in PAH patients (p < 0.0001). ET-1 correlated positively with right atrial pressure (RAP), indexed total pulmonary resistance, and negatively with cardiac index and venous saturation of oxygen (Svo(2)). ET-3 correlated positively with 6MWD. ET-1/ET-3 ratio correlated positively with RAP, negatively with Svo(2) and 6MWD, and was also associated with NYHA functional class. ET-1/ET-3 ratio was associated with prognosis in this sample of PAH patients treated with specific therapies.. PAH is characterized by elevated ET-1 and ET-1/ET-3 ratio and decreased ET-3 plasma concentrations. All of them correlate with hemodynamic and clinical markers of disease severity. ET-1/ET-3 ratio might be a novel prognostic factor in PAH. These preliminary data should be validated in a large prospective multicenter cohort of PAH patients.

    Topics: Adult; Biomarkers; Case-Control Studies; Endothelin-1; Endothelin-3; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prognosis; Statistics, Nonparametric

2007
Sitaxsentan for the prevention of experimental shunt-induced pulmonary hypertension.
    Pediatric research, 2007, Volume: 61, Issue:3

    We previously reported on the partial prevention of experimental shunt-induced pulmonary arterial hypertension (PAH) by the nonselective endothelin (ET) ET-A/ET-B receptor antagonist bosentan. As the respective roles of the ET-A and ET-B receptor signaling in the pathobiology of the disease remain undefined, we investigated the effects of selective ET-A receptor blockade by sitaxsentan in the same early stage PAH model. Twenty-one 3-wk-old piglets were randomized to placebo or sitaxsentan therapy (1.5 mg/kg/d), after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry and real-time-quantitative-PCR for ET-1, angiopoietin-1, and bone morphogenetic receptor (BMPR) signaling molecules. Three months of left to right shunting induced an increase in pulmonary vascular resistance (PVR) and medial thickness, an overexpression of ET-1, ET-B receptor, and angiopoietin-1, and a decreased expression of BMPR-2 and BMPR-1A. Pretreatment with sitaxsentan prevented shunt-induced increase in PVR and decreased medial thickness by 64%. Sitaxsentan therapy completely prevented the decreased expression of BMPR-2 and limited the overexpression of ET-1, ET-B and angiopoietin-1, and the decreased expression of BMPR-1A. In conclusion, selective ET-A receptor blockade partially prevents shunt-induced PAH.

    Topics: Anastomosis, Surgical; Angiopoietin-1; Animals; Bone Morphogenetic Protein Receptors; Brachiocephalic Trunk; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Isoxazoles; Pulmonary Artery; RNA, Messenger; Swine; Thiophenes

2007
Endothelin 1, its endothelin type A receptor, connective tissue growth factor, platelet-derived growth factor, and adrenomedullin expression in lungs of pulmonary hypertensive and nonhypertensive chickens.
    Poultry science, 2007, Volume: 86, Issue:5

    Twenty-four 1-d-old broilers were distributed in 2 groups, pulmonary hypertensive broilers (PHB) and pulmonary nonhypertensive broilers (NPHB), to estimate possible differences between them in the expression of endothelin 1 (ET-1) and its type A receptor, connective tissue growth factor, platelet-derived growth factor, and adrenomedullin expression in the lungs. For this purpose, total RNA extraction and real-time PCR analysis were used. Endothelin 1 mRNA levels in the lungs of PHB were significantly higher than the corresponding level in NPHB (P < 0.001). In contrast, the opposite was true for ET-1 type A receptor mRNA levels (P < 0.001). Connective tissue growth factor mRNA levels in the lungs of PHB were significantly higher than in the lungs of NPHB (P < 0.01). However, no differences were encountered between the 2 groups of broilers in platelet-derived growth factor mRNA expression (P > 0.05). Adrenomedullin mRNA levels in the lungs of PHB were significantly higher than in NPHB (P < 0.01). It has been demonstrated for the first time that ET-1, connective tissue growth factor, and adrenomedullin are upregulated in the lungs of PHB. Furthermore, it is suggested that these peptides may play a major role in pulmonary hypertension pathophysiology. Present data might provide clues for future research directions such as genetic selection and therapeutic intervention to revert the process of pulmonary vasoconstriction and vascular remodeling. Major research goals could be to find endothelium-derived factors that probably trigger endothelial dysfunction, as well as possible interactions with already identified molecules which also intervene in the pulmonary response to hypoxia.

    Topics: Adrenomedullin; Animals; Chickens; Connective Tissue Growth Factor; Endothelin-1; Gene Expression Regulation; Hypertension, Pulmonary; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Lung; Male; Platelet-Derived Growth Factor; Poultry Diseases; Receptor, Endothelin A; RNA, Messenger

2007
Pulmonary vascular changes in piglets with increased pulmonary blood flow and pressure.
    Virchows Archiv : an international journal of pathology, 2007, Volume: 450, Issue:6

    In this model of pulmonary vascular disease, high pulmonary blood flow was created by an anastomosis between the left subclavian artery and the main pulmonary artery [Blalock-Taussig (BT) shunt] in 4-week-old piglets (n = 6). Additional ligation of the left pulmonary artery (LPA) was used to increase pulmonary artery pressure (n = 6). Seven piglets were sham-operated. After 3 months, mean pulmonary artery pressure was higher in animals with BT shunt and LPA ligation (22 +/- 5; mean+/-SD) compared to sham-operated animals (15 +/- 2). In addition, thickening of the medial coat (20.1 +/- 2.8% versus 13.6 +/- 3.1% wall thickness) and increased immunostaining for vascular endothelial growth factor A (VEGF-A) were observed. Relative gene expression for endothelin-converting enzyme-1 (ECE-1) mRNA was 1.8 times higher, and VEGF-A mRNA was 2.5 times higher in pigs with BT shunt and LPA ligation compared with sham-operated animals. VEGF receptor-1 and VEGF receptor-2 mRNA was lower in shunted animals and in animals with additional ligation of LPA. Upregulation of ECE-1 and VEGF-A, as well as changes in VEGFR expression in the pulmonary hypertensive lung, may contribute to pulmonary vascular changes.

    Topics: Animals; Animals, Newborn; Aspartic Acid Endopeptidases; Blood Pressure; Cyclic GMP; Endothelin-1; Endothelin-Converting Enzymes; Hypertension, Pulmonary; Immunohistochemistry; Isoenzymes; Lung; Metalloendopeptidases; Nitrates; Nitrites; Pulmonary Artery; Pulmonary Circulation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Staining and Labeling; Swine; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

2007
Vasoconstrictor effect of endothelin-1 on hypertensive pulmonary arterial smooth muscle involves Rho-kinase and protein kinase C.
    American journal of physiology. Lung cellular and molecular physiology, 2007, Volume: 293, Issue:2

    Although one of the common characteristics of pulmonary hypertension is abnormal sustained vasoconstriction, the signaling pathways that mediate this heightened pulmonary vascular response are still not well defined. Protein kinase C (PKC) and Rho-kinase are regulators of smooth muscle contraction induced by G protein-coupled receptor agonists including endothelin-1 (ET-1), which has been implicated as a signaling pathway in pulmonary hypertension. Toward this end, it was hypothesized that both Rho-kinase and PKC mediate the pulmonary vascular response to ET-1 in hypertensive pulmonary arterial smooth muscle, and therefore, the purpose of this study was to determine the role of PKC and Rho-kinase signaling in ET-1-induced vasoconstriction in both normotensive (Sprague-Dawley) and hypertensive (Fawn-Hooded) rat pulmonary arterial smooth muscle. Results indicate that ET-1 caused greater vasoconstriction in hypertensive pulmonary arteries compared with the normal vessels, and treatment with the PKC antagonists chelerythrine, rottlerin, and Gö 6983 inhibited the vasoconstrictor response to ET-1 in the hypertensive vessels. In addition, the specific Rho-kinase inhibitor Y-27632 significantly attenuated the effect of ET-1 in both normotensive and hypertensive phenotypes, with greater inhibition occurring in the hypertensive arteries. Furthermore, Western blot analysis revealed that ET-1 increased RhoA expression in both normotensive and hypertensive pulmonary arteries, with expression being greater in the hypertensive state. These results suggest that both PKC and Rho/Rho-kinase mediate the heightened pulmonary vascular response to ET-1 in hypertensive pulmonary arterial smooth muscle.

    Topics: Amides; Animals; Blotting, Western; Carbazoles; Endothelin-1; Enzyme Inhibitors; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Indoles; Intracellular Signaling Peptides and Proteins; Male; Maleimides; Muscle, Smooth, Vascular; Potassium Chloride; Protein Kinase C; Protein Serine-Threonine Kinases; Pulmonary Artery; Pyridines; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Species Specificity; Vasoconstriction

2007
Right ventricular myocardial isovolumic relaxation time as novel method for evaluation of pulmonary hypertension: correlation with endothelin-1 levels.
    Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography, 2007, Volume: 20, Issue:5

    Noninvasive assessment of pulmonary artery systolic pressure (PASP) has several limitations. Right ventricular (RV) isovolumic relaxation time (IVRT) is sensitive to changes in PASP. Blood pool-derived RV IVRT correlates well with PASP. However, because of complex parameter derivation, the method is rarely used. Endothelin (ET)-1 levels are elevated in congestive heart failure in relation with the severity of pulmonary hypertension.. We sought to validate the measurement of pulsed wave (PW) Doppler tissue imaging (DTI)-derived myocardial RV IVRT as a predictor of PASP against invasively measured PASP and correlate this with ET-1 levels.. This study enrolled 53 patients with pulmonary hypertension and 20 age- and sex-matched healthy individuals as a control group. Transthoracic echocardiography with DTI and assessment of plasma level of ET-1 were performed just before right heart catheterization. PW DTI and M-mode echocardiography were used for assessment of tricuspid annular systolic motion. Ejection fraction of RV was estimated by Simpson's rule. Blood pool-derived IVRT and PW DTI-derived IVRT were estimated and corrected for heart rate (IVRTc).. Echocardiographically derived PASP, myocardial PW DTI-derived IVRTc, blood pool-derived IVRTc, and ET-1 levels were significantly higher in patients than in control subjects (68.66 +/- 21.88 vs 18.78 +/- 7.47 mm Hg, 121.75 +/- 49.11 vs 28.33 +/- 25.1 milliseconds, 77.21 +/- 42.66 vs 26.79 +/- 19.85 milliseconds, and 7.04 +/- 2.45 vs 1.35 +/- 1.12 pg/mL, respectively, P < .001 for all). A strong positive correlation was found between invasively measured PASP and PW DTI-derived IVRTc (r = .86), blood pool-derived IVRTc (r = .75), and ET-1 level (r = .94), and between PW DTI-derived IVRTc and ET-1 levels (r = .82), whereas strong negative correlation was detected between ET-1 levels and both RV ejection fraction (r = -.73) and RV Tei index (r = -.73, P < .001 for all correlations).. Tricuspid annular PW DTI-derived IVRTc correlates very strongly with both invasively measured PASP and ET-1 levels. Therefore, it can be used to predict PASP. It can even be considered as an alternative to tricuspid regurgitation-derived PASP when tricuspid regurgitation is nonrecordable. However, caution should be taken while examining patients with significantly reduced RV function.

    Topics: Blood Flow Velocity; Echocardiography, Doppler, Pulsed; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Immunoenzyme Techniques; Male; Middle Aged; Myocardial Contraction; Pulmonary Wedge Pressure; ROC Curve; Severity of Illness Index; Stroke Volume; Tricuspid Valve; Ventricular Function, Right

2007
Cardiac sympathetic rejuvenation: a link between nerve function and cardiac hypertrophy.
    Circulation research, 2007, Jun-22, Volume: 100, Issue:12

    Neuronal function and innervation density is regulated by target organ-derived neurotrophic factors. Although cardiac hypertrophy drastically alternates the expression of various growth factors such as endothelin-1, angiotensin II, and leukemia inhibitory factor, little is known about nerve growth factor expression and its effect on the cardiac sympathetic nerves. This study investigated the impact of pressure overload-induced cardiac hypertrophy on the innervation density and cellular function of cardiac sympathetic nerves, including kinetics of norepinephrine synthesis and reuptake, and neuronal gene expression. Right ventricular hypertrophy was induced by monocrotaline treatment in Wistar rats. Newly developed cardiac sympathetic nerves expressing beta(3)-tubulin (axonal marker), GAP43 (growth-associated cone marker), and tyrosine hydroxylase were markedly increased only in the right ventricle, in parallel with nerve growth factor upregulation. However, norepinephrine and dopamine content was paradoxically attenuated, and the protein and kinase activity of tyrosine hydroxylase were markedly downregulated in the right ventricle. The reuptake of [(125)I]-metaiodobenzylguanidine and [(3)H]-norepinephrine were also significantly diminished in the right ventricle, indicating functional downregulation in cardiac sympathetic nerves. Interestingly, we found cardiac sympathetic nerves in hypertrophic right ventricles strongly expressed highly polysialylated neural cell adhesion molecule (PSA-NCAM) (an immature neuron marker) as well as neonatal heart. Taken together, pressure overload induced anatomical sympathetic hyperinnervation but simultaneously caused deterioration of neuronal cellular function. This phenomenon was explained by the rejuvenation of cardiac sympathetic nerves as well as the hypertrophic cardiomyocytes, which also showed the fetal form gene expression.

    Topics: Adrenergic Fibers; Animals; Dopamine; Endothelin-1; GAP-43 Protein; Gene Expression Regulation; Heart Failure; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Kinetics; Male; Monocrotaline; Myocytes, Cardiac; Nerve Growth Factor; Neural Cell Adhesion Molecule L1; Norepinephrine; Rats; Rats, Wistar; Sialic Acids; Tubulin; Tyrosine 3-Monooxygenase; Up-Regulation

2007
Forever young?: nerve growth factor, sympathetic fibers, and right ventricle pressure overload.
    Circulation research, 2007, Jun-22, Volume: 100, Issue:12

    Topics: Adrenergic Fibers; Angiotensin II; Animals; Calcium; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Mice; Nerve Growth Factor; Rats; Tyrosine 3-Monooxygenase; Vasoconstriction; Ventricular Dysfunction, Right

2007
Oral sildenafil prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats.
    Interactive cardiovascular and thoracic surgery, 2007, Volume: 6, Issue:5

    The endothelin system plays an important role in the development of pulmonary hypertension. Several studies have suggested that interfering with the function of the endothelin system will be helpful in pulmonary hypertension treatment. In the present study, we investigated the preventive and therapeutic effects of sildenafil on pulmonary hypertension in monocrotaline-treated rats. In the preventive study, the level of mean pulmonary arterial pressure, right ventricular divide, left ventricular and septum, small pulmonary arterial morphologic and elastic fiber changes were highly improved in the treated group (P<0.05). The expressions of endothelin-1 A type receptors on small pulmonary arterial hypertension were significantly reduced in the sildenafil-treated group (P<0.05). The ET-1 level in plasma was increased in the sildenafil-treated group, but did not reach significance. Emphysema, interstitial pneumonia were significantly improved in the sildenafil-treated group. The same findings were also observed in the therapeutic study. The present results suggest that sildenafil can prevent and reverse the development of pulmonary hypertension in monocrotaline-treated rats by improving the function of endothelin system in pulmonary arteries.

    Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Lung Diseases, Interstitial; Male; Monocrotaline; Piperazines; Pulmonary Artery; Pulmonary Emphysema; Purines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents

2007
Atrasentan treatment of pulmonary vascular disease in piglets with increased pulmonary blood flow.
    Journal of cardiovascular pharmacology, 2007, Volume: 50, Issue:3

    We studied the effect of chronic endothelin A receptor blockade by atrasentan on the pulmonary endothelin-1 system and vascular endothelial growth factor (VEGF) expression in piglets with high pulmonary blood flow. Twenty-five 4-week-old piglets with high pulmonary blood flow were randomized to three groups: sham operated (n = 8), placebo (water) (n = 7), or treatment with atrasentan (2 mg/kg per day) (n = 10). After 3 months, mean pulmonary arterial pressure (PAP) was higher in the placebo group than in the sham group [18 +/- 2 mm Hg versus 14 +/- 1 mm Hg; P < 0.05 (ANOVA)]. Atrasentan treatment was associated with lower cardiac output, PAP (14 +/- 1 mm Hg), and medial wall thickness of pulmonary arteries (diameter: 50-150 microM) compared with placebo [13.6 +/- 3.0% versus 18.1 +/- 4.2%; P < 0.05 (ANOVA)]. Quantitative real-time polymerase chain reaction for endothelin-1, endothelin B receptor, and endothelin-converting enzyme-1 mRNA in lung tissue did not differ. However, immunostaining as well as mRNA for VEGF were lower in atrasentan-treated animals (relative gene expression: atrasentan versus placebo: 0.8 +/- 0.3 versus 1.5 +/- 0.3; P = 0.009). Atrasentan treatment effectively reduces medial hypertrophy in piglets with chronic pulmonary hyperperfusion. Chronic endothelin A receptor blockade by atrasentan may interfere with the expression of VEGF.

    Topics: Animals; Atrasentan; Blood Pressure; Cardiac Output; Chronic Disease; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Hypertension, Pulmonary; Hypertrophy; Immunohistochemistry; Lung; Pulmonary Artery; Pulmonary Circulation; Pyrrolidines; Random Allocation; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Swine; Vascular Endothelial Growth Factor A

2007
The change of plasma endothelin-1 levels before and after surgery with or without Down syndrome.
    Paediatric anaesthesia, 2007, Volume: 17, Issue:11

    The present study aimed to elucidate the pathophysiological roles of endothelin (ET)-1 in patients with pulmonary hypertension and pulmonary vascular obstructive disease secondary to congenital heart disease and compare the plasma levels of ET-1 between children with and without Down syndrome.. Subjects comprised 32 children with congenital heart disease aged 0.5-14 months. Patients were classified into two groups: those with Down syndrome (Group D, n = 16); and those with nonDown syndrome (Group ND, n = 16). Heparinized blood samples were taken from a radial arterial line and plasma ET-1 levels were measured preoperatively, during cardiopulmonary bypass (CPB), a few minutes after termination of CPB, and 2, 6 and 24 h after discontinuation of CPB.. Plasma ET-1 levels were significantly higher in Group D than in Group ND at all times except for a few minutes after termination of CPB. In both groups, peak ET-1 values were obtained at 6 h after CPB. At 24 h after CPB, ET-1 concentrations returned to baseline levels before CPB in Group ND, but not in Group D. A correlation was identified between preoperative pulmonary to systemic pressure ratio and ET-1 concentration before and after CPB in both groups.. Pre- and postoperative plasma ET-1 concentrations reflect pre- and postoperative pulmonary artery conditions in both groups. Specific features in Down syndrome could be associated with ET injury and might cause persistent increases in ET concentration and prolong artificial respiration.

    Topics: Cardiac Catheterization; Cardiopulmonary Bypass; Down Syndrome; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Linear Models; Lung Diseases, Obstructive; Male; Monitoring, Intraoperative; Time Factors

2007
Endothelin-1 and serotonin are involved in activation of RhoA/Rho kinase signaling in the chronically hypoxic hypertensive rat pulmonary circulation.
    Journal of cardiovascular pharmacology, 2007, Volume: 50, Issue:6

    We have previously reported that vasoconstrictor sensitivity to KCl (a receptor-independent and voltage-gated Ca influx-mediated vasoconstrictor) is augmented in the chronically hypoxic hypertensive rat pulmonary circulation probably through increased Rho kinase-mediated Ca sensitization. However, the upstream mechanism by which the RhoA/Rho kinase signaling pathway is activated is unknown. This study examined if endogenous endothelin-1 (ET-1) and serotonin (5-HT) play roles in the Rho kinase-mediated augmented vasoconstrictor response to KCl and the activation of RhoA in chronically hypoxic hypertensive rat pulmonary arteries. The augmented KCl vasoconstriction in hypertensive lungs was reduced by the ETA receptor antagonist BQ123, while a dual ETA/B antagonist had no further effects. A combination of BQ123 and a 5-HT1B/1D receptor antagonist, GR127935, was more effective than either agent alone. The combined antagonists also reduced augmented contractile sensitivity to KCl in hypertensive intrapulmonary arteries. Membrane-to-cytosol ratio of RhoA expression in hypertensive arteries was greater than that in normotensive arteries and was reduced by BQ123 and GR127935. These results suggest that stimulation of ETA and 5-HT1B/1D receptors by endogenous ET-1 and 5-HT, respectively, is involved in RhoA/Rho kinase-mediated increased Ca sensitization in the chronically hypoxic hypertensive rat pulmonary circulation.

    Topics: Amides; Animals; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Enzyme Activation; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Lung; Male; Peptides, Cyclic; Perfusion; Potassium Chloride; Pulmonary Artery; Pulmonary Circulation; Pyridines; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; rhoA GTP-Binding Protein; Serotonin; Signal Transduction; Vasoconstriction

2007
[Changes of the levels of adrenomedulin, endothelin-1 and nitric oxide in children with pulmonary hypertension secondary to congenital heart disease].
    Zhonghua er ke za zhi = Chinese journal of pediatrics, 2007, Volume: 45, Issue:10

    Topics: Adrenomedullin; Child; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension; Hypertension, Pulmonary; Male; Nitric Oxide

2007
[The vasoactive material and pulmonary vascular structural remodeling in rats].
    Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 2006, Volume: 22, Issue:1

    To investigate the role of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) on pulmonary vascular structural remodeling in rats and pika.. The Wistar rats which reside at 2 260 m were carried to 3 417 m. After they were fed 24 hours,2 weeks and 3 weeks respectively, the level of VEGF and ET-1 were measured using a kit by ELISA method. Pulmonary tissue was taken out to stain with elastica-Van Gieson. The amount of pulmonary arteries (< 100 microm) and the component ratio of MA, PMA,and NMA were calculated by using a light microscope. The ratio of right ventricle weight to left ventricle plus septum weight (RV/LV + S) were measured.. The ET-1 was significantly different in pika as compared with 24 h, 2 weeks, 3 weeks hypoxic rats (P < 0.01) respectively. The levels of VEGF in 2 weeks, 3 weeks rats were much higher than that of pika but no difference was found between pika and 24 h hypoxic rats. The ratio of MA, PMA obviously increased, and NMA decreased significantly, right ventricular hypertrophy was developed in differ groups of hypoxic rats.. The VEGF and ET-1 participate the muscularization of pulmonary vessels during hypoxia and play an important role in the process of hypoxic pulmonary hypertension in rats, however the VEGF and ET-1 may be maintainable only normal organic function in pika.

    Topics: Animals; Endothelin-1; Female; Hypertension, Pulmonary; Hypoxia; Lagomorpha; Lung; Male; Pulmonary Artery; Rats; Rats, Wistar; Vascular Endothelial Growth Factor A

2006
Vasoactive mediators and pulmonary hypertension after cigarette smoke exposure in the guinea pig.
    Journal of applied physiology (Bethesda, Md. : 1985), 2006, Volume: 100, Issue:2

    The pathogenesis of pulmonary hypertension in patients with chronic obstructive pulmonary disease is not understood. We have previously shown increased levels of mediators that control vasoconstriction (endothelin-1), vascular cell proliferation (endothelin-1 and vascular endothelial growth factor), and vasodilation (endothelial nitric oxide synthase) in the intrapulmonary arteries of animals exposed to cigarette smoke. To determine whether these mediators could be implicated in the structural remodeling of the arterial vasculature and increased pulmonary arterial pressure caused by chronic cigarette smoke exposure, guinea pigs were exposed to daily cigarette smoke for 6 mo. Pulmonary arterial pressures were measured. Intrapulmonary artery structure was analyzed by morphometry, artery mediator protein expression by immunohistochemistry, and artery mediator gene expression by laser capture microdissection and real-time RT-PCR. We found that the smoke-exposed animals developed increases in pulmonary arterial pressure and increased muscularization of the small pulmonary arteries. Gene expression and protein levels of all three mediators were increased, and pulmonary arterial pressure correlated both with the levels of mediator production and with the degree of arterial muscularization. We conclude that chronic smoke exposure produces increased vasoactive mediator expression in the small intrapulmonary arteries and that these mediators are associated with vascular remodeling as well as increased pulmonary arterial pressure. These findings support the idea that hypertension in chronic obstructive pulmonary disease is a result of direct cigarette smoke-mediated effects on the vasculature and suggest that interference with endothelin and VEGF production and activity or augmentation of nitric oxide levels may be beneficial.

    Topics: Animals; Disease Models, Animal; Endothelin-1; Guinea Pigs; Hypertension, Pulmonary; Male; Muscle, Smooth, Vascular; Nicotiana; Nitric Oxide Synthase Type III; Pulmonary Artery; Pulmonary Wedge Pressure; RNA, Messenger; Smoke; Vascular Endothelial Growth Factor A

2006
Hypoxia-induced reactive oxygen species downregulate ETB receptor-mediated contraction of rat pulmonary arteries.
    American journal of physiology. Lung cellular and molecular physiology, 2006, Volume: 290, Issue:3

    Production of reactive oxygen species (ROS) may be increased during hypoxia in pulmonary arteries. In this study, the role of ROS in the effect of hypoxia on endothelin (ET) type B (ETB) receptor-mediated vasocontraction in lungs was determined. In rat intrapulmonary (approximately 0.63 mm ID) arteries, contraction induced by IRL-1620 (a selective ETB receptor agonist) was significantly attenuated after 4 h of hypoxia (30 mmHg Po2) compared with normoxic control (140 mmHg Po2). The effect was abolished by tiron, a scavenger of superoxide anions, but not by polyethylene glycol (PEG)-conjugated catalase, which scavenges H2O2. The hypoxic effect on ETB receptor-mediated vasoconstriction was also abolished by endothelium denudation but not by nitro-L-arginine and indomethacin. Exposure for 4 h to exogenous superoxide anions, but not H2O2, attenuated the vasoconstriction induced by IRL-1620. Confocal study showed that hypoxia increased ROS production in pulmonary arteries that were scavenged by PEG-conjugated SOD. In endothelium-intact pulmonary arteries, the ETB receptor protein was reduced after 4 h of exposure to hypoxia, exogenous superoxide anions, or ET-1. BQ-788, a selective ETB receptor antagonist, prevented these effects. ET-1 production was stimulated in endothelium-intact arteries after 4 h of exposure to hypoxia or exogenous superoxide anions. This effect was blunted by PEG-conjugated SOD. These results demonstrate that exposure to hypoxia attenuates ETB receptor-mediated contraction of rat pulmonary arteries. A hypoxia-induced production of superoxide anions may increase ET-1 release from the endothelium and result in downregulation of ETB receptors on smooth muscle.

    Topics: Animals; Down-Regulation; Endothelin-1; Endothelins; Endothelium, Vascular; Hypertension, Pulmonary; Hypoxia; Lung; Male; Muscle Contraction; Muscle, Smooth, Vascular; Peptide Fragments; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptor, Endothelin B; Superoxides; Vasoconstriction

2006
Inhaled nitric oxide induced NOS inhibition and rebound pulmonary hypertension: a role for superoxide and peroxynitrite in the intact lamb.
    American journal of physiology. Lung cellular and molecular physiology, 2006, Volume: 290, Issue:2

    Previous in vivo studies indicate that inhaled nitric oxide (NO) decreases nitric oxide synthase (NOS) activity and that this decrease is associated with significant increases in pulmonary vascular resistance (PVR) upon the acute withdrawal of inhaled NO (rebound pulmonary hypertension). In vitro studies suggest that superoxide and peroxynitrite production during inhaled NO therapy may mediate these effects, but in vivo data are lacking. The objective of this study was to determine the role of superoxide in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy in vivo. In control lambs, 24 h of inhaled NO (40 ppm) decreased NOS activity by 40% (P<0.05) and increased endothelin-1 levels by 64% (P<0.05). Withdrawal of NO resulted in an acute increase in PVR (60.7%, P<0.05). Associated with these changes, superoxide and peroxynitrite levels increased more than twofold (P<0.05) following 24 h of inhaled NO therapy. However, in lambs treated with polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) during inhaled NO therapy, there was no change in NOS activity, no increase in superoxide or peroxynitrite levels, and no increase in PVR upon the withdrawal of inhaled NO. In addition, endothelial NOS nitration was 18-fold higher (P<0.05) in control lambs than in PEG-SOD-treated lambs following 24 h of inhaled NO. These data suggest that superoxide and peroxynitrite participate in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy. Reactive oxygen species scavenging may be a useful therapeutic strategy to ameliorate alterations in endogenous NO signaling during inhaled NO therapy.

    Topics: Administration, Inhalation; Animals; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Lung; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Peroxynitrous Acid; Polyethylene Glycols; Sheep; Superoxide Dismutase; Superoxides

2006
Genistein, a phytoestrogen, attenuates monocrotaline-induced pulmonary hypertension.
    Respiration; international review of thoracic diseases, 2006, Volume: 73, Issue:1

    Pulmonary hypertension is characterized by high pulmonary blood pressure, vascular remodeling, and right ventricular hypertrophy. Although recent studies suggest that an imbalance between endothelial mediators on pulmonary vasculature may contribute to the development of pulmonary hypertension, the pathogenesis is not fully understood and the treatment of pulmonary hypertension is still unresolved.. The purpose of this study was to investigate whether genistein, a phytoestrogen derived from soybean, would prevent the development of monocrotaline (MCT)-induced pulmonary hypertension in rats. Hemodynamic parameters of catheterized rats and morphological feature of lungs were evaluated among MCT-treated rats receiving or not receiving genistein. Furthermore, examination of expression in endothelial nitric oxide synthase and endothelin-1 peptide level was performed.. Daily supplementation with either genistein (0.2 mg/kg) or vehicle was started 2 days prior to a single-dose injection of MCT (60 mg/kg). On day 28, rats underwent catheterization, and right ventricular hypertrophy and morphological features were assessed. Furthermore, endothelial nitric oxide synthase and endothelin-1 were examined by Western blot analysis and radioimmunoassay, respectively, in homogenated lungs.. In rats that received daily supplementation of genistein, mean pulmonary arterial pressure was significantly reduced, whereas mean systemic arterial pressure and heart rate were unaltered compared with MCT control rats on day 28 after MCT injection. Right ventricular hypertrophy, medial wall thickness of pulmonary arteries corresponding to the terminal bronchioles, and the degree of neo-muscularization of more distal arteries were less severe in genistein-treated rats. Genistein supplementation improved MCT-induced downregulation of expression of endothelial nitric oxide synthase in the lungs. However, endothelin-1 peptide levels did not differ among all groups of lungs.. We conclude that daily supplementation of genistein potently attenuates MCT-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling in rats. The underlying mechanism responsible for this effect may be partly related to the restoration of a decreased expression of endothelial nitric oxide synthase.

    Topics: Animals; Blotting, Western; Down-Regulation; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Genistein; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Immunohistochemistry; Lung; Male; Monocrotaline; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Vascular Resistance

2006
Etiology-specific endothelin-1 clearance in human precapillary pulmonary hypertension.
    Chest, 2006, Volume: 129, Issue:3

    Endothelin (ET)-1 is a mediator of vascular remodeling seen in human pulmonary hypertension (PH), and it is normally cleared via endothelial ET-B receptors. Increased levels of ET-1 are found in precapillary PH, partly from increased synthesis. We hypothesized that the endothelial dysfunction and vascular remodeling seen in human precapillary PH would also reduce ET-1 clearance.. Case series from a single institutional PH center.. Thirty-four patients with pulmonary arterial hypertension (PAH; idiopathic [IPAH], n = 19; connective tissue disease [CTD], n = 15) and 11 patients with chronic thromboembolic PH were studied.. Using indicator dilution methods, the first-pass extraction of radiolabeled ET-1 through the pulmonary circulation, and permeability surface (PS) area, an index of functional microvascular surface available for ET-1 clearance, were determined. Mean extraction for IPAH and thromboembolic PH groups was normal, but it was reduced in PAH from CTD; 69% of all patients studied had normal extraction. The mean PS product was reduced significantly for all three etiologies as compared to normal, but 58% of IPAH patients and 40% of CTD-related PAH patients had normal PS products.. Receptor-mediated ET-1 extraction and functional vascular surface area for clearance vary between etiologies of PAH. However, contrary to our hypothesis, endothelial ET-B receptor-mediated extraction is preserved in many patients. The scientifically significant finding of our study is that high ET-1 levels seen in patients with PAH must be predominantly due to excess synthesis rather than reduced clearance. The finding that endothelial ET-B receptors are still present and functional in PAH may also be of relevance to the choice of selective vs nonselective ET receptor antagonists.

    Topics: Cyclohexanones; Endothelin-1; Endothelium, Vascular; Female; Glucosides; Humans; Hypertension, Pulmonary; Indicator Dilution Techniques; Male; Microcirculation; Pulmonary Diffusing Capacity; Thermodilution

2006
Ghrelin reverses molecular, structural and hemodynamic alterations of the right ventricle in pulmonary hypertension.
    Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology, 2006, Volume: 25, Issue:1

    Ghrelin is an endogenous peptide that has a dual effect by activating specific receptors and by stimulating release of growth hormone. There is increasing evidence that ghrelin has a potent vasodilator effect. Recently, we demonstrated that exogenous administration of ghrelin modulates its endogenous levels and attenuates the majority of alterations induced by monocrotaline (MCT). In the present study, we evaluate the effects of chronic administration of ghrelin on hemodynamic and morphometric parameters of the right ventricle, as well as on myocardial levels of SERCA2a and endothelin-1. Adult Wistar rats were injected with MCT (60 mg/kg, sc) or just the vehicle (day 0). One week later, the animals treated with MCT were randomly divided into two groups and treated with ghrelin (100 microg/kg, bid, sc) or with a similar volume of vehicle. Between days 21-25 the animals were instrumented to record right ventricular (RV) pressures and samples were collected for morphological and molecular analysis. Ghrelin treatment attenuated the effects of MCT, namely: RV myocyte fiber diameter, pulmonary vascular remodeling (evaluated by % medial wall thickness of peripheral arteries), RV peak systolic pressure, RV end-diastolic pressure, time constant tau, and SERCA2a and endothelin-1 mRNA levels. Chronic ghrelin administration attenuates MCT-induced pulmonary hypertension, vascular remodeling and RV hypertrophy. These results suggest a potential therapeutic role for the ghrelin-growth hormone axis in pulmonary hypertension.

    Topics: Animals; Calcium-Transporting ATPases; Endothelin-1; Ghrelin; Growth Hormone; Hemodynamics; Hypertension, Pulmonary; Male; Myocardium; Peptide Hormones; Rats; Rats, Wistar; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Ventricular Dysfunction, Right

2006
[Influence of Radix Astragali on nitric oxide and endothelin-1 in pulmonary tissue in hypoxemic pulmonary hypertension in rats].
    Zhonghua er ke za zhi = Chinese journal of pediatrics, 2006, Volume: 44, Issue:1

    To study the influence of Radix Astragali (RA) on pulmonary tissue endothelin-1 (ET-1) and nitric oxide (NO) in hypoxic pulmonary hypertension rats.. Twenty one healthy male Wistar rats weighing 210-310 g were divided into three group at random with 7 in each. The rats in control group were raised in ordinary room condition; those in hypoxic group were raised in ordinary pressure hypoxic box [concentration of O(2) was (10.0 +/- 0.5)%] for 8 hours a day, for 30 days; those in RA group were raised in the same condition as hypoxic group and treated with an intraperitoneal injection of RA 8 g/kg per day. The rats in the control group and hypoxic group were given the same volume of intraperitoneal injection of normal saline. Mean pulmonary arterial pressure (mPAP), mean carotid artery pressure (mCAP) were measured via right cardiac catheterization, concentration of NO in pulmonary tissue was measured by radioimmunoassay.. (1) The mPAP (mm Hg) (21.9 +/- 1.6) and ET-1 (pg/ml) (309.1 +/- 58.1) in hypoxemic group were significantly higher than those in RA group (16.2 +/- 0.8, 287.7 +/- 57.5) and control group (15.3 +/- 0.8, 241.1 +/- 52.5) (P < 0.01, < 0.05), but the difference between RA group and control group was not significant. (2) NO (micromol/L) in pulmonary tissue in hypoxemic group (6.5 +/- 0.3) was lower than that in RA group and control group (9.2 +/- 0.9), NO in RA group was higher than that in hypoxic group but lower than that in control group (P < 0.05). (3) There was no significant difference in mCAP among the three groups (P > 0.05). (4) Under electron microscope, the endothelial cells of arterioles of the lung tissue of control group were flat and had normal morphology. However, in the lung tissue of hypoxic group, there were proliferation, hypertrophy and swelling of endothelial cells of pulmonary medium and small arteries and plenty of mitochondria and endoplasmic reticula in cytoplasm.. Chronic hypoxia can result in reconstruction and endothelial lesion in pulmonary arterioles of rats, elevation of mPAP and ET-1 in pulmonary tissue, and decrease of NO. Injection of Radix Astraglai can reverse the reconstruction of pulmonary vessels partially, regulate the concentration of ET-1 and NO in pulmonary tissue, which may have certain therapeutic effects on pulmonary arteriolar changes induced by hypoxia.

    Topics: Animals; Drugs, Chinese Herbal; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Lung; Male; Nitric Oxide; Radioimmunoassay; Random Allocation; Rats; Rats, Wistar

2006
[Reverse remodeling -- paradigm shift in the treatment of pulmonary hypertension].
    Deutsche medizinische Wochenschrift (1946), 2006, Apr-21, Volume: 131, Issue:16

    Topics: Benzamides; Cell Division; Drug Therapy, Combination; Endothelin-1; Endothelium, Vascular; Fibromuscular Dysplasia; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Muscle, Smooth, Vascular; Phosphodiesterase Inhibitors; Piperazines; Prostaglandins; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Embolism; Pyrimidines; Vasodilator Agents

2006
Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocrotaline-induced pulmonary hypertensive rats.
    American journal of physiology. Heart and circulatory physiology, 2006, Volume: 291, Issue:4

    In monocrotaline (MCT)-induced pulmonary hypertension (PH), only the right ventricle (RV) endures overload, but both ventricles are exposed to enhanced neuroendocrine stimulation. To assess whether in long-standing PH the left ventricular (LV) myocardium molecular/contractile phenotype can be disturbed, we evaluated myocardial function, histology, and gene expression of autocrine/paracrine systems in rats with severe PH 6 wk after subcutaneous injection of 60 mg/kg MCT. The overloaded RV underwent myocardial hypertrophy (P < 0.001) and fibrosis (P = 0.014) as well as increased expression of angiotensin-converting enzyme (ACE) (8-fold; P < 0.001), endothelin-1 (ET-1) (6-fold; P < 0.001), and type B natriuretic peptide (BNP) (15-fold; P < 0.001). Despite the similar upregulation of ET-1 (8-fold; P < 0.001) and overexpression of ACE (4-fold; P < 0.001) without BNP elevation, the nonoverloaded LV myocardium was neither hypertrophic nor fibrotic. LV indexes of contractility (P < 0.001) and relaxation (P = 0.03) were abnormal, however, and LV muscle strips from MCT-treated compared with sham rats presented negative (P = 0.003) force-frequency relationships (FFR). Despite higher ET-1 production, BQ-123 (ET(A) antagonist) did not alter LV MCT-treated muscle strip contractility distinctly (P = 0.005) from the negative inotropic effect exerted on shams. Chronic daily therapy with 250 mg/kg bosentan (dual endothelin receptor antagonist) after MCT injection not only attenuated RV hypertrophy and local neuroendocrine activation but also completely reverted FFR of LV muscle strips to positive values. In conclusion, the LV myocardium is altered in advanced MCT-induced PH, undergoing neuroendocrine activation and contractile dysfunction in the absence of hypertrophy or fibrosis. Neuroendocrine mediators, particularly ET-1, may participate in this functional deterioration.

    Topics: Angiotensinogen; Animals; Antihypertensive Agents; Bosentan; Cytochrome P-450 CYP11B2; Endothelin-1; Gene Expression Regulation; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; Myocardial Contraction; Natriuretic Peptide, Brain; Neurotransmitter Agents; Peptides, Cyclic; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; RNA, Messenger; Sulfonamides; Ventricular Function; Ventricular Remodeling

2006
Porcine pulmonary artery and bronchial responses to endothelin-1 and norepinephrine on recovery from hypoxic pulmonary hypertension.
    Pediatric research, 2006, Volume: 60, Issue:1

    Many infants recovering from acute lung disease and pulmonary hypertension still have evidence of reactive airways disease at one year of age, suggesting longer-term airway effects. We hypothesized that parallel changes in smooth muscle would occur in airways and pulmonary arteries from animals with pulmonary hypertension and during normoxic recovery. Thus, two-hour-old piglets were subjected to 3 d chronic hypobaric hypoxia and 3-d-old piglets were subjected to 11 d hypoxia. Some animals were allowed to recover in room air for 3 or 6 d. The amount of smooth muscle and responses of isolated paired bronchial and pulmonary artery rings to endothelin-1 (ET-1) and norepinephrine were studied at the end of hypoxic exposure, on recovery and in age-matched control animals. In all hypoxia induced pulmonary hypertensive animals, smooth muscle area and ET-1 contractile response was increased in the pulmonary arteries and bronchi. Norepinephrine-induced relaxant response was impaired significantly in both bronchi and pulmonary arteries. After 3 d recovery, pulmonary arterial smooth muscle area decreased by 65%, and ET-1-induced contractile responses were normal for age. In the airways, ET-1 contractile response only normalized after six days and bronchial smooth muscle was still increased. After 6 d recovery pulmonary arterial norepinephrine-induced relaxant response had returned to normal, but bronchial response remained impaired. Thus during pulmonary hypertension, both bronchial and pulmonary arterial smooth muscle area and contractile responses are increased. On recovery, regression of bronchial structural and functional abnormalities is slower than in pulmonary arteries.

    Topics: Animals; Animals, Newborn; Blood Pressure; Bronchi; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Muscle Contraction; Muscle, Smooth; Muscle, Smooth, Vascular; Norepinephrine; Pulmonary Artery; Recovery of Function; Swine; Time Factors; Vasoconstriction

2006
Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction.
    The Journal of physiology, 2006, Jul-15, Volume: 574, Issue:Pt 2

    We previously observed that pulmonary hypertension secondary to myocardial infarction (MI) in swine is characterized by elevated plasma endothelin (ET) levels and pulmonary vascular resistance (PVR). Consequently, we tested the hypothesis that an increased ET-mediated vasoconstrictor influence contributes to secondary pulmonary hypertension after MI and investigated the involvement of ET(A) and ET(B) receptor subtypes. Chronically instrumented swine with (MI swine; n = 25) or without (normal swine; n = 19) MI were studied at rest and during treadmill exercise (up to 4 km h(-1)), in the absence and presence of the ET(A) antagonist EMD 122946 or the mixed ET(A)/ET(B) antagonist tezosentan. In normal swine, exercise caused a small decrease in PVR. ET(A) blockade had no effect on PVR at rest or during exercise. Conversely, ET(A)/ET(B) blockade decreased PVR but only during exercise (at 4 km h(-1), from 3.0 +/- 0.1 to 2.3 +/- 0.1 mmHg min l(-1); P

    Topics: Animals; Blood Pressure; Consciousness; Endothelin Receptor Antagonists; Endothelin-1; Female; Hemodynamics; Hypertension, Pulmonary; Male; Myocardial Infarction; Physical Conditioning, Animal; Pulmonary Circulation; Pyridines; Receptors, Endothelin; Rest; Swine; Tetrazoles; Vasoconstriction; Vasodilator Agents

2006
[Impact of hydrogen sulfide donor on pulmonary vascular structure and vasoactive peptides in rats with pulmonary hypertension induced by high pulmonary blood flow].
    Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae, 2006, Volume: 28, Issue:2

    To explore the impact of hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS), on pulmonary vascular structure and vasoactive peptides in rats with pulmonary hypertension induced by high pulmonary blood flow.. Thirty-two male Wistar rats, weighing 120-140 g, were randomly divided into shunt group (n=8), shunt + NaHS group (n=8), sham group (n=8), and sham + NaHS group (n=8). Rats in shunt group and shunt + NaHS group were subjected to an abdominal aorta-inferior vena cava shunt to create an animal model of high pulmonary flow. In the sham group and sham + NaHS group, rats experienced the same experimental processes except the shunting procedure. Rats in shunt + NaHS group and sham + NaHS group were intraperitoneally injected with an exogenous H2S donor--NaHS, at a dose of 56 micromol/(kg x d). Meanwhile, rats in shunt group and sham group were injected with the same volume of physiological saline. After 11 weeks of experiment, systolic pulmonary artery pressure (SPAP) of each rat was evaluated by using a right cardiac catheterization procedure. Heart tissues were separated as right ventricular (RV) and left ventricular plus septum (LV + SP), and the ratio of RV to LV + SP [RV/(LV + SP)] was calculated. The morphologic changes including micro-and ultra-structural changes of pulmonary arteries of rats were observed under optical microscope and electro-microscope, respectively. The percentage of muscular artery (MA) in small pulmonary arteries was calculated. The change of relative medial thickness (RMT) of pulmonary arteries was examined. H2S concentration in plasma was evaluated by modified sulfide electrode method. Endothelin-1 (ET-1), atrial natriuretic peptide (ANP), calcitonin gene related peptide (CGRP), and proadrenomedullin peptide (PAMP) were calculated by radioimmunoassay kit.. After 11 weeks of shunt, compared with sham group, SPAP increased by 48.63% (P < 0.01 ) and RV/ (LV + SP) increased by 21.95% (P < 0.01). Plasma H2S decreased significantly (P < 0.01). The percentage of MA increased significantly (P < 0.01); RMT increased significantly (P < 0.01). The changes of ultra-structure of pulmonary arteries showed that endothelial cells became swollen and desquamation, internal elastic lamina became irregular, and smooth muscular cells increased in size, showing synthetic phenotype. After the rats with shunt was administered with NaHS for 11 weeks, plasma H2S increased significantly (P < 0.01). SPAP decreased by 19.82% and RV/(LV + SP) decreased by 7.31% (P < 0.01). The percentage of MA decreased significantly and RMT decreased significantly (P < 0.01). The changes of ultra-structure of the pulmonary arteries showed lighten significantly. Plasma ET-1, ANP, and CGRP decreased significantly (all P < 0.01), whereas PAMP increased significantly than that of shunt group (P < 0.01).. The reduced production of endogenous H2S is one of mechanism of pulmonary hypertension and pulmonary vascular structure remodeling in rats with high pulmonary blood flow. H2S plays an important regulatory effect on vasoactive peptide ET-1,+ ANP, CGRP and PAMP.

    Topics: Animals; Atrial Natriuretic Factor; Calcitonin Gene-Related Peptide; Disease Models, Animal; Endothelin-1; Hydrogen Sulfide; Hypertension, Pulmonary; Lung; Male; Peptides; Pulmonary Circulation; Random Allocation; Rats; Rats, Sprague-Dawley; Sulfides

2006
Effects of sildenafil on pulmonary hypertension and levels of ET-1, eNOS, and cGMP in aorta-banded rats.
    Experimental biology and medicine (Maywood, N.J.), 2006, Volume: 231, Issue:6

    Sildenafil, an oral phosphodiesterase Type 5 inhibitor, has vasodilatory effects through a cGMP-dependent mechanism. We previously showed that aortic banding could result in left ventricular overloading and pulmonary hypertension (PH). In this study, we investigated whether early administration of sildenafil, either immediately after or 2 weeks after aortic banding, could ameliorate the development of PH and alter gene expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS), and alter the levels of cGMP in rats undergoing an ascending aortic banding. Rats (n = 32) were divided into sham-operated and banding groups with or without treatment. The banded rats were further divided into three groups: (i) receiving saline on Days 1-28 (AOB28; n = 8), (ii) receiving saline on Days 1-14 followed by treatment with 50 mg/kg/day sildenafil on Days 15-28 (AOB28/Sil(15-28); n = 8), and (iii) receiving 50 mg/kg/day sildenafil on days 1-28 (AOB28/Sil(1-28); n = 8). The sham-operated rats were administrated saline on Days 1-28 (n = 8). Four weeks after banding, there was a significant development of PH with pulmonary vascular remodeling. Although both sildenafil-treatment groups had significant increases in cGMP and had reductions in the thickening in the medial layer of pulmonary arteriole, notable attenuation of PH occurred only in the AOB28/Sil(1-28) group. PreproET-1 and eNOS messenger RNA (mRNA) expressions were measured by competitive reverse transcription polymerase chain reaction, and eNOS protein was determined by Western blotting. Sildenafil did not alter the elevated ET-1 or preproET-1 mRNA in banded rats. Interestingly, pulmonary eNOS increased in the AOB28/Sil(1-28) group. In conclusion, early treatment with sildenafil inhibited the rise in pulmonary arterial pressure and pulmonary vascular remodeling in PH secondary to heart failure, and cGMP, but not ET-1, might be involved. Clinically, early repeated administration of sildenafil may offer an alternative in protecting against PH in heart failure.

    Topics: Animals; Cyclic GMP; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Male; Nitric Oxide Synthase Type III; Phosphodiesterase Inhibitors; Piperazines; Purines; Random Allocation; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones

2006
The effects of debanding on the lung expression of ET-1, eNOS, and cGMP in rats with left ventricular pressure overload.
    Experimental biology and medicine (Maywood, N.J.), 2006, Volume: 231, Issue:6

    Pulmonary hypertension (PH) usually develops secondary to left ventricular (LV) dysfunction; therefore, it is also called retrograde PH. To investigate our hypothesis that PH is at least partially reversible, as in some congenital heart diseases, in a rat model we investigated whether release of constriction could attenuate pulmonary vascular remodeling and change the expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS). We used rats with LV dysfunction produced by an ascending aortic banding. In this study, there were four groups enrolled: 4-weeks banded (AOB(1-28); n = 7), 7-weeks banded (AOB(1-49); n = 7), debanded groups (AOB(1-28)/DeB(29-49); n = 7), and rats receiving a sham operation (n = 7). Subsequently, there was significant attenuation of medial hypertrophy in pulmonary arterioles and reversal of PH in the AOB(1-28)/DeB(29-49) group (sham, 19 +/- 1.3 mm Hg; AOB(1-28), 31 +/- 2.7 mm Hg; AOB(1-49), 32 +/- 2.7 mm Hg; and AOB(1-28)/DeB(29-49), 20 +/- 1.3 mm Hg). PreproET-1 mRNA and eNOS mRNA were measured by competitive reverse transcriptase (RT) polymerase chain reaction (PCR), and eNOS was measured by Western blotting. Compared with the banded groups, debanding significantly decreased pulmonary preproET-1 mRNA, pulmonary ET-1 (sham, 210 +/- 12 pg/g protein; AOB(1-28), 242 +/- 12 pg/g protein; AOB(1-49), 370 +/- 49 pg/g protein; and AOB(1-28)/DeB(29-49), 206 +/- 1.9 pg/g protein), and plasma ET-1 levels (sham, 10.1 +/- 1.5 pg/ml; AOB(1-28), 13.4 +/- 2.0 pg/ml; AOB(1-49), 15.4 +/- 2.0 pg/ml; and AOB(1-28)/DeB(29-49), 10.3 +/- 0.9 pg/ml protein). Debanding could not, however, alter pulmonary eNOS, eNOS mRNA, or cGMP. These findings suggest that pulmonary vascular remodeling, increased pulmonary arterial pressure, and upregulation of ET-1 gene expression are all reversible. We infer that it is the upregulated gene expression of ET-1, not eNOS, that is closely related to the development of the PH secondary to 4 weeks of aortic banding.

    Topics: Animals; Cyclic GMP; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Lung; Male; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Ventricular Dysfunction, Left

2006
Polycythemia, HIF-1alpha and pulmonary hypertension in Chuvash.
    Haematologica, 2006, Volume: 91, Issue:6

    Topics: Altitude; Anemia, Hemolytic; Blood Viscosity; Endothelin-1; Homozygote; Humans; Hypertension, Pulmonary; Hypoxia-Inducible Factor 1, alpha Subunit; Mutation; Polycythemia; Russia; Signal Transduction

2006
Endothelin-1, vascular endothelial growth factor and systolic pulmonary artery pressure in patients with Chuvash polycythemia.
    Haematologica, 2006, Volume: 91, Issue:6

    Endothelin-1 has been associated with development of hypoxia-related pulmonary hypertension and vascular endothelial growth factor (VEGF) with protection from this complication. In Chuvash polycythemia, homozygous germline von Hippel-Lindau (VHL) 598C->T leads to up-regulation during normoxia of hypoxia inducible factor-1a and several hypoxia-controlled genes including erythropoietin and VEGF. We postulated that endothelin-1 and pulmonary artery pressure may be elevated in Chuvash polycythemia.. Systolic pulmonary artery blood pressure was estimated by Doppler echocardiography and plasma concentrations of endothelin-1, VEGF and erythropoietin were determined in 14 patients with Chuvash polycythemia and 14 controls. Results. Plasma endothelin-1 (p=0.010), VEGF (p=0.022) and erythropoietin (p<0.0005) concentrations and Doppler-estimated systolic pulmonary artery pressures (p<0.0005) were higher in the patients while systolic systemic blood pressures were lower (p=0.001). Five (36%) patients and no controls had mild pulmonary hypertension defined as systolic pulmonary artery pressure (c) 35 mmHg. Among the patients with Chuvash polycythemia, the trends of association of estimated pulmonary artery pressure with plasma concentrations of endothelin-1 (R = +0.236), VEGF (R = -0.389) and erythropoietin (R = +0.220) were not statistically significant.. Estimated systolic pulmonary artery pressure and plasma concentrations of endothelin-1 and VEGF are increased in patients with Chuvash polycythemia patients. The lack of significant associations of estimated systolic pulmonary artery pressure with plasma endothelin-1 and VEGF levels could conceivably be due to the small sample size. Further studies are indicated, especially in view of the reported efficacy of endothelin-1 receptor blockers in treating hypoxia-associated pulmonary hypertension.

    Topics: Altitude; Electrocardiography; Endothelin-1; Humans; Hypertension, Pulmonary; Hypoxia; Mutation; Polycythemia; Polymorphism, Single Nucleotide; Pulmonary Artery; Reference Values; Russia; Systole; Vascular Endothelial Growth Factor A

2006
Enhanced alpha1-adrenergic trophic activity in pulmonary artery of hypoxic pulmonary hypertensive rats.
    American journal of physiology. Heart and circulatory physiology, 2006, Volume: 291, Issue:5

    Mechanisms that induce the excessive proliferation of vascular wall cells in hypoxic pulmonary hypertension (PH) are not fully understood. Alveolar hypoxia causes sympathoexcitation, and norepinephrine can stimulate alpha(1)-adrenoceptor (alpha(1)-AR)-dependent hypertrophy/hyperplasia of smooth muscle cells and adventitial fibroblasts. Adrenergic trophic activity is augmented in systemic arteries by injury and altered shear stress, which are key pathogenic stimuli in hypoxic PH, and contributes to neointimal formation and flow-mediated hypertrophic remodeling. Here we examined whether norepinephrine stimulates growth of the pulmonary artery (PA) and whether this is augmented in PH. PA from normoxic and hypoxic rats [9 days of 0.1 fraction of inspired O(2) (Fi(O(2)))] was studied in organ culture, where wall tension, Po(2), and Pco(2) were maintained at values present in normal and hypoxic PH rats. Norepinephrine treatment for 72 h increased DNA and protein content modestly in normoxic PA (+10%, P < 0.05). In hypoxic PA, these effects were augmented threefold (P < 0.05), and protein synthesis was increased 34-fold (P < 0.05). Inferior thoracic vena cava from normoxic or hypoxic rats was unaffected. Norepinephrine-induced growth in hypoxic PA was dose dependent, had efficacy greater than or equal to endothelin-1, required the presence of wall tension, and was inhibited by alpha(1A)-AR antagonist. In hypoxic pulmonary vasculature, alpha(1A)-AR was downregulated the least among alpha(1)-AR subtypes. These data demonstrate that norepinephrine has trophic activity in the PA that is augmented by PH. If evident in vivo in the pulmonary vasculature, adrenergic-induced growth may contribute to the vascular hyperplasia that participates in hypoxic PH.

    Topics: Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-1 Receptor Antagonists; Animals; DNA; Dose-Response Relationship, Drug; Endothelin-1; Fibroblasts; Hypertension, Pulmonary; Hypoxia; Male; Muscle, Smooth, Vascular; Norepinephrine; Organ Culture Techniques; Proteins; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Time Factors

2006
NOS2 polymorphisms associated with the susceptibility to pulmonary arterial hypertension with systemic sclerosis: contribution to the transcriptional activity.
    Arthritis research & therapy, 2006, Volume: 8, Issue:4

    Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis. One of several complications of SSc, pulmonary arterial hypertension (PAH) can be refractory to treatment, both novel and established. In the present study we investigated the ratio of circulating nitric oxide to endothelin-1 in patients with both SSc and PAH, and determined whether polymorphisms in NOS2 (the nitric oxide synthase 2 gene) are associated with susceptibility to PAH. Endothelin-1 in plasma and nitric oxide metabolites (nitrate and nitrite) in serum were measured. The nitric oxide/endothelin-1 ratio was significantly lower in patients with both SSc and PAH than in patients with SSc only or in healthy control individuals. We confirmed the presence of two single nucleotide polymorphisms at positions -1,026 and -277 and a pentanucleotide repeat (CCTTT) at -2.5 kilobases. There were significant differences in single nucleotide polymorphisms between patients with SSc who had PAH and those who did not, and between patients with both SSc and PAH and healthy control individuals. The CCTTT repeat was significantly shorter in patients with both SSc and PAH than in patients with SSc only or in healthy control individuals. Transcriptional activity were analyzed using the luciferase reporter assay. The transcriptional activity of NOS2 was much greater in fibroblasts transfected by a vector with a long allele of the CCTTT repeat than in those transfected by a vector with a short allele. Polymorphisms in the NOS2 gene are associated with transcriptional activity of the NOS2 gene and with susceptibility to SSc-related PAH.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Endothelin-1; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase Type II; Osmolar Concentration; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Scleroderma, Systemic; Tandem Repeat Sequences; Transcription, Genetic

2006
Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat.
    American journal of physiology. Lung cellular and molecular physiology, 2006, Volume: 291, Issue:5

    Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO(2)) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO(2) would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO(2) was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O(2)) or moderate hypoxia (13% O(2)). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO(2) (but not to 5.5% CO(2)) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals (P < 0.05), whereas both concentrations of CO(2) normalized right ventricular performance. Exposure to 10% CO(2) attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO(2) on the lung and consequent modulating effects on the endothelin pathway.

    Topics: Animals; Animals, Newborn; Body Weight; Carbon Dioxide; Carboxylic Acids; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Female; Hematocrit; Hypercapnia; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Indans; Oxidative Stress; Oxygen; Pregnancy; Pulmonary Artery; Pulmonary Circulation; Rats; Up-Regulation

2006
Endothelin-1 inhibits apoptosis of pulmonary arterial smooth muscle in the neonatal rat.
    Pediatric research, 2006, Volume: 60, Issue:3

    Vascular wall remodeling in pulmonary hypertension is contributed to by an aberration in the normal balance between proliferation and apoptosis of smooth muscle. We observed that endothelin (ET)-1 is a critical mediator of vascular remodeling in neonatal rats chronically exposed to 60% O(2), but has no direct proliferative effects on cultured neonatal rat pulmonary artery smooth muscle cells (PASMCs). These findings led us to hypothesize that ET-1 may modulate remodeling by inhibiting apoptosis of smooth muscle. ET-1 (0.1 microM) was found to significantly attenuate both Paclitaxel- and serum deprivation-induced PASMC apoptosis, likely through stimulation of the ET(A) receptor (ET(A)R). ET-1 also prevented Paclitaxel-induced up-regulation of pro-apoptotic Bax and cleaved (activated) caspase-3. In rat pups exposed from birth to 60% O(2) for 7 d, arterial wall expression of Bax was decreased and expression of both ET(A)R and anti-apoptotic Bcl-xL were increased. Furthermore, increased numbers of TUNEL-positive cells were evident in the walls of pulmonary arteries from 60% O(2)-exposed animals treated with a combined ET receptor antagonist, SB217242, relative to air-exposed and vehicle-treated groups. Together, these findings suggest that ET-1 mediates remodeling of neonatal rat pulmonary arteries by inhibiting smooth muscle apoptosis.

    Topics: Animals; Animals, Newborn; Apoptosis; Cells, Cultured; Disease Models, Animal; Endothelin-1; Female; Hypertension, Pulmonary; Inhibitor of Apoptosis Proteins; Muscle, Smooth; Oxygen; Pulmonary Artery; Rats; Rats, Sprague-Dawley

2006
Hemodynamic and clinical correlates of endothelin-1 in chronic thromboembolic pulmonary hypertension.
    Circulation journal : official journal of the Japanese Circulation Society, 2006, Volume: 70, Issue:8

    In non-thromboembolic pulmonary hypertension, endothelin (ET)-1 levels are increased and correlate with the hemodynamic severity of the disease. Whether such correlations exist in chronic thromboembolic pulmonary hypertension (CTEPH) is unknown, nor whether ET-1 levels correlate with hemodynamic outcome after pulmonary endarterectomy (PEA).. ET-1 levels were determined by ELISA. ET-levels were increased in 35 CTEPH patients (1.62+/-0.21 pg/ml) compared with healthy controls (n=11: 0.75+/-0.06 pg/ml, p<0.02). ET-1 levels correlated (all p<0.0001) with mean pulmonary artery pressure (mPAP) (r=0.70), cardiac index (r=-0.76), total pulmonary resistance (r=0.72), mixed venous oxygen saturation (r=-0.87), and the distance walked in the 6-min walk test (r=-0.59; p<0.005; n=23). Three months after PEA, ET-1 levels had decreased (p<0.002), and were similar between patients with and without residual pulmonary hypertension (p=0.4). Preoperative ET-1 levels, however, were higher in patients with bad postoperative outcome; that is, patients who either died because of persistent pulmonary hypertension or had residual pulmonary hypertension after PEA (2.68+/-0.48 pg/ml, and 1.13+/-0.15 pg/ml, respectively; p<0.002). The levels also correlated with hemodynamic outcome after PEA (mPAP: r=0.67, p<0.0001). By receiver-operator characteristic curve analysis, ET-1>1.77 pg/ml detected a bad postoperative outcome with a sensitivity and specificity of 79% and 85%, respectively, and a likelihood ratio of 5.2.. ET-1 levels in CTEPH closely correlated with the hemodynamic and clinical severity of disease in a large cohort of patients. Preoperative ET-1 levels may be useful for better identification of patients at risk for persistent pulmonary hypertension after PEA.

    Topics: Adolescent; Adult; Aged; Endarterectomy; Endothelin-1; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Artery; Pulmonary Embolism; Sensitivity and Specificity; Severity of Illness Index; Treatment Outcome; Vascular Resistance

2006
Angiopoietin/Tie2 pathway influences smooth muscle hyperplasia in idiopathic pulmonary hypertension.
    American journal of respiratory and critical care medicine, 2006, Nov-01, Volume: 174, Issue:9

    Angiopoietins are involved in blood vessel maturation and remodeling.. One consequence of endothelium-specific tyrosine kinase-2 (Tie2) receptor activation by angiopoietin-1 (Ang1) is the release of endothelium-derived growth factors that recruit vascular wall cells. We investigated this process in idiopathic pulmonary arterial hypertension (iPAH).. Ang1, Ang2, and total and phosphorylated Tie2 expression (mRNA and protein) was evaluated in human lung specimens and in cultured pulmonary artery smooth muscle cells (PA-SMCs) and pulmonary endothelial cells (P-ECs) isolated from patients with iPAH and control subjects. Media collected from Ang1-treated P-ECs were assessed for their PA-SMC growth-promoting effect.. Tie2 receptor was fourfold higher in lungs and P-ECs from patients with iPAH than in those from control subjects, with a parallel increase in phosphorylated lung Tie2 receptor. In contrast, Ang1 and Ang2 expression in lungs, P-ECs, and PA-SMCs did not differ. Incubation of PA-SMCs with medium collected from P-EC cultures induced marked proliferation, and this effect was stronger when using P-ECs from patients with iPAH than from control subjects. Ang1 pretreatment of P-ECs from either patients or control subjects induced a further increase in PA-SMC proliferation. Fluoxetine, an inhibitor of the mitogenic action of serotonin, reduced the growth-promoting effect of P-EC media. Ang1 added to P-ECs from patients with iPAH increased the production of endothelin-1 (ET-1) and serotonin, but not of platelet-derived growth factor-BB or epidermal growth factor, and increased the amount of mRNA encoding tryptophan hydroxylase-1 (the rate-limiting enzyme of serotonin synthesis), preproET-1, and ET-1-converting enzyme.. The Ang1/Tie2 pathway is potentiated in iPAH, contributing to PA-SMC hyperplasia via increased stimulation of endothelium-derived growth factors synthesis by P-ECs.

    Topics: Angiopoietin-1; Aspartic Acid Endopeptidases; Blotting, Western; Endothelial Cells; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Female; Fluoxetine; Humans; Hyperplasia; Hypertension, Pulmonary; Immunohistochemistry; Male; Metalloendopeptidases; Muscle, Smooth, Vascular; Receptor, TIE-2; Selective Serotonin Reuptake Inhibitors

2006
HLA-B35 upregulates the production of endothelin-1 in HLA-transfected cells: a possible pathogenetic role in pulmonary hypertension.
    Tissue antigens, 2006, Volume: 68, Issue:3

    HLA-B35 is associated with an increased risk for developing isolated pulmonary hypertension (iPHT) in systemic sclerosis, but the mechanisms underlying this association have not been fully elucidated yet. Endothelin-1 (ET-1) is the main pathogenetic molecule implied in the development of iPHT; therefore, we sought to determine if ECV304 cells transfected with the HLA-B35 allele produce increased amounts of ET-1 after incubation with physiological concentrations of interleukin-1 beta (IL-1beta). ECV304 cells transfected with HLA-B*3501 and HLA-B*0801 polymorphic alpha chain or with pIRESneo2 were incubated with 100 U/ml of IL-1beta for 6, 12, 24, 36 and 48 h. ET-1 levels were determined using EIA kit (CAYMAN Chemical, Ann Arbor, MI) in supernatants from different cell cultures; the relative expression of the preproendothelin-1 (PPET-1) gene was also determined by reverse transcription-polymerase chain reaction. Cells expressing the HLA-B35 allele showed significantly increased levels of ET-1 at all the selected times compared with controls or HLA-B8-transfected cells. The relative expression of the PPET-1 gene was also increased in a proportionally direct manner. The HLA-B35 allele influences the production of ET-1 in HLA-B35-transfected ECV304 cells by promoting the expression of its precursor, PPET-1. Our results provide an explanation for the epidemiological association existing between iPHT and HLA-B35.

    Topics: Alleles; Cell Line; Endothelial Cells; Endothelin-1; HLA-B Antigens; HLA-B35 Antigen; HLA-B8 Antigen; Humans; Hypertension, Pulmonary; Interleukin-1; RNA, Messenger; Scleroderma, Systemic; Transfection; Up-Regulation

2006
Endothelin-1 and the pulmonary vascular response to altitude: a new therapeutic target?
    Circulation, 2006, Sep-26, Volume: 114, Issue:13

    Topics: Altitude; Altitude Sickness; Bosentan; Diuresis; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Hypoxia; Kidney Diseases; Muscle, Smooth, Vascular; Potassium Channels, Voltage-Gated; Randomized Controlled Trials as Topic; Receptors, Endothelin; Sulfonamides; Vasoconstriction; Ventricular Function, Right

2006
Endothelial alterations during inhaled NO in lambs with pulmonary hypertension: implications for rebound hypertension.
    American journal of physiology. Lung cellular and molecular physiology, 2005, Volume: 288, Issue:1

    Clinically significant increases in pulmonary vascular resistance (PVR) have been noted upon acute withdrawal of inhaled nitric oxide (iNO). Previous studies in the normal pulmonary circulation demonstrate that iNO increases endothelin-1 (ET-1) levels and decreases endogenous nitric oxide synthase (NOS) activity, implicating an endothelial etiology for the increase in resistance upon iNO withdrawal. However, the effect of iNO on endogenous endothelial function in the clinically relevant pulmonary hypertensive circulation is unknown. The objective of this study was to determine the effects of iNO on endogenous NO-cGMP and ET-1 signaling in lambs with preexisting pulmonary hypertension secondary to increased pulmonary blood flow. Eight fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt lambs). After delivery (4 wk), the shunt lambs were mechanically ventilated with iNO (40 ppm) for 24 h. After 24 h of inhaled NO, plasma ET-1 levels increased by 34.8% independently of changes in protein levels (P < 0.05). Contrary to findings in normal lambs, total NOS activity did not decrease during iNO. In fact, Western blot analysis demonstrated that tissue endothelial NOS protein levels decreased by 43% such that NOS activity relative to protein levels actually increased during iNO (P < 0.05). In addition, the beta-subunit of soluble guanylate cyclase decreased by 70%, whereas phosphodiesterase 5 levels were unchanged (P < 0.05). Withdrawal of iNO was associated with an acute increase in PVR, which exceeded baseline PVR by 45%, and a decrease in cGMP concentrations to levels that were below baseline. These data suggest that the endothelial response to iNO and the potential mechanisms of rebound pulmonary hypertension are dependent upon the underlying pulmonary vasculature.

    Topics: Administration, Inhalation; Animals; Animals, Newborn; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Hypertension, Pulmonary; Lung; Nitric Oxide; Nitric Oxide Synthase; Sheep; Signal Transduction; Vascular Resistance

2005
Portopulmonary hypertension in cirrhosis: the pathogenetic challenge.
    Gut, 2005, Volume: 54, Issue:2

    Topics: Endothelin-1; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis

2005
A role for platelet-derived growth factor beta-receptor in a newborn rat model of endothelin-mediated pulmonary vascular remodeling.
    American journal of physiology. Lung cellular and molecular physiology, 2005, Volume: 288, Issue:6

    Newborn rats exposed to 60% O2 for 14 days develop endothelin (ET)-1-dependent pulmonary hypertension with vascular remodeling, characterized by increased smooth muscle cell (SMC) proliferation and medial thickening of pulmonary resistance arteries. Using immunohistochemistry and Western blot analyses, we examined the effect of exposure to 60% O2 on expression in the lung of receptors for the platelet-derived growth factors (PDGF), which are implicated in the pathogenesis of arterial smooth muscle hyperplasia. We observed a marked O2-induced upregulation of PDGF-alpha and -beta receptors (PDGF-alphaR and -betaR) on arterial smooth muscle. This led us to examine pulmonary vascular PDGF receptor expression in 60% O2-exposed rats given SB-217242, a combined ET receptor antagonist, which we found prevented the O2-induced upregulation of PDGF-betaR, but not PDGF-alphaR, on arterial smooth muscle. PDGF-BB, a major PDGF-betaR ligand, was found to be a potent in vitro inducer of hyperplasia and DNA synthesis in cultured pulmonary artery SMC from infant rats. A critical role for PDGF-betaR ligands in arterial SMC proliferation was confirmed in vivo using a truncated soluble PDGF-betaR intervention, which attenuated SMC proliferation induced by exposure to 60% O2. Collectively, these data are consistent with a major role for PDGF-betaR-mediated SMC proliferation, acting downstream of increased ET-1 in a newborn rat model of 60% O2-induced pulmonary hypertension.

    Topics: Animals; Animals, Newborn; Becaplermin; Carboxylic Acids; Cell Proliferation; Endothelin Receptor Antagonists; Endothelin-1; Female; Hyperplasia; Hypertension, Pulmonary; Indans; Ligands; Models, Animal; Muscle, Smooth, Vascular; Oxygen; Platelet-Derived Growth Factor; Pregnancy; Proto-Oncogene Proteins c-sis; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptor, Platelet-Derived Growth Factor alpha; Receptor, Platelet-Derived Growth Factor beta; Receptors, Endothelin; Up-Regulation

2005
Expression of endothelin-1 in the brain and lung of rats exposed to permanent hypobaric hypoxia.
    Brain research, 2005, Mar-02, Volume: 1036, Issue:1-2

    High-altitude hypoxia causes pulmonary hypertension in humans and animals. Endothelin-1 (ET-1) is a novel and long-lasting vasoconstrictor. However, no study has dealt with the effects of a hypobaric hypoxic environment (HHE) on ET-1 activity in the brain. We examined 134 male rats permanently exposed to the equivalent of 5500 m altitude for 1 to 8 weeks. In these HHE rats, the mean pulmonary arterial pressure was significantly raised. The level of ET-1 protein, measured by enzyme immunoassay, increased rapidly in the lungs on exposure to HHE, but decreased in the brain. The level of ET-1 mRNA, measured by semiquantitative RT-PCR, was raised at 1, 4, and 6 weeks' exposure in the lungs and at 4 or more weeks' exposure in 3 of 8 brain regions. By in situ hybridization and immunohistochemistry of brain sections, ET-1 mRNA and protein were detected in the endothelial cells, neurons, and astrocyte-like cells in control rats. In HHE rats, the immunoreactive intensity for ET-1 protein decreased rapidly with time in these cells within the brain, although a few weakly ET-1 protein-positive cells were detected until 8 weeks' exposure to HHE. Only a few weakly ET-1 mRNA-positive endothelial cells were detected in any HHE rats. Although the reactivity for ET-1 mRNA had decreased significantly in neurons and astrocyte-like cells at 1 and 2 weeks' exposure to HHE, it was again strong in both types of cells at 4 weeks' exposure to HHE. These results raise the possibility that during exposure to HHE, ET-1 production in the lung may play a role in the development of pulmonary hypertension, while a decrease in ET-1 production within the brain may help to protect neurons by preventing or limiting the constriction of cerebral microvessels during the hypoxia induced by HHE.

    Topics: Altitude Sickness; Animals; Astrocytes; Brain; Cerebrovascular Circulation; Disease Models, Animal; Down-Regulation; Endothelial Cells; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Hypoxia, Brain; Immunohistochemistry; Lung; Male; Neurons; Rats; Rats, Wistar; Regional Blood Flow; RNA, Messenger; Time Factors; Up-Regulation; Vasoconstriction

2005
Calpain inhibition decreases endothelin-1 levels and pulmonary hypertension after cardiopulmonary bypass with deep hypothermic circulatory arrest.
    Critical care medicine, 2005, Volume: 33, Issue:3

    Cardiopulmonary bypass in infants and children can result in cardiopulmonary dysfunction through ischemia and reperfusion injury. Pulmonary hypertension and injury are particularly common and morbid complications of neonatal cardiac surgery. Inhibition of calpain, a cysteine protease, has been shown to inhibit reperfusion injury in adult organ systems. The hypothesis is that calpain inhibition can alleviate the cardiopulmonary dysfunction seen in immature animals following ischemia and reperfusion with cardiopulmonary bypass.. Animal case study.. Medical laboratory.. Crossbred piglets (5-7 kg).. Piglets were cooled with cardiopulmonary bypass to 18 degrees C followed by deep hypothermic circulatory arrest for 120 mins. Animals were rewarmed to 38 degrees C on cardiopulmonary bypass and maintained for 120 mins. Six animals were administered calpain inhibitor (Z-Leu-Leu-Tyr-fluoromethyl ketone; 1 mg/kg, intravenously) 60 mins before cardiopulmonary bypass. Nine animals were administered saline as a control. Plasma endothelin-1, pulmonary and hemodynamic function, and markers of leukocyte activity and injury were measured.. Calpain inhibition prevented the increased pulmonary vascular resistance seen in control animals (95.7 +/- 39.4 vs. 325.3 +/- 83.6 dyne.sec/cm, respectively, 120 mins after cardiopulmonary bypass and deep hypothermic circulatory arrest, p = .05). The attenuation in pulmonary vascular resistance was associated with a blunted plasma endothelin-1 response (4.91 +/- 1.72 pg/mL with calpain inhibition vs. 10.66 +/- 6.21 pg/mL in controls, p < .05). Pulmonary function after cardiopulmonary bypass was better maintained after calpain inhibition compared with controls: Po2/Fio2 ratio (507.2 +/- 46.5 vs. 344.7 +/- 140.5, respectively, p < .05) and alveolar-arterial gradient (40.0 +/- 17.2 vs. 128.1 +/- 85.2 mm Hg, respectively, p < .05). Systemic oxygen delivery was higher after calpain inhibition compared with controls (759 +/- 171 vs. 277 +/- 46 mL/min, respectively, p < .001). In addition, endothelial nitric oxide synthase activity in lung tissue was maintained with calpain inhibition.. The reduction in plasma endothelin-1 and maintenance of lung endothelial nitric oxide levels after cardiopulmonary bypass and deep hypothermic circulatory arrest with calpain inhibition were associated with reduced pulmonary vascular resistance. Improved gas exchange and higher systemic oxygen delivery suggest that calpain inhibition may be advantageous for reducing postoperative cardiopulmonary dysfunction commonly associated with pediatric heart surgery and cardiopulmonary bypass.

    Topics: Animals; Animals, Newborn; Calpain; Cardiopulmonary Bypass; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Hypothermia, Induced; Reperfusion Injury; Swine; Vascular Resistance

2005
Calpain: A new target in pulmonary hypertension?
    Critical care medicine, 2005, Volume: 33, Issue:3

    Topics: Animals; Animals, Newborn; Calpain; Cardiopulmonary Bypass; Endothelin-1; Humans; Hypertension, Pulmonary; Reperfusion Injury; Swine

2005
The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access.
    Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2005, Volume: 20, Issue:8

    We recently have shown a high incidence of unexplained pulmonary hypertension (PHT) in end-stage renal disease (ESRD) patients on chronic haemodialysis (HD) therapy via arterio-venous (A-V) access. This study evaluated the possibility that PHT in these patients is triggered or aggravated by chronic HD via surgical A-V access, and the role of endothelin-1 (ET-1) and nitric oxide (NO) in this syndrome.. Forty-two HD patients underwent clinical evaluation. Pulmonary artery pressure (PAP) was evaluated using Doppler echocardiography. Levels of ET-1 and NO metabolites in plasma were determined before and after the HD procedure and were compared between subgroups of patients with and without PHT.. Out of 42 HD patients studied, 20 patients (48%) had PHT (PAP = 46+/-2; range 36-82 mmHg) while the rest had a normal PAP (29+/-1 mmHg) (P<0.0001). HD patients with PHT had higher cardiac output compared with those with normal PAP (6.0+/-1.2 vs 5.2+/-0.9 l/min, P<0.034). HD patients, with or without PHT, had elevated plasma ET-1 levels compared with controls (1.6+/-0.7 and 2.4+/-0.8 fmol/ml vs 1.0+/-0.2, P<0.05) that remained unchanged after the HD procedure. HD patients without PHT and control subjects showed similar basal plasma levels of NO2 + NO3 (24.2+/-5.2 vs 19.7+/-3.1 microM, P>0.05) that was significantly higher compared with HD patients with PHT (14.3+/-2.3 microM, P<0.05). HD therapy caused a significant increase in plasma NO metabolites that was greater in patients without PHT (from 24.2+/-5.2 to 77.1+/-9.6 microM, P<0.0001, and from 14.3+/-2.3 to 39.9+/-11.4 microM, P<0.0074, respectively). Significant declines in PAP (from 49.8+/-2.8 to 38.6+/-2.2 mmHg, P<0.004) and cardiac output (CO) (from 7.6+/-0.6 to 6.1+/-0.3 l/min, P<0.03) were found in 11 HD patients with PHT that underwent successful transplantation. Similarly, temporary closure of the A-V access by a sphygmomanometer in eight patients with PHT resulted in a transient decrease in CO (from 6.4+/-0.6 to 5.3+/- 0.5 l/min, P = 0.18) and systolic PAP (from 47.2+/-3.8 to 34.6+/-2.8 mmHg, P<0.028).. This study demonstrates a high prevalence of PHT among patients with ESRD on chronic HD via a surgical A-V fistula. In view of the vasodilatory and antimitogenic properties of NO, it is possible that the attenuated basal and HD-induced NO production in patients with PHT contributes to the increased pulmonary vascular tone. Furthermore, the partial restoration of normal PAP and CO in HD patients that underwent either temporal A-V shunt closure or successful transplantation indicates that excessive pulmonary blood flow is involved in the pathogenesis of the disease.

    Topics: Adult; Aged; Aged, 80 and over; Arteriovenous Shunt, Surgical; Cardiac Output; Echocardiography, Doppler; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Nitric Oxide; Pulmonary Artery; Pulmonary Wedge Pressure; Renal Dialysis

2005
The value of B-type natriuretic peptide and big endothelin-1 for detection of severe pulmonary hypertension in heart transplant candidates.
    European journal of heart failure, 2005, Volume: 7, Issue:7

    Severe pulmonary hypertension (PH) and increased pulmonary vascular resistance (PVR) are important risk factors that predict early postoperative mortality after orthotopic heart transplantation. The aim of our study was to determine the value of B-type natriuretic peptide (BNP) and big endothelin-1 (big ET1) for prediction of severe PH in heart transplant candidates.. The study population included 43 potential heart transplant candidates (38 males, mean age 52 +/- 7 years). All underwent repeated right-heart catheterizations (2-5 studies) at an interval of 3-4 months, giving a total of 124 examinations, associated with blood sampling for BNP and big ET1 analysis. Severe PH was defined as the mean pulmonary artery pressure (MPAP) > 40 mmHg.. Significantly high PVR (PVR > 3.0 Wood units and TPG > 15 mmHg) was noted on 12 occasions in 10 patients; always in the presence of severe PH. Low BNP levels (<67 pg/ml) ruled out the presence of severe PH with a 100% sensitivity, however, with a low specificity (34%). An increase in plasma BNP > 30 pg/ml (>40% of initial value) in subjects with a previous MPAP< or =40 mmHg detected development of severe PH with a 100% sensitivity and an 80-88% specificity. As a total of 58% of patients presented repeatedly with MPAP< or =40 mmHg, serial BNP testing could reduce the need for hemodynamic studies in this subgroup down to 12-20%.. Serial BNP testing in hemodynamically stable heart transplant candidates with MPAP< or =40 mmHg allows reliable detection of development of severe PH, and may significantly reduce the need for repeated right-heart catheterizations in these patients.

    Topics: Adult; Aged; Biomarkers; Cardiac Catheterization; Endothelin-1; Female; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Pulmonary Wedge Pressure; Radioimmunoassay; Retrospective Studies; Severity of Illness Index

2005
[Expression and pathological implication of transforming growth factor-beta1 mRNA and endothelin-1 mRNA in intraacinar pulmonary arterioles of congenital heart disease accompanied with pulmonary hypertension].
    Zhonghua bing li xue za zhi = Chinese journal of pathology, 2005, Volume: 34, Issue:3

    To study the expression and pathological implication of transforming growth factor-1 (TGF-1) and endothelin-1 (ET-1) in intraacinar pulmonary arterioles of children with congenital heart disease and pulmonary hypertension (HP).. Forty-one children with left-to-right shunt congenital heart disease were studied including 25 cases of HP (group A), 16 cases without HP (group B) and 10 children without congenital heart disease as the contols (group C). Expression of TGF-beta1 mRNA and ET-1 mRNA in intraacinar pulmonary arteriolar (IAPA) was studied using in-situ hybridization and image pattern analysis of their absorption values (A value). Changes of the intraacinar arterioles and lung tissue were studied by elastic fiber staining and electronic microscopy respectively.. (1) There was a significant difference in the amount of intraacinar pulmonary arterioles (partial-muscular and muscular) counted in either group A or B in comparing with that of group C (F values 149.96 and 142.01 respectively, P < 0.01); (2) Electronic microscopy demonstrated endothelial proliferation of the small arteries, thickening of arteriolar wall, increased density of collagen fibers at adventitia and increased thickness of the capillary basal membrane; (3) The A value of TGF-beta1 mRNA expressed in the pulmonary arterioles of groups A and B by in-situ hybridization were 0.1988 +/- 0.0498 and 0.1098 +/- 0.0428 respectively, however, the expression was weak in group C (A value: 0.0578 +/- 0.0096). There were all significant between each two groups (F = 45.95, P < 0.01). The expression of ET-1 mRNA was markedly increased as well in the endothelial cells of pulmonary arterioles in both groups A and B, with A values of 0.1692 +/- 0.0205 and 0.1004 +/- 0.0140 respectively, whereas the expression was weak in group C (A value of 0.0746 +/- 0.0119). There were all significant between each two groups (F = 139.996, P < 0.01).. The number of intraacinar pulmonary partial-muscular and muscular arterioles in patients with left-to-right shunt congenital heart defect is drastically increased, along with marked restructuring of the pulmonary vasculatures. In addition, there seems a correlation present between the overexpression of TGF-beta1 mRNA and ET-1 mRNA in intraacinar pulmonary arterioles and the occurrence of pulmonary hypertension in patients with congenital heart disease.

    Topics: Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Lung; Male; Pulmonary Artery; RNA, Messenger; Transforming Growth Factor beta1

2005
[The experimental study on pathological changes of pulmonary tissues in portal hypertensive rabbits with schistosomal cirrhosis].
    Zhonghua wai ke za zhi [Chinese journal of surgery], 2005, May-01, Volume: 43, Issue:9

    To investigate the pathologic features of the pulmonary tissue in portal hypertensive rabbits with schistosomal cirrhosis, and to study the role of endothelin-1 (ET-1) and nitric oxide (NO) in pathogenesis of portal hypertensive pulmonary vasculopathy.. The experimental group included 10 rabbits infected percutaneously with cercariae of Schistosomiasis Japonica. The control group included 10 normal rabbits. HE stain, Masson trichrome stain and transmission electron microscopy were applied to detect the pathologic features of the pulmonary tissue. The expression and distribution of endothelin-1 (ET-1) and nitric oxide synthase (NOS) in the lung tissues were analyzed by immunohistochemistry.. After 120 d, the pathological morphology alteration of the pulmonary tissue was observed in the rabbits in experimental group. Both of ET-1 and NOS-containing cells were more abundant in distribution and expression in the lung tissue of experimental group than those of the control group. There was significant difference between the two groups in the parameter of area, lightness and gray level of ET-1 and NOS (P < 0.01).. Pulmonary pathologic changes occur in the portal hypertensive rabbits with schistosomal cirrhosis. ET-1 and NOS-containing cells are more abundant in pulmonary vessel of portal hypertension, then followed by dilation of intrapulmonary vessel. It is deduced that ET-1 and NO might play an important role in the pathogenesis of portal hypertensive pulmonary vasculopathy.

    Topics: Animals; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Liver Cirrhosis, Experimental; Lung; Male; Nitric Oxide Synthase; Rabbits; Schistosomiasis

2005
[Effect of endothelin-1 on voltage-gated K+ current in the pulmonary artery smooth muscle cells of chronic hypoxic rats].
    Yao xue xue bao = Acta pharmaceutica Sinica, 2005, Volume: 40, Issue:4

    To investigate the effect of endothelin-1 (ET-1) on voltage-gated K+ current in the pulmonary artery smooth muscle cells (PASMCs) of chronic hypoxic rats.. Twelve male Wistar rats matched with age and body weight were randomly divided into control and chronic hypoxic groups. Single PASMCs were obtained with acute enzyme (collagnase plus papain) dispersing method. Using the whole cell patch clamp technique in freshly isolated PASMCs from normoxic and hypoxic rats, the effects of ET-1 on voltage-gated K+ current were recorded.. The resting membrane potential (Em) in PASMCs from chronic hypoxic rats was significantly depolarized to (-32.6 +/- 1.3) mV compared with (-42.1 +/- 2.8) mV in PASMCs from normoxic rats (P < 0.01, n = 20). In chronic hypoxic rats, the IKv was smaller than that in normotensive rats [+50 mV, the peak current density of control group reduced from (136 +/- 24) pA/pF to (98 +/- 12) pA/pF, percent inhibition was (28.4 +/- 2.4)%, P < 0.01, n = 6]. Application of ET-1 (1 x 10(-8) mol x L(-1)) also depolarized PASMCs of chronic hypoxic rats from (-32.6 +/- 1.3) mV to (-21.5 +/- 1.7) mV (P < 0.05, n = 20) compared with the ET-1 induced depolarization from (-42.1 +/- 2.8) mV to (-22.6 +/- 1.4) mV (P < 0.05, n = 20). The change in membrane potential induced by ET-1 was not significantly different between PASMCs from normoxic and hypoxic rats. ET-1 (1 x 10(-10) to 1 x 10(-7) mol x L(-1)) caused concentration-dependent inhibition of K+ current in PASMCs both from normoxic and hypoxic rats. At higher concentration (1 x 10(-8) - 1 x 10(-7) mol x L(-1)), the effect of ET-1 on K+ current in PASMCs from hypoxic rats was greater than that of normoxic rats [+50 mV, the peak current density of control group reduced from (136 +/- 24) pA/pF to (40 +/- 10) pA/pF, percent inhibition was (71 +/- 7)%, that of hypoxic group was (98 +/- 6) pA/pF to (16 +/- 3) pA/pF, percent inhibition was (85 +/- 10)% at 1 x 10(-7) mol x L(-2), n = 6, P < 0.01].. Chronic hypoxia did not change the effect of ET-1 on the passive electrical properties of PASMCs. In both normotensive and chronic hypoxic hypertensive PASMCs, exogenous ET-1 could cause concentration-dependent inhibition of voltage-gated K+ current, and the inhibition of K+ current in PASMCs from chronic hypoxic rats was greater than that from normoxic rats at higher concentration (1 x 10(-8) - 1 x 10(-7) mol x L(-1)). Chronic hypoxia might alter the sensitivity of PASMCs to ET-1, perhaps PASMCs exposed to chronic hypoxia were more susceptible to ET-1 mediated IKv inhibition.

    Topics: Animals; Dose-Response Relationship, Drug; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Membrane Potentials; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Patch-Clamp Techniques; Potassium Channels, Voltage-Gated; Pulmonary Artery; Random Allocation; Rats; Rats, Wistar

2005
[Course of pulmonary artery hypertension disease].
    Krankenpflege Journal, 2005, Volume: 43, Issue:4-6

    Topics: Antihypertensive Agents; Biomarkers; Bosentan; Endothelin-1; Humans; Hypertension, Pulmonary; Pilot Projects; Prognosis; Randomized Controlled Trials as Topic; Sulfonamides

2005
CPU 86017, p-chlorobenzyltetrahydroberberine chloride, attenuates monocrotaline-induced pulmonary hypertension by suppressing endothelin pathway.
    Acta pharmacologica Sinica, 2005, Volume: 26, Issue:11

    To elucidate the involvement of the endothelin (ET) pathway in the pathogenesis of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and the therapeutic effect of CPU 86017 (p-chlorobenzyltetrahydroberberine chloride) in rats.. Rats were injected with a single dose (60 mg/kg, sc) of MCT and given CPU 86017 (20, 40, and 80 mg/kg-1/d-1, po) or saline for 28 d. The hemodynamics, mRNA expression, and vascular activity were evaluated.. Right ventricular systolic pressure and central venous pressures were elevated markedly in the PAH model and decreased by CPU 86017. In the PAH group, the endothelin-1 (ET-1) in serum and lungs was dramatically increased by 54% (79.9 pg/mL, P<0.01) and 93% (166.2 pg/mL, P<0.01), and mRNA levels of preproET-1, eNOS, and iNOS also increased dramatically compared with control. Compared with PAH group, CPU 86017 decreased the content of ET-1 to the normal level in lung tissue, but was less effective in serum. The level of NO was significantly increased in CPU 86017 at 80 and 40 mg/kg-1/d-1 groups in tissue, whereas the difference in serum was not significant. A significant reduction in MDA production and an increase in the SOD activity in the serum and lungs was observed in all three CPU 86017 groups. CPU 86017 80 mg/kg-1/d-1 po increased the activity of cNOS by 33% (P<0.01). The up-regulation of eNOS and iNOS mRNA levels induced by MCT was significantly reversed in 3 CPU 86017 groups, and preproET-1 mRNA abundance was also reduced notably in CPU 86017 80 mg/kg-1/d-1 group vs the PAH group. The KCl-induced vasoconstrictions in the calcium-free medium decreased markedly in PAH group but recovered partially after CPU 86017 intervention. The constrictions in the presence of Ca(2+) was not improved by CPU 86017. The phenylephrine-induced vasoconstrictions in the calcium-free medium decreased markedly in PAH group but not recovered after CPU 86017 intervention. The constrictions in the presence of Ca(2+) completely returned to the normal after CPU 86017 intervention.. CPU 86017 suppressed MCT-induced PAH mainly through an indirect suppression of the ET-1 system, which was involved in the pathogenesis of the disease.

    Topics: Animals; Berberine; Blood Pressure; Calcium Channel Blockers; Endothelin-1; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vasoconstriction

2005
Pharmacological efficacy of CPU 86017 on hypoxic pulmonary hypertension in rats: mediated by direct inhibition of calcium channels and antioxidant action, but indirect effects on the ET-1 pathway.
    Journal of cardiovascular pharmacology, 2005, Volume: 46, Issue:6

    Endothelin-1 (ET-1) plays a key role in the pathogenesis of pulmonary hypertension. The present study was conducted to examine the effects of a novel compound p-chlorobenzyltetrahydroberberine (CPU 86017) on endothelin-1 system of hypoxia-induced pulmonary hypertension in rats. SD male rats were divided into control, untreated pulmonary hypertension, nifedipine (10 mg/kg p.o.), and CPU 86017 (80, 40, and 20 mg/kg p.o.) groups. The pulmonary hypertension was established by housing the rats in a hypoxic (10 +/- 0.5% oxygen) chamber 8 hours per day for 4 weeks. Hemodynamic and morphologic assessment exhibited a significant increase in the central vein pressure (CVP), right ventricular systolic pressure (RVSP), and pulmonary arteriole remodeling in the pulmonary hypertensive rats, which were improved by CPU 86017 80 and 40 mg/kg administration (P < 0.01). The elevated pulmonary endothelin-1 level and the over-active preproET-1 and iNOS mRNA expression were also decreased significantly (P < 0.01) in CPU 86017 groups. The maladjustment of redox enzyme system in pulmonary hypertension rats was corrected after treatment. We concluded that CPU 86017 improves pulmonary hypertension mainly to suppress the endothelin-1 pathway at the upstream and downstream via calcium antagonism and antioxidative action, then, resulting in a relief in pathogenesis of the disease.

    Topics: Animals; Antioxidants; Berberine; Calcium Channel Blockers; Calcium Channels, L-Type; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Malondialdehyde; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Pulmonary Artery; Rats; Rats, Sprague-Dawley

2005
Training does not affect the alteration in pulmonary artery vasoreactivity in pulmonary hypertensive rats.
    European journal of pharmacology, 2005, Dec-19, Volume: 527, Issue:1-3

    This study examined the effects of training on intrinsic vasorelaxation and vasoconstriction properties of pulmonary hypertensive rat arteries. Fifty seven male Wistar rats were randomly assigned to 4 groups: normotensive sedentary (n = 14), normotensive trained (n = 15), pulmonary hypertensive sedentary (n = 15) and pulmonary hypertensive trained (n = 13). Pulmonary hypertension was obtained using a chronic hypoxia exposure model. Endothelium-dependent vasorelaxation to acetylcholine (10(-8)-10(-4) M), endothelium-independent vasorelaxation to sodium nitro-prusside (10(-8)-10(-4) M), and vasoconstriction to epinephrine (10(-9)-10(-4) M) and endothelin-1 (10(-12)-10(-7) M) were assessed on isolated rings of large pulmonary arteries. Alterations in endothelium-dependent and -independent vasorelaxation properties as well as enhanced vasoconstrictor responses were obtained in pulmonary hypertensive rats. Chronic exercise did not affect those pulmonary vasoreactivity alterations. A predominant effect of chronic hypoxia over training seems to be partially responsible for this phenomenon, probably through impairment in nitric oxide bioavailability and vascular smooth muscle sensitivity.

    Topics: Acetylcholine; Animals; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Epinephrine; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Male; Nitroprusside; Physical Conditioning, Animal; Potassium Chloride; Pulmonary Artery; Random Allocation; Rats; Rats, Wistar; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

2005
Interleukin-6 causes mild pulmonary hypertension and augments hypoxia-induced pulmonary hypertension in mice.
    Chest, 2005, Volume: 128, Issue:6 Suppl

    Topics: Animals; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Interleukin-6; Male; Mice; Mice, Inbred C57BL

2005
Chronic hypoxia-enhanced murine pulmonary vasoconstriction: role of superoxide and gp91phox.
    Chest, 2005, Volume: 128, Issue:6 Suppl

    Chronic hypoxia (CH) is a common cause of pulmonary hypertension (PH). Accumulating evidence suggests that changes in the activity of endothelin (ET)-1 receptors may play an important role in CH-induced PH. After 3 weeks of CH (10% O2) exposure, we found that the isolated intra-pulmonary artery (PA) constrictor response to ET-1 was significantly increased in wild-type (wt) mice. The administration of Cu/Zn superoxide dismutase (SOD) markedly reduced the CH-enhanced maximal PA constrictor response to ET-1, demonstrating the contribution of superoxide to CH-enhanced PA constrictor responses. Using mice that are completely deficient in gp91phox (a subunit protein of the superoxide producing nicotinamide adenine dinucleotide phosphate [NADPH] oxidase), we found that CH-enhanced PA constriction to ET-1 was completely blocked (decreases in mean [+/- SE] maximal isometric tension from 5.43 +/- 0.35 to 3.33 +/- 0.19 mN; n = 7; p < 0.01). Using a lucigenin-enhanced chemiluminescence technique to measure superoxide, we found that the 3 weeks of CH significantly increased superoxide levels in PA isolated from wt mice. The addition of ET-1 further increased superoxide production. To demonstrate that the increased chemiluminescence is due to superoxide generation, we added Cu/Zn SOD, which markedly decreased chemiluminescence, demonstrating the specificity of this assay. When gp91phox knockout mice were exposed to CH, they had significantly reduced levels of superoxide compared to CH-treated wt mice. Our results demonstrate that the CH-enhanced PA constrictor response to ET-1 is mediated by NADPH oxidase (gp91phox)-derived superoxide overproduction that may contribute to the pathogenesis of CH-induced PH.

    Topics: Animals; Chronic Disease; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Luminescence; Luminescent Measurements; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; NADPH Oxidase 2; NADPH Oxidases; Pulmonary Artery; Superoxides; Vasoconstriction

2005
Pulmonary endothelin-1 clearance in human pulmonary arterial hypertension.
    Chest, 2005, Volume: 128, Issue:6 Suppl

    Topics: Endothelin-1; Humans; Hypertension, Pulmonary; Lung

2005
[The study in the mechanism of the re-hypoxic injury in pigs with acute hypoxia].
    Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 2004, Volume: 20, Issue:2

    Topics: Animals; Blood Gas Analysis; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Oxygen; Oxygen Inhalation Therapy; Swine

2004
Role of endothelin-1 and thromboxane A2 in the pulmonary hypertension induced by heparin-protamine interaction in anesthetized dogs.
    Journal of cardiovascular pharmacology, 2004, Volume: 43, Issue:1

    This study aimed to study the role of thromboxane A2 (TXA2) and endothelin-1 (ET-1) in the pulmonary hypertension induced by interaction of heparin-protamine in anesthetized dogs. The effect of inhaled nitric oxide (NO) was also investigated in this model. Dogs were anesthetized and instrumented for acquisition of mean arterial blood pressure, mean arterial pulmonary pressure (MPAP), and pulmonary pressure gradient (PPG). Cardiac index (CI), heart rate, and index of systemic vascular resistance were also obtained. Intravenous administration of heparin (500 IU/kg) 3 minutes before protamine (10 mg/kg) caused marked pulmonary hypertension, as evaluated by the increase in MPAP and PPG. This was accompanied by systemic hypotension, CI decrease, and tachycardia. Indomethacin (10 mg/kg), dazoxiben (10 mg/kg), or tezosentan (10-mg/kg bolus plus 10-mg/kg/h infusion) significantly reduced the increase in MPAP and PPG, but had no effect on the systemic hypotension. Similar results were obtained with inhaled NO (3 ppm). Plasma TXB2 levels were markedly elevated during the pulmonary hypertension, and this was abolished in indomethacin-treated dogs. Our study shows that interaction of heparin-protamine in anesthetized dogs lead to TXA2- and ET-1-mediated pulmonary hypertension. Drugs that interfere with the synthesis of these mediators as well as inhaled NO may be of beneficial value to control this disorder.

    Topics: Administration, Inhalation; Animals; Dogs; Endothelin-1; Female; Heparin Antagonists; Hypertension, Pulmonary; Male; Nitric Oxide; Protamines; Thromboxane A2; Thromboxane B2

2004
Upregulation of endothelial nitric oxide synthase and endothelin-1 in pulmonary hypertension secondary to heart failure in aorta-banded rats.
    Pediatric pulmonology, 2004, Volume: 37, Issue:3

    This study assessed alterations in expression of pulmonary endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) in rats with pulmonary hypertension (PH) after the ascending aorta had been banded. Rats were studied 12 weeks after banding, which resulted in left heart failure with elevated pulmonary arterial pressure (banded: 31.3 +/- 5.9 (mean +/- SD) mmHg; sham: 20.0 +/- 4.7 mmHg, P<0.05). Competitive reverse transcription-polymerase chain reaction demonstrated significant increases in pulmonary expression of preproET-1 mRNA and eNOS mRNA. Western blot analysis indicated increased pulmonary eNOS protein. Radioimmunoassays indicated increased plasma ET-1 concentrations in the pulmonary artery (banded: 12.4 +/- 1.5 pg/ml; sham: 9.0 +/- 1.3 pg/ml, P<0.01) and increased ET-1 content in lungs (banded: 240 +/- 21 ng/g protein; sham: 203 +/- 20 ng/g protein, P<0.05). There was increased immunohistochemical staining of eNOS and ET-1 in the pulmonary vascular endothelium of aorta-banded rats. Even in the presence of increased eNOS expression, it was not clear how nitric oxide (NO) production (decreased, unchanged, or increased) was involved in the compensatory mechanism to offset pulmonary vasoconstriction. Increased ET-1 expression may be important in mediating PH secondary to aortic banding, and may offer insights into the use of ET-1 antagonists in treating patients with PH secondary to heart failure.

    Topics: Animals; Aorta; Disease Models, Animal; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Immunohistochemistry; Male; Nitric Oxide Synthase; Rats; Rats, Wistar; Up-Regulation

2004
Preoperative glucocorticoids decrease pulmonary hypertension in piglets after cardiopulmonary bypass and circulatory arrest.
    The Annals of thoracic surgery, 2004, Volume: 77, Issue:3

    Glucocorticoids during cardiopulmonary bypass benefit pediatric patients undergoing repair of congenital heart defects and are routine therapy, but underlying mechanisms have not been fully examined. The hypothesis was that glucocorticoids could improve cardiopulmonary recovery after cardiopulmonary bypass and deep hypothermic circulatory arrest.. Crossbred piglets (5 to 7 kg) were cooled with cardiopulmonary bypass, followed by 120-min deep hypothermic circulatory arrest. Animals were then warmed to 38 degrees C, removed from bypass, and maintained for 120 min. Methylprednisolone (60 mg/kg) was administered in the cardiopulmonary bypass pump prime (intraoperative glucocorticoids) or 6 hours before bypass (30 mg/kg) in addition to the intraoperative dose (30 mg/kg; preoperative and intraoperative glucocorticoids). Controls (no glucocorticoids) received saline.. Pulmonary vascular resistance in controls increased from a baseline of 152 +/- 40 to 364 +/- 29 dynes. s/cm(5) at 2 hours of recovery (p < 0.001). Intraoperative glucocorticoids did not alleviate the increase in pulmonary vascular resistance (301 +/- 55 dynes. s/cm(5) at 2 hours of recovery, p < 0.001). However, animals receiving pre and intraoperative glucocorticoids had no increase in pulmonary vascular resistance (155 +/- 54 dynes. s/cm(5)). Plasma endothelin-1 in controls increased from 1.3 +/- 0.2 at baseline to 9.9 +/- 2.0 pg/mL at 2 hours recovery (p < 0.01), whereas glucocorticoid-treated animals had lower endothelin-1 levels (4.5 +/- 2.1 pg/ml, preoperative and intraoperative glucocorticoids; 4.9 +/- 1.7 pg/mL, intraoperative glucocorticoids) at the end of recovery (p < 0.05). Intracellular adhesion molecule-1 in lung tissue was lower in animals receiving pre and intraoperative glucocorticoids (p < 0.05). Myeloperoxidase activity was elevated in control lungs at 2 hours of recovery compared with glucocorticoid-treated groups (p < 0.05). Inhibitor kappaBalpha, the inhibitor of nuclear factor-kappaB, was higher in lungs of animals receiving glucocorticoids compared with controls (p < 0.05).. Glucocorticoids prevented pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circulatory arrest, which was associated with reduced plasma endothelin-1. Glucocorticoids also reduced pulmonary intercellular adhesion molecule-1 and myeloperoxidase activity. Inhibition of nuclear factor-kappaB, along with reduced neutrophil activation, contributed to glucocorticoid alleviation of pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circulatory arrest.

    Topics: Animals; Cardiopulmonary Bypass; Cell Adhesion Molecules; Endothelin-1; Glucocorticoids; Heart Arrest, Induced; Hypertension, Pulmonary; Hypothermia, Induced; Lung; Methylprednisolone; Neutrophil Activation; NF-kappa B; Peroxidase; Preoperative Care; Pulmonary Circulation; Swine; Vascular Resistance

2004
Nitric oxide formation and plasma L-arginine levels in pulmonary hypertensive rats.
    Respiratory medicine, 2004, Volume: 98, Issue:3

    The elevation of plasma L-arginine levels stimulates nitric oxide (NO) synthesis, but the underlying mechanisms are not yet understood. We examined the role of physiological changes in pulmonary arteries on endogenous NO production. Male Wistar rats were divided into following groups: (1) control rats receiving normal water orally, (2) ARG rats receiving L-arginine water orally, (3) MCT rats injected with monocrotaline (MCT) on day 0 and receiving normal water orally, and (4) MCT+ARG rats injected with MCT on day 0 and receiving L-arginine water orally. The rats were studied after 23 days of dietary intervention. In MCT+ARG rats, supplemental L-arginine exhibited a significant pulmonary vasodilatory effect, as shown by a decreased pulmonary arterial pressure (PAP) (P<0.001), decreased right ventricular hypertrophy (P<0.01), and improved endothelium-dependent relaxation (P<0.01). Also L-arginine inhibited the elevation of plasma endothelin-1 (P<0.01). Oral L-arginine administration increased plasma L-arginine levels about twofold, but in only MCT+ARG rats (i.e., not in ARG rats) did the urinary nitrate excretion significantly increase (P<0.05), which is an indicator of endogenous NO formation. Oral administration of L-arginine is effective against pulmonary vascular remodeling. The data also suggest that the initial elevation of PAP is important for the induction of endogenous NO synthesis.

    Topics: Animals; Arginine; Blood Pressure; Body Weight; Endothelin-1; Endothelium, Vascular; Hypertension, Pulmonary; Male; Nitrates; Nitric Oxide; Pulmonary Artery; Rats; Rats, Wistar

2004
New therapies for pulmonary hypertension in neonates and children.
    Pediatric pulmonology. Supplement, 2004, Volume: 26

    Topics: Antihypertensive Agents; Arginine; Child; Endothelin-1; Epoprostenol; Exercise Tolerance; Humans; Hypertension, Pulmonary; Infant, Newborn

2004
In vitro hypoxia differentially affects constriction and relaxation responses of isolated pulmonary arteries from broiler and leghorn chickens.
    Poultry science, 2004, Volume: 83, Issue:5

    Under normoxic conditions in vitro, isolated pulmonary arteries from broilers exhibit reduced endothelium-dependent relaxation responses when compared with Leghorns. In vivo, hypoxia increases the susceptibility of broiler chickens to pulmonary hypertension syndrome (PHS), whereas Leghorns are considered resistant to PHS. Because L-arginine supplementation decreases the incidence of PHS in vivo and improves the relaxation responses of broiler isolated pulmonary arteries in vitro, we hypothesized that in vitro hypoxia would further reduce the relaxation responses of broilers to endothelium-derived nitric oxide (EDNO)-dependent vasodilators and that L-arginine supplementation would alleviate this impairment. As a test of this hypothesis, pulmonary arteries from broiler and Leghorn chickens were isolated and exposed to normoxia or hypoxia in the presence or absence of L-arginine while their constriction and relaxation responses to vasoactive compounds were recorded. In broilers, hypoxia did not affect the constriction responses of isolated pulmonary arteries but decreased EDNO-dependent acetylcholine-induced relaxation responses. In contrast, in Leghorns hypoxia increased endothelin-1-induced vasoconstriction responses and reduced the EDNO-dependent relaxation responses only to the lowest concentration of acetylcholine used. L-Arginine supplementation augmented the relaxation responses to acetylcholine in broilers and Leghorns under normoxia but failed to augment them under hypoxia. Relaxation responses to the NO donor, sodium nitroprusside, were not affected by hypoxia in Leghorns but were increased by hypoxia in broilers. These results suggest that the increased incidence of PHS in broiler chickens reared under hypoxia may be associated with a hypoxia-induced reduction in the synthesis or activity of EDNO in the pulmonary circulation.

    Topics: Acetylcholine; Animals; Arginine; Body Weight; Chickens; Endothelin-1; Endothelium, Vascular; Heart Ventricles; Hypertension, Pulmonary; Hypoxia; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Organ Size; Oxygen; Potassium Chloride; Poultry Diseases; Pulmonary Artery

2004
Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure.
    American journal of physiology. Lung cellular and molecular physiology, 2004, Volume: 287, Issue:3

    Endothelin receptor blockade is an emerging therapy for pulmonary hypertension. However, hemodynamic and structural effects and potential changes in endogenous nitric oxide (NO)-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in pulmonary hypertension secondary to congenital heart disease are unknown. Therefore, the objectives of this study were to determine hemodynamic and structural effects and potential changes in endogenous NO-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in a lamb model of increased pulmonary blood flow following in utero placement of an aortopulmonary shunt. Immediately after spontaneous birth, shunt lambs were treated lifelong with either an endothelin A receptor antagonist (PD-156707) or placebo. At 4 wk of age, PD-156707-treated shunt lambs (n = 6) had lower pulmonary vascular resistance and right atrial pressure than placebo-treated shunt lambs (n = 8, P < 0.05). Smooth muscle thickness or arterial number per unit area was not different between the two groups. However, the number of alveolar profiles per unit area was increased in the PD-156707-treated shunt lambs (190.7 +/- 5.6 vs. 132.9 +/- 10.0, P < 0.05). Plasma endothelin-1 and cGMP levels and lung NOS activity, cGMP, eNOS, preproendothelin-1, endothelin-converting enzyme-1, endothelin A, and endothelin B receptor protein levels were similar in both groups. We conclude that chronic endothelin A receptor blockade attenuates the progression of pulmonary hypertension and augments alveolar growth in lambs with increased pulmonary blood flow.

    Topics: Animals; Aspartic Acid Endopeptidases; Cyclic GMP; Endothelin A Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Female; Hypertension, Pulmonary; Metalloendopeptidases; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Pregnancy; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Sheep

2004
Bosentan inhibits transient receptor potential channel expression in pulmonary vascular myocytes.
    American journal of respiratory and critical care medicine, 2004, Nov-15, Volume: 170, Issue:10

    Bosentan, a dual endothelin receptor blocker, has been used clinically to treat idiopathic pulmonary arterial hypertension (IPAH). However, the mechanism of its antiproliferative effect on pulmonary artery smooth muscle cells (PASMCs) remains unclear. A rise in cytoplasmic Ca2+ stimulates PASMC proliferation and the canonical transient receptor potential (TRPC) channels are an important pathway for Ca2+ entry during PASMC proliferation. Bosentan (20-50 microM) significantly inhibited endothelin-1- or platelet-derived growth factor (PDGF)-mediated PASMC growth and [3H]thymidine uptake. In PASMCs, endothelin-1 (1 microM) and PDGF (10 ng/ml) both upregulated protein expression of TRPC6, whereas bosentan markedly downregulated TRPC6 protein levels. Furthermore, TRPC6 expression in PASMCs from patients with IPAH was greater than in normal PASMCs, and the antiproliferative effect of bosentan was significantly enhanced in IPAH-PASMCs in comparison with normal PASMCs. These observations demonstrate that the antiproliferative effect of bosentan on PASMCs involves the downregulation of TRPC6 channels via a mechanism possibly independent of endothelin receptor blockade. The greater effect of bosentan on IPAH-PASMCs than on normal PASMCs suggests that increased TRPC6 expression and function may be involved in the overgrowth of PASMCs in patients with IPAH.

    Topics: Animals; Blotting, Western; Bosentan; Calcium Channel Blockers; Calcium Channels; Cell Proliferation; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Hypertension, Pulmonary; Male; Myocytes, Smooth Muscle; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Reference Values; Sampling Studies; Sensitivity and Specificity; Sulfonamides; Up-Regulation

2004
Sildenafil citrate alleviates pulmonary hypertension after hypoxia and reoxygenation with cardiopulmonary bypass.
    Journal of the American College of Surgeons, 2004, Volume: 199, Issue:4

    Sudden reoxygenation of hypoxic neonates undergoing cardiac operation exacerbates the systemic inflammatory response to cardiopulmonary bypass secondary to reoxygenation injury, worsening cardiopulmonary dysfunction. Reports suggest sildenafil decreases pulmonary hypertension and may affect myocardial function. Sildenafil's efficacy for treating postbypass cardiopulmonary dysfunction remains unknown.. Fourteen neonatal piglets (5 to 7 kg) underwent 90 minutes of hypoxia, 60 minutes of reoxygenation with cardiopulmonary bypass, and 120 minutes of recovery. Six animals received 50 mg oral sildenafil and eight received saline at hypoxia. Data are presented as mean +/- SD.. Sildenafil prevented the high pulmonary vascular resistance observed in controls (controls baseline 81 +/- 37 dynes. s/cm(5) versus recovery 230 +/- 93 dynes. s/cm(5), p = 0.004; sildenafil baseline 38 +/- 17 dynes. s/cm(5) versus recovery 101 +/- 60 dynes. s/cm(5), p = 0.003). Despite lower pulmonary vascular resistance after sildenafil, arterial endothelin-1 (ET-1) was increased in both groups (control baseline 1.3 +/- 0.5 pg/mL versus recovery 4.5 +/- 3.7 pg/mL, p = 0.01; sildenafil baseline 1.3 +/- 0.3 pg/mL versus recovery 9.8 +/- 4.9 pg/mL, p = 0.003). Intravenous nitric oxide (NO) levels were preserved after sildenafil treatment (sildenafil baseline 340 +/- 77 nM versus recovery 394 +/- 85 nM). IV NO levels in controls were decreased when compared with baseline (control baseline 364 +/- 83 nM versus recovery 257 +/- 97 nM, p = 0.028). Although levels of exhaled NO decreased in both groups, the sildenafil-treated animals had higher levels of exhaled NO when compared with controls at the end of recovery (0.6 +/- 0.4 parts per billion versus 1.8 +/- 0.9 parts per billion, respectively, p = 0.029).. Sildenafil alleviated pulmonary hypertension after reoxygenation with cardiopulmonary bypass. Despite increased ET-1 levels, pulmonary vascular resistance was lower with sildenafil treatment, suggesting sildenafil's effect on the pulmonary vasculature is capable of countering vasoconstriction by ET-1. Further study into the role of sildenafil in perioperative therapy and its interactions with ET-1 are warranted.

    Topics: Animals; Animals, Newborn; Cardiopulmonary Bypass; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Myocardial Reperfusion Injury; Piperazines; Purines; Sildenafil Citrate; Sulfones; Swine; Treatment Outcome; Vasodilator Agents

2004
Signaling molecules in overcirculation-induced pulmonary hypertension in piglets: effects of sildenafil therapy.
    Circulation, 2004, Oct-12, Volume: 110, Issue:15

    The phosphodiesterase type-5 (PDE-5) inhibitor sildenafil has been reported to improve pulmonary arterial hypertension (PAH), but the mechanisms that account for this effect are incompletely understood. Severe pulmonary hypertension has been characterized by defects in a signaling pathway involving angiopoietin-1 and the bone morphogenetic receptor-2 (BMPR-2). We investigated the effects of sildenafil on hemodynamics and signaling molecules in a piglet overcirculation-induced model of early PAH.. Thirty 3-week-old piglets were randomized to placebo or sildenafil therapy 0.75 mg/kg TID after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by pulmonary tissue sampling for morphometry, immunohistochemistry or radioimmunoassay, and real-time quantitative-polymerase chain reaction. Chronic systemic-to-pulmonary shunting increased pulmonary mRNA for angiopoietin-1, endothelin-1 (ET-1), angiotensin II, inducible nitric oxide synthase, vascular endothelial growth factor, and PDE-5. Pulmonary messenger RNA for BMPR-1A and BMPR-2 decreased. Pulmonary angiotensin II, ET-1, and vascular endothelial growth factor proteins increased. Pulmonary artery pressure increased from 20+/-2 to 33+/-1 mm Hg, and arteriolar medial thickness increased by 91%. The expressions of angiopoietin-1, ET-1, and angiotensin II were tightly correlated to pulmonary hypertension. Sildenafil prevented the increase in pulmonary artery pressure, limited the increase in medial thickness to 41%, and corrected associated biological perturbations except for the angiopoietin-1/BMPR-2 pathway, PDE-5, and angiotensin II.. Sildenafil partially prevents overcirculation-induced PAH and associated changes in signaling molecules. Angiotensin II, PDE-5, and angiopoietin-1/BMPR-2 signaling may play a dominant role in the early stages of the disease.

    Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Anastomosis, Surgical; Angiopoietin-1; Angiotensin II; Animals; Arterioles; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Protein Receptors, Type II; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Evaluation, Preclinical; Endothelin-1; Gene Expression Regulation; Hyperplasia; Hypertension, Pulmonary; Models, Animal; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Protein Serine-Threonine Kinases; Pulmonary Artery; Purines; Random Allocation; Receptors, Growth Factor; RNA, Messenger; Signal Transduction; Sildenafil Citrate; Subclavian Artery; Sulfones; Sus scrofa; Vascular Endothelial Growth Factor A

2004
Reduced pulmonary clearance of endothelin in congestive heart failure: a marker of secondary pulmonary hypertension.
    Journal of cardiac failure, 2004, Volume: 10, Issue:5

    Endothelin-1 (ET-1) levels are elevated in congestive heart failure (CHF) in relation with the severity of pulmonary hypertension. We evaluated whether a reduced pulmonary ET-1 clearance could contribute to this elevation.. We determined pulmonary ET-1 clearance in 24 patients with CHF in relation with hemodynamics, plasma ET-1, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Pulmonary ET-1 extraction, measured by the single bolus indicator-dilution technique, was reduced to 32 +/- 14% in comparison to historic controls (47 +/- 7%). Plasma ET-1 clearance by the lungs (924 +/- 588 mL/min) was also much lower than in controls (1424 +/- 79 mL/min). Clearance correlated inversely with mean pulmonary artery pressure (PAP, r = -.47, P = .017) and pulmonary capillary wedge pressure (r = -.47, P = .017) and positively with the rate of left ventricular (LV) relaxation LV -dP/dt (r = .593, P = .004). After multivariate analysis, only mean PAP and LV -dP/dt were independently correlated with ET-1 clearance (r = -.40, P = .03, and r = .55, P = .005, respectively). Plasma ET-1 levels did not correlate with clearance (r = .038, P = .86), and there was no significant arteriovenous ET-1 gradient. There was a mild nonsignificant correlation between plasma ET-1 and pulmonary artery systolic pressure (r = .38, P = .06), but a strong correlation with right atrial pressure (r = .696, P < .0001) and NT-proBNP levels (r = .51, P = .001), which were maintained after multivariate linear regression (r = .60, P = .001, and r = .32, P = .04, respectively).. Pulmonary ET-1 clearance is reduced in CHF in relation with the severity of pulmonary hypertension. This reduced clearance does not significantly modulate plasma ET-1 levels. Whether this is only a marker of secondary pulmonary hypertension or could modulate pulmonary vascular tone will require further studies.

    Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Pressure; Endothelin-1; Female; Heart Failure; Humans; Hypertension, Pulmonary; Indicator Dilution Techniques; Lung; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Protein Precursors; Pulmonary Circulation; Pulmonary Wedge Pressure; Regression Analysis; Ventricular Function

2004
Cytokines in portopulmonary hypertension.
    Gut, 2004, Volume: 53, Issue:11

    Topics: Cytokines; Endothelin-1; Humans; Hypertension, Portal; Hypertension, Pulmonary

2004
Hepatocyte growth factor suppresses vascular medial hyperplasia and matrix accumulation in advanced pulmonary hypertension of rats.
    Circulation, 2004, Nov-02, Volume: 110, Issue:18

    Pulmonary hypertension (PH) is a progressive disease characterized by raised pulmonary vascular resistance, thought to be curable only through lung transplantation. Pathophysiologically, proliferation of pulmonary artery smooth muscle cells triggers pulmonary arterial stenosis and/or regurgitation, especially in advanced PH.. Using a rat model of advanced pulmonary vascular disease produced by injecting monocrotaline, we show that hepatocyte growth factor (HGF) targets pulmonary arterioles and blocks the progression of PH. In these rats, endogenous HGF production was dramatically downregulated during developing experimental PH, but c-Met/HGF receptor was abundant in the medial layers of pulmonary arterioles. HGF gene transfection 2 weeks after the monocrotaline injection resulted in milder medial hyperplasia in lung arterioles and inhibited overgrowth of pulmonary artery smooth muscle cells. Notably, exogenous HGF reduced lung expression levels of endothelin-1 and transforming growth factor-beta, which are critically involved in PH-linked fibrogenic events. Overall, medial wall thickening of pulmonary arteries was almost completely prevented by HGF, and the total collagen deposition in the lung decreased; both effects contributed to the suppression of pulmonary artery hypertension.. Our results suggest that the loss of endogenous HGF may be a feature of the pathogenesis of PH and that HGF supplementation may minimize pathological lung conditions, even advanced PH.

    Topics: Animals; Arterioles; Collagen; Endothelin-1; Extracellular Matrix; Fibrosis; Genetic Therapy; Hepatocyte Growth Factor; Humans; Hyperplasia; Hypertension, Pulmonary; Male; Monocrotaline; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Proto-Oncogene Proteins c-met; Rats; Rats, Wistar; Transfection; Transforming Growth Factor beta; Tunica Media

2004
Tezosentan, a combined parenteral endothelin receptor antagonist, produces pulmonary vasodilation in lambs with acute and chronic pulmonary hypertension.
    Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies, 2004, Volume: 5, Issue:6

    To investigate the hemodynamic effects of tezosentan in the intact lamb both at rest and during acute and chronic pulmonary hypertension.. Prospective, randomized experimental study.. University-based research laboratory.. Lambs with and without pulmonary hypertension.. Six newborn lambs were instrumented to measure vascular pressures and left pulmonary blood flow. The hemodynamic effects of tezosentan (0.5, 1.0, 5.0 mg/kg, intravenously) were studied at rest and during U46619-induced pulmonary hypertension. Following in utero placement of an aortopulmonary vascular graft, nine additional lambs with increased pulmonary blood flow and chronic pulmonary hypertension (shunt) were also studied at 1 wk (n = 5) and 8 wks (n = 4) of age.. At rest, tezosentan had no significant effect on any of the variables. During acute U46619-induced pulmonary hypertension, tezosentan caused a dose-dependent decrease in pulmonary arterial pressure (from 5.9% +/- 4.7 to 16.0% +/- 10.7; p < .05) and pulmonary vascular resistance (from 6.2% +/- 8.0 to 21% +/- 8.8; p < .05). Mean systemic arterial pressure was unchanged. In 1- and 8-wk-old shunt lambs with increased pulmonary blood flow, tezosentan (1 mg/kg) produced potent nonselective pulmonary vasodilation.. Tezosentan, a combined endothelin receptor antagonist optimized for parenteral use, induces potent selective pulmonary vasodilation during acute U46619-induced pulmonary hypertension and potent nonselective vasodilation in chronic pulmonary hypertension secondary to increased pulmonary blood flow. In general, the hemodynamic effects of bolus doses of tezosentan occurred within 60 secs of administration and lasted approximately 5-10 mins. The hemodynamic profile of intravenous tezosentan may make it a useful adjunct therapy for acute pulmonary hypertensive disorders and warrants further study.

    Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Disease; Animals; Animals, Newborn; Chronic Disease; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hypertension, Pulmonary; Injections, Intra-Arterial; Pulmonary Circulation; Pyridines; Random Allocation; Sheep; Tetrazoles; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

2004
Tezosentan, another selective selection for pulmonary hypertension, or not?
    Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies, 2004, Volume: 5, Issue:6

    Topics: Animals; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension, Pulmonary; Pulmonary Circulation; Pyridines; Tetrazoles; Vasodilation; Vasodilator Agents

2004
Effects of ET-A receptor blockade on eNOS gene expression in chronic hypoxic rat lungs.
    Journal of applied physiology (Bethesda, Md. : 1985), 2003, Volume: 94, Issue:2

    We tested the hypothesis that pulmonary endothelial nitric oxide synthase (eNOS) gene expression is primarily regulated by hemodynamic factors and is thus increased in rats with chronic hypoxic pulmonary hypertension. Furthermore, we examined the role of endothelin (ET)-1 in this regulatory process, since ET-1 is able to induce eNOS via activation of the ET-B receptor. Therefore, chronic hypoxic rats (10% O(2)) were treated with the selective ET-A receptor antagonist LU-135252 (50 mg x kg(-1) x day(-1)). Right ventricular systolic pressure and cross-sectional medial vascular wall area of pulmonary arteries rose significantly, and eNOS mRNA levels increased 1.8- and 2.6-fold after 2 and 4 wk of hypoxia, respectively (each P < 0.05). Pulmonary ET-1 mRNA and ET-1 plasma levels increased significantly after 4 wk of hypoxia (each P < 0.05). LU-135252 reduced right ventricular systolic pressure, vascular remodeling, and eNOS gene expression in chronic hypoxic rats (each P < 0.05), whereas ET-1 production was not altered. We conclude that eNOS expression in chronic hypoxic rat lungs is modified predominantly by hemodynamic factors, whereas the ET-B receptor-mediated pathway and hypoxia seem to be less important.

    Topics: Animals; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression; Glyceraldehyde-3-Phosphate Dehydrogenases; Hematocrit; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Phenylpropionates; Pressure; Pulmonary Artery; Pulmonary Circulation; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; RNA, Messenger; Systole; Ventricular Function, Right

2003
[Hopes and experiences in the treatment of severe pulmonary hypertension].
    Revista espanola de cardiologia, 2003, Volume: 56, Issue:3

    Topics: Antihypertensive Agents; Endothelin-1; Epoprostenol; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

2003
Endothelin-I receptor antagonist for the treatment of pulmonary arterial hypertension in systemic sclerosis.
    Current rheumatology reports, 2003, Volume: 5, Issue:2

    Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Lung; Randomized Controlled Trials as Topic; Scleroderma, Systemic; Sulfonamides; Treatment Outcome

2003
Bosentan for the prevention of overcirculation-induced experimental pulmonary arterial hypertension.
    Circulation, 2003, Mar-11, Volume: 107, Issue:9

    The dual endothelin-receptor antagonist bosentan has been reported to improve pulmonary arterial hypertension, but the role of endothelins in the pathogenesis of the condition remains uncertain. We investigated the roles of endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and tenascin in overcirculation-induced pulmonary hypertension in piglets, as a model of early pulmonary arterial hypertension, with or without bosentan therapy.. Thirty 3-week-old piglets were randomized to placebo or to bosentan 15 mg/kg BID after the anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by cardiac and pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative PCR. Chronic systemic-to-pulmonary shunting increased circulating plasma ET-1, pulmonary mRNA for ET-1, ET(B) receptor, inducible NO synthase, VEGF, and pulmonary ET-1 and VEGF proteins. There were increases in myocardial mRNA for ET(A) receptor and VEGF and in myocardial VEGF protein. Pulmonary and myocardial tissue mRNA for tenascin did not change. Normalized-flow pulmonary artery pressure increased from 20 (2) to 33 (1) mm Hg [mean (SEM)], arteriolar medial thickness increased on average by 83%, and these changes were completely prevented by bosentan therapy. Right ventricular end-systolic elastance increased in proportion to pulmonary arterial elastance with or without bosentan.. Experimental overcirculation-induced pulmonary arterial hypertension appears to be causally related to an activation of the pulmonary ET-1 system and as such is completely prevented by the dual endothelin receptor antagonist bosentan.

    Topics: Animals; Antihypertensive Agents; Bosentan; Endothelial Growth Factors; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hemodynamics; Hypertension, Pulmonary; Intercellular Signaling Peptides and Proteins; Lung; Lymphokines; Myocardium; Nitric Oxide; Pulmonary Artery; Pulmonary Circulation; RNA, Messenger; Sulfonamides; Swine; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

2003
Endothelin-1 and functional tissue factor: a possible relationship with severity in primary pulmonary hypertension.
    Heart and vessels, 2003, Volume: 18, Issue:1

    Although dysfunctional endothelium, vasoconstriction, and in situ thrombosis are characteristics of primary pulmonary hypertension, the role that plasma vasomotor and coagulation factors play in this phenomenon are not completely understood. The aim of this work was to ascertain the diagnostic value of endothelin-1, thrombomodulin, tissue factor, and tissue factor pathway inhibitor, as well as their correlation with endothelial dysfunction in primary pulmonary hypertension patients. We analyzed the plasmatic concentration and chromogenic of the above-mentioned molecules using immunoenzymatic techniques. Patients were divided into responders and nonresponders on the basis of their hemodynamic response to a vasodilator trial. We found a continuous increase in endothelin-1 levels and a continuous decrease in functional tissue factor in the control group, responders, and nonresponders, respectively. Moreover, the patients showed a moderate decrease in thrombomodulin levels compared with the control group, without statistical significance. These results support a previous description of a decrease in thrombomodulin levels in primary pulmonary hypertension patients and suggests that an alteration of endothelin-1 and functional tissue factor could be related to a worsening of endothelial function and, indirectly, with the clinical severity of primary pulmonary hypertension.

    Topics: Endothelin-1; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Lipoproteins; Prognosis; Thrombomodulin; Thromboplastin; von Willebrand Factor

2003
[An effective case of nitric oxide inhalation therapy in pulmonary hypertensive crisis in cardiopulmonary bypass following palliative operation for ventricular septal defect with pulmonary hypertension].
    Kyobu geka. The Japanese journal of thoracic surgery, 2003, Volume: 56, Issue:5

    A 4-month-old female with ventricular septal defect (VSD) and severe pulmonary hypertension (PH) underwent a patch closure for VSD. She could not be weaned from cardiopulmonary bypass (CPB) after the intracardiac repair due to PH crisis. Nitric oxide inhalation therapy during partial CPB enabled her to be weaned from CPB. This therapy could be gradually taped off and quit 7 days after the operation. Nitric oxide inhaled therapy is considered to be an excellent treatment for PH crisis during CPB in congenital cardiac surgery. The causes of PH crisis were also discussed in reference to the date of endothelin-1 (ET-1) measured during the operation.

    Topics: Administration, Inhalation; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Endothelin-1; Female; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Infant; Nitric Oxide

2003
Heterozygous deficiency of hypoxia-inducible factor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia.
    The Journal of clinical investigation, 2003, Volume: 111, Issue:10

    Chronic hypoxia induces pulmonary vascular remodeling, leading to pulmonary hypertension, right ventricular hypertrophy, and heart failure. Heterozygous deficiency of hypoxia-inducible factor-1alpha (HIF-1alpha), which mediates the cellular response to hypoxia by increasing expression of genes involved in erythropoiesis and angiogenesis, has been previously shown to delay hypoxia-induced pulmonary hypertension. HIF-2alpha is a homologue of HIF-1alpha and is abundantly expressed in the lung, but its role in pulmonary hypertension remains unknown. Therefore, we analyzed the pulmonary response of WT and viable heterozygous HIF-2alpha-deficient (Hif2alpha(+/-)) mice after exposure to 10% O(2) for 4 weeks. In contrast to WT mice, Hif2alpha(+/-) mice were fully protected against pulmonary hypertension and right ventricular hypertrophy, unveiling a critical role of HIF-2alpha in hypoxia-induced pulmonary vascular remodeling. Pulmonary expression levels of endothelin-1 and plasma catecholamine levels were increased threefold and 12-fold respectively in WT but not in Hif2alpha(+/-) mice after hypoxia, suggesting that HIF-2alpha-mediated upregulation of these vasoconstrictors contributes to the development of hypoxic pulmonary vascular remodeling.

    Topics: Animals; Atmosphere Exposure Chambers; Basic Helix-Loop-Helix Transcription Factors; Catecholamines; Endothelin-1; Fetal Viability; Hematocrit; Heterozygote; Hypertension, Pulmonary; Hypoxia; Lung; Mice; Mice, Transgenic; Phenotype; Pulmonary Artery; RNA, Messenger; Time; Trans-Activators; Up-Regulation; Ventricular Dysfunction, Right

2003
Pilot intervention: aerosolized adrenomedullin reduces pulmonary hypertension.
    The Journal of pharmacology and experimental therapeutics, 2003, Volume: 306, Issue:3

    In pulmonary hypertension, systemic infusion of adrenomedullin (ADM), a potent vasodilator peptide, leads to pulmonary vasodilatation. However, systemic blood pressure declines alike. The present study investigated the effect of aerosolized ADM on pulmonary arterial pressure in surfactant-depleted newborn piglets with pulmonary hypertension. Animals randomly received aerosolized ADM (ADM, n = 6), aerosolized ADM combined with intravenous application of NG-nitro-l-arginine methylester to inhibit nitric-oxide (NO) synthases (ADM + l-NAME, n = 5), or aerosolized normal saline solution (control, n = 6). Aerosol therapy was performed in 30-min intervals for 5 h. After a total experimental period of 8 h, mRNA expression of endothelial and inducible NO synthase and endothelin-1 (ET-1) in lung tissue was quantified using TaqMan real-time polymerase chain reaction. Aerosolized ADM reduced mean pulmonary artery pressure (MPAP) compared with control (p < 0.001; at the end of the study, Delta-MPAP -13.5 +/- 1.4 versus -6.2 +/- 2.4 mm Hg). PaO2 significantly increased in the ADM (DeltaPaO2 243.3 mm Hg) and the ADM + l-NAME group (DeltaPaO2 217.4 mm Hg) compared with the control group (DeltaPaO2 82.9 mm Hg; p < 0.001). Aerosolized ADM did not influence mean systemic arterial pressure (baseline 63.2 +/- 2.7 versus end of the study 66.3 +/- 6.5 mm Hg; not significant). NO synthases gene expressions were 20 to 30% lower with ADM compared with control. ET-1 gene expression was significantly reduced (>50%) after ADM aerosol therapy (p < 0.001). Aerosolized adrenomedullin significantly reduced MPAP without lowering the systemic arterial pressure and improved profoundly the arterial oxygen tension. This effect seems to be mediated at least in part by the reduction of ET-1.

    Topics: Adrenomedullin; Aerosols; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Nitric Oxide Synthase; Oxygen; Peptides; Swine

2003
Activation of the right ventricular endothelin (ET) system in the monocrotaline model of pulmonary hypertension: response to chronic ETA receptor blockade.
    Clinical science (London, England : 1979), 2003, Volume: 105, Issue:6

    Although activation of the endothelin (ET) system contributes to pulmonary hypertension, modifications of the cardiopulmonary ET system and its responses to chronic ET receptor blockade are not well known. To investigate this, rats were injected with monocrotaline (60 mg/kg intraperitoneal) or saline, followed with treatment with the selective ETA receptor antagonist LU135252 (LU; 50 mg.kg(-1).day(-1)) or with saline. After 3 weeks, haemodynamics, cardiac hypertrophy, ET-1 levels and cardiopulmonary ET-receptor-binding profile were evaluated. Monocrotaline (n =7) elicited marked pulmonary hypertension and right ventricular hypertrophy compared with controls (n =8). Both variables were substantially attenuated by LU therapy (n =8; P <0.05 for both). After monocrotaline, right ventricular ET-1 levels were more significantly increased than in the left ventricle (+198% compared with +127%; P <0.05). ETB receptor density was augmented (3-fold) in the right ventricle, whereas that of ETA receptors was not affected. LU treatment also significantly attenuated these alterations (P <0.05). In the lungs, ET-1 levels were not increased after monocrotaline, whereas the balance of ETB to ETA receptors was altered, with a trend toward a lower percentage of ETB than in the control rats. LU treatment did not affect these variables in the lungs. Therefore monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy are associated with the up-regulation of ET-1 and ETB receptors in the right ventricle. These alterations are attenuated with the reduction of pulmonary hypertension and right ventricular hypertrophy after chronic blockade of the ETA receptors, supporting the role of the ET system in right ventricular hypertrophy.

    Topics: Animals; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Endothelins; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Phenylpropionates; Pyrimidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

2003
Treatment of pulmonary arterial hypertension: a step forward.
    Chest, 2003, Volume: 124, Issue:1

    Topics: Antihypertensive Agents; Bosentan; Endothelin-1; Epoprostenol; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Sulfonamides

2003
Portopulmonary hypertension: an increasingly important complication of cirrhosis.
    Gastroenterology, 2003, Volume: 125, Issue:2

    Topics: Echocardiography, Doppler; Endothelin-1; Hemodynamics; Humans; Hypertension, Pulmonary; Liver Cirrhosis; Nitric Oxide; Prospective Studies; Pulmonary Artery

2003
Portopulmonary hypertension in decompensated cirrhosis with refractory ascites.
    Gut, 2003, Volume: 52, Issue:9

    The prevalence of portopulmonary hypertension (PPHTN) in patients with cirrhosis and refractory ascites is unknown. Its presence may preclude patients from receiving a transjugular intrahepatic portosystemic shunt or liver transplantation as a definitive treatment for their end stage cirrhosis.. To determine the prevalence, possible aetiological factors, and predictive factors for the development of PPHTN in these patients.. Sixty two patients (53 males, nine females; mean age 54.5 (1.4) years) with biopsy proven cirrhosis and refractory ascites underwent angiographic measurements of pulmonary and splanchnic haemodynamics. Endothelin 1 levels were measured from the pulmonary artery. Forty nine patients underwent radionuclide angiography for measurements of central blood volume, pulmonary vascular, and cardiac chamber volumes. Forty seven patients also underwent two dimensional echocardiography for measurements of cardiac structural and functional parameters. Cardiac output, and systemic and pulmonary vascular resistance were calculated.. Ten patients (16.1%) fulfilled the criteria for PPHTN (mean pulmonary artery pressure >/= 25 mm Hg and pulmonary vascular resistance >/= 120 dynxs/cm(5)), with significantly higher mean right atrial (15.4 (1.2) v 7.9 (0.5) mm Hg; p<0.001), and right ventricular pressures (24.7 (1.5) v 14.7 (0.6) mm Hg; p<0.001), and endothelin 1 levels (3.04 (0.40) v 1.98 (0.12) pg/ml; p=0.02). No significant differences in any of the other parameters measured were detected between the two groups. A right atrial pressure of >/= 14 mm Hg had a 83% positive predictive value for the presence of PPHTN.. Portopulmonary hypertension is common in cirrhosis with refractory ascites, possibly due to excess endothelin 1 in the pulmonary circulation. An elevated right atrial pressure >/= 14 mm Hg predicts the presence of PPHTN, which may be helpful in deciding management options in these patients.

    Topics: Ascites; Echocardiography; Endothelin-1; Female; Heart Atria; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Male; Middle Aged; Radionuclide Angiography

2003
[Changes of NO and ET-1 in the blood of patients with chronic pulmonary heart disease].
    Hunan yi ke da xue xue bao = Hunan yike daxue xuebao = Bulletin of Hunan Medical University, 2003, Feb-28, Volume: 28, Issue:1

    To study the changes of nitric oxide (NO), and endothelin-1 (ET-1) in patients with chronic pulmonary heart disease (CPHD), and to understand its pathophysiology, observe its severity, assess its prognosis and find clues to some new management methods.. Forty-five patients with CPHD at the acute exacerbation stage, 20 patients with CPHD at the stable stage and 18 healthy controls were studied. The NO and ET-1 levels were measured by spectrophotometry and radioimmunoassay respectively.. 1. The ratio of ET-1/NO in the patients with CPHD at the acute exacerbation stage was higher than that in the patients at the stable stage (P < 0.05), and heathily controls (P < 0.05), the ratio of ET-1/NO in the patients with CPHD at the stable stage was higher than that in the control group (P < 0.05); 2. The NO level in the patients with CPHD at the acute exacerbation stage or stable stage was positively related with PO2(r = 0.85, P < 0.05, r = 0.72, P < 0.05), but negatively related with PCO2(r = -0.54, P < 0.05, r = -0.52, P < 0.05); the ET-1 level in the patients with CPHD at the acute exacerbation stage or stable stage was negatively related with PO2(r = -0.72, P < 0.05, r = -0.53, P < 0.05), but positively related with PCO2(r = 0.55, P < 0.05, r = 0.53, P < 0.05); 3. The serial changes of NO and ET-1 also demonstrated these correlations; 4. The NO level was elevated in those patients with better symptomatic improvement following management (P < 0.05), while the ET-1 level and the ratio of ET-1/NO decreased significantly in the patients with symptomatic improvement (P < 0.05), and there was no significant change in the patients with no symptomatic improvement following management or in the dead patients(P > 0.05).. The imbalance between ET-1 and NO exists in patients with CPHD, and it is closely associated with hypoxia and may play an important role in the occurrence and development of pulmonary hypertension and CPHD. NO and ET-1 can serve as indicators to observe the disease severity and assess its prognosis.

    Topics: Aged; Aged, 80 and over; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Prognosis; Pulmonary Heart Disease

2003
Sildenafil prevents change in RhoA expression induced by chronic hypoxia in rat pulmonary artery.
    Circulation research, 2003, Oct-03, Volume: 93, Issue:7

    Exposure to chronic hypoxia (CH) induces a sustained pulmonary hypertension associated with structural and functional changes in the pulmonary arterial bed, including alterations of contractile properties. The small G-protein RhoA and its effector Rho kinase play a major role in the sustained rise in tension induced by vasoconstrictors. The aim of this study was to analyze the effect of CH on the RhoA/Rho kinase signaling pathway in the rat pulmonary artery. Maximal contraction of pulmonary artery rings to endothelin-1, noradrenaline, and the thromboxane A2 analog U46619 was markedly decreased in rats exposed to CH (10% O2, 2 weeks). This CH-induced decrease response to agonists was attributable to the abolition of RhoA-mediated Ca2+ sensitization of the contraction. Real-time reverse transcriptase-polymerase chain reaction and Western blot analysis revealed a decrease in RhoA mRNA (79.4+/-6.0%, n=4) and RhoA (81.1+/-8.0%, n=4) expression in the main pulmonary artery from CH rats, whereas RhoA expression was not modified in arterial smooth muscle cells and arteries exposed to hypoxia and high intraluminal pressure, respectively. Treatment of rats with sildenafil (25 mg/kg per day) throughout 2 weeks of exposure to CH prevented CH-induced downregulation of RhoA, reduction of contraction, and pulmonary artery remodeling. These findings indicate that CH-induced downregulation of RhoA expression, leading to the abolition of RhoA/Rho kinase-mediated Ca2+ sensitization of contraction, is responsible for the decreased responses to contracting agonists in the pulmonary artery of CH rats. These alterations are prevented by sildenafil, indicating a major role of the NO/cyclic GMP pathway in CH-induced altered RhoA signaling in the pulmonary artery.

    Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blotting, Western; Calcium; Dose-Response Relationship, Drug; Endothelin-1; Gene Expression Regulation; Hypertension, Pulmonary; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Norepinephrine; Piperazines; Potassium Chloride; Protein Serine-Threonine Kinases; Pulmonary Artery; Purines; Rats; rho-Associated Kinases; rhoA GTP-Binding Protein; RNA, Messenger; Sildenafil Citrate; Sulfones; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

2003
Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow.
    Circulation, 2003, Sep-30, Volume: 108, Issue:13

    Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow.. Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2+/-113.8 versus 209.8+/-61.8 pg/g, P<0.05). In shunt lambs (n=9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ETA receptor antagonist PD 156707 (n=3). This pulmonary vasoconstriction was mimicked by exogenous Ala1,3,11,15 ET-1 (4 Ala ET-1), the ETB receptor agonist, and was blocked by the ETB receptor antagonist BQ 788 (n=3). However, in control lambs (n=7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ETB receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs.. Over time, increased pulmonary blood flow and/or pressure results in the emergence of ETB-mediated vasoconstriction, which coincides with the emergence of ETB receptors on smooth muscle cells. These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.

    Topics: Animals; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Defects, Congenital; Hemodynamics; Hypertension, Pulmonary; Lung; Muscle, Smooth, Vascular; Oligopeptides; Piperidines; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sheep; Vasoconstriction

2003
Role of adrenomedullin in congenital heart disease associated with pulmonary hypertension.
    Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban, 2003, Volume: 23, Issue:3

    The changes of adrenomedullin (ADM), endothelin-1 (ET-1) and nitric oxide (NO) levels before and after operation in congenital heart disease (CHD) associated with pulmonary hypertension (PH) were observed in order to investigate their role in CHD with PH and their clinical significance. The CHD patients were divided into 3 groups according to pulmonary artery systolic pressure (PASP): Non-PH group: PASP < or = 30 mmHg (n = 11); mild-PH group: PASP 31-49 mmHg (n = 10); moderate or severe-PH group: PASP > or = 50 mmHg (n = 12). The control group consisted of 15 health children. Plasma ADM, ET-1 and NO levels were determined by radioimmunoassay and colorimetry methods. The correlation between ADM and ET-1, NO, PASP was analyzed. The changes in plasma ADM, ET-1 and plasma NO on the 7th day after operation among the groups were compared. The results showed that plasma ADM levels in non-PH group were significantly higher than that in control group (P < 0.05), but there was no significant difference in ET-1 and NO levels between the two groups (P > 0.05). ADM and ET-1 levels in mild-PH group were significantly elevated as compared with those in non-PH group (both P < 0.05), but NO levels were decreased (P < 0.05). ADM and ET-1 levels in moderate or severe-PH groups were increased as compared with those in mild-PH group (both P < 0.01), but NO level significantly declined (P < 0.05). On the 7th day after operation, plasma ADM and ET-1 levels in PH group were significantly decreased (P < 0.05, P < 0.01) as compared with those before operation, but there was no significant difference in NO levels (P > 0.05). But NO levels in non-PH group were significantly increased (P < 0.05). Plasma ADM levels in CHD were positively correlated with PASP and ET-1 (r = 0.77, P < 0.01; r = 0.82, P < 0.01), negatively correlated with NO (r = -0.56, P < 0.05). It was concluded that during the progression of PH in the cases of CHD, plasma ADM, ET-1 and NO might play an important role in the development of PH. The increased ADM may represent a compensatory mechanism. It can interact with NO and ET-1 to regulate pulmonary circulation in the pathophysiology of PH with CHD. ADM may be involved in the defence mechanism against further increase of pulmonary arterial pressure. ADM could be used as a reliable indicator of the severity of CHD associated PH.

    Topics: Adolescent; Adrenomedullin; Child; Child, Preschool; Endothelin-1; Female; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Infant; Male; Nitric Oxide; Peptides; Postoperative Period

2003
Endothelin-1 levels in interstitial lung disease patients during sleep.
    Sleep & breathing = Schlaf & Atmung, 2003, Volume: 7, Issue:3

    Hypoxemia stimulates endothelin-1 (ET-1) secretion. The reduction in alveolar ventilation during sleep is considered sufficient to account for the hypoxemia observed in patients with respiratory diseases.. The aim of this study was to evaluate the arterial ET-1 levels and their relationship with pulmonary hypertension in patients with interstitial lung disease (ILD) during sleep.. We examined 38 patients with ILD using formal polysomnography (electroencephalogram, electrocardiogram, airflow, respiratory muscle movement, oximeter) to detect the presence of nocturnal, nonapneic, oxyhemoglobin desaturation. All patients desaturated below a baseline sleep saturation of 90% for 5 minutes or more, reaching a nadir saturation of at least 85%. Each patient had already undergone right heart catheterization with a Swan-Ganz catheter for measuring hemodynamic parameters. Sampling of arterial blood from a radial artery line for determination of blood gases and ET-1 values was performed simultaneously, after 5 minutes of the first desaturation.. At rest, arterial ET-1 levels were higher in ILD patients (1.73 +/- 0.37 mgr/mL) than in controls (1.22 +/- 0.15 mgr/mL) ( p < 0.001). Also, the patients with pulmonary hypertension (Pa > 20 mm Hg) presented significantly higher arterial ET-1 levels (1.86 +/- 0.32 mgr/mL) than those without pulmonary hypertension (1.31 +/- 0.13 mgr/mL) ( p < 0.001). Arterial ET-1 levels were significantly correlated with mean pulmonary arterial pressure (PAP) (r = 0.749, p < 0.001), and arterial oxygen partial pressure (PaO2) (r = 0.79, p < 0.001). At sleep, during desaturation, arterial ET-1 levels significantly increased in all patients (2.46 +/- 0.13 mgr/mL) as compared with resting values ( p < 0.001). Arterial ET-1 levels were significantly correlated with PAP (r = 0.657, p < 0.001) and PaO2 (r = 0.93, p < 0.001).. According to our study, arterial ET-1 is markedly increased in ILD patients, especially in those with pulmonary hypertension.

    Topics: Electrocardiography; Electroencephalography; Endothelin-1; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Lung Diseases, Interstitial; Male; Middle Aged; Oximetry; Polysomnography; Sleep

2003
[Changes of vasoactive factors in lung tissue of newborn piglets with persistent pulmonary hypertension and effect of magnesium sulphate].
    Zhonghua er ke za zhi = Chinese journal of pediatrics, 2003, Volume: 41, Issue:2

    Topics: Angiotensins; Animals; Animals, Newborn; Biomarkers; Endothelin-1; Hypertension, Pulmonary; Lung; Magnesium Sulfate; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Swine; Vasomotor System

2003
Thromboxane A(2) receptors mediate pulmonary hypertension in 60% oxygen-exposed newborn rats by a cyclooxygenase-independent mechanism.
    American journal of respiratory and critical care medicine, 2002, Jul-15, Volume: 166, Issue:2

    Endothelin-1 (ET-1) mediates the development of pulmonary hypertension (PHT) in newborn rats exposed to 60% O(2) for 14 days, a model for human chronic neonatal lung injury. ET-1 production by d-14 rat pulmonary artery smooth muscle cells in vitro was markedly increased by thromboxane (TX) A(2) receptor agonists and inhibited by a competitive antagonist. We hypothesized that stimulation of the TX A(2) receptor contributed to O(2)-mediated PHT in vivo. Newborn rat pups received daily intraperitoneal injections of L670596, a competitive TX A(2) receptor antagonist, or 5,5-dimethyl-3-(3-fluorophenyl)4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 inhibitor, during 14 days of 60% O(2) or air exposure. L670596, but not DFU, prevented 60% O(2)-mediated right ventricular and small pulmonary vessel smooth muscle hypertrophy. Lung ET-1 content was significantly reduced by L670596 in 60% O(2)-exposed animals. We conclude that TX A(2) receptor activation, though not by TX A(2), caused upregulation of ET-1 and PHT in this model. A likely mediator is the stable lipid peroxidation product, 8-iso-prostane, which acts as an incidental ligand of the TX A(2) receptor and is a potent inducer of ET-1 production by cultured d-14 rat pulmonary artery smooth muscle cells in vitro.

    Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Blotting, Western; Carbazoles; Cells, Cultured; Cyclooxygenase Inhibitors; Dinoprost; Endothelin-1; F2-Isoprostanes; Furans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Immunohistochemistry; Lung; Muscle, Smooth, Vascular; Oxygen; Prostaglandin Antagonists; Prostaglandin-Endoperoxide Synthases; Pulmonary Artery; Rats; Receptors, Thromboxane; Thromboxane B2; Up-Regulation; Vasoconstrictor Agents

2002
Immunohistochemical study of endothelin-1 and matrix metalloproteinases in plexogenic pulmonary arteriopathy.
    Pathology, research and practice, 2002, Volume: 198, Issue:6

    The matrix metalloproteinases (MMPs) and endothelin-1, a potent vasoconstrictor and mitogen for smooth muscle cells, have been shown to be involved in the pathogenesis of various vascular disorders. However, the expression of endothelin-1 and the activation of MMPs have not been fully evaluated in plexogenic pulmonary arteriopathy (PPA). Immunohistochemical and confocal microscopic studies were conducted to evaluate the reactivity of lung tissue from six patients with pulmonary hypertension for alpha-smooth muscle actin (alpha-SMA), desmin, vimentin, factor VIII, endothelin-1, various types of MMPs (MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9), membrane type-MMPs (MT-MMPs), tissue inhibitors of MMPs (TIMPs), and type IV collagen. Four major arterial morphological abnormalities were recognized in PPA: muscularization of pulmonary arterioles, onion-skin lesions, cellular and mature plexiform lesions, and atheromas in elastic pulmonary arteries. Reactivity for MMP-2 and MT-1-MMP was found in endothelial cells and, to a lesser extent, in myofibroblasts proliferating in various lesions of PPA. Increased expression of endothelin-1 was observed in the latter cells and in endothelial cells. Some myofibroblasts were positive for MMP-3 and MMP-7 in the vascular lesions except for mature plexiform lesions. MMP-1, MMP-9 and TIMP-2 tended to be positive only in the atheromatous lesions. Staining for type IV collagen showed focal thinning and discontinuities of the endothelial basement membrane in plexiform lesions. This study demonstrates colocalization of MMP-2 with MT-1-MMP and increased expression of endothelin-1 in various arterial lesions of PPA. These changes may play important roles in the remodeling of arterial structures, particularly of basement membranes, in this disorder.

    Topics: Adolescent; Adult; Biomarkers; Collagen Type IV; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Immunohistochemistry; Male; Matrix Metalloproteinases; Microscopy, Confocal; Middle Aged; Peripheral Vascular Diseases; Pulmonary Alveoli; Pulmonary Artery

2002
Effects of increased pulmonary flow on the expression of endothelial nitric oxide synthase and endothelin-1 in the rat.
    Clinical science (London, England : 1979), 2002, Volume: 103 Suppl 48

    The purpose of the study was to assess whether increased pulmonary flow and subsequent development of pulmonary vascular remodelling could alter the expression of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) in the rat lung. Nine 42-day-old Wistar rats underwent abdominal aortocaval shunt to increase pulmonary blood flow for 12 weeks. The shunt resulted in significant medial hypertrophy of pulmonary artery without significant alterations in pulmonary or systemic blood pressure. Using competitive reverse transcription-PCR, significant increases in the preproET-1 mRNA expression and eNOS mRNA expression in the lungs of rats with abdominal aortocaval shunt were detected. Increased eNOS protein in the lung of shunt rats was also found by Western blot analysis. However, the plasma ET-1 concentration in the pulmonary artery (sham: 5+/-0.7 pg/ml; shunt: 6+/-0.8 pg/ml) or the lung ET-1 content (sham: 218+/-41 ng/g protein; shunt: 224+/-40 ng/g protein) was unchanged. There was an elevated immunohistochemical expression of eNOS, but not ET-1, in the pulmonary vascular endothelium in rats with the shunt. These results suggest that eNOS and ET-1 may be involved in remodelling prior to the development of pulmonary hypertension.

    Topics: Animals; Endothelin-1; Endothelins; Endothelium, Vascular; Hypertension, Pulmonary; Hypertrophy; Immunohistochemistry; Lung; Models, Animal; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Protein Precursors; Pulmonary Artery; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

2002
Interaction of endogenous endothelin-1 and inhaled nitric oxide in term and preterm infants.
    Clinical science (London, England : 1979), 2002, Volume: 103 Suppl 48

    The peptide endothelin-1 (ET-1) plays an unknown role in the pathogenesis and progression of two important neonatal pulmonary disorders, chronic lung disease (CLD) of prematurity and persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (INO) is a proven vasodilator therapy in PPHN and is an experimental therapy in CLD. We sought to determine the effects, if any, of the interaction of inhaled INO with ET-1 in these two separate disorders. Infants (n=21) with PPHN (mean gestation age, 39.4 weeks; mean birth weight, 3470 g) were treated with INO. All infants were <72 h of age at baseline. Plasma obtained at baseline and after 24 h of INO therapy was assessed for ET-1. The change in ET-1 levels with INO was inversely correlated with change in arterial partial pressure of O(2) (r=-0.71, P=0.0003). A separate group of 33 patients with CLD (mean gestational age, 27 weeks; mean birth weight, 740 g; mean age, 19 days) had tracheal aspirate levels of ET-1 obtained before, during, and after 7 days' administration of INO. Values were normalized by soluble secretory component of IgA. Tracheal aspirate ET-1 levels were detectable before INO therapy. There was no significant change during or after treatment with INO. There was not a significant correlation between baseline fractional inspired O(2) and ET-1 levels. There was a non-significant trend in the correlation between the change in ET-1 and the change in interleukin-8 levels in tracheal aspirate. This report confirms the presence of ET-1 in tracheal aspirate of premature infants who are developing CLD and reaffirms the presence of ET-1 in plasma of infants with PPHN. Short-term INO therapy was associated with a decrease in plasma ET-1 levels in PPHN, but did not affect tracheal aspirate ET-1 in CLD. Given the vasconstrictive, profibrotic, and proinflammatory properties of ET-1, specific ET-1 receptor antagonists could be considered as candidates for trials as adjunct therapy in either or both of these disorders.

    Topics: Administration, Inhalation; Biomarkers; Endothelin-1; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Interleukin-8; Nitric Oxide; Persistent Fetal Circulation Syndrome; Pulmonary Disease, Chronic Obstructive

2002
Effect of L-NAME on pulmonary arterial pressure, plasma nitric oxide and pulmonary hypertension syndrome morbidity in broilers.
    British poultry science, 2002, Volume: 43, Issue:4

    1. Experiments were conducted to evaluate the effect of a synthetic inhibitor of nitric oxide (NO) synthase (L-NAME) on pulmonary arterial pressure (PAP) and pulmonary hypertension syndrome (PHS) morbidity in broilers. 2. In Experiment 1, broilers were infused intravenously with L-NAME, and the mean pulmonary arterial pressure (mean PAP) and plasma NO were measured at 0, 1, 2 and 4 h after the start of infusion. The mean PAP increased and plasma NO was reduced at 1 to 2 h in broilers treated with L-NAME. 3. In Experiment 2, 180 Arbor Acres broilers were evenly divided into three groups: a control group (group C), and two groups exposed to low environmental temperatures and fed a 3, 3, 5-triiodothyronine (T3) supplemented diet alone (group A) or also including 100 ppm L-NAME (group B). 4. The PHS morbidity of group A was higher than for group C but lower than for group B. Plasma endothelin-1 was higher in broilers in groups A and B than in group C. Plasma NO was not significantly lower in broilers of group B when compared with those in group A. 5. The right/total ventricular weight ratio (RV/TV) and mean PAP were higher in groups A and B than in group C, and the RV/TV ratio increased one week earlier in group B than in group A. 6. These results suggest that L-NAME increases broiler PAP by inhibiting the endogenous synthesis of NO, leading to pulmonary hypertension, right ventricular hypertrophy and the increased morbidity of PHS in broilers.

    Topics: Animals; Blood Pressure; Chickens; Dose-Response Relationship, Drug; Endothelin-1; Enzyme Inhibitors; Hypertension, Pulmonary; Incidence; Injections, Intravenous; Morbidity; NG-Nitroarginine Methyl Ester; Nitric Oxide; Poultry Diseases; Pulmonary Artery; Random Allocation; Syndrome; Vascular Resistance; Vasodilation

2002
Cyclooxygenase-2 acts as an endogenous brake on endothelin-1 release by human pulmonary artery smooth muscle cells: implications for pulmonary hypertension.
    Molecular pharmacology, 2002, Volume: 62, Issue:5

    Endothelin-1 is a potent vasoconstrictor and comitogen for vascular smooth muscle. As such, it has been implicated in pulmonary vascular remodeling and in the development of pulmonary hypertension. Prostacyclin has been shown to be an effective therapy for human pulmonary hypertension, reducing morbidity and mortality, although the mechanism of its action is unknown. Here, we show that the combination of TNF-alpha and IFN-gamma induces the release of endothelin-1 from human pulmonary artery smooth muscle cells via increased transcription of prepro endothelin-1. The release of endothelin-1 and the transcription of prepro endothelin-1 mRNA were inhibited by the activity of coinduced cyclooxygenase-2. Endothelin-1 release was also inhibited by a prostacyclin-mimetic (cicaprost). Thus, under inflammatory conditions, in which vascular smooth muscle is an important source of endothelin-1, the induction of cyclooxygenase-2 represents an endogenous "braking" mechanism. In addition, the beneficial effects of prostacyclin in the treatment of pulmonary hypertension may be caused, at least in part, by the inhibition of endothelin-1 release. Finally, we suggest that these observations may help to explain why patients with pulmonary hypertension experience exacerbations after taking indomethacin and that the newly introduced selective cyclooxygenase-2 inhibitors may increase endothelin-1 production in susceptible patients, leading to vascular remodeling and the development of pulmonary hypertension.

    Topics: Cyclic AMP; Cyclooxygenase 2; Endothelin-1; Epoprostenol; Humans; Hypertension, Pulmonary; Interferon-gamma; Interleukin-1; Isoenzymes; Membrane Proteins; Muscle, Smooth, Vascular; Prostaglandin-Endoperoxide Synthases; Pulmonary Artery; RNA, Messenger; Transcription, Genetic; Tumor Necrosis Factor-alpha

2002
Pulmonary hypertension, left ventricular dysfunction and plasma serotonin: commentary on Deuchar et al.
    British journal of pharmacology, 2002, Volume: 137, Issue:6

    Topics: Animals; Endothelin-1; Hypertension, Pulmonary; Nitric Oxide; Serotonin; Ventricular Dysfunction, Left

2002
Expression of hypoxia-inducible factor-1 alpha and endothelin-1 gene in hypoxic pulmonary hypertension.
    Zhonghua bing li xue za zhi = Chinese journal of pathology, 2002, Volume: 31, Issue:2

    To investigate the expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) and endothelin-1 (ET-1) gene in hypoxic pulmonary hypertension (HPH).. The animal model of HPH was replicated. The elastic fiber staining was applied to show the intraacinar pulmonary artery (IAPA). Radioimmunoassay (RIA) and in situ hybridization (ISH) were used for detection of HIF-1a and. ET-1.. ISH showed that HIF-1alpha mRNA was expressed in the IAPA of all hypoxic rat. The expression was stronger in the H14 d (0.256 9 +/- 0.046 8) and H28 d (0.225 8 +/- 0.045 3) groups than in the H5 d (0.1455 +/- 0.072 2) and control (0.110 9 +/- 0.022 4) groups (P < 0.05), the expression of ET-1 mRNA in the H14 d (0.412 2 +/- 0.078 3) and H28 d (0.368 4 +/- 0.072 9) groups was also stronger than that in the H5 d (0.201 7 +/- 0.034 9) and control (0.185 5 +/- 0.036 1) groups (P < 0.05). The amount of ET-1 in pulmonary arteial blood in the H14 d [(158.78 +/- 25.14) pg/ml] and H28 d [(142.93 +/- 23.38) pg/ml] groups was significantly higher than that in the H5 d [(79.68 +/- 12.54) pg/ml] and control [(65.37 +/- 10.82) pg/ml] groups (P < 0.05). The mean pulmonary arterial pressure (mPAP) in the H14 d [(34.0 +/- 5.8) mm Hg] and H 28 d [(29.0 +/- 4.7) mm Hg] groups was markedly higher than that in the H5 d [(19.0 +/- 3.5) mm Hg] and control [(17.0 +/- 2.8) mm Hg] groups (P < 0.05). A positive rank correlation existed between the mPAP and the amount of ET-1 (rs = 0.747, P < 0.05).. Expression of HIF-1alpha and ET-1 mRNA in IAPA increase under long-term hypoxic condition and both show consistent expression, indicating that the expression of HIF-1a and ET-1 gene contribute to pathogenesis of HPH.

    Topics: Animals; Endothelin-1; Gene Expression; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Rats; Rats, Wistar; RNA, Messenger; Transcription Factors

2002
[A clinical study on the relationship between endogenous carbon monoxide and hypoxic pulmonary hypertension].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2002, Volume: 25, Issue:9

    To study the plasma level of endogenous carbon monoxide (CO) in patients with chronic cor pulmonale (CCP) and its relationship with endothelin-1 (ET-1) and hypoxic pulmonary hypertension (HPH).. There were examinations on the plasma levels of endogenous CO and ET-1 in 33 patients with CCP, and their correlation with PaO(2) and the ratio of right ventricular pre-ejection period to the pulmonary flow acceleration time (RVPEP/AT), an indicator of pulmonary hypertension. Thirty healthy subjects served as normal controls.. The levels of endogenous CO, ET-1 and the ET-1/CO ratio in acute exacerbation and remission in the CCP group [CO: (1.34 +/- 0.18) mg/L, (1.07 +/- 0.14) mg/L; ET-1: (82 +/- 15) ng/L, (57 +/- 10) ng/L; ET-1/CO: 61 +/- 6, 53 +/- 5] were higher than those in the normal control group [CO: (0.55 +/- 0.12) mg/L, P < 0.001; ET-1: (27 +/- 9) ng/L, P < 0.001; ET-1/CO: 48 +/- 7, P < 0.05]. The levels of plasma endogenous CO, ET-1, and the ET-1/CO ratio in acute exacerbation were higher than those in the remission stage (P < 0.001, P < 0.001, P < 0.05). The level of endogenous CO was negatively correlated with PaO(2) (r = -0.733, P < 0.01; r = -0.672, P < 0.01) and positively correlated with RVPEP/AT (r = 0.620, P < 0.01; r = 0.557, P < 0.01). The ET-1/CO ratio was positively correlated with RVPEP/AT (r = 0.501, P < 0.01; r = 0.485, P < 0.05) in patients with acute exacerbation or in remission.. The increased level of plasma endogenous CO in patients with CCP suggests the involvement of CO in the pathophysiologic process of HPH. An imbalance between ET-1 and CO may be involved in the development of HPH.

    Topics: Adult; Aged; Aged, 80 and over; Carbon Monoxide; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Oxygen

2002
Endothelin-A receptor blockade in porcine pulmonary hypertension.
    Pediatric research, 2002, Volume: 52, Issue:6

    Endothelin-1 can cause pulmonary vasoconstriction via endothelin-A (ET(A)) receptor activation. We hypothesized that ET(A) blockers (EMD 122946 and BQ 610) would reduce hypoxia-induced (HYP) but not group B streptococcal infusion (GBS)-induced pulmonary hypertension in a juvenile whole animal model. Pulmonary hypertension was created by exposing chronically instrumented piglets to HYP (n = 12) or heat-killed GBS (n = 11). ET(A) blockade was produced by increasing bolus doses of EMD122946 or BQ 610. Pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), left atrial pressure, central venous pressure, and cardiac output were continuously measured. Pulmonary and systemic vascular resistance indices (PVRI and SVRI) were calculated. HYP doubled PAP and PVRI. Both ET(A) blockers decreased PAP and PVRI in a dose-dependent manner in HYP, with high doses decreasing PVRI to baseline and reducing PAP by 50%. GBS also doubled both PAP and PVRI. EMD 122946 did not change PAP or PVRI in GBS, although BQ 610 markedly increased PVRI (>100% increase with 0.15 mg/kg) and showed a trend toward increasing PAP. Both models showed minimal (<25%) changes in SAP or SVRI. Neither ETA blocker changed baseline hemodynamics in the absence of HYP or GBS. PaO(2) did not change with GBS but decreased with BQ 610. ET(A) receptor blockade attenuated hypoxic, but not GBS induced pulmonary hypertension. BQ 610 worsened PVRI and oxygenation in the GBS model. Differences in response to ET(A) blockade in pulmonary hypertension may be seen depending on the etiology (hypoxia versus infection-associated), and the specific ET(A) antagonist used.

    Topics: Animals; Blood Pressure; Carbon Dioxide; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Hypoxia; Infant, Newborn; NG-Nitroarginine Methyl Ester; Oligopeptides; Oxygen; Pulmonary Circulation; Receptor, Endothelin A; Streptococcal Infections; Streptococcus agalactiae; Sus scrofa; Thiazoles

2002
Effects of tetrandrine on smooth muscle contraction induced by mediators in pulmonary hypertension.
    Acta pharmacologica Sinica, 2002, Volume: 23, Issue:12

    In attempt to characterize tetrandrine on pulmonary hypertension, biological activities induced by a range of mediators implicated in the pathogenesis of pulmonary hypertension were investigated.. Pulmonary artery rings and tracheal segments were contracted with couples of bioactive substances in which a series experiments including effects of tetrandrine on calcium agonist, endothelin, thromboxane A2, angiotensin II, neuropeptide Y, histamine, 5-methyl furmethide were performed, the influences of tetrandrine in the concentration of 1 to 30 micromol/L were investigated.. Tetrandrine inhibited calcium agonist BayK8644, endothelin-1 and thromboxane A2 mimetic U46619, angiotensin II- and neuropeptide Y-induced contractile responses with depression of the maximal contraction of pulmonary artery rings in a varying extent. Tetrandrine inhibited leukotriene E4-induced concentration-response curve in a competitive antagonist manner with a pKB of (5.29+/-0.11) without any influence leukotriene C4, leukotriene D4, histamine, and 5-methyl furmethide induced contractile responses of guinea pig trachea.. Tetrandrine may produce multiple pharmacological effects against calcium channel antagonist, U46619, endothelin-1,angiotension II, and neuropeptide Y induced vasoconstriction in rat pulmonary arteries in varying extent and inhibition of leukotriene E4 rather than C4, D4, histamine, and 5-methyl furmethide induced contractile responses on rat tracheal segments. These pharmacological characteristics are considered to contribute to its antihypertensive action during pulmonary hypertension.

    Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Alkaloids; Angiotensin II; Animals; Antihypertensive Agents; Benzylisoquinolines; Endothelin-1; Guinea Pigs; Hypertension, Pulmonary; Male; Muscle Contraction; Muscle, Smooth, Vascular; Neuropeptide Y; Pulmonary Artery; Rats; Rats, Sprague-Dawley; SRS-A

2002
Defective intracellular calcium handling in monocrotaline-induced right ventricular hypertrophy: protective effect of long-term endothelin-A receptor blockade with 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)- 4-oxobut-2-enoate-sodium (PD 155080
    The Journal of pharmacology and experimental therapeutics, 2002, Volume: 300, Issue:2

    We studied the effect of long-term treatment with the oral endothelin (ET) ET(A) antagonist 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)-4-oxobut-2-enoate-sodium (PD 155080; PD) on right ventricular intracellular calcium (Ca(2+)(i)) handling and cardiac and pulmonary artery function in control rats and rats with monocrotaline (MCT)-induced right-heart hypertrophy. Rats were given an intraperitoneal injection of either saline (controls; n = 9) or MCT (50 mg/kg; n = 12), resulting in pulmonary hypertension-induced myocardial hypertrophy, or MCT followed by the daily administration of PD (50 mg/kg) for 9 weeks (n = 9). After 9 weeks, right ventricular pressure was measured, and the hearts were removed and perfused in vitro. Right ventricular function and Ca(2+)(i) transients were recorded simultaneously on a beat-to-beat basis using aequorin. Surviving animals in the MCT group (58%) developed significant hypertrophy and had 2-fold higher right ventricular pressure and a prolonged duration of isovolumic contraction that correlated with a similar prolongation of the Ca(2+)(i) transient, indicating a reduced rate of Ca(2+) sequestration in hypertrophy (P < 0.05 versus control). In the PD group, all animals survived, and right ventricular pressure, diastolic relaxation, Ca(2+) transport kinetics, and peak systolic and end-diastolic wall stress were all normalized (P > 0.05 versus control); and pulmonary artery endothelial function was partly restored (P < 0.05 versus MCT and control groups). These results demonstrate for the first time that long-term ET(A) receptor antagonism normalizes myocardial cytosolic Ca(2+) modulation, which may contribute to the antihypertrophic and cardioprotective effect of ET(A) receptor therapy in this model.

    Topics: Aequorin; Animals; Calcium; Calcium Signaling; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Female; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; In Vitro Techniques; Luminescent Measurements; Monocrotaline; Myocardial Contraction; Perfusion; Poisons; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Ventricular Function, Right

2002
Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension.
    Circulation, 2002, Jan-29, Volume: 105, Issue:4

    Increased serine elastase activity has been implicated in the vascular remodeling associated with chronic hypoxia-related pulmonary hypertension in rats.. In this study we determined the time course of hypoxia-induced serine elastase activity in the murine lung and related this to initiation of a proteolytic cascade characterized by an increase in matrix metalloproteinases (MMPs). We then used transgenic mice in which overexpression of the selective serine elastase inhibitor elafin was targeted to the cardiovascular system to determine whether upregulation of a naturally occurring serine elastase inhibitor suppresses MMPs and the hemodynamic and structural response to chronic hypoxia (air at 380 mm Hg). In nontransgenic but not in elafin-transgenic mice, we documented a transient increase in serine elastase activity after 12 hours of hypoxic exposure attributed to a 30-kDa protein as determined by elastin zymography and fluorophosphonate/fluorophosphate-biotin labeling. Two days after hypoxia, the pro-forms of MMP-2 and MMP-9 were induced in the nontransgenic mice, but MMP-9 was suppressed in elafin-transgenic mice. Acute hypoxic vasoconstriction was similar in nontransgenic and elafin-transgenic littermates. Chronic hypoxia for 26 days resulted in >1-fold increase in right ventricular pressure (P<0.004) in nontransgenic compared with control or elafin-transgenic littermates. In the latter mice, normalization of the right ventricular pressure was associated with reduced muscularization and preservation of the number of distal vessels (P<0.04 for both comparisons).. Modulation of the severity of chronic hypoxia-induced pulmonary vascular disease could be a function of endogenously expressed serine elastase inhibitors.

    Topics: Actins; Animals; Elastin; Endothelin-1; Hematocrit; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Kinetics; Matrix Metalloproteinases; Mice; Mice, Transgenic; Pressure; Proteinase Inhibitory Proteins, Secretory; Proteins; Pulmonary Artery; RNA, Messenger; Serine Proteinase Inhibitors; Up-Regulation; Ventricular Pressure

2002
Pulmonary hypertension secondary to left ventricular dysfunction: the role of nitric oxide and endothelin-1 in the control of pulmonary vascular tone.
    British journal of pharmacology, 2002, Volume: 135, Issue:4

    1. Using an in vivo model of pulmonary hypertension (PHT) secondary to left ventricular dysfunction (LVD), the pulmonary arterial response to the nitric oxide synthase (NOS) blocker L-NAME (30 micromol.min(-1) i.v.) and the subsequent responses to cumulatively administered endothelin-1 (ET-1) (0.001 -- 4 nmol.kg(-1) i.v.) or big ET-1 (0.1 -- 2.0 nmol.kg(-1) i.v.) were studied. Additionally, the effect of the non-selective ET-1 receptor antagonist, SB209670, was investigated. 2. Eight weeks after coronary artery ligation or sham operation, rabbits demonstrated increased mean pulmonary arterial pressure (PAP) accompanied by right ventricular hypertrophy. 3. Blockade of NOS caused a greater increase in basal PAP (increased by 7.7 +/- 1.1 mmHg c.f. 3.8 +/- 1.0 mmHg in controls, P<0.05) and uncovered a greater pulmonary pressor response to exogenous ET-1 in rabbits with PHT (increased by 10.2 +/- 2.3 mmHg c.f. 4.9 +/- 1.0 mmHg in controls, P<0.05). 4. Big ET-1 evoked a pulmonary pressor effect, in both groups of rabbits, that was increased following blockade of NOS and was more potent in rabbits with PHT. 5. The non-selective ET-1 receptor antagonist, SB209670, reduced basal PAP (from 16.9 mmHg to 15.9 mmHg, P < 0.05) in rabbits with PHT and blocked the response to ET-1 in the presence of L-NAME. 6. In conclusion, the results demonstrate that basal NO activity masks a pulmonary pressor response to exogenously administered ET-1. An increased responsiveness to ET-1 was shown in the pulmonary arterial bed of rabbits with PHT secondary to LVD, implicating a pathophysiological role for ET-1 in this model.

    Topics: Animals; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Enzyme Inhibitors; Hemodynamics; Hypertension, Pulmonary; Indans; Lung; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Protein Precursors; Pulmonary Artery; Rabbits; Receptor, Endothelin A; Receptor, Endothelin B; Ultrasonography; Ventricular Dysfunction, Left

2002
Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats.
    American journal of physiology. Lung cellular and molecular physiology, 2002, Volume: 282, Issue:4

    Mechanisms by which endothelin (ET)-1 mediates chronic pulmonary hypertension remain incompletely understood. Although activation of the ET type A (ET(A)) receptor causes vasoconstriction, stimulation of ET type B (ET(B)) receptors can elicit vasodilation or vasoconstriction. We hypothesized that the ET(B) receptor attenuates the development of hypoxic pulmonary hypertension and studied a genetic rat model of ET(B) receptor deficiency (transgenic sl/sl). After 3 wk of severe hypoxia, the transgenic sl/sl pulmonary vasculature lacked expression of mRNA for the ET(B) receptor and developed exaggerated pulmonary hypertension that was characterized by elevated pulmonary arterial pressure, diminished cardiac output, and increased total pulmonary resistance. Plasma ET-1 was fivefold higher in transgenic sl/sl rats than in transgenic controls. Although mRNA for prepro-ET-1 was not different, mRNA for ET-converting enzyme-1 was higher in transgenic sl/sl than in transgenic control lungs. Hypertensive lungs of sl/sl rats also produced less nitric oxide metabolites and 6-ketoprostaglandin F(1alpha), a metabolite of prostacyclin, than transgenic controls. These findings suggest that the ET(B) receptor plays a protective role in the pulmonary hypertensive response to chronic hypoxia.

    Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Genetically Modified; Blotting, Northern; Cytochrome P-450 Enzyme System; Endothelin-1; Endothelins; Epoprostenol; Female; Gene Expression; Hypertension, Pulmonary; Hypoxia; In Situ Hybridization; Intramolecular Oxidoreductases; Lung; Male; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Protein Precursors; Pulmonary Circulation; Rats; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger

2002
Inhaled nitric oxide increases endothelin-1 levels: a potential cause of rebound pulmonary hypertension.
    Critical care medicine, 2002, Volume: 30, Issue:1

    Inhaled nitric oxide (iNO) is front-line therapy for pulmonary hypertension after repair of congenital heart disease. However, little clinical data exists regarding the effects of iNO on regulators of pulmonary vascular resistance. An imbalance between primary vasodilators, such as NO, and vasoconstrictors, such as endothelin-1 (ET-1), has been implicated in rebound pulmonary hypertension upon iNO withdrawal. The objective of this study was to determine whether iNO therapy alters plasma ET-1 levels.. This is a prospective study involving pediatric and adult patients at risk for pulmonary hypertension.. Pediatric patients were in the cardiac intensive care unit and adult patients were in a tertiary-care hospital.. Group 1 included children with congenital heart disease requiring iNO for treatment of pulmonary hypertension after cardiopulmonary bypass (n = 15), group 2 was adults receiving iNO (n = 10), and group 3 included children at risk for pulmonary hypertension after bypass that did not require iNO (n = 8).. Dosages of iNO were 2-60 ppm. The duration of therapy ranged from 23 to 188 hrs in group 1 and 29 to 108 hrs in group 2.. Arterial blood was obtained for the measurement of ET-1 levels before and during iNO therapy and 24 hrs after iNO withdrawal. Group 1 mean ET-1 levels increased to 127% of baseline by 12 hrs of iNO, remained elevated at 48 hrs (p < .05), then decreased to 71% of iNO levels 24 hrs after withdrawal (p < .01). Group 2 ET-1 levels increased to 147%, and 137% of baseline at 12 and 24 hrs of iNO therapy, then fell to 68% of baseline within 24 hrs of discontinuing iNO. ET-1 levels in group 3 decreased after surgery (p < .05).. These data suggest that iNO increased plasma ET-1 levels, which subsequently decreased when iNO was discontinued. Increased circulating ET-1 levels might contribute to rebound pulmonary hypertension upon iNO withdrawal.

    Topics: Administration, Inhalation; Adult; Aged; Endothelin-1; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Middle Aged; Nitric Oxide; Substance Withdrawal Syndrome; Vasodilator Agents

2002
ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery.
    American journal of physiology. Lung cellular and molecular physiology, 2002, Volume: 283, Issue:1

    We examined gene and surface expression and activity of the endothelin (ET)-1 receptors (ETA and ETB) in subendothelial (L1) and inner medial (L2) cells from the main pulmonary artery of sheep with continuous air embolization (CAE)-induced chronic pulmonary hypertension (CPH). According to quantitative real-time RT-PCR, basal gene expression of both receptors was significantly higher in L2 than L1 cells, and hypertensive L2 cells showed significantly higher gene expression of ETB than controls. Expression of both genes in hypertensive L1 cells was similar to controls. Fluorescence-activated cell sorter analysis confirmed the increased distribution of ET(B) in hypertensive L2 cells. Although only the ETA receptors in control L2 cells showed significant binding of [125I]-labeled ET-1 at 1 h, both receptors bound ET-1 to hypertensive cells. Exposure to exogenous ET-1 for 18 h revealed that only the L2 cells internalized ET-1, and internalization by hypertensive L2 cells was significantly reduced when compared with controls. Treatment with ETA (BQ-610) and ETB (BQ-788) receptor antagonists demonstrated that both receptors contributed to internalization of ET-1 in control L2 cells, whereas in hypertensive cells only when both receptor antagonists were used in combination was significant suppression of ET-1 internalization found. We conclude that in sheep receiving CAE, alterations in ETB receptors in cells of the L2 layer may contribute to the maintenance of CPH via alterations in their expression, distribution, and activity.

    Topics: Animals; Cells, Cultured; Embolism, Air; Endothelin-1; Flow Cytometry; Gene Expression; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Pulmonary Artery; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sheep

2002
Estradiol attenuates hypoxia-induced pulmonary endothelin-1 gene expression.
    American journal of physiology. Lung cellular and molecular physiology, 2002, Volume: 283, Issue:1

    The ovarian hormone 17beta-estradiol (E2beta) attenuates chronic hypoxia-induced pulmonary hypertension. We hypothesized that E2beta attenuates this response to hypoxia by decreasing pulmonary expression of the vasoactive and mitogenic peptide endothelin-1 (ET-1). To test this hypothesis, we measured preproET-1 mRNA and ET-1 peptide levels in the lungs of adult female normoxic and hypoxic (24 h or 4 wk at barometric pressure = 380 mmHg) rats with intact ovaries and in hypoxic ovariectomized (OVX) rats administered E2beta or vehicle via subcutaneous osmotic pumps. Hypoxic exposure increased lung preproET-1 mRNA levels in OVX vehicle-treated rats, but not in rats with intact ovaries. In addition, E2beta replacement prevented hypoxia-mediated increases in preproET-1 mRNA and ET-1 peptide expression. Considering that hypoxic induction of ET-1 gene expression is mediated by a hypoxia-inducible transcription factor(s) (HIF), we further hypothesized that E2beta-induced attenuation of pulmonary ET-1 expression during hypoxia results from decreased HIF activity. We found that E2beta abolished HIF-dependent increases in reporter gene activity. Further experiments demonstrated that overexpression of the transcriptional coactivator cAMP response element binding protein (CREB) binding protein (CBP)/p300, a factor common to both the estrogen receptor and HIF pathways, eliminated E2beta-mediated attenuation of hypoxia-induced ET-1 promoter activity. We conclude that E2beta inhibits hypoxic induction of ET-1 gene expression by interfering with HIF activity, possibly through competition for limiting quantities of CBP/p300.

    Topics: Animals; Binding, Competitive; CREB-Binding Protein; DNA-Binding Proteins; Endothelin-1; Endothelins; Estradiol; Female; Gene Expression; Genes, Reporter; Hematocrit; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Lung; Nuclear Proteins; Organ Size; Protein Precursors; Rats; Rats, Sprague-Dawley; Response Elements; RNA, Messenger; Trans-Activators; Transcription Factors; Transcription, Genetic; Uterus

2002
Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension.
    Cardiovascular research, 2002, Volume: 55, Issue:1

    The regulation of pulmonary prostacyclin synthesis is not completely understood. We tested the hypothesis that prostacyclin production is predominantly stimulated by hemodynamic factors, such as increased shear-stress, and is thus increased in rats with chronic hypoxic pulmonary hypertension.. To this end, we determined pulmonary prostacyclin synthase (PGIS) gene expression, circulating levels of the stable prostacyclin metabolite 6-keto prostaglandin F(1alpha) (6-keto-PGF(1alpha)), pulmonary endothelin (ET)-1 gene expression, and ET-1 plasma levels in rats exposed to 4 weeks of hypoxia (10% O(2)) in the presence or absence of either the nitric oxide (NO) donor molsidomine (MD, 15 mg/kg/day) or the ET-A receptor antagonist LU135252 (LU, 50 mg/kg/day).. Right ventricular systolic pressure (RVSP), the cross-sectional medial vascular wall area of pulmonary arteries, and ET-1 production increased significantly during hypoxia. PGIS mRNA levels increased 1.7-fold, and 6-keto-PGF(1alpha) plasma levels rose from 8.2+/-0.8 to 12.2+/-2.2 ng/ml during hypoxia (each P<0.05 vs. normoxic controls). MD and LU reduced RVSP and pulmonary vascular remodeling similarly (each P<0.05 vs. hypoxia), but only MD inhibited pulmonary ET-1 formation (P<0.05 vs. hypoxia). Nevertheless, both drugs attenuated the increase in PGIS gene expression and plasma 6-keto-PGF(1alpha) levels (each P<0.05 vs. hypoxia).. Our data suggest that prostacyclin production in hypertensive rat lungs is predominantly increased by hemodynamic factors while hypoxia, NO and ET-1 per are less important stimuli, and that this increase may serve as a compensatory mechanism to partially negate the hypoxia-induced elevation in pulmonary vascular tone.

    Topics: 6-Ketoprostaglandin F1 alpha; Animals; Chronic Disease; Cytochrome P-450 Enzyme System; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Intramolecular Oxidoreductases; Male; Models, Animal; Molsidomine; Nitric Oxide Donors; Phenylpropionates; Pulmonary Artery; Pyrimidines; Random Allocation; Rats; Rats, Wistar; Receptor, Endothelin A; RNA, Messenger; Systole; Ventricular Pressure

2002
[The effect of ETA receptor antagonist WS009A on the pathogenesis of hypoxic pulmonary hypertension in rats].
    Hua xi yi ke da xue xue bao = Journal of West China University of Medical Sciences = Huaxi yike daxue xuebao, 2001, Volume: 32, Issue:3

    To investigate the effect of ETA receptor antagonist, WS009A, on the pathogenesis of hypoxic pulmonary hypertension in rats.. In the course of chronic hypoxia, rats were treated with WS009A (10 mg/kg) by a siliastic catheter inserted in the left external jugular vein.. The measured values of mean pulmonary arterial pressure (mPAP) were 2.7 +/- 0.33, 3.97 +/- 0.47 [symbol: see text] 2.39 +/- 0.27 kPa in the control, the hypoxic and the WS009A treated groups, respectively. The percentages of vascular wall area/total vascular area (MA%) were 0.26 +/- 0.03, 0.52 +/- 0.04, 0.32 +/- 0.07, respectively. The percentages of vascular wall thickness/vascular external diameter(MT%) were 0.14 +/- 0.02, 0.31 +/- 0.03, 0.18 +/- 0.05, respectively. The ratios of right ventricular wall to left ventricle plus septum[RV/(LV + S)] were 0.24 +/- 0.02, 0.35 +/- 0.03, 0.26 +/- 0.03, respectively. The variance analysis revealed there were decreases in mPAP and the ratio of RV/(LV + S) in WS009A group (P < 0.01, compared with those in hypoxic group). There were no haemodynamic and right ventricular hypertrophy differences between WS009A group and control group. The MT% and MA% in WS009A groups were higher than those in controls, but there were significantly decreased MT% and MA% in WS009A group as compared with those in hypoxic group (P < 0.01).. The ETA receptor antagonist, WS009A, attenuates the pulmonary vascular wall remodelling and the pulmonary hypertension induced by chronic hypoxia.

    Topics: Animals; Anthraquinones; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Pulmonary Artery; Random Allocation; Rats; Rats, Wistar

2001
Inhaled nitric oxide-induced rebound pulmonary hypertension: role for endothelin-1.
    American journal of physiology. Heart and circulatory physiology, 2001, Volume: 280, Issue:2

    Clinically significant increases in pulmonary vascular resistance have been noted on acute withdrawal of inhaled nitric oxide (NO). Endothelin (ET)-1 is a vasoactive peptide produced by the vascular endothelium that may participate in the pathophysiology of pulmonary hypertension. The objectives of this study were to determine the effects of inhaled NO on endogenous ET-1 production in vivo in the intact lamb and to determine the potential role of ET-1 in the rebound pulmonary hypertension associated with the withdrawal of inhaled NO. Seven 1-mo-old vehicle-treated control lambs and six PD-156707 (an ET(A) receptor antagonist)-treated lambs were mechanically ventilated. Inhaled NO (40 parts per million) was administered for 24 h and then acutely withdrawn. After 24 h of inhaled NO, plasma ET-1 levels increased by 119.5 +/- 42.2% (P < 0.05). Western blot analysis revealed that protein levels of preproET-1, endothelin-converting enzyme-1alpha, and ET(A) and ET(B) receptors were unchanged. On acute withdrawal of NO, pulmonary vascular resistance (PVR) increased by 77.8% (P < 0.05) in control lambs but was unchanged (-5.5%) in PD-156707-treated lambs. Inhaled NO increased plasma ET-1 concentrations but not gene expression in the intact lamb, and ET(A) receptor blockade prevented the increase in PVR after NO withdrawal. These data suggest a role for ET-1 in the rebound pulmonary hypertension noted on acute withdrawal of inhaled NO.

    Topics: Administration, Inhalation; Animals; Animals, Newborn; Blotting, Western; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Hypertension, Pulmonary; Lung; Metalloendopeptidases; Nitric Oxide; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Respiration, Artificial; Sheep; Substance Withdrawal Syndrome; Vascular Resistance

2001
The NO donor molsidomine reduces endothelin-1 gene expression in chronic hypoxic rat lungs.
    American journal of physiology. Lung cellular and molecular physiology, 2001, Volume: 280, Issue:2

    We investigated the effects of the nitric oxide (NO) donor molsidomine and the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) on pulmonary endothelin (ET)-1 gene expression and ET-1 plasma levels in chronic hypoxic rats. Two and four weeks of hypoxia (10% O2) significantly increased right ventricular systolic pressure, the medial cross-sectional vascular wall area of the pulmonary arteries, and pulmonary ET-1 mRNA expression (2-fold and 3.2-fold, respectively). ET-1 plasma levels were elevated after 4 wk of hypoxia. In rats exposed to 4 wk of hypoxia, molsidomine (15 mg x kg(-1) x day(-1)) given either from the beginning or after 2 wk of hypoxia significantly reduced pulmonary hypertension, pulmonary vascular remodeling, pulmonary ET-1 gene expression, and ET-1 plasma levels. L-NAME administration (45 mg x kg(-1) x day(-1)) in rats subjected to 2 wk of hypoxia did not modify these parameters. Our findings suggest that in chronic hypoxic rats, exogenously administered NO acts in part by suppressing the formation of ET-1. In contrast, inhibition of endogenous NO production exerts only minor effects on the pulmonary circulation and pulmonary ET-1 synthesis in these animals.

    Topics: Animals; Chronic Disease; Disease Models, Animal; Endothelin-1; Enzyme Inhibitors; Gene Expression Regulation; Glyceraldehyde-3-Phosphate Dehydrogenases; Hematocrit; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Molsidomine; NG-Nitroarginine Methyl Ester; Nitric Oxide Donors; Nitric Oxide Synthase; Pulmonary Artery; Rats; Rats, Wistar; RNA, Messenger; Vasodilator Agents

2001
Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium.
    Hypertension (Dallas, Tex. : 1979), 2001, Volume: 37, Issue:2

    We examined whether overproduction of endogenous nitric oxide (NO) can prevent hypoxia-induced pulmonary hypertension and vascular remodeling by using endothelial NO-overexpressing (eNOS-Tg) mice. Male eNOS-Tg mice and their littermates (wild-type, WT) were maintained in normoxic or 10% hypoxic condition for 3 weeks. In normoxia, eNOS protein levels, Ca(2+)-dependent NOS activity, and cGMP levels in the lung of eNOS-Tg mice were higher than those of WT mice. Activity of eNOS and cGMP production in the lung did not change significantly by hypoxic exposure in either genotype. Chronic hypoxia did not induce iNOS expression nor increase its activity in either genotype. Plasma and lung endothelin-1 levels were increased by chronic hypoxia, but these levels were not significantly different between the 2 genotypes. In hemodynamic analysis, right ventricular systolic pressure (RVSP) in eNOS-Tg mice was similar to that in WT mice in normoxia. Chronic hypoxia increased RVSP and induced right ventricular hypertrophy in both genotypes; however, the degrees of these increases were significantly smaller in eNOS-Tg mice. Histological examination revealed that hypoxic mice showed medial wall thickening in pulmonary arteries. However, the increase of the wall thickening in small arteries (diameter <80 microm) by chronic hypoxia was inhibited in eNOS-Tg mice. Furthermore, muscularization of small arterioles was significantly attenuated in eNOS-Tg mice. Thus, we demonstrated directly that overproduction of eNOS-derived NO can inhibit not only the increase in RVSP associated with pulmonary hypertension but also remodeling of the pulmonary vasculature and right ventricular hypertrophy induced by chronic hypoxia.

    Topics: Animals; Blood Pressure; Blood Vessels; Cyclic GMP; Endothelin-1; Female; Genotype; Heart Rate; Hematocrit; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Immunoblotting; Lung; Male; Mice; Mice, Transgenic; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Ventricular Function, Right; Ventricular Pressure

2001
Endothelin B receptor deficiency potentiates ET-1 and hypoxic pulmonary vasoconstriction.
    American journal of physiology. Lung cellular and molecular physiology, 2001, Volume: 280, Issue:5

    Endothelin (ET)-1 contributes to the regulation of pulmonary vascular tone by stimulation of the ET(A) and ET(B) receptors. Although activation of the ET(A) receptor causes vasoconstriction, stimulation of the ET(B) receptors can elicit either vasodilation or vasoconstriction. To examine the physiological role of the ET(B) receptor in the pulmonary circulation, we studied a genetic rat model of ET(B) receptor deficiency [transgenic(sl/sl)]. We hypothesized that deficiency of the ET(B) receptor would predispose the transgenic(sl/sl) rat lung circulation to enhanced pulmonary vasoconstriction. We found that the lungs of transgenic(sl/sl) rats are ET(B) deficient because they lack ET(B) mRNA in the pulmonary vasculature, have minimal ET(B) receptors as determined with an ET-1 radioligand binding assay, and lack ET-1-mediated pulmonary vasodilation. The transgenic(sl/sl) rats have higher basal pulmonary arterial pressure and vasopressor responses to brief hypoxia or ET-1 infusion. Plasma ET-1 levels are elevated and endothelial nitric oxide synthase protein content and nitric oxide production are diminished in the transgenic(sl/sl) rat lung. These findings suggest that the ET(B) receptor plays a major physiological role in modulating resting pulmonary vascular tone and reactivity to acute hypoxia. We speculate that impaired ET(B) receptor activity can contribute to the pathogenesis of pulmonary hypertension.

    Topics: Animals; Animals, Genetically Modified; Blood Pressure; Dopamine beta-Hydroxylase; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Situ Hybridization; In Vitro Techniques; Lung; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Promoter Regions, Genetic; Pulmonary Artery; Pulmonary Circulation; Radioligand Assay; Rats; Rats, Inbred Strains; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Vascular Resistance; Vasoconstriction

2001
Endothelin-1 plasma concentration increases in the early phase of pulmonary hypertension development during respiratory distress syndrome: a study in newborn lambs.
    Early human development, 2001, Volume: 63, Issue:1

    Elevated plasma concentrations of endothelin-1 (ET-1) have been reported with pulmonary hypertension during respiratory distress syndrome (RDS). However, the exact role of ET-1 in the development of pulmonary hypertension during RDS is unclear. The relative time-course of changes in ET-1 concentrations and pulmonary artery pressure (P(ap)) during RDS may give insight in the role of ET-1.. ET-1 and P(ap) changes were studied in an experimental model of RDS, induced by lung lavages in seven newborn lambs. Five other lambs served as controls.. Lung lavages induced a twofold increase of mean P(ap) (from 15 to 34 mm Hg) that remained present throughout the 4-h study period. Along with the increased P(ap), ET-1 plasma concentration showed a significant increase 15 min after induction of RDS at all three sample locations (pulmonary artery 198%, aorta 181% and right atrium 195% compared to baseline). This increased concentration remained high at 1 and 4 h of RDS. In control animals, no significant changes in ET-1 concentrations were observed. Plotting ET-1 concentration values against mean P(ap), in RDS and control animals at all time points, a correlation was found between the severity of the pulmonary hypertension and ET-1 concentration.. This experimental model of RDS shows that ET-1 concentration increases concomitant with the development of pulmonary hypertension, from an early time point onward. More severe pulmonary hypertension is associated with higher ET-1 concentrations, but whether ET-1 is a marker or a mediator of pulmonary hypertension remains as yet unsettled.

    Topics: Animals; Animals, Newborn; Arteries; Blood Pressure; Carbon Dioxide; Disease Models, Animal; Endothelin-1; Hemodynamics; Humans; Hydrogen-Ion Concentration; Hypertension, Pulmonary; Infant, Newborn; Kinetics; Oxygen; Pulmonary Artery; Respiratory Distress Syndrome, Newborn; Sheep; Vascular Resistance

2001
Effect of chronic hypoxia on agonist-induced tone and calcium signaling in rat pulmonary artery.
    American journal of physiology. Lung cellular and molecular physiology, 2001, Volume: 281, Issue:1

    The effect of chronic hypoxia (CH) for 14 days on Ca2+ signaling and contraction induced by agonists in the rat main pulmonary artery (MPA) was investigated. In MPA myocytes obtained from control (normoxic) rats, endothelin (ET)-1, angiotensin II (ANG II), and ATP induced oscillations in intracellular Ca2+ concentration ([Ca2+]i) in 85-90% of cells, whereas they disappeared in myocytes from chronically hypoxic rats together with a decrease in the percentage of responding cells. However, both the amount of mobilized Ca2+ and the sources of Ca2+ implicated in the agonist-induced response were not changed. Analysis of the transient caffeine-induced [Ca2+]i response revealed that recovery of the resting [Ca2+]i value was delayed in myocytes from chronically hypoxic rats. The maximal contraction induced by ET-1 or ANG II in MPA rings from chronically hypoxic rats was decreased by 30% compared with control values. Moreover, the D-600- and thapsigargin-resistant component of contraction was decreased by 40% in chronically hypoxic rats. These data indicate that CH alters pulmonary arterial reactivity as a consequence of an effect on both Ca2+ signaling and Ca2+ sensitivity of the contractile apparatus. A Ca2+ reuptake mechanism appears as a CH-sensitive phenomenon that may account for the main effect of CH on Ca2+ signaling.

    Topics: Adenosine Triphosphate; Angiotensin II; Animals; Caffeine; Calcium; Calcium Signaling; Chronic Disease; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Indoles; Intracellular Membranes; Male; Muscle, Smooth, Vascular; Pulmonary Artery; Rats; Rats, Wistar; Reference Values; Vasoconstriction; Vasodilator Agents; Vasomotor System

2001
Mild hypoxia causes severe pulmonary hypertension in fawn-hooded but not in Tester Moriyama rats.
    Respiration physiology, 2001, Volume: 127, Issue:1

    The purpose of this study was to test whether the Tester Moriyama rat (TMR), a strain that has a serotonin platelet storage-pool deficiency similar to that of the fawn-hooded rat (FHR), develops severe pulmonary hypertension (PH) upon exposure to mild hypoxia. We compared hemodynamic parameters in catheterized 10-week-old FHR, TMR, and control Wistar rats that had been raised from birth to 10 weeks of age under normoxia (PI(O(2)) approximately 150 mmHg) or mild hypobaric hypoxia (PI(O(2)) approximately 120 mmHg). Mean pulmonary artery pressure and right ventricle to left ventricle plus septum weight ratio were much higher in the mildly hypoxic FHR compared with the normoxic FHR. These parameters were only increased slightly by exposure to mild hypoxia in the TMR and Wistar rats. Mild hypoxia did not affect mean systemic artery pressure in any of the rat strains. Exposure of FHR to mild hypoxia from 4 to 10 weeks of age did not lead to development of PH. Endothelin-1 (ET-1) mRNA and peptide levels were increased in the hypertensive lungs of mildly hypoxic FHR compared with the normotensive lungs of normoxic FHR, and of normoxic and mildly hypoxic TMR and Wistar rats. These results suggest that mild hypoxia causes severe PH and upregulation of lung ET-1 expression in neonatal FHR but not in neonatal TMR, and that the period from birth to 4 weeks of age is critical for the development of the severe PH in the FHR. A serotonin PSPD does not predispose rats to hypoxia-induced PH.

    Topics: Animals; Blood Pressure; Blotting, Northern; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Lung; Male; Platelet Storage Pool Deficiency; Radioimmunoassay; Rats; Rats, Mutant Strains; Rats, Wistar; RNA, Messenger; Serotonin; Species Specificity

2001
Endogenously released endothelin-1 from human pulmonary artery smooth muscle promotes cellular proliferation: relevance to pathogenesis of pulmonary hypertension and vascular remodeling.
    American journal of respiratory cell and molecular biology, 2001, Volume: 25, Issue:1

    Endothelin (ET)-1 is a potent vasoconstrictor and comitogen/ proliferation factor for vascular smooth muscle (VSM). As such, it has been implicated in the vascular wall remodeling observed in pulmonary hypertension (PH). Although the endothelium is considered the main source of ET-1, it can be released by other cells including VSM and may mediate proliferation in an autocrine manner. We investigated this possibility using human pulmonary artery smooth-muscle (HPASM) cells. Serum stimulated the release of ET-1 from HPASM cells in a concentration-dependent fashion and caused proliferation as determined by [(3)H]thymidine uptake and increase in cell number. Addition of an ET-A receptor antagonist (BQ123) or an inhibitor of ET-1 synthesis (phosphoramidon) reduced the proliferation induced by serum, confirming an autocrine role for ET-1. In addition, treatment of HPASM cells with two drug types used in the management of PH-cicaprost, a stable prostacyclin-mimetic; or diltiazem, a calcium-channel blocker-reduced ET-1 release from these cells. We conclude that ET-1 released from HPASM cells has an autocrine function in serum-induced proliferation, with important implications for the pathogenesis of human vascular remodeling. Drugs used in the treatment of PH may act, at least in part, by inhibiting this autocrine loop.

    Topics: Base Sequence; Cell Division; DNA Primers; Endothelin-1; Endothelins; Humans; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Protein Precursors; Pulmonary Artery; RNA, Messenger; Transcription, Genetic; Vasodilator Agents

2001
Gadolinium chloride inhibits pulmonary macrophage influx and prevents O(2)-induced pulmonary hypertension in the neonatal rat.
    Pediatric research, 2001, Volume: 50, Issue:2

    Newborn rats exposed to 60% O(2) for 14 d demonstrated a bronchopulmonary dysplasia-like lung morphology and pulmonary hypertension. A 21-aminosteroid antioxidant, U74389G, attenuated both pulmonary hypertension and macrophage accumulation in the O(2)-exposed lungs. To determine whether macrophage accumulation played an essential role in the development of pulmonary hypertension in this model, pups were treated with gadolinium chloride (GdCl(3)) to reduce lung macrophage content. Treatment of 60% O(2)-exposed animals with GdCl(3) prevented right ventricular hypertrophy (p < 0.05) and smooth muscle hyperplasia around pulmonary vessels, but had no effect on morphologic changes in the lung parenchyma. In addition, GdCl(3) inhibited 60% O(2)-mediated increases in endothelin-1, 8-isoprostane, and nitrotyrosine residues. Organotypic cultures of fetal rat distal lung cells were subjected to cyclical mechanical strain to assess the potential role of GdCl(3)-induced blockade of stretch-mediated cation channels in these effects. Mechanical strain caused a moderate increase of endothelin-1 (p < 0.05), which was unaffected by GdCl(3), but had no effect on 8-isoprostane or nitric oxide synthesis. A critical role for endothelin-1 in O(2)-mediated pulmonary hypertension was confirmed using the combined endothelin receptor antagonist SB217242. We concluded that pulmonary macrophage accumulation, in response to 60% O(2), mediated pulmonary hypertension through up-regulation of endothelin-1.

    Topics: Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Cell Movement; Cells, Cultured; Dinoprost; Endothelin-1; F2-Isoprostanes; Gadolinium; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Infant, Newborn; Macrophages, Alveolar; Oxygen; Rats; Rats, Sprague-Dawley; Tyrosine

2001
Endothelin-A receptor antagonist prevents neonatal pulmonary hypertension in meconium aspiration in piglets.
    Journal of the Formosan Medical Association = Taiwan yi zhi, 2001, Volume: 100, Issue:6

    In order to test the hypothesis that endothelin-1 (ET-1) directly contributes to the pathophysiology of pulmonary hypertension induced by meconium aspiration, we randomized 12 anesthetized and paralyzed piglets to receive BQ-123, a selective endothelin-A receptor antagonist (BQ group), or normal saline (NS group) after meconium aspiration. The animals were instilled with meconium mixture (3 mL/kg) via an endotracheal tube, and then given intravenous BQ-123 (2 mg/hr) or normal saline. Plasma ET-1 concentrations, arterial blood gases, and hemodynamics were measured at baseline and at 60, 120, 180, and 240 minutes after instillation. The results showed that plasma ET-1 concentrations were similar in both groups. However, in the BQ group, pulmonary artery pressure was significantly lower after 120 minutes (p < 0.05 at 120 min, p < 0.01 at 180 and 240 min) and pulmonary vascular resistance was significantly lower after 180 minutes (p < 0.01) than in the NS group. No significant difference was found in systemic hemodynamics. These data suggest that ET-1 directly contributes to the pathophysiology of pulmonary hypertension induced by meconium aspiration.

    Topics: Animals; Animals, Newborn; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Humans; Hypertension, Pulmonary; Infant, Newborn; Meconium Aspiration Syndrome; Peptides, Cyclic; Swine

2001
Role for endothelin-1-induced superoxide and peroxynitrite production in rebound pulmonary hypertension associated with inhaled nitric oxide therapy.
    Circulation research, 2001, Aug-17, Volume: 89, Issue:4

    Our previous studies have demonstrated that inhaled nitric oxide (NO) decreases nitric oxide synthase (NOS) activity in vivo and that this inhibition is associated with rebound pulmonary hypertension upon acute withdrawal of inhaled NO. We have also demonstrated that inhaled NO elevates plasma endothelin-1 (ET-1) levels and that pretreatment with PD156707, an ETA receptor antagonist, blocks the rebound hypertension. The objectives of this study were to further elucidate the role of ET-1 in the rebound pulmonary hypertension upon acute withdrawal of inhaled NO. Inhaled NO (40 ppm) delivered to thirteen 4-week-old lambs decreased NOS activity by 36.2% in control lambs (P<0.05), whereas NOS activity was preserved in PD156707-treated lambs. When primary cultures of pulmonary artery smooth muscle cells were exposed to ET-1, superoxide production increased by 33% (P<0.05). This increase was blocked by a preincubation with PD156707. Furthermore, cotreatment of cells with ET-1 and NO increased peroxynitrite levels by 26% (P<0.05), whereas preincubation of purified human endothelial nitric oxide synthase (eNOS) protein with peroxynitrite generated a nitrated enzyme with 50% activity relative to control (P<0.05). Western blot analysis of peripheral lung extracts obtained after 24 hours of inhaled NO revealed a 90% reduction in 3-nitrotyrosine residues (P<0.05) in PD156707-treated lambs. The nitration of eNOS was also reduced by 40% in PD156707-treated lambs (P<0.05). These data suggest that the reduction of NOS activity associated with inhaled NO therapy may involve ETA receptor-mediated superoxide production. ETA receptor antagonists may prevent rebound pulmonary hypertension by protecting endogenous eNOS activity during inhaled NO therapy.

    Topics: Administration, Inhalation; Animals; Blotting, Western; Cells, Cultured; Dioxoles; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Activation; Humans; Hypertension, Pulmonary; Lung; Microscopy, Fluorescence; Muscle, Smooth, Vascular; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Pulmonary Artery; Receptor, Endothelin A; Secondary Prevention; Sheep; Superoxides; Tyrosine

2001
TBC3711, an ET(A) receptor antagonist, reduces neonatal hypoxia-induced pulmonary hypertension in piglets.
    Pediatric research, 2001, Volume: 50, Issue:3

    The pulmonary vasculature of newborns with persistent pulmonary hypertension is characterized by active vasoconstriction and vascular remodeling. It has been suggested that endothelin-1 (ET-1), a potent vasoconstrictor and growth promoter, may be involved in the pathogenesis of persistent pulmonary hypertension of the newborn. To determine whether treatment with an ET(A) receptor antagonist can reverse pulmonary hypertension in the neonate, 1-d-old piglets were exposed to hypoxia for 3 d to induce pulmonary hypertension and then treated for the remainder of the 14 d with an orally active, nonpeptidic ET(A) antagonist (TBC3711, 22 mg x kg(-1) x d(-1)). At the end of the exposure, Hb, pulmonary artery pressure, right ventricle to left ventricle plus septum weight ratio, percentage wall thickness, ET-1 circulating levels, perfusion pressure, and dilator response to the nitric oxide (NO) donor, SIN-1 (3-morpholinosydnonimine-N-ethylcarbamide) in isolated perfused lungs were determined. Exhaled NO and hemodynamic variables were also examined in an intact anesthetized animal preparation that had undergone the same treatment. By 3 d of exposure to hypoxia, piglets had already developed significant pulmonary hypertension as estimated by their pulmonary artery pressure (24.0 +/- 1.3 mm Hg versus 14.2 +/- 3.4 mm Hg) and percentage wall thickness (26.6 +/- 5.9% versus 18.7 +/- 2.4% for vessels 0-30 microm). Whereas further exposure to hypoxia for 14 d did not enhance the increase in pulmonary artery pressure and percentage wall thickness, it did augment the right ventricle to left ventricle plus septum weight ratio (0.71 +/- 0.09 versus 0.35 +/- 0.01). ET-1 circulating levels were increased only when exposure to hypoxia was prolonged to 14 d (5.1 +/- 2.4 pg/mL versus 1.0 +/- 0.4 pg/mL). Treatment with TBC3711 from d 3 to d 14, once pulmonary hypertensive changes were established and while hypoxic exposure persisted, caused significant reduction in the right ventricle to left ventricle plus septum weight ratio (0.60 +/- 0.06), pulmonary artery pressure (20.0 +/- 4.8 mm Hg), and percentage wall thickness (18.5 +/- 3.3%) and restored the dilator response to the NO donor SIN-1. Prolonged hypoxia markedly reduced exhaled NO concentrations (0.3 +/- 0.6 ppb), although treatment of hypoxic animals with TBC3711 restored the concentration of exhaled NO (4.4 +/- 2.8 ppb) to the level of normoxic controls (4.9 +/- 3.0 ppb). Lastly, treatment with TBC3711 increased ET-1 circulat

    Topics: Animals; Animals, Newborn; Cell Line; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Hypoxia; Iodine Radioisotopes; Lung; Molsidomine; Nitric Oxide; Receptor, Endothelin A; Swine; Vasodilator Agents

2001
Intravascular ultrasound assessment of pulmonary vascular disease in patients with pulmonary hypertension.
    Chest, 2001, Volume: 120, Issue:3

    Measurements of pulmonary pressure and resistance are still considered to be the "gold standard" in the evaluation of pulmonary hypertension (PH), despite their limitations in predicting irreversible disease. Hemodynamic assessment also only provides a global evaluation of the pulmonary vascular bed, whereas PH is an inhomogeneous disease of the vessel wall.. We assessed the value of intravascular ultrasound (IVUS) in 30 patients with suspected PH and correlated the structural changes in distal pulmonary arteries found on IVUS with conventional hemodynamic data. Plasma endothelin (ET)-1 levels and pulmonary ET-1 extraction also were measured as markers of the severity of PH. The anatomic abnormalities revealed by IVUS were more severe in the lower lobes than in the upper lobes, as evidenced by the greater percentage of wall thickness (WT), the smaller lumen diameter/WT and lumen area/total vessel area (p < 0.05 for each). IVUS anatomic indexes correlated directly with hemodynamic data (eg, with pulmonary arterial systolic pressure; r = 0.56; p < 0.001) and ET-1 levels but inversely with pulmonary ET-1 extraction.. Patients with PH have greater pulmonary arterial WT that is more severe in the lower lobes than in the upper lobes. The severity of structural abnormalities found on IVUS is directly correlated with hemodynamic findings and ET-1 levels. IVUS may provide useful additional information in the assessment of patients with PH.

    Topics: Adult; Aged; Endothelin-1; Endothelium, Vascular; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Artery; Pulmonary Circulation; Ultrasonography, Interventional

2001
Flow-induced pressure differentially regulates endothelin-1, urotensin II, adrenomedullin, and relaxin in pulmonary vascular endothelium.
    Biochemical and biophysical research communications, 2001, Nov-23, Volume: 289, Issue:1

    We hypothesized that increased pulmonary vascular pressure--one of the characteristics of congestive heart failure--directly regulates pulmonary endothelial vasoconstrictors (endothelin-1, urotensin II) and vasodilators (adrenomedullin, relaxin). To this end, we subjected pulmonary artery endothelial cells in a novel flow-chamber model to different shear stresses (17, 29, and 46 dyn/cm(2)) at low and elevated levels of downstream pressure (10 and 30 mm Hg). Application of elevated pressure over 16 h increased gene expression and peptide secretion of endothelin-1 at all shear levels, whereas secretion of adrenomedullin rose via decreased expression of its clearance receptor. In contrast, preprourotensin II mRNA and urotensin II peptide decreased in response to elevated pressure, and relaxin remained unaffected. This is the first study to identify pressure as key regulator of mediator synthesis by pulmonary vascular endothelium. Pressure-induced mediator regulation may represent an early event in the development of secondary pulmonary hypertension.

    Topics: Adrenomedullin; Animals; Cattle; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Gene Expression; Hemodynamics; Humans; Hypertension, Pulmonary; Models, Cardiovascular; Peptides; Pressure; Pulmonary Artery; Receptors, Adrenomedullin; Receptors, Peptide; Relaxin; RNA, Messenger; Urotensins; Vasoconstriction

2001
Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension.
    Chest, 2001, Volume: 120, Issue:5

    Primary pulmonary hypertension (PPH) is a rare disease of unknown etiology that is characterized by a poor prognosis. This study was undertaken to investigate possible correlations between endothelin (ET)-1 and big ET-1 plasma levels and the severity of PPH.. Sixteen consecutive patients with PPH were included.. Hemodynamics of patients with PPH were measured by right-heart catheterization, and a 6-min walk test was performed.. Plasma levels of the biologically active peptide ET-1 and its precursor big ET-1 were determined in blood samples from the pulmonary artery, peripheral artery, and peripheral vein by radioimmunoassay.. A strong correlation was shown between pulmonary vascular resistance, mean pulmonary artery pressure, cardiac output, cardiac index, 6-min walk data, and elevated plasma levels of big ET-1 as well as mature ET-1 plasma levels at all sites of blood sampling (p < 0.01 and p < 0.05, respectively).. Levels of circulating ET-1 might become a prognostic marker for patients with PPH and serve as a tool for the selection of patients who may benefit from treatment with ET-receptor antagonists.

    Topics: Adult; Aged; Biomarkers; Blood Pressure; Cardiac Output; Endothelin-1; Endothelins; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prognosis; Protein Precursors; Pulmonary Artery; Vascular Resistance

2001
[The roles of vascular endothellial growth factor and endothelin-1 on pulmonary vascular remodelling in rats with hypoxia-induced pulmonary hypertension].
    Zhonghua nei ke za zhi, 2001, Volume: 40, Issue:8

    To investigate the roles of the vascular endothelial growth factor(VEGF) and endothelin-1(ET-1) in pulmonary vascular remodelling in rats with hypoxia-induced pulmonary hypertension(HPH) and the effect of pinacidil on VEGF and ET-1 in rats with HPH.. 46 male Wister rats were divided into three groups i.e. control group, hypoxic group and treated group (hypoxic rats treated with pinacidil for 4 weeks). Rat models with chronic HPH were established by chronic hypobaric hypoxia [(10.0 +/- 0.5)% O2, 4 weeks]. The levels of VEGF and ET-1 in serum and the mean pulmonary arterial pressure (mPAP) and the weight ratio of right ventricle (RV)/left ventricle and septum (LV + S) [RV/(LV + S)] were measured and the small pulmonary arterial morphologic changes were observed with morphometric analysis under microscopes in the three groups.. (1) The levels of VEGF[(118.73 +/- 55.40) ng/L] and ET-1[(221.2 +/- 56.2) ng/L] in serum, mPAP [(28.4 +/- 2.8) mm Hg, 1 mm Hg = 0.133 kPa] and RV/(LV + S) (0.296 +/- 0.033) were significantly higher in the hypoxic group than those in the control group (P < 0.01). Morphometry showed that the external diameter of the small pulmonary arteries became smaller and the ratio of vascular wall thickness to external diameter (MT%) (25.70 +/- 2.58)% and ratio of vascular wall area to total area (MA%) (75.300 +/- 5.600)% significantly increased in the hypoxic group. (2) The levels of VEGF[(78.20 +/- 16.45) ng/L] and ET-1[(181.6 +/- 30.5) ng/L] in serum, mPAP[(23.3 +/- 2.6) mm Hg], RV/(LV + S) (0.266 +/- 0.037), MT%(22.10 +/- 2.51)% and MA% (66.900 +/- 0.061)% significantly decreased in the treated group.. VEGF and ET-1 play important roles in the development of HPH and pulmonary vascular remodelling. Pinacidil may partly inhibit the development of HPH and pulmonary vascular remodelling by decreasing VEGF and ET-1.

    Topics: Animals; Endothelial Growth Factors; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Lymphokines; Male; Pulmonary Veins; Rats; Rats, Wistar; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

2001
[Effects of long-term treatment with prostacyclin on plasma adrenomedullin in patients with primary pulmonary hypertension].
    Journal of cardiology, 2001, Volume: 38, Issue:5

    This study investigated whether plasma levels of adrenomedullin, a potent vasodilating endogenous neurohumoral mediator, are useful for assessing the severity of primary pulmonary hypertension.. Seventeen pediatric patients with primary pulmonary hypertension (eight girls, nine boys, mean age 12 +/- 4 years) were enrolled in this study. Thirteen patients in New York Heart Association (NYHA) classes III and IV had been treated with long-term continuous intravenous prostacyclin (PGI2) infusion therapy, and four patients in classes I and II had received beraprost sodium, an oral PGI2 analogue. Blood samples were taken from all patients at the first visit. Plasma levels of atrial and brain natriuretic peptide (ANP, BNP) and endothelin-1, and mature-type adrenomedullin were measured. The relationships were investigated between neurohumoral mediator levels and NYHA class, pulmonary hemodynamics, and exercise capacity assessed by 6-minute walk test. The changes in neurohumoral mediator levels at 1 month, 3 months, and 6 to 12 months were also evaluated in 11 survivors with long-term PGI2 treatment.. All neurohumoral mediator levels were positively correlated with severity of NYHA class. Patients in class IV demonstrated significantly elevated neurohumoral mediator levels, except endothelin-1, in comparison with patients in classes I-III. Neurohumoral mediator levels had a significant negative correlation with exercise capacity. Stepwise regression analysis revealed that the BNP to ANP ratio (BNP/ANP) was the most powerful independent factor for total pulmonary resistance (r = 0.85, p = 0.0071) and cardiac index (r = 0.84, p = 0.009). Adrenomedullin was significantly correlated with BNP (r = 0.53, p = 0.03), endothelin-1 (r = 0.66, p = 0.006), and BNP/ANP (r = 0.73, p = 0.0009). ANP and BNP decreased from 196 +/- 213 and 494 +/- 361 pg/ml at baseline to 74 +/- 47 and 153 +/- 133 pg/ml at 1 month, respectively. There was an apparent re-increase in both ANP (187 +/- 194 pg/ml) and BNP (466 +/- 621 pg/ml) at 3 months, regardless of improvement in NYHA class and exercise capacity after long-term PGI2 treatment. In contrast, adrenomedullin decreased from 3.0 +/- 2.2 (baseline) to 1.7 +/- 0.7 fmol/ml at 1 month and 1.6 +/- 0.5 fmol/ml at 3 months. Adrenomedullin was slightly increased at 6-12 months (2.1 +/- 0.9 fmol/ml) without statistical significance. There was a significant relationship between the changes in adrenomedullin at 3 months compared to values at initiation of PGI2 therapy and the changes in mean pulmonary arterial pressure (r = 0.97, p = 0.0041).. Plasma levels of neurohumoral mediators are useful for assessing the severity of primary pulmonary hypertension. In particular, adrenomedullin was valuable for evaluating both cardiac performance and pulmonary hemodynamics after long-term treatment with PGI2 in patients with primary pulmonary hypertension.

    Topics: Adolescent; Adrenomedullin; Antihypertensive Agents; Atrial Natriuretic Factor; Child; Child, Preschool; Endothelin-1; Epoprostenol; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Natriuretic Peptide, Brain; Peptides

2001
The role of endothelin-1 in strain-related susceptibility to develop hypoxic pulmonary hypertension in rats.
    Respiration physiology, 2001, Nov-01, Volume: 128, Issue:2

    The Hilltop (H) strain compared to the Madison (M) strain of Sprague-Dawley rats develops severe pulmonary hypertension in response to chronic hypoxia. We tested the hypothesis that endothelin-1 (ET-1) contributes to these strain-related differences. Plasma ET-1 content was not modified by chronic hypoxia in either strain. The lung ET-1 peptide and preproET-1 mRNA content were significantly increased to the same magnitude in both strains at 2 and 3 weeks of hypoxia. The ET(A) receptor mRNA increased more at 3 weeks of hypoxia in the lungs of H rats than in M rats, but not at other time points. The ET(B) receptor mRNA was not modified by hypoxia in either strain. After 3 days of normoxic recovery following 2 weeks of hypoxia, ET-1 protein and mRNA levels decreased to baseline levels in both rat strains. We conclude that ET-1 does not contribute to the development of cardiopulmonary differences between the H and M strains in response to hypoxia.

    Topics: Animals; Chronic Disease; Endothelin-1; Endothelins; Genetic Predisposition to Disease; Hematocrit; Hypertension, Pulmonary; Hypoxia; Immunoblotting; Lung; Male; Organ Size; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reference Standards; Reverse Transcriptase Polymerase Chain Reaction; RNA Probes; RNA, Messenger; Species Specificity; Ventricular Function

2001
[The effect of O2 therapy on mixed venous concentration of endothelin-1 in chronic obstructive pulmonary disease].
    Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society, 2001, Volume: 39, Issue:10

    Pulmonary hypertension (PH) is an important factor in the prognosis of cases of chronic obstructive pulmonary disease (COPD), and endothelin-1 (ET-1) is a major factor in the development of PH in COPD. Oxygen (O2) therapy improves the prognosis of COPD by suppressing the development of PH. We therefore assessed the correlation of PH and ET-1, and the effect of O2 therapy on the plasma ET-1 concentration. In COPD patients, the plasma ET-1 level in mixed venous blood, but not in arterial blood, was negatively correlated with mixed venous O2 tension and positively correlated with pulmonary vascular resistance. No such correlation, however, was observed in the case of plasma HANP or plasma BNP. O2 administration significantly suppressed the plasma ET-1 level. This level in mixed venous blood was thought to serve as a marker of PH in COPD. and O2 administration decreased the plasma ET-1 level in mixed venous blood. It consequently attenuated PH.

    Topics: Aged; Endothelin-1; Humans; Hypertension, Pulmonary; Oxygen; Oxygen Inhalation Therapy; Prognosis; Pulmonary Disease, Chronic Obstructive

2001
Arterial endothelin-1 in interstitial lung disease patients with pulmonary hypertension.
    Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace, 2001, Volume: 56, Issue:5

    The aim of this study was to evaluate the plasma arterial levels of Endothelin-1 (ET-1) and their relationship with hypoxia and pulmonary hypertension (PH) in patients with interstitial lung disease (ILD). Incremental cycle ergometry was performed in all patients up to maximal capacity. ET-1 levels during exercise (2.2 +/- 0.36 pgr/ml) were significantly higher than at rest (1.73 +/- 0.37 pgr/ml) (p < 0.001). ET-1 levels were also significantly correlated with arterial oxygen (PaO2) (r = -0.935, p < 0.001) and mean pulmonary arterial pressure (Ppa) (r = 0.657, p < 0.001). Increased pulmonary and peripheral blood levels of ET-1 have been described in, and postulated to contribute to, the pathophysiology of several lung diseases. In agreement with this, in the current study, the plasma arterial levels of ET-1 were also found to be significantly elevated in patients with various interstitial lung disorders during exercise, especially in those with severe hypoxia and pulmonary hypertension.

    Topics: Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Lung Diseases, Interstitial; Male; Middle Aged

2001
[The change and distribution of endothelin-1 in lung of hypoxic pulmonary hypertension rat].
    Hua xi yi ke da xue xue bao = Journal of West China University of Medical Sciences = Huaxi yike daxue xuebao, 2000, Volume: 31, Issue:1

    This study was aimed to determine the distribution and change of ET-1 in the lung of rat with chronic hypoxic pulmonary hypertension. Immunohistochemical analysis (Avidin-Biotion Complex) was used to localize the ET-1 immunoreactivity in the rat lung. The ET-1 concentration in plasma and in lung homogenate was measured by radioimmunoassay. In normal rats, the mean ET-1 concentration in venous plasma was 2.25 +/- 0.68 ng/L, in arterial plasma 1.52 +/- 0.63 ng/L and in lung 1.75 +/- 0.46 ng/L. There was no significant increase of ET-1 level in rats exposed to hypoxia for 2 hours, but there was significant increase of ET-1 after 24 hours hypoxia, and the high levels of ET-1 were maintained in the sustained hypoxia. There was significant correlation between the ET-1 level in arterial plasma(or in lung homogenate) and the maen pulmonary artery pressure. Similaryly, there was significant negative correlation between ET-1 in arterial plasma(or in lung homogenate) and PaO2. Immunohistochemical analysis revealed that the ET-1 immunoreactivity was seen in the endothelium of pulmonary arteries, particularly more positive staining was seen in the band between the endothelium and the smooth muscle cells. Chronic hypoxia elevated the mean pulmonary arterial pressure, caused vessel remodelling and the right ventricular hypertrophy. These changes were accompained by an increase of ET-1 in plasma and lung homogenate. The expression and production of ET-1 were localized to endothelium and airway epithelium in the lungs.

    Topics: Animals; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Immunohistochemistry; Lung; Male; Random Allocation; Rats; Rats, Wistar

2000
[Effects of endothelin receptor antagonist on the hypoxic pulmonary hypertension].
    Hua xi yi ke da xue xue bao = Journal of West China University of Medical Sciences = Huaxi yike daxue xuebao, 2000, Volume: 31, Issue:3

    This investigation was made to elucidate the role of endothelin (ET) in hypoxic pulmonary hypertension and the preventing effects of BQ-123, an ETA receptor antagonist. Thirty male Wistar rats were divided into three groups and exposed to air, isobaric hypoxia or isobaric hypoxia plus BQ-123 for 3 weeks. The pulmonary artery pressure was measured by right cardiac catheterization. The plasma level of ET-1 was measured by RIA method. Histologic sections of the lungs were examined by a computerized image analyser. In hypoxic rats, the pulmonary artery pressure and the thickness of wall of arteriole were significantly increased, and right ventricular hypertrophy was developed. The plasma level of VEGF in rats treated with hypoxia (192.3 +/- 43.1 pg/ml) was significantly increased as compared with that of normal rats (128.2 +/- 28.1 pg/ml), P < 0.01. Chronic BQ-123 treatment prevented the developments of pulmonary hypertension, thickening of pulmonary arteriole and right ventricular hypertrophy induced by hypoxia. These result indicate that chronic hypoxia can result in hypoxic pulmonary hypertension and increased plasma level of ET-1, and the ETA receptor antagonist can prevent hypoxic pulmonary hypertension.

    Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Peptides, Cyclic; Pulmonary Artery; Rats; Rats, Wistar

2000
Altered regulation of the ET-1 cascade in lambs with increased pulmonary blood flow and pulmonary hypertension.
    Pediatric research, 2000, Volume: 47, Issue:1

    Plasma concentrations of endothelin-1 (ET-1) are increased in children with congenital heart disease associated with increased pulmonary blood flow. However, the role of ET-1 in the pathophysiology of pulmonary hypertension remains unclear. Preproendothelin-1 gene expression is increased in adults with advanced pulmonary hypertension. To characterize potential early molecular alterations in the ET-1 cascade induced by increased pulmonary blood flow and pulmonary hypertension, fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). RNase protection assays and Western blot analysis were performed on lung tissue prepared from 4-wk-old shunt lambs and age-matched controls. Endothelin-converting enzyme-1 [the enzyme responsible for the production of active ET-1 from big ET-1, mRNA (411%, p<0.05)] and protein (170%, p<0.05) were increased in lung tissue prepared from shunt lambs, compared with age-matched controls. Endothelin type A receptor (the receptor that mediates vasoconstriction), mRNA (246%, p<0.05), and protein (176%, p<0.05) also were increased in lung tissue prepared from shunt lambs compared with age-matched controls. Conversely, endothelin type B receptor (the receptor that mediates vasodilation), mRNA (46%, p<0.05), and protein (65%, p<0.05) were decreased in shunt lambs. Both the mRNA and protein levels for preproendothelin-were unchanged. Thus we conclude that increased pulmonary blood flow and pulmonary hypertension induce early alterations in the ET-1 cascade that result in increased ET-1 production, increased ET-1-mediated vasoconstriction, and decreased vasodilation. These early alterations in gene expression may contribute to the development of pulmonary hypertension and its associated enhanced pulmonary vascular reactivity.

    Topics: Animals; Base Sequence; DNA Primers; Endothelin-1; Female; Hypertension, Pulmonary; Lung; Pregnancy; Receptors, Endothelin; Regional Blood Flow; RNA, Messenger; Sheep

2000
Platelet-activating factor and bacteremia-induced pulmonary hypertension.
    The Journal of surgical research, 2000, Volume: 88, Issue:2

    Acute lung injury is a common complication of gram-negative sepsis. Pulmonary hypertension and increased lung vascular permeability are central features of lung injury following experimental bacteremia. Platelet-activating factor is a prominent proinflammatory mediator during bacterial sepsis. Our previous studies have demonstrated that exogenous administration of platelet-activating factor (PAF) induces pulmonary edema without causing pulmonary hypertension. Interestingly, inhibition of PAF activity during Escherichia coli bacteremia prevents the development of both pulmonary hypertension and pulmonary edema. These data suggest that PAF contributes to pulmonary hypertension during sepsis, but that this is unlikely to be a direct vascular effect of PAF. The goal of the present study was to investigate the mechanism by which acute E. coli bacteremia induces pulmonary injury and to define the role that PAF plays in this injury. We hypothesized that the effects of PAF on pulmonary hypertension during bacteremia are due to the effects of PAF on other vascular mediators. Several studies suggest that PAF induces the expression of endothelin-1 (ET), a potent peptide vasoconstrictor. Further, our previous studies have implicated ET as a central mediator of systemic vasoconstriction during bacteremia. We therefore sought to assess whether ET is modulated by PAF. E. coli has also been demonstrated to increase endothelial production of nitric oxide (NO), which contributes to maintenance of basal vascular tone in the pulmonary circulation. We hypothesized that PAF might increase pulmonary vascular resistance during bacteremia by activating neutrophils, increasing expression of ET, and decreasing the tonic release of NO. Furthermore, we hypothesized that hypoxic vasoconstriction did not contribute to pulmonary vasoconstriction during the first 120 min of E. coli bacteremia.. Pulmonary artery pressure (PAP), blood pressure (BP), heart rate (HR), and arterial blood gases (ABG) were measured in anesthetized spontaneously breathing adult male Sprague-Dawley rats. E. coli (10(9) CFU/100 g body wt) was injected at t = 0, and hemodynamic data were obtained at 10-min intervals and ABG data at 30-min intervals for a total of 120 min. Sham animals were treated equally but received normal saline in place of E. coli. In treatment groups, a 2.5 mg/kg dose of WEB 2086, a PAF receptor antagonist, was administered intravenously 15 min prior to the onset of sepsis or sham sepsis. The groups were (1) intravenous E. coli (n = 5); (2) intravenous WEB 2086 pretreatment + intravenous E. coli (n = 5); (3) intravenous WEB 2086 alone (n = 5); and (4) intravenous normal saline (n = 6). Nitric oxide metabolites (NOx) and ET concentrations were assayed from arterial serum samples obtained at the end of the protocol. Lung tissue was harvested for measurement of myeloperoxidase (MPO) activity and pulmonary histology.. E. coli bacteremia increased HR, PAP, and respiratory rate early during sepsis (within 20 min), while hypoxemia, hypotension, and hemoconcentration were not manifest until the second hour. Pretreatment with WEB 2086 completely abrogated all of these changes. E. coli bacteremia increased the activity of serum ET, lung MPO, and neutrophil sequestration in the lung parenchyma via a PAF-dependent mechanism. However, the mechanism of increased production of NO appears to be PAF independent.. These data support the hypothesis that E. coli bacteremia rapidly induces pulmonary hypertension stimulated by PAF and mediated at least in part by endothelin-1 and neutrophil activation and sequestration in the lung. Microvascular injury with leak is also mediated by PAF during E. coli bacteremia, but the time course of resultant hypoxemia and hemoconcentration is slower than that of pulmonary hypertension. The contribution of hypoxic vasoconstriction in exacerbating pulmonary hypertension in gram-negative sepsis is probably a late

    Topics: Animals; Bacteremia; Endothelin-1; Escherichia coli Infections; Hemodynamics; Hemoglobins; Hypertension, Pulmonary; Male; Neutrophils; Nitric Oxide; Oxygen; Peroxidase; Platelet Activating Factor; Rats; Rats, Sprague-Dawley

2000
Influence of valve replacement on plasma endothelin-1 level in mitral stenosis.
    The Journal of heart valve disease, 2000, Volume: 9, Issue:1

    The rise of pressure in the pulmonary circulation during the course of mitral stenosis leads to pathomorphological changes and a reduction in vascular compliance. Endothelial dysfunction is also promoted, with increased expression of endothelin. This aim of this study was to evaluate whether the increase in endothelin-1 levels in pulmonary hypertension due to advanced mitral stenosis is reversible after valve replacement.. Thirty-nine patients with isolated, longlasting post-rheumatic mitral stenosis were enrolled. During preoperative Swan-Ganz catheterization blood samples were withdrawn from the pulmonary artery and capillaries for measurement of endothelin-1 (ET-1). Similar examinations were performed six months after mitral valve replacement. Hemodynamic parameters were measured also during 25-W exercise effort.. The mean preoperative hemodynamic parameters of the pulmonary circulation were moderately increased. Mean plasma levels of ET-1 were about three-fold higher than normal. Capillary levels of ET-1 were significantly higher than those in the pulmonary artery (1.78+/-1.22 versus 1.03+/-1.16 pg/ml, p <0.05). There was no significant correlation between ET-1 level and any hemodynamic or clinical parameters, except NYHA functional class. After surgery, pulmonary capillary levels of ET-1 fell significantly, but were still high (1.78+/-1.22 versus 1.41+/-1.00 pg/ml); ET-1 levels in the pulmonary artery were unchanged. Patients with persistently high ET-1 levels had significantly worse exercise hemodynamic parameters, especially of pulmonary arterial compliance.. In patients with long-lasting, severe mitral stenosis, ET-1 levels remained increased and the ET-1 concentration gradient across the pulmonary circulation persisted for six months after valve replacement. High ET-1 capillary levels are correlated with poor exercise tolerance and poor exercise compliance of the pulmonary vessels.

    Topics: Endothelin-1; Endothelium, Vascular; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Mitral Valve; Mitral Valve Stenosis; Prospective Studies

2000
Antenatal dexamethasone enhances endothelin receptorB expression in hypoplastic lung in nitrofen-induced diaphragmatic hernia in rats.
    Journal of pediatric surgery, 2000, Volume: 35, Issue:2

    The hypoplastic lung and persistent pulmonary hypertension (PPH) are the principle causes of high mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Endothelin-1 (ET-1), which is produced by vascular endothelial cells and some leukocytes, plays a key role in modulating pulmonary vascular tone in PPH. Two different receptors (ET(A) and ET(B)) for ET-1 have been characterized. Binding of ET-1 to ET(A), which is present on smooth muscle cells in fetal lung, results in vasoconstriction. However, binding of ET-1 to ET(B), which is present on endothelial cells results in vasodilation mediated by endogenous nitric oxide. Antenatal glucocorticoid therapy has been shown to prevent abnormal pulmonary arterial structural changes in animal model with CDH. The aim of this study was to investigate the effect of antenatal glucocorticoid administration on ET-1 system in nitrofen-induced CDH hypoplastic lung in rats.. A CDH model was induced in pregnant rats after administration of nitrofen on day 9.5 of gestation. Dexamethasone (Dex) was given intraperitoneally on days 18.5 and 19.5 of gestation. Cesarean section was performed on day 21 of gestation. Rat ET-1 protein expression was measured in solubilized lung tissue extracts, by sandwich type enzyme-linked immunosorbent assay (ELISA) analysis. Reverse transcription polymerase chain reaction was performed to evaluate the relative amount of ET-1, ET(A), and ET(B) mRNA expression.. The ET-1 protein and mRNA expression of ET-1 and both receptors were increased significantly in CDH lung compared with controls. Although there was no significant difference in ET(A) mRNA expression between CDH lung with Dex treatment and without Dex treatment, ET(B) mRNA expression was elevated significantly in CDH lung with Dex treatment compared with CDH lung without Dex treatment.. These findings suggest that antenatal glucocorticoid therapy may modulate pulmonary vascular tone in CDH hypoplastic lung by selectively upregulating local expression of ET(B).

    Topics: Animals; Dexamethasone; Disease Models, Animal; Endothelin-1; Female; Glucocorticoids; Herbicides; Hernia, Diaphragmatic; Hypertension, Pulmonary; Phenyl Ethers; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

2000
In vivo gene transfer of prepro-calcitonin gene-related peptide to the lung attenuates chronic hypoxia-induced pulmonary hypertension in the mouse.
    Circulation, 2000, Feb-29, Volume: 101, Issue:8

    Calcitonin gene-related peptide (CGRP) is believed to play an important role in maintaining low pulmonary vascular resistance (PVR) and in modulating pulmonary vascular responses to chronic hypoxia; however, the effects of adenovirally mediated gene transfer of CGRP on the response to hypoxia are unknown.. In the present study, an adenoviral vector encoding prepro-CGRP (AdRSVCGRP) was used to examine the effects of in vivo gene transfer of CGRP on increases in PVR, right ventricular mass (RVM), and pulmonary vascular remodeling that occur in chronic hypoxia in the mouse. Intratracheal administration of AdRSVCGRP, followed by 16 days of chronic hypoxia (FIO(2) 0.10), increased lung CGRP and cAMP levels. The increase in pulmonary arterial pressure (PAP), PVR, RVM, and pulmonary vascular remodeling in response to chronic hypoxia was attenuated in animals overexpressing prepro-CGRP, whereas systemic pressure was not altered while in chronically hypoxic mice, angiotensin II and endothelin-1-induced increases in PAP were reduced, whereas decreases in PAP in response to CGRP and adrenomedullin were not changed and decreases in PAP in response to a cAMP phosphodiesterase inhibitor were enhanced by AdRSVCGRP.. In vivo CGRP lung gene transfer attenuates the increase in PVR and RVM, pulmonary vascular remodeling, and pressor responses in chronically hypoxic mice, suggesting that CGRP gene transfer alone and with a cAMP phosphodiesterase inhibitor may be useful for the treatment of pulmonary hypertensive disorders.

    Topics: Adenoviridae; Adrenomedullin; Animals; beta-Galactosidase; Calcitonin Gene-Related Peptide; Cyclic AMP; Cyclic GMP; Endothelin-1; Genes, Reporter; Genetic Therapy; Genetic Vectors; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Lung; Mice; NG-Nitroarginine Methyl Ester; Peptides; Phosphodiesterase Inhibitors; Potassium Channels; Protein Precursors; Purinones; Recombinant Fusion Proteins; Rolipram; Second Messenger Systems; Transfection; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

2000
Oxygen-mediated pulmonary vasodilation and plasma levels of endothelin-1, atrial natriuretic peptide and cyclic GMP in patients with left-to-right shunt and pulmonary hypertension.
    Zeitschrift fur Kardiologie, 2000, Volume: 89, Issue:2

    This study was performed to evaluate the role of endogenous endothelin-1 (ET-1), atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) in patients with left-to-right shunt and pulmonary hypertension. Further objectives were to study a possible feedback mechanism between ANP and ET-1 and to examine the influence of ANP on cGMP plasma levels. Finally, the role of these hormones in oxygen-mediated pulmonary vasodilation was examined. Plasma concentrations of ET-1, ANP and cGMP were studied in 39 patients with congenital heart disease and left-to-right shunt. Blood samples were taken from the pulmonary artery and pulmonary vein at cardiac catheterization at baseline and after breathing oxygen for 20 min. Patients were grouped according to the presence or absence of pulmonary hypertension (defined as mean Pp/Ps > or = 0.5). Patients with pulmonary hypertension (n = 18) were found to have significantly higher plasma ANP (665 [59-1358] versus 267 [47-832] pg/ml) and cGMP (21.5 [3.6-82.2] versus 7.8 [0-14.6] nM/L) levels than patients without pulmonary hypertension (n = 21). Pulmonary venous ET-1 plasma concentrations were above normal limits in one patient only. ANP plasma levels were not related to ET-1 and cGMP concentrations. There was no transpulmonary gradient for any of the factors. Pulmonary vasodilation in response to oxygen was found in 7 of 18 patients with PH, but was not associated with significant changes in ET-1, ANP or cGMP plasma concentrations. Patients with congenital heart disease and PH show an increase both in vasoconstrictive and vasodilating factors. The mechanism of oxygen-mediated vasodilation in these patients remains to be elucidated.

    Topics: Adolescent; Atrial Natriuretic Factor; Child; Child, Preschool; Cyclic GMP; Endothelin-1; Feedback; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Lung; Male; Oxygen Inhalation Therapy; Reference Values; Vasodilation

2000
Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension.
    The European respiratory journal, 2000, Volume: 15, Issue:4

    It is well known that endothelin (ET)-1 mediates vascular remodelling in various kinds of clinical and experimental pulmonary hypertension. The aim of this study was to investigate whether ET-1 is associated with the development of pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Pulmonary hypertension was induced in 10 mongrel dogs by repeated embolization with ceramic beads. In five of the dogs, bosentan, a nonselective ET receptor antagonist, was administered throughout the study. Haemodynamic measurements and plasma ET-1 assays were performed every 2 months. Eight months after initial embolization, computer-assisted morphometry and immunohistochemistry were performed on the lung tissue including that from three control dogs. Pulmonary arterial pressure and pulmonary vascular resistance were increased in all embolized dogs, compared to baseline. In nontreated embolized dogs, plasma ET-1 concentration and pulmonary arterial wall thickness were increased compared to control animals, and ET-1 immunoreactivity was detected in thickened pulmonary arteries. In bosentan treated dogs, pulmonary arterial walls were not significantly thickened. Pulmonary vascular remodelling, associated with elevated plasma endothelin-1 levels and positive endothelin-1 immunoreactivity in lung tissue is attenuated by the endothelin receptor antagonist, bosentan. These findings suggest that endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension.

    Topics: Analysis of Variance; Animals; Antihypertensive Agents; Bosentan; Chronic Disease; Culture Techniques; Disease Models, Animal; Dogs; Endothelin-1; Female; Hemodynamics; Hypertension, Pulmonary; Immunohistochemistry; Lung; Male; Probability; Pulmonary Artery; Pulmonary Circulation; Pulmonary Embolism; Reference Values; Sulfonamides; Tomography, Emission-Computed; Vascular Resistance

2000
ET(A)-receptor blockade and ET(B)-receptor stimulation in experimental congenital diaphragmatic hernia.
    American journal of physiology. Lung cellular and molecular physiology, 2000, Volume: 278, Issue:5

    The aim of this study was to assess the role of nitric oxide (NO) and endothelin (ET)-1 in the pathophysiology of persistent pulmonary hypertension of the newborn in fetal lambs with a surgically created congenital diaphragmatic hernia (CDH). The pulmonary vascular response to various agonists and antagonists was assessed in vivo between 128 and 132 days gestation. Age-matched fetal lambs served as control animals. Control and CDH lambs had similar pulmonary vasodilator responses to acetylcholine, sodium nitroprusside, zaprinast, and dipyridamole. The ET(A)-receptor antagonist BQ-123 caused a significantly greater pulmonary vasodilatation in CDH than in control animals. The ET(B)-receptor agonist sarafotoxin 6c induced a biphasic response, with a sustained pulmonary vasoconstriction after a transient pulmonary vasodilatation that was not seen in CDH animals. We conclude that the NO signaling pathway in vivo is intact in experimental CDH. In contrast, ET(A)-receptor blockade and ET(B)-receptor stimulation significantly differed in CDH animals compared with control animals. Imbalance of ET-1-receptor activation favoring pulmonary vasoconstriction rather than altered NO-mediated pulmonary vasodilatation is likely to account for persistent pulmonary hypertension of the newborn in fetal lambs with a surgically created CDH.

    Topics: Acetylcholine; Animals; Antihypertensive Agents; Cyclic GMP; Dipyridamole; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Nitric Oxide; Nitroprusside; Peptides, Cyclic; Phosphodiesterase Inhibitors; Pregnancy; Pulmonary Circulation; Purinones; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sheep; Vasoconstrictor Agents; Vasodilator Agents; Viper Venoms

2000
Attenuation of pulmonary vascular hypertension and cardiac hypertrophy with sitaxsentan sodium, an orally active ET(A) receptor antagonist.
    Pulmonary pharmacology & therapeutics, 2000, Volume: 13, Issue:2

    Effects of sitaxsentan (TBC11251), an orally active, highly selective antagonist of endothelin A receptors, were examined on the development and maintenance of pulmonary hypertension, pulmonary vascular remodeling, and cardiac hypertrophy in the rat. The pulmonary vasoconstrictor response to acute hypoxia (10% O(2)for 90 min) was prevented with sitaxsentan (5 mg/kg infused iv 10 min prior to the onset of hypoxia) while BQ-788 (a specific endothelin B receptor antagonist) was without effect. The same dose of sitaxsentan delivered iv 50 min after the onset of hypoxia reversed the established pulmonary vasoconstriction. In a 2-week model of hypoxia using 10% O(2), treatment with sitaxsentan (15 mg/kg per day in drinking water) attenuated pulmonary hypertension and the associated right ventricular hypertrophy, and prevented the remodeling of small pulmonary arteries (50-100 microM) without affecting systemic arterial blood pressure or heart rate. Institution of sitaxsentan treatment (15 and 30 mg/kg per day in drinking water) for 4 weeks after 2 weeks of untreated hypoxia produced a significant, dose dependent reversal of the established pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling despite continued hypoxic exposure. Sitaxsentan blocked increased plasma endothelin levels in the prevention protocol but did not affect the established elevated levels in the intervention study. Sitaxsentan dose dependently (10 and 50 mg/kg per day in the drinking water) attenuated right ventricular systolic pressure, right heart hypertrophy, and pulmonary vascular remodeling observed 3 weeks after a single subcutaneous injection of monocrotaline. These findings support the hypothesis that endothelin-1 plays a significant role in the development of pulmonary hypertension, pulmonary vascular remodeling, and the associated cardiac hypertrophy, and further suggest that specific endothelin-A receptor blockade may be useful in the treatment of pulmonary hypertension of diverse etiologies.

    Topics: Animals; Cardiomegaly; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypertrophy; Hypoxia; Isoxazoles; Male; Monocrotaline; Oxygen; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Thiophenes; Vasoconstriction; Weight Gain

2000
Contractile responses to human urotensin-II in rat and human pulmonary arteries: effect of endothelial factors and chronic hypoxia in the rat.
    British journal of pharmacology, 2000, Volume: 130, Issue:2

    Responses to human urotensin-II (hU-II) were investigated in human and rat pulmonary arteries. Rat pulmonary arteries: hU-II was a potent vasoconstrictor of main pulmonary arteries (2 - 3 mm i.d.) (pEC(50), 8.55+/-0.08, n=21) and was approximately 4 fold more potent than endothelin-1 [ET-1] (P<0.01), although its E(max) was considerably less (approximately 2.5 fold, P<0.001). The potency of hU-II increased 2.5 fold with endothelium removal (P<0.05) and after raising vascular tone with ET-1 (P<0.01). E(max) was enhanced approximately 1.5 fold in the presence of N(omega)-nitro-L-arginine methylester (L-NAME, 100 microM, P<0.01) and approximately 2 fold in vessels from pulmonary hypertensive rats exposed to 2 weeks chronic hypoxia (P<0.05). hU-II did not constrict smaller pulmonary arteries. Human pulmonary arteries ( approximately 250 microm i.d.): in the presence of L-NAME, 3 out of 10 vessels contracted to hU-II and this contraction was highly variable. hU-II is, therefore, a potent vasoconstrictor of rat main pulmonary arteries and this response is increased by endothelial factors, vascular tone and onset of pulmonary hypertension. Inhibition of nitric oxide synthase uncovers contractile responses to hU-II in human pulmonary arteries.

    Topics: Animals; Dose-Response Relationship, Drug; Drug Interactions; Endothelial Growth Factors; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Humans; Hypertension, Pulmonary; Hypoxia; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxygen; Pulmonary Artery; Rats; Rats, Wistar; Urotensins; Vasoconstriction

2000
[Soluble P-selectin - a marker of platelet activation and vessel wall injury: increase of soluble P-selectin in plasma of patients with myocardial infarction, massive atherosclerosis and primary pulmonary hypertension].
    Terapevticheskii arkhiv, 2000, Volume: 72, Issue:4

    A comparative analysis of the content of the soluble form of cell adhesion protein P-selectin in the blood plasma of patients with acute myocardial infarction (AMI), massive atherosclerosis (MA) and primary pulmonary hypertension (PPH), investigation of the relationship between plasma content of P-selectin and known markers of platelets and endothelial cells activation, preliminary assessment of the prognostic value of P-selectin determination.. This study included 16 patients with AMI, 20 patients with MA, 21 patients with PPH and 18 healthy donors. The follow-up was 1-5 years. End-points in the group of patients with AMI were recurrent acute coronary syndrome and coronary artery by-pass operation, in the group with MA--thrombotic complications (acute coronary syndrome, ischemic stroke) and in the group with PPH--death. P-selectin was measured by ELISA and platelet factor 4 (PF4), thromboxane B2 (TXB2), endothelin-I and stable prostacyclin metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) by means of commercial ELISA kits.. Mean level of P-selectin in blood plasma of patients with AMI (1 day) (361 +/- 18 ng/ml), MA (410 +/- 31 ng/ml) and PPH (627 +/- 83 ng/ml) was increased in comparison with the group of healthy donors (269 +/- 12 ng/ml) (everywhere p < 0.001). In AMI, P-selectin was increased on day 1 only, on days 2, 3 and 10-14 of the disease the level of P-selectin was significantly lower than on day 1 and did not differ from the control level in the group of donors. In patients with MA a significant correlation was detected between plasma content of P-selectin and platelet activation marker PF4 (r = 0.606, P = 0.007) and in patients with PPH between the content of P-selectin and another platelet activation marker TXB2 (r = 0.622, p = 0.013). However, no correlation was found in PPH patients between the content of P-selectin and markers of endothelial activation and/or damage (endothelin-1 and 6-keto-PGF1 alpha). Difference in the concentration of P-selectin in patients with or without end-points during the follow-up period was detected in patients with AMI (353 +/- 14 ng/ml and 451 +/- 24 ng/ml, p = 0.009) and PPH (477 +/- 58 ng/ml and 927 +/- 184 ng/ml, p = 0.017) but not with MA (426 +/- 37 ng/ml and 361 +/- 24 ng/ml, p = 0.295).. The level of P-selectin in plasma was increased in patients with acute thrombosis (AMI, 1 day) as well as in patients without clinical signs of thrombosis but with a massive injury of the vasculature (MA and PPH). The increase of P-selectin was, presumably, caused by its secretion from activated platelets since its concentration in plasma correlated with platelet concentration but not endothelial activation markers. Preliminary data indicate that blood plasma soluble P-selectin may be considered as a potential prognostic marker in AMI and PPH.

    Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Arteriosclerosis; Biomarkers; Blood Coagulation; Blood Vessels; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Myocardial Infarction; P-Selectin; Platelet Activation; Platelet Factor 4; Prognosis; Solubility; Thromboxane B2

2000
Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice.
    American journal of respiratory cell and molecular biology, 2000, Volume: 23, Issue:1

    The pulmonary endothelin (ET) system has been implicated in the pathogenesis of chronic lung diseases such as pulmonary hypertension, asthma, chronic obstructive lung disease, idiopathic pulmonary fibrosis, and bronchiolitis obliterans. However, the etiologic role of ET-1 in these diseases has not yet been established. We recently demonstrated that ET-1 transgenic mice, generated using the human prepro-ET-1 expression cassette including the cis-acting transcriptional regulatory elements, had predominant transgene expression in lung, brain, and kidney. We used these mice in the present study to analyze the pathophysiologic consequences of long-term pulmonary overexpression of ET-1. We found that ET-1 overexpression in the lungs did not result in significant pulmonary hypertension, but did result in development of a progressive pulmonary fibrosis and recruitment of inflammatory cells (predominantly CD4-positive cells). Our study provides evidence that a long-term activated pulmonary ET system, without any other stimuli, produces chronic lymphocytic inflammation and lung fibrosis. This suggests that overexpression of ET-1 may be a central event in the pathogenesis of lung diseases associated with fibrosis and chronic inflammation, such as pulmonary fibrosis and bronchiolitis.

    Topics: Animals; Apoptosis; Blood Gas Analysis; Bronchi; CD4-Positive T-Lymphocytes; Cell Division; Chronic Disease; Endothelin-1; Humans; Hypertension, Pulmonary; Immunohistochemistry; Inflammation; Lung; Male; Mice; Mice, Transgenic; Neovascularization, Physiologic; Organ Size; Organ Specificity; Pulmonary Artery; Pulmonary Fibrosis; Receptors, Endothelin; Transgenes; Ventricular Pressure

2000
Raised plasma adrenomedullin patients with systemic sclerosis complicated by pulmonary hypertension.
    Annals of the rheumatic diseases, 2000, Volume: 59, Issue:6

    Topics: Adrenomedullin; Adult; Aged; Case-Control Studies; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Peptides; Scleroderma, Systemic

2000
Differences in time-related cardiopulmonary responses to hypoxia in three rat strains.
    Clinical and experimental hypertension (New York, N.Y. : 1993), 2000, Volume: 22, Issue:5

    The cardiopulmonary profile of three rat strains (Sprague-Dawley, Wistar and High altitude-sensitive) was compared upon exposure to hypoxia (9% O2) for 0, 7 or 14 days. No differences were observed among the in vitro contractile (ET-1) and relaxant (carbachol) responses of pulmonary artery isolated from the three strains during normoxia. Chronic hypoxia decreased ET-1 contractile responses and diminished relaxant responses to carbachol similarly in all strains. In Sprague-Dawley, Wistar and High altitude-sensitive rats, pulmonary arterial pressure rose time-dependently and was elevated by 108%, 116% and 167%, respectively, after 14 days of hypoxia compared to normoxic controls. Right ventricular hypertrophy was increased by 51%, 93% and 55%, respectively, at 14 days. Hypoxia-induced hypertrophy and medial thickening in the pulmonary vasculature were more pronounced in High altitude-sensitive rats. Sprague-Dawley exhibited hypoxia-induced airway hyperresponsiveness to intravenous methacholine, but there were no hypoxia- or strain-related differences in in vitro tracheal contractility. Although each strain exhibited greater sensitivity for a particular hypoxia-induced parameter, pulmonary vascular functional and structural changes suggest that High altitude-sensitive rats represent a choice model of hypoxia-induced pulmonary hypertension.

    Topics: Altitude; Animals; Carbachol; Disease Models, Animal; Endothelin-1; Endothelins; Hypertension, Pulmonary; Hypertrophy; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Male; Methacholine Chloride; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Rats, Wistar; Species Specificity; Trachea; Vasoconstriction; Vasodilation

2000
Endothelin-1 and O2-mediated pulmonary hypertension in neonatal rats: a role for products of lipid peroxidation.
    Pediatric research, 2000, Volume: 48, Issue:3

    We hypothesized that reactive O2 species, or their intermediary products, generated during exposure to elevated O2 lead to pathologic endothelin-1 expression in the newborn lung. Endothelin-1 expression and 8-isoprostane content (an in vivo marker of lipid peroxidation) were examined and found to be elevated (p < 0.05) in the lungs of newborn rats with abnormal lung morphology and pulmonary hypertension, as assessed by right ventricular hypertrophy, after a 14-d exposure to 60% O2. The antioxidant and lipid hydroperoxide scavenger, U74389G (10 mg/kg), given by daily i.p. injection prevented O2-dependent right ventricular hypertrophy (p < 0.05 compared with vehicle-treated controls), but had no effect on abnormal lung morphology. Additionally, we observed that 8-isoprostane caused marked endothelin-1 mRNA up-regulation in vitro in primary rat fetal lung cell cultures. We conclude that reactive O2 species, or their bioactive intermediaries, are causative in O2-mediated pulmonary hypertension and endothelin-1 up-regulation. It is likely that the bioactive lipid peroxidation product, 8-isoprostane, plays a key role in pathologic endothelin-1 expression and pulmonary hypertension during oxidant stress.

    Topics: Animals; Animals, Newborn; Endothelin-1; Hypertension, Pulmonary; Lipid Peroxidation; Oxygen; Rats; Reactive Oxygen Species

2000
Prolonged endothelin B receptor blockade causes pulmonary hypertension in the ovine fetus.
    American journal of physiology. Lung cellular and molecular physiology, 2000, Volume: 279, Issue:4

    Endothelin (ET)-1 contributes to regulation of pulmonary vascular tone and structure in the normal ovine fetus and in models of perinatal pulmonary hypertension. The hemodynamic effects of ET-1 are due to activation of its receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, whereas the ET(B) receptor mediates vasodilation. In a lamb model of chronic intrauterine pulmonary hypertension, ET(B) receptor activity and gene expression are decreased. To determine whether prolonged ET(B) receptor blockade causes pulmonary hypertension, we studied the hemodynamic effects of selective ET(B) receptor blockade with BQ-788. Animals were treated with an infusion of either BQ-788 or vehicle for 7 days. Prolonged BQ-788 treatment increased pulmonary arterial pressure and pulmonary vascular resistance (P < 0.05). The pulmonary vasodilator response to sarafotoxin 6c, a selective ET(B) receptor agonist, was attenuated after 7 days of BQ-788 treatment, demonstrating pharmacological blockade of the ET(B) receptor. Animals treated with BQ-788 had greater right ventricular hypertrophy and muscularization of small pulmonary arteries (P < 0. 05). Lung ET-1 levels were threefold higher in the animals treated with BQ-788 (P < 0.05). We conclude that prolonged selective ET(B) receptor blockade causes severe pulmonary hypertension and pulmonary vascular remodeling in the late-gestation ovine fetus.

    Topics: Animals; Antihypertensive Agents; Blood Pressure; Carbon Dioxide; Endothelin Receptor Antagonists; Endothelin-1; Female; Gestational Age; Hemodynamics; Hypertension, Pulmonary; Oligopeptides; Oxygen; Piperidines; Pregnancy; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reference Values; Sheep; Vascular Resistance

2000
Garlic elicits a nitric oxide-dependent relaxation and inhibits hypoxic pulmonary vasoconstriction in rats.
    Clinical and experimental pharmacology & physiology, 2000, Volume: 27, Issue:10

    1. The aims of the present study were to determine the characteristics of garlic extract-induced relaxation in rat isolated pulmonary arteries, its susceptibility to changes in oxygen tension and its protective effect against hypoxic pulmonary vasoconstriction. 2. In normoxia, garlic extract (3-500 microg/mL) produced a dose- and nitric oxide (NO)-dependent relaxation. Following 60 min hypoxia, maximum garlic relaxation was reduced compared with control (mean (-SEM) -86 +/- 3 vs-69 +/- 2% of phenylephrine (PE) precontraction, respectively), but recovered after 60 min reoxygenation (-85 +/- 3% PE precontraction). 3. Acetylcholine (0.1 micromol/L)-induced NO-dependent relaxation was reduced from a control value of -76 +/- 1% to -46 +/- 4% during hypoxia and was further reduced to -35 +/- 2 % after reoxygenation. 4. In endothelium-intact arteries, hypoxic exposure resulted in a triphasic response: early transient contraction (+24 +/- 4%), followed by transient relaxation (-37 +/- 7%) and then sustained contraction (+62 +/- 5%). 5. Pretreatment with NG-nitro-L-arginine methyl ester abolished the early transient contraction, moderately attenuated the sustained contraction and had no effect on the transient relaxation. Mechanical endothelial disruption inhibited all hypoxia-induced vascular changes. 6. Garlic pretreatment had no effect on the early transient contraction (+25 +/- 4%), but inhibited the transient relaxation (-5 +/- 3%; P<0.05) and the sustained contraction (+26 +/- 5%; 7. Garlic also significantly inhibited endothelin-l-induced contractions in a dose-dependent manner. 8. These findings show that garlic extract modulates the production and function of both endothelium-derived relaxing and constricting factors and this may contribute to its protective effect against hypoxic pulmonary vasoconstriction.

    Topics: Acetylcholine; Animals; Blood Pressure; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Garlic; Hypertension, Pulmonary; Hypoxia; Male; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Phytotherapy; Plant Extracts; Plants, Medicinal; Pulmonary Artery; Rats; Vasodilation

2000
Hypotensive effect of endothelin-1 via endothelin-B-receptor pathway on pulmonary circulation is enhanced in rats with pulmonary hypertension.
    Journal of cardiovascular pharmacology, 2000, Volume: 36, Issue:5 Suppl 1

    The pharmacological characterization of endothelin-1 (ET-1) in the pulmonary circulation in pulmonary hypertension (PH) is not known precisely. We investigated the effect of intravenous injection of ET-1 (1000 pmol/kg) on right ventricular systolic pressure (RVSP) (which is equal to systolic pulmonary arterial pressure) in rats with monocrotaline-induced PH. ET-1 decreased RVSP in PH rats; however, ET-1 did not alter RVSP in control rats, suggesting that ET-1 causes dilatation of the pulmonary artery in PH rats. Under pretreatment with the endothelin-A- (ET(A)) receptor antagonist BMS 193884, ET-1 decreased RVSP in PH rats more than in control rats, suggesting that pulmonary vasodilator action of ET-I mediated via the ET(B)-receptor pathway is augmented in PH rats. Under pretreatment with the ET(A/B)-receptor antagonist SB 209670, the effect of ET-1 in lowering pulmonary arterial pressure was abolished in both groups of rats. These results suggest that the hypotensive effect of ET-1 on pulmonary circulation mediated via the ET(B)-receptor pathway is enhanced in PH rats compared with control normal rats. It is considered that the blockade of only the ET(A)-receptor pathway is preferable to the blockade of both the ET(A)- and ET(B)-receptor pathways in the treatment of PH.

    Topics: Animals; Antihypertensive Agents; Blood Pressure; Endothelin-1; Hypertension, Pulmonary; Indans; Male; Oxazoles; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sulfonamides

2000
Endothelin-1 and right-sided heart failure in rats: effects of an endothelin receptor antagonist on the failing right ventricle.
    Journal of cardiovascular pharmacology, 2000, Volume: 36, Issue:5 Suppl 1

    The development of pulmonary hypertension (PH) causes right-sided heart failure. We investigated whether chronic treatment with the endothelin-A- (ETA) receptor antagonist BMS-193884 in rats with monocrotaline- (MCT) induced PH improves right-sided heart failure. Administration of BMS-193884 (100mg/kg) was commenced on the day before treatment with MCT. At 19 days, hemodynamics were measured under anesthesia and hearts were removed. The right ventricular systolic pressure (RVSP), an indicator for pulmonary hypertension, was remarkably elevated in the PH group compared with the normal control group. BMS-193884 effectively prevented this elevation. The central venous pressure, an indicator for right-sided heart failure, was markedly increased in the PH group. This increase was reduced to the normal level by BMS-193884. In the failing right ventricle of the PH group, the expression of atrial natriuretic peptide (ANP) mRNA, which is a molecular marker for the failing heart, was markedly increased. BMS-193884 greatly prevented this increase. The present study suggests that ET-1 contributes to the right-sided heart failure caused by PH and that an ETA-receptor antagonist is a beneficial drug which improves both hemodynamics and cardiac gene expression in the failing right ventricle.

    Topics: Animals; Cardiac Output, Low; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Male; Monocrotaline; Oxazoles; Rats; Rats, Wistar; Receptor, Endothelin A; Sulfonamides

2000
Endothelin-A-receptors in human aorta and pulmonary arteries are downregulated in patients with cardiovascular disease: an adaptive response to increased levels of endothelin-1?
    Journal of cardiovascular pharmacology, 2000, Volume: 36, Issue:5 Suppl 1

    Circulating levels of endothelin-1 (ET-1) are elevated in a number of pathophysiological conditions. Our aim was to determine the effect of overexpression of the peptide on ET receptors in human blood vessels. Aorta and pulmonary arteries were removed from patients with dilated cardiomyopathy (CDM), ischaemic heart disease (IHD), and primary pulmonary hypertension (PPH) and compared with controls. Sections of the medial (smooth muscle) layer were incubated with [125I]ET-1 and increasing concentrations of FR139317, an endothelin-A- (ET(A)) selective antagonist. FR139317 competed for the binding of iodinated ET-1 monophasically, indicating that all vessels examined expressed ET(A)-receptors in the media. ET(B)-receptors could not be detected, either in the control vessels or in those from patients with disease. There was no change in affinity (K(D)) but there was a significant (*p < 0.05) reduction in ET(A)-receptor density (Bmax) by 20-50% in diseased tissues, compared with controls. These results suggest that ET(A)-receptors are downregulated as an adaptive response to increased levels of ET-1.

    Topics: Adaptation, Physiological; Adult; Aorta; Cardiomyopathy, Dilated; Down-Regulation; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Myocardial Ischemia; Pulmonary Artery; Receptor, Endothelin A; Receptors, Endothelin

2000
Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats.
    American journal of respiratory cell and molecular biology, 2000, Volume: 23, Issue:6

    Chronic hypoxic pulmonary hypertension (PH) is associated with vasoconstriction and structural remodeling of pulmonary vessels including narrowing of the arterial lumen and loss of distal functional arteries. To test whether lung overexpression of the angiogenic factor vascular endothelial growth factor (VEGF) is beneficial in hypoxic PH, recombinant adenovirus encoding the human VEGF 165 gene under the control of a cytomegalovirus promoter (Ad. VEGF) or control vector containing no gene in the expression cassette (Ad.Null) was administered intratracheally to rats. With Ad. VEGF (10(8) plaque-forming units [pfu]), VEGF protein was present in bronchoalveolar lavage fluid as early as 2 d and until 17 d after gene transfer, but was not detected in serum. Only small patchy areas of mononuclear cells without cell damage, edema, or hemorrhage were observed on lung histology with no significant change in lung permeability. In rats pretreated with Ad.VEGF (10(8) pfu) 2 d before a 2-wk exposure to hypoxia (10% O(2)), lower values versus Ad. Null-pretreated controls were found for pulmonary artery pressure (25 +/- 1 versus 30 +/- 2 mm Hg, P < 0.05), right ventricular over left ventricular-plus-septum weight (0.37 +/- 0.01 versus 0.47 +/- 0. 02, P < 0.001), normalized wall thickness of 50- to 200-microm vessels (P < 0.001), and muscularization of distal vessels (P < 0. 001). Pretreatment with Ad.VEGF (10(8) pfu) increased endothelial nitric oxide synthase activity in lung tissue and partially restored endothelium-dependent vasodilation in isolated lungs from chronically hypoxic rats, as assessed by improvement of ionophore A23187-induced vasodilation and attenuation of endothelin-1 (300 pmol)-induced vasoconstriction, an effect abolished in the presence of nitro-L-arginine methylester. We conclude that adenoviral-mediated VEGF overexpression in the lungs attenuates development of hypoxic PH, in part by protecting endothelium-dependent function.

    Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenoviridae; Animals; Bronchoalveolar Lavage Fluid; Calcimycin; Capillary Permeability; DNA, Recombinant; Dose-Response Relationship, Drug; Endothelial Growth Factors; Endothelin-1; Gene Expression Regulation; Gene Transfer, Horizontal; Humans; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Ionophores; Lung; Lymphokines; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vasodilation

2000
Pulmonary vasoreactivity and vasoactive mediators in children with pulmonary hypertension.
    Zeitschrift fur Kardiologie, 2000, Volume: 89, Issue:11

    We assessed the effect of oxygen, nitric oxide (NO) and prostanoids (prostacyclin and iloprost) on pulmonary hemodynamics and plasma levels of vasoactive mediators in children with pulmonary hypertension (PH). It is not known whether the hemodynamic response during acute vasodilator testing correlates with changes in plasma levels of endothelin-1 (ET-1), cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). In this retrospective analysis 14 children at a median age of 4 years and 3 months [1.8 months-13 years] with a median pulmonary resistance to perfusion of 10.1 [2.1-37.7]. Wood-Units x m2 were studied. Diagnoses included PH due to congenital heart disease (AVSD n = 5; VSD n = 2; PDA n = 1) or unknown causes (n = 6). The ratios of pulmonary/systemic pressure (Pp/Ps) and of pulmonary/systemic resistance (Rp/Rs) were recorded a) at baseline, b) during oxygen (FiO2 = 1.0) and c) while on NO (80 ppm max., at FiO2 = 0.23). In 13 out of 14 children prostanoids were given additionally: 7 received prostacyclin (i.v.) and 6 were given iloprost which was nebulized. ET-1, cGMP and cAMP were measured in blood samples taken from the pulmonary vein or left ventricle at baseline, during increased FiO2, during NO inhalation and while on prostanoids. Pulmonary vasodilation in response to oxygen was found in 2/14 patients. 4/14 patients responded to NO and 2/7 to prostacyclin i.v. Increased FiO2 was not associated with changes in plasma concentrations of ET-1, cGMP or cAMP. NO inhalation was followed by an increase in cGMP levels from 10.9 [5.5-55.4] nM/L to 21.3 [6.4-76.3] nM/L independent from the individual hemodynamic response. Oxygen and NO identify most children with reactive pulmonary vasculature. cGMP plasma levels do not correlate with individual hemodynamic responses to NO.

    Topics: Adolescent; Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Iloprost; Infant; Male; Nitric Oxide; Oxygen Inhalation Therapy; Retrospective Studies; Vasodilation

2000
Interaction of acetylcholine and endothelin-1 in the modulation of pulmonary arterial pressure.
    Critical care medicine, 2000, Volume: 28, Issue:12

    The study was designed to investigate the effects of acetylcholine (ACh) on pulmonary circulation with special regard to mediators that could be involved in the mediation of ACh-induced effects. ACh has been reported to induce either vasodilation or vasoconstriction in the pulmonary circulation of different species.. Prospective experimental study in rabbits.. Experimental laboratory in a university teaching hospital.. Sixty-six adult rabbits of either sex.. The experiments were performed on 66 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. ACh was injected in various concentrations after pulmonary artery preconstriction and in untreated lungs.. Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. Perfusate samples were taken intermittently to determine endothelin-1 (ET-1), thromboxane A2 (TXA2), and prostacyclin (PGI2) concentrations. ACh in final dosages from 10(-5) to 10(-2) M (n = 6 each) was injected into the pulmonary artery of lungs treated with U46619 to induce pulmonary arterial hypertension or was injected into untreated lungs. To analyze the potential mechanisms of action, ACh (10(-5) M) was administered in additional experiments after pretreatment with either ETA receptor antagonist BQ123 (10(-6) M; n = 6) or the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). In preconstricted pulmonary vessels, ACh (10(-3) and 10(-2) M) initially induced a PAP rise for 10 mins followed by a sustained decrease. In untreated lungs, ACh induced an immediate dose-dependent increase in PAP, requiring as long as 30 mins to return to predrug levels. Simultaneously, significantly elevated TXA2 and PGI2 levels were observed. Furthermore, ET-1 was detected in the perfusate, which was free from ET-1 before ACh administration. Pretreatment with BQ123 reduced substantially the ACh (10(-5) M)-induced PAP increase and the release of TXA2 and PGI2. At 5 mins, the PAP maximum was reduced from 18.5 +/- 3.2 mm Hg to 9.9 +/- 0.65 mm Hg by BQ123 pretreatment (p < .01). An inhibition of PAP increase was also observed after diclofenac pretreatment (11.6 +/- 0.4 mm Hg at 5 mins; p < .05). Inhibitory effects at 5 mins were significantly more pronounced in the BQ123 group compared with the diclofenac group.. The effects of ACh on the pulmonary circulation of isolated rabbit lungs depend on ACh concentration and the basal tone of the arterial vasculature. In lungs with a normal pulmonary vascular resistance, ACh administration causes vasoconstriction via the release of ET-1 and TXA2, whereas vasodilation is induced in preconstricted pulmonary vessels.

    Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Cyclooxygenase Inhibitors; Diclofenac; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Interactions; Endothelin Receptor Antagonists; Endothelin-1; Female; Hypertension, Pulmonary; In Vitro Techniques; Male; Peptides, Cyclic; Pulmonary Circulation; Pulmonary Wedge Pressure; Rabbits; Thromboxane A2; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

2000
[A study of the effects of L-arginine in pathogenesis of hypoxic pulmonary hypertension].
    Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 2000, Volume: 16, Issue:4

    To investigate the role of nitric oxide (NO), nitric oxide synthase (NOS) and endothelin-1 (ET-1) in the pathogenesis of hypoxic pulmonary hypertension and inhibiting effects of L-Arginine.. 30 rats were divided into 3 groups, normal control group (group NC); Hypoxic group (group HP): exposed to 10% O2 8 h/day, 3 weeks; Hypoxic + L-arginine (group LT): fed L-arginine 200 mg/kg before hypoxia. After exposed to hypoxia 21 days, hemodynamics were measured. Lung speciments were examined by light and electronic microscopes and morphometric analysis. NO, ET-1 levels in lung tissue were measured, the cNOS quantitative in the pulmonary endothelium were examined.. In HP group, the mean pulmonary arterial pressure (m PAP), pulmonary vascular resistance (PVR) the percentage of completely muscular coattype medial muscle layer of pulmonary artery in intra-acine and ET-1 level of HP group increased (P < 0.01), but NO and cNOS level decreased (P < 0.01). Examined by electron micrograph, endothelium cells appeared swollen, broken and pealed of, basal lamina parted. The changes above in LT group reversed partly. But the changes above were still several than that of group NC (P < 0.05).. The structure remodel of pulmonary arteries and endothelium lesion in hypoxia cause m PAP, PVP arising, that are correlated with the levels of ET-1 increasing and NO, cNOS decreasing. For L-arginine can partly supply NO, it may partly reverse the changes of HPH.

    Topics: Animals; Arginine; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar

2000
Endothelin receptor blockade prevents the rise in pulmonary vascular resistance after cardiopulmonary bypass in lambs with increased pulmonary blood flow.
    The Journal of thoracic and cardiovascular surgery, 1999, Volume: 117, Issue:2

    Children with increased pulmonary blood flow may experience morbidity as the result of increased pulmonary vascular resistance after operations in which cardiopulmonary bypass is used. Plasma levels of endothelin-1, a potent vasoactive substance implicated in pulmonary hypertension, are increased after cardiopulmonary bypass.. In a lamb model of increased pulmonary blood flow after in utero placement of an aortopulmonary shunt, we characterized the changes in pulmonary vascular resistance induced by hypothermic cardiopulmonary bypass and investigated the role of endothelin-1 and endothelin-A receptor activation in postbypass pulmonary hypertension.. In eleven 1-month-old lambs, the shunt was closed, and vascular pressures and blood flows were monitored. An infusion of a selective endothelin-A receptor blocker (PD 156707; 1.0 mg/kg/h) or drug vehicle (saline solution) was then begun 30 minutes before cardiopulmonary bypass and continued for 4 hours after bypass. The hemodynamic variables were monitored, and plasma endothelin-1 concentrations were determined before, during, and for 6 hours after cardiopulmonary bypass.. After 90 minutes of hypothermic cardiopulmonary bypass, both pulmonary arterial pressure and pulmonary vascular resistance increased significantly in saline-treated lambs during the 6-hour study period (P <.05). In lambs pretreated with PD 156707, pulmonary arterial pressure and pulmonary vascular resistance decreased (P <. 05). After bypass, plasma endothelin-1 concentrations increased in all lambs; there was a positive correlation between postbypass pulmonary vascular resistance and plasma endothelin-1 concentrations (P <.05).. This study suggests that endothelin-A receptor-induced pulmonary vasoconstriction mediates, in part, the rise in pulmonary vascular resistance after cardiopulmonary bypass. Endothelin-A receptor antagonists may decrease morbidity in children at risk for postbypass pulmonary hypertension. This potential therapy warrants further investigation.

    Topics: Analysis of Variance; Animals; Cardiopulmonary Bypass; Dioxoles; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Female; Fetus; Hemodynamics; Hypertension, Pulmonary; Linear Models; Pregnancy; Pulmonary Artery; Pulmonary Circulation; Receptors, Endothelin; Sheep; Time Factors; Vascular Resistance

1999
Endothelin-1 is elevated in monocrotaline pulmonary hypertension.
    The American journal of physiology, 1999, Volume: 276, Issue:2

    These studies document striking pulmonary vasoconstrictor response to nitric oxide synthase (NOS) inhibition in monocrotaline (MCT) pulmonary hypertension in rats. This constriction is caused by elevated endothelin (ET)-1 production acting on ETA receptors. Isolated, red blood cell plus buffer-perfused lungs from rats were studied 3 wk after MCT (60 mg/kg) or saline injection. MCT-injected rats developed pulmonary hypertension, right ventricular hypertrophy, and heightened pulmonary vasoconstriction to ANG II and the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA). In MCT-injected lungs, the magnitude of the pulmonary pressor response to NOS inhibition correlated strongly with the extent of pulmonary hypertension. Pretreatment of isolated MCT-injected lungs with combined ETA (BQ-123) plus ETB (BQ-788) antagonists or ETA antagonist alone prevented the L-NMMA-induced constriction. Addition of ETA antagonist reversed established L-NMMA-induced constriction; ETB antagonist did not. ET-1 concentrations were elevated in MCT-injected lung perfusate compared with sham-injected lung perfusate, but ET-1 levels did not differ before and after NOS inhibition. NOS inhibition enhanced hypoxic pulmonary vasoconstriction in both sham- and MCT-injected lungs, but the enhancement was greater in MCT-injected lungs. Results suggest that in MCT pulmonary hypertension, elevated endogenous ET-1 production acting through ETA receptors causes pulmonary vasoconstriction that is normally masked by endogenous NO production.

    Topics: Angiotensin II; Animals; Drug Combinations; Endothelin-1; Endothelins; Enzyme Inhibitors; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Lung; Male; Monocrotaline; Oligopeptides; omega-N-Methylarginine; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Vasoconstriction

1999
Differential roles of endothelin-1 in the development of secondary pulmonary hypertension in patients with left heart failure with or without acute exacerbation.
    Journal of cardiac failure, 1999, Volume: 5, Issue:1

    The aim of this study was to investigate the contribution of endothelin-1 (ET-1) to the development of secondary pulmonary hypertension (PH) in patients with left heart failure (HF).. The subjects were 40 patients with left HF with (group 1; n = 20) and without (group 2; n = 20) acute exacerbation. Before treatment, the ET-1 level in the pulmonary capillary wedge region was three times greater in patients of group 2 than group 1, although there was no significant difference in mean pulmonary artery pressure (mPAP) or pulmonary vascular resistance index (PVRI) between the two groups. Also, the ET-1 level significantly correlated with mPAP and PVRI for both groups, but with different slopes of the regression lines. After treatment of group 1, the extent of reduction in the ET-1 level significantly correlated with that in mPAP and in PVRI, whereas the ET-1 level itself correlated with mPAP, with the regression lines approximating those of group 2.. Our findings suggest that ET-1 may have differential roles in the development of secondary PH in patients with left HF with or without acute exacerbation.

    Topics: Aged; Blood Pressure; Endothelin-1; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Vascular Resistance

1999
Effect of SB 217242 on hypoxia-induced cardiopulmonary changes in the high altitude-sensitive rat.
    Pulmonary pharmacology & therapeutics, 1999, Volume: 12, Issue:1

    The effects of SB 217242, a non-peptide endothelin (ET) receptor antagonist, were investigated against hypoxia-induced cardiopulmonary changes in high altitude-sensitive rats. In isolated pulmonary artery rings, SB 217242 (30 n m) antagonized ET-1-induced contractions with a p KB of 8.0. There was no difference in the sensitivity to ET-1 or the potency of SB 217242 in pulmonary artery from normoxic rats vs. rats exposed to hypoxia (9% O2) for 14 days. However, there was a marked reduction in the maximum response to ET-1, but not to KCl or phenylephrine, in pulmonary artery from hypoxic rats; this phenomenon was inhibited by treatment of animals with SB 217242 (10.8 mg/day, ip by osmotic pump) for the 14-day hypoxic period. Furthermore, there was a significant reduction in carbachol-induced, endothelium-dependent relaxation of precontracted pulmonary artery from hypoxic animals; SB 217242 treatment during the hypoxic period did not influence this difference. Vehicle-treated rats exposed to 14-day hypoxia had 173% higher pulmonary artery pressures and 75% higher right/left+septum ventricular mass ratios compared to normoxic animals. SB 217242 (3.6 or 10.8 mg/day, ip) markedly reduced (80 and 95%, respectively) hypoxia-induced increases in pulmonary artery pressure. Right ventricular hypertrophy was inhibited by 40% at the 10.8 mg/day dose. Marked medial thickening and luminal stenosis of small and medium-sized pulmonary arteries was observed in hypoxic rats. The SB 217242-treated, hypoxia-exposed rats had comparable small and medium-sized arteries to normoxic rats. Rats treated with SB 217242 (10.8 mg/day) for the last 14 days of a 28-day hypoxic exposure had significantly lower pulmonary artery pressures than those of vehicle-treated rats. In addition, the effects of the selective ETA receptor antagonist, SB 247083, and the selective ETB receptor antagonist, A-192621 (3.6 or 10.8 mg/day, ip), were compared against hypoxia-induced increases in pulmonary artery pressure and plasma ET concentrations. SB 247083, but not A-192621, inhibited hypoxia-induced pulmonary hypertension, whereas A-192621, but not SB 247083, significantly exacerbated hypoxia-induced increases in ET concentrations, suggesting that hypoxia-induced pulmonary pressor responses are mediated via ETA receptor activation, while ETB receptor blockade may alter clearance of hypoxia-induced elevated plasma ET. The inhibitory effects of SB 217242 on the functional and remodeling changes induced by

    Topics: Altitude; Animals; Benzofurans; Carboxylic Acids; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Indans; Male; Propionates; Pulmonary Artery; Pyrrolidines; Random Allocation; Rats; Receptors, Endothelin

1999
Altered endothelial function in lambs with pulmonary hypertension and acute lung injury.
    Pediatric pulmonology, 1999, Volume: 27, Issue:3

    Acute lung injury produces pulmonary hypertension, altered vascular reactivity, and endothelial injury. To determine whether acute lung injury impairs the endothelium-dependent regulation of pulmonary vascular tone, 16 lambs were studied during U46619-induced pulmonary hypertension without acute lung injury, or air embolization-induced pulmonary hypertension with acute lung injury. The hemodynamic responses to endothelium-dependent (acetylcholine, ATP, ET-1, and 4 Ala ET-1 [an ETb receptor agonist]) and endothelium-independent (nitroprusside and isoproterenol) vasodilators were compared. During U46619-induced pulmonary hypertension, all vasodilators decreased pulmonary arterial pressure and vascular resistance (P < 0.05). During air embolization-induced pulmonary hypertension, the pulmonary vasodilating effects of acetylcholine, ATP, and 4 Ala ET-1 were attenuated (P < 0.05); the pulmonary vasodilating effects of nitroprusside and isoproterenol were unchanged; and the pulmonary vasodilating effects of ET-1 were reversed, producing pulmonary vasoconstriction (P < 0.05). During air embolization, the pulmonary vasoconstricting effects of ET-1 were blocked by BQ 123, an ETa receptor antagonist. The systemic effects of the vasoactive drugs were similar during both conditions. We conclude that pulmonary hypertension with acute lung injury induced by air embolization results in endothelial dysfunction; there is selective impairment of endothelium-dependent pulmonary vasodilation and an altered response to ET-1 from pulmonary vasodilation to vasoconstriction. This altered response to ET-1 is associated with decreased ETb receptor-mediated vasodilation and increased ETa receptor-mediated vasoconstriction. Endothelial injury and dysfunction account, in part, for the altered regulation of pulmonary vascular tone during pulmonary hypertension with acute lung injury.

    Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Disease; Animals; Disease Models, Animal; Embolism, Air; Endothelin-1; Endothelium, Vascular; Hemodynamics; Hypertension, Pulmonary; Lung; Lung Injury; Nitric Oxide; Pulmonary Circulation; Random Allocation; Reference Values; Respiration, Artificial; Sheep; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

1999
High-dose enoximone to evaluate reversibility of pulmonary hypertension: is there a diagnostic value of neurohormonal measurements?
    American heart journal, 1999, Volume: 137, Issue:5

    Heart transplantation is associated with a reduction of the neurohumoral activation seen in patients with severe congestive heart failure. In this study, we investigated whether pharmacologically induced complex hemodynamic improvement during assessment of reversibility of pulmonary hypertension with a phosphodiesterase inhibitor is able to induce neurohormonal changes of diagnostic importance.. Twenty-one patients with New York Heart Association class III-IV heart failure underwent infusion of 3 mg/kg enoximone over a period of 30 minutes. Before and after drug infusion, we determined the plasma concentrations of atrial natriuretic peptide, endothelin-I, angiotensin-II, aldosterone, norepinephrine, epinephrine, and angiotensin-converting enzyme activity sampled from a peripheral vein and the pulmonary artery. In addition to the expected significant reduction of pulmonary hypertension and enhancement of cardiac output, increased levels of the vasoconstrictors endothelin-I, angiotensin-II, and norepinephrine were observed. Aldosterone fell after enoximone infusion; a higher baseline aldosterone level correlated to the degree of reduction of the pulmonary arteriolar resistance by enoximone. Baseline atrial natriuretic peptide levels correlated with parameters, indicating the severity of heart failure. However, the plasma concentration of this peptide did not change significantly after enoximone infusion.. Acute hemodynamic improvement after enoximone bolus in candidates for heart transplantation is not accompanied by a reduction of the enhanced neurohumoral activity in these patients. The reaction of the investigated hormones cannot predict the individual degree of reversibility of pulmonary hypertension.

    Topics: Angiotensin II; Atrial Natriuretic Factor; Biomarkers; Cardiac Catheterization; Catecholamines; Endothelin-1; Enoximone; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Peptidyl-Dipeptidase A; Phosphodiesterase Inhibitors; Prognosis; Pulmonary Artery; Pulmonary Veins; Severity of Illness Index

1999
Acute pulmonary hypertension after cardiopulmonary bypass in pig: the role of endogenous endothelin.
    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 1999, Volume: 15, Issue:3

    Acute pulmonary hypertension occurring after cardiopulmonary bypass can be a cause of post-operative morbidity and mortality. The purpose of this study was to investigate whether bosentan, a non-peptidic mixed endothelin antagonist affected the pulmonary hypertension induced by experimental cardiopulmonary bypass.. Pigs were anesthetized and instrumented to determine hemodynamic measurements. Pigs were randomized to receive either 3 mg/kg bolus + 7 mg/kg per h bosentan (n = 8) or saline (n = 7). All pigs underwent 90 min of cardiopulmonary bypass and were further observed for a 120-min period.. In the control group, cardiopulmonary bypass induced a dramatic pulmonary hypertension (+78 +/- 13%, P < 0.005) and accompanied an increase of pulmonary vascular resistance (+228 +/- 50%, P < 0.005), whereas, in the treated group, bosentan completely prevented these deleterious effects of cardiopulmonary bypass with only a moderate decrease of systemic vascular resistance (-19 +/- 14.6%, P < 0.05).. The present findings support the hypothesis that endogenous endothelin is a mediator of acute pulmonary hypertension occurring after cardiopulmonary bypass. Bosentan, a mixed endothelin antagonist completely prevented pulmonary hypertension after cardiopulmonary bypass and may, therefore, have therapeutic applications in the management of patients following cardiac surgery.

    Topics: Acute Disease; Animals; Antihypertensive Agents; Bosentan; Cardiopulmonary Bypass; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Sulfonamides; Swine

1999
Endothelin-1- and endothelin-receptors in lung biopsies of patients with pulmonary hypertension due to congenital heart disease.
    Clinical chemistry and laboratory medicine, 1999, Volume: 37, Issue:4

    Endothelin-1 (ET-1), with its vasoconstrictive and proliferation-stimulating effects, could play a role in the pathogenesis of primary pulmonary hypertension. We investigated the relationship between the ET-1 like immunoreactivity and the ET-receptor density, the grade of the pulmonary vasculopathy, and properties of the pulmonary circulation in patients with pulmonary hypertension due to congenital heart disease. Twenty-six patients with a median age of 1 year and 1 month (6 weeks - 17 years - 9 months) were assigned to group I (n = 15) with a pulmonary to systemic flow ratio (Qp/Qs) > or = 1.5 and a pulmonary to systemic resistance ratio (Rp/Rs) < or = 0.3 ("high flow - low resistance group") and to group II (n = 11) with a Qp/Qs < 1.5 and an Rp/Rs > 0.3 ("low flow - high resistance group"). Patients belonging to group II showed a higher ET(A)-receptor density in lung arteries (p < 0.05) and parenchyma (p < 0.01) than patients in group I. Patients with the highest ET-1 like immunoreactivity in lung artery walls also showed a trend towards a higher ET(A)-receptor density. The ET(B)-receptor expression was low and not related to any of the above factors. Our results suggest that the paracrine lung ET-1 system is up-regulated in pediatric patients with secondary pulmonary hypertension associated with congenital heart disease.

    Topics: Adolescent; Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Immunohistochemistry; Infant; Lung; Male; Receptors, Endothelin

1999
Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo. Effect on agonist-induced and flow-mediated vascular responses.
    Circulation research, 1999, Jun-25, Volume: 84, Issue:12

    The effects of transfer of the endothelial nitric oxide synthase (eNOS) gene to the lung were studied in mice. After intratracheal administration of AdCMVbetagal, expression of the beta-galactosidase reporter gene was detected in pulmonary airway cells, in alveolar cells, and in small pulmonary arteries. Gene expression with AdCMVbetagal peaked 1 day after administration and decayed over a 7- to 14-day period, whereas gene expression after AdRSVbetagal transfection peaked on day 5 and was sustained over a 21- to 28-day period. One day after administration of AdCMVeNOS, eNOS protein levels were increased, and there was a small reduction in mean pulmonary arterial pressure and pulmonary vascular resistance. The pressure-flow relationship in the pulmonary vascular bed was shifted to the right in animals transfected with eNOS, and pulmonary vasodepressor responses to bradykinin and the type V cGMP-selective phosphodiesterase inhibitor zaprinast were enhanced, whereas systemic responses were not altered. Pulmonary vasopressor responses to endothelin-1 (ET-1), angiotensin II, and ventilatory hypoxia were reduced significantly in animals transfected with the eNOS gene, whereas pressor responses to norepinephrine and U46619 were not changed. Systemic pressor responses to ET-1 and angiotensin II were similar in eNOS-transfected mice and in control mice. Intratracheal administration of AdRSVeNOS attenuated the increase in pulmonary arterial pressure in mice exposed to the fibrogenic anticancer agent bleomycin. These data suggest that transfer of the eNOS gene in vivo can selectively reduce pulmonary vascular resistance and pulmonary pressor responses to ET-1, angiotensin II, and hypoxia; enhance pulmonary depressor responses; and attenuate pulmonary hypertension induced by bleomycin. Moreover, these data suggest that in vivo gene transfer may be a useful therapeutic intervention for the treatment of pulmonary hypertensive disorders.

    Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenoviridae; Angiotensin II; Animals; Antimetabolites, Antineoplastic; beta-Galactosidase; Bleomycin; Blood Flow Velocity; Blood Pressure; Bradykinin; Cyclic GMP; Endothelin-1; Gene Transfer Techniques; Genes, Reporter; Hypertension, Pulmonary; Hypoxia; Mice; Mice, Inbred Strains; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Norepinephrine; Phosphodiesterase Inhibitors; Pulmonary Alveoli; Pulmonary Artery; Pulmonary Circulation; Pulmonary Wedge Pressure; Purinones; Sympathomimetics; Vasoconstrictor Agents

1999
Continuous infusion of epoprostenol improves the net balance between pulmonary endothelin-1 clearance and release in primary pulmonary hypertension.
    Circulation, 1999, Jun-29, Volume: 99, Issue:25

    Primary pulmonary hypertension results from progressive narrowing of the precapillary pulmonary vasculature. A variety of endothelial abnormalities have been identified, including a net reduction in pulmonary clearance of the vasoconstrictor and smooth muscle mitogen endothelin-1. In many patients, net pulmonary release of endothelin-1 is observed. Chronic infusions of epoprostenol (prostacyclin) improve functional capacity, survival, and hemodynamics in patients with advanced primary pulmonary hypertension. We hypothesized that the epoprostenol infusions, as compared with conventional therapy, might alter the abnormal pulmonary endothelin-1 homeostasis.. Using a subset of patients from a larger randomized study comparing epoprostenol plus conventional therapy (n=11 in the present study) with conventional therapy alone (n=7 in the present study), we determined the ratio of plasma endothelin-1 levels in systemic arterial blood leaving the lung to levels in mixed venous blood entering the lung both before randomization and after 88 days of continuous therapy. There were no differences between the 2 groups before therapy, but by day 88, the epoprostenol-treated group had a greater proportion of patients (82%) with an arterial/venous ratio <1 than did the conventional therapy group, in which only 29% of patients had a ratio <1 (P<0.05).. These results suggest that continuous epoprostenol therapy may have a beneficial effect on the balance between endothelin-1 clearance and release in many patients with primary pulmonary hypertension and may provide one explanation for the salutary effect of epoprostenol in this disease.

    Topics: Antihypertensive Agents; Arteries; Endothelin-1; Epoprostenol; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Randomized Controlled Trials as Topic; Time Factors; Veins

1999
ET-1 infusion increases systemic vascular resistance and depresses cardiac output in patients with chronic hypoxaemia and pulmonary hypertension.
    Scandinavian cardiovascular journal : SCJ, 1999, Volume: 33, Issue:3

    The pulmonary vascular effects of the endothelium-derived peptide endothelin (ET) vary depending on the existing vascular tone, modes of administration and species studied; ET can cause both pulmonary vasodilatation and vasoconstriction. Increased plasma levels of ET have been reported in hypoxic pulmonary hypertension, although it is unclear whether ET is a mediator or a marker of hypoxia-induced increase in pulmonary vascular resistance (PVR). In our study, the plasma levels of ET-1 and the functional effects of ET-1 infusion in patients (n = 4) with chronic hypoxaemia and elevated PVR were evaluated. At rest, the arterial and venous ET-1-levels (13 +/- 2 and 12 +/- 1 fmol/ml, respectively) were significantly higher than those detected in venous plasma of an age-matched healthy control group (7 +/- 1 fmol/ml). Consecutive 10 min infusions of ET-1 at 1, 5, 10 and 15 ng/kg/min into the pulmonary artery decreased cardiac output (by 32%) and stroke volume (by 33%) and increased the systemic vascular resistance (by 62%) and arteriovenous oxygen difference (by 83%) at the highest dose. No deleterious effect was observed in the pulmonary circulation. The present study therefore suggests that intra-pulmonarily administered ET does not attenuate the increased PVR associated with chronic hypoxaemia.

    Topics: Abdominal Pain; Aged; Carbon Dioxide; Cardiac Output; Case-Control Studies; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Oxygen; Partial Pressure; Vascular Resistance; Vasoconstriction

1999
Plasma endothelin-1 levels in patients with left-to-right shunt with or without pulmonary hypertension.
    International journal of cardiology, 1999, Jul-01, Volume: 70, Issue:1

    The aim of this study was to evaluate the role of endothelin-1 (ET-1) in pathophysiology of pulmonary hypertension (PH) secondary to congenital heart disease with left-to-right shunt. Twenty-three children (12 male, 11 female) aged 0.58-13 years were enrolled the study. Blood samples were drawn from superior vena cava, right atrium, right ventricle, pulmonary artery and pulmonary wedge or pulmonary vein during cardiac catheterization. Plasma ET-1 levels were assayed by ELISA. Patients were divided into two groups according to the presence or absence of PH. Plasma ET-1 levels of the study group were compared to the peripheral venous and arterial ET-1 levels of 11 healthy infants and children (aged 0.75-13 years). Plasma ET-1 levels in patients with left-to-right shunt were found significantly higher than those of controls. However, plasma ET-1 levels were similar between the two groups of the patients. Pulmonary venous ET-1 levels were higher than the levels of superior vena cava, this suggested an increased production of ET-1 in pulmonary vascular bed in patients with PH. No correlations were found between plasma ET-1 levels and pulmonary arterial pressure, pulmonary vascular resistance and pulmonary blood flow in the patients. Plasma ET-1 levels of the patients with left-to-right shunt were increased independently from pulmonary arterial pressure and pulmonary vascular resistance. This increase was related to the production of ET-1 in pulmonary vascular bed in patients with PH. ET-1 could not be found to be directly related to the development of PH in the patients with left-to-right shunt.

    Topics: Adolescent; Blood Pressure; Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Pulmonary Artery; Vascular Resistance

1999
Effects of the endothelin ET(A) receptor antagonist, TA-0201, on pulmonary arteries isolated from hypoxic rats.
    European journal of pharmacology, 1999, Jul-09, Volume: 376, Issue:3

    To investigate the roles of endothelin-1 in the pathogenesis of hypoxic pulmonary hypertension, we studied the effects of a selective endothelin ET(A) receptor antagonist, TA-0201 (N-(6-(2-(5-Bromopyrimidin-2-yloxy) ethoxy)-5-(4-methylphenyl) pyrimidin-4-yl)-4-(2-hydroxy-1,1-dimethylethyl) benzensulfonamide sodium salt sesquihydrate), on helical strips of pulmonary arteries isolated from hypoxia-induced pulmonary hypertensive rats as compared with those of normoxic rats. Endothelin-1-induced maximum contractions were significantly inhibited by exposure to hypoxia in the pulmonary arterial strips, but not in the mesenteric arterial strips. The hypoxia also induced right ventricular hypertrophy in rats. Addition of TA-0201 to the bath inhibited the endothelin-1-induced contraction of pulmonary arterial strips isolated from hypoxic rats more effectively than in those of normoxic rats. Oral administration of TA-0201 to hypoxic rats inhibited the hypoxia-induced right ventricular hypertrophy, and decreased the maximum contractile response to endothelin-1 in pulmonary arterial strips isolated from these rats. Those inhibitory effects induced by the oral administration of TA-0201 were not observed in the pulmonary arteries from normoxic rats or in the mesenteric arteries from both hypoxic and normoxic rats. These results suggest that endothelin-1 has important pathophysiological roles in hypoxia-induced pulmonary hypertension, and that TA-0201 may inhibit the endothelin-l-induced contraction through a change in the function of endothelin ET(A) receptor as well as competitive inhibition for endothelin ET(A) receptor.

    Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Pulmonary Artery; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Sulfonamides; Vasoconstriction; Vasoconstrictor Agents

1999
Functional effects of 4-aminopyridine (4-AP) on pulmonary and systemic vessels from normoxic control and hypoxic pulmonary hypertensive rats.
    Naunyn-Schmiedeberg's archives of pharmacology, 1999, Volume: 360, Issue:3

    The effects of the outward rectifying potassium channel blocker, 4-aminopyridine, on contractile tone and on contractile responses to the spasmogens, 5-hydroxytryptamine and endothelin-1, were examined in pulmonary arteries (main and intralobar) and systemic vessels (aorta and mesenteric artery) from rats with and without hypoxic pulmonary hypertension. Hypoxic pulmonary hypertension was induced by exposure of rats to 10% oxygen for 1 week. The development of pulmonary hypertension was associated with (i) depolarization of the cell membrane in intralobar pulmonary artery, but not aorta, and (ii) an increase in sensitivity to 5-hydroxytryptamine in pulmonary, but not systemic, vessels; sensitivity to endothelin-1 was unchanged. 4-Aminopyridine contracted all of the vessels studied. In pulmonary hypertension the sensitivity to 4-aminopyridine was increased ten-fold in pulmonary vessels but was unchanged in systemic vessels. Threshold concentrations of 4-aminopyridine (< or =3x10(-3) M) augmented contractions to 5-hydroxytryptamine in main pulmonary artery and aorta from control rats but failed to augment contractions to 5-hydroxytryptamine in main pulmonary artery from pulmonary hypertensive rats. Responses to endothelin-1 were not augmented by 4-aminopyridine. The membrane depolarization and the increases in sensitivity to 4-aminopyridine and 5-hydroxytryptamine seen in pulmonary hypertension are compatible with the concept that potassium channel function is altered in pulmonary, but not systemic, vessels from pulmonary hypertensive rats. Our data suggest that in main pulmonary artery a common mechanism is responsible for (i) the augmentation of 5-hydroxytryptamine responses by 4-aminopyridine in control rats, and (ii) the sensitization to 5-hydroxytryptamine seen in pulmonary hypertensive, compared with control, rats in the absence of 4-aminopyridine. Hence, we conclude that the sensitization to 5-hydroxytryptamine may be due to downregulation of 4-aminopyridine-sensitive potassium channels.

    Topics: 4-Aminopyridine; Animals; Aorta; Arteries; Endothelin-1; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Male; Membrane Potentials; Mesenteric Arteries; Potassium Channel Blockers; Pulmonary Artery; Rats; Rats, Wistar; Serotonin; Vasoconstriction

1999
Effect of modified ultrafiltration on plasma thromboxane B2, leukotriene B4, and endothelin-1 in infants undergoing cardiopulmonary bypass.
    The Annals of thoracic surgery, 1999, Volume: 68, Issue:4

    Plasma thromboxane B2 (TXB2), leukotriene B4 (LTB4), and endothelin-1 (ET-1) levels increase on cardiopulmonary bypass (CPB). Elevated levels of TXB2 and ET-1 have been correlated with postoperative pulmonary hypertension in infants undergoing repair of congenital heart defects. LTB4 is a potent chemotactic cytokine whose levels correlate with leukocyte-mediated injury. Modified ultrafiltration (MUF) has been associated with improved hemodynamics and pulmonary function, in addition to its beneficial effects on fluid balance and blood conservation. Recent investigations have suggested that removal of cytokines may be the cause of the improved cardiopulmonary function seen with MUF.. Plasma TXB2, ET-1, and LTB4 levels were measured in 34 infants undergoing CPB: 22 underwent MUF (group 1), and 12 did not (group 2). Samples were obtained at various time points. All patients underwent conventional ultrafiltration during the rewarming phase of cardiopulmonary bypass.. In group 1, mean end-CPB TXB2 level was 101.2 pg/mL versus 46.9 pg/mL post-MUF (p < 0.05). The mean TXB2 level 1 hour post-CPB (54.1 pg/mL) was not significantly different from the post-MUF level. In group 2, the mean end-CPB TXB2 level was 123.6 pg/mL versus 53.2 pg/mL 1 hour post-CPB. Hence, TXB2 levels decreased by similar amounts and to similar levels by 1 hour post-CPB in both groups. ET-1 levels increased after CPB and were unaffected by MUF: 1.45, 1.80, 2.55 pg/mL at end-CPB, post-MUF, and 1 hour post-CPB, respectively, in group 1; and 1.51, and 2.73 pg/mL at end-CPB and 1 hour post-CPB in group 2. LTB4 levels post-MUF were 119% of pre-MUF values, and were similar at 1 hour post-CPB in both groups.. Despite reduction in TXB2 by MUF, values were similar and approached baseline 1 hour post-CPB in both groups. LTB4 levels increased slightly with MUF. ET-1 levels increased during and post-CPB and were unaffected by MUF. MUF does not appear to have a significant effect on post-CPB levels of TXB2, ET-1, and LTB4. Therefore, the improved hemodynamics observed with MUF do not appear to be related to removal of these cytokines.

    Topics: Cardiopulmonary Bypass; Endothelin-1; Female; Heart Defects, Congenital; Hemofiltration; Humans; Hypertension, Pulmonary; Infant; Leukotriene B4; Male; Postoperative Complications; Risk Factors; Thromboxane B2; Treatment Outcome

1999
ZD1611, an orally active endothelin-A receptor antagonist, prevents chronic hypoxia-induced pulmonary hypertension in the rat.
    Pulmonary pharmacology & therapeutics, 1999, Volume: 12, Issue:5

    Endothelin-1 (ET-1) is a potent vasoconstrictor and comitogen implicated in the pathogenesis of pulmonary hypertension (PH). We evaluated the effects of an ET(A)receptor-selective antagonist, ZD1611, on hypoxia-induced PH in rats. <> and <> paradigms were established in which rats were administered placebo or ZD1611 (1-3 mg/kg, q.i.dpo) concomitant with hypoxic exposure (10% O(2)1 ATM) for 14 days or beginning after 7-day hypoxic exposure for 21 days. Compared with normoxic controls, hypoxic exposure plus placebo increased (P<0.05) hematocrit, mass ratio of right ventricle over left ventricle plus septum (RV/LV+S), and right intraventricular peak systolic pressure (RVSP). These latter two effects were decreased (P<0.05) by ZD1611 in both experimental paradigms [RV/LV+S(%)::RVSP(%); prophylactic, 14::32; therapeutic, 28::37]. Hypoxic exposure did not change mean systemic arterial pressure (MSAP). ZD1611 did not affect MSAP, plasma ET-1 concentrations, or blood gases measured when rats respired room air. In mechanistic studies, ZD1611 decreased (P<0.01) smooth muscle hypertrophy of small pulmonary arteries and abolished hypoxia-induced decreases in sensitivity and maximum contraction to ET-1 in isolated extralobar branch pulmonary artery. In conclusion, the ET(A)receptor-selective antagonist, ZD1611, attenuates hypoxia-induced PH in the rat.

    Topics: Anesthesia; Animals; Blood Gas Analysis; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Hematocrit; Hypertension, Pulmonary; Hypoxia; Isometric Contraction; Male; Muscle, Smooth, Vascular; Organ Size; Pulmonary Artery; Pulmonary Circulation; Pyrazines; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sulfonamides; Ventricular Function, Right

1999
Effects of physiological or pathological pressure load in vivo on myocardial expression of ET-1 and receptors.
    The American journal of physiology, 1999, Volume: 277, Issue:5

    Endothelin (ET)-1 has potent positive inotropic and chronotropic activity in the heart and induces cardiac hypertrophy. The production of ET-1 in the heart is reported to be increased under some conditions. In normal circulation, the pressure load to the left ventricle (LV) is much greater than that to the right ventricle (RV). In this study, we investigated the gene expression of the myocardial ET-1 system (ET-1, ET(A) receptor, and ET(B) receptor) in the RV and LV of normal rats and also investigated these genes in hypertrophied RV due to pathological pulmonary hypertension (PH). Normal rats showed no differences between the RV and LV in the gene expression of either ET-1, ET(A) receptor, or ET(B) receptor in either the adult stage (11 wk old) or the neonatal stage (1 and 8 days old). On the other hand, the expression of both atrial natriuretic peptide (ANP) mRNA and B-type natriuretic peptide (BNP) mRNA was significantly greater in the LV than in the RV in adult rats. Gene expression of ET-1, ET(A) receptor, and ET(B) receptor in the RV was markedly higher in rats with monocrotaline-induced (pathological) PH than that in control rats. The expression of ANP mRNA and BNP mRNA in the RV was also markedly higher in the rats with PH. In conclusion, the data suggest that gene expression of the ET-1 system in the myocardium is not affected by physiological pressure load in either the adult stage or neonatal stage; however, it is enhanced by pathological pressure overload such as that in PH.

    Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; DNA, Complementary; Endothelin-1; Endothelins; Gene Expression; Hypertension, Pulmonary; Male; Monocrotaline; Myocardium; Natriuretic Peptide, Brain; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Ventricular Function, Left; Ventricular Function, Right

1999
The pathophysiology of pulmonary hypertension in congenital heart disease.
    Artificial organs, 1999, Volume: 23, Issue:11

    Congenital heart disease with increased pulmonary blood flow commonly leads to the development of pulmonary hypertension and increased vascular reactivity. These serious sequelae are associated with the following two major categories of congenital heart defects: those resulting in increased pulmonary blood flow and increased pulmonary arterial pressure and those resulting in increased pulmonary venous pressure. Recent evidence that the pulmonary vascular endothelium is an important determinant of vascular tone has led to the hypothesis that endothelial injury, secondary to congenital heart disease with increased pulmonary blood flow, disrupts these regulatory mechanisms and thereby plays a role in the development of pulmonary hypertension and its associated increased vascular reactivity. In many animal models, endothelial dysfunction is a precursor for smooth muscle dysfunction, and there is an apparent progression from endothelial dysfunction to smooth muscle dysfunction as vascular changes progress. We established a chronic model of pulmonary hypertension with increased pulmonary blood flow in young lambs by placing a systemic-to-pulmonary shunt in utero. In this model, we found significant physiologic and molecular alternations of both the nitric oxide (NO) and endothelin signaling pathways, two important mechanisms by which the endothelium regulates pulmonary vascular tone. These alterations occur extremely early and precede severe anatomic changes. Early endothelial damage may contribute to the development of pulmonary hypertension and its associated enhanced pulmonary vascular reactivity.

    Topics: Animals; Blood Pressure; Cyclic GMP; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Heart Defects, Congenital; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Nitric Oxide; Pulmonary Circulation; Sheep; Signal Transduction; Vasodilator Agents; Vasomotor System; Venous Pressure

1999
Expression of endothelin-1 in rats developing hypobaric hypoxia-induced pulmonary hypertension.
    Laboratory investigation; a journal of technical methods and pathology, 1999, Volume: 79, Issue:11

    Experimental pulmonary hypertension induced in a hypobaric hypoxic environment (HHE) is characterized by structural remodeling of the heart and pulmonary arteries. Endothelin-1 (ET-1), a 21-amino acid peptide, is a novel and long-lasting vasoconstrictor that increases pulmonary arterial pressure in both in vivo and in vitro experiments. To study the effects of HHE on ET-1 activity in the lungs, 59 male rats were subjected to the equivalent of an altitude of 5500 m for 1 to 4 weeks. In rats exposed to HHE, the mean pulmonary arterial pressure increased significantly from 15.2+/-0.3 (ground level) to 30.6+/-1.5 mm Hg (5500-m level) at 4 weeks, whereas their mean systemic arterial pressure remained normal. The levels of ET-1 mRNA and protein, measured respectively by Northern blot analysis and enzyme immunoassay, increased rapidly in the lungs on exposure to HHE. By in situ hybridization and immunohistochemistry, respectively, ET-1 mRNA and protein were detected in control rats in nonciliated bronchiolar epithelial cells and alveolar epithelial cells, as well as in the endothelial cells of pulmonary arteries, but minimally in the smooth muscle cells of pulmonary arteries. ET-1 mRNA- and protein-reactive smooth muscle cells in pulmonary arteries and ET-1 mRNA-reactive airway epithelial cells were significantly more abundant in rats exposed to HHE than in ground level controls. These results suggest the possibility that in smooth muscle cells in pulmonary arteries and airway epithelial cells, ET-1 may play an autocrine or paracrine role in the remodeling of blood vessels during the development of the pulmonary hypertension that is induced by HHE.

    Topics: Altitude; Animals; Blood Pressure; Endothelin-1; Endothelins; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Immunohistochemistry; In Situ Hybridization; Lung; Male; Osmolar Concentration; Protein Precursors; Pulmonary Artery; Rats; Rats, Wistar; Reference Values; RNA, Messenger; Tunica Media

1999
Bosentan prevents hypoxia-reoxygenation-induced pulmonary hypertension and improves pulmonary function.
    The Annals of thoracic surgery, 1999, Volume: 68, Issue:5

    Acute hypoxia results in increased pulmonary vascular resistance. Despite reoxygenation, pulmonary vascular resistance remains elevated and pulmonary function is altered. Endothelin-1 might contribute to hypoxia-reoxygenation-induced pulmonary hypertension and to reoxygenation injury by stimulating leukocytes. This study was carried out using an established model of hypoxia and reoxygenation to determine whether endothelin-1 blockade with Bosentan could prevent hypoxia-reoxygenation-induced pulmonary hypertension and reoxygenation injury.. Twenty neonatal piglets underwent 90 minutes of hypoxia, 60 minutes of reoxygenation on cardiopulmonary bypass, and 2 hours of recovery. Control animals (n = 12) received no drug treatment, whereas the treatment group (n = 8) received the endothelin-1 receptor antagonist, Bosentan, throughout hypoxia.. In controls, pulmonary vascular resistance increased during hypoxia to 491% of baseline and remained elevated after reoxygenation; however in the Bosentan group, it increased to only 160% of baseline by end-hypoxia, then decreased to 76% at end-recovery. Arterial endothelin-1 levels in controls increased to 591% of baseline after reoxygenation. Arterial nitrite levels decreased during hypoxia in controls but were maintained in the Bosentan group. Consequently, animals in the Bosentan group had better postreoxygenation pulmonary vascular resistance, A-a gradient, and airway resistance along with lower myeloperoxidase levels than controls.. Acute hypoxia and postreoxygenation pulmonary hypertension was attenuated by Bosentan, which maintained nitric oxide levels during hypoxia, decreased leukocyte-mediated injury, and improved pulmonary function.

    Topics: Animals; Animals, Newborn; Antihypertensive Agents; Bosentan; Cardiopulmonary Bypass; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Nitric Oxide; Oxygen; Pulmonary Artery; Receptor, Endothelin A; Receptors, Endothelin; Sulfonamides; Swine; Vascular Resistance

1999
[Plasma concentrations of endothelin-1 and endothelin-2 in patients with pulmonary hypertension].
    Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego, 1999, Volume: 7, Issue:39

    Increased pressure in pulmonary artery is connected among other things with increased endothelin plasma concentration. The aim of the study was to assess plasma endothelin concentration in patients with pulmonary hypertension. The analysis comprised 22 patients with increased pressure in pulmonary artery in the course of pulmonary thromboembolism or chronic exacerbated left ventricular failure and 10 patients with chronic exacerbated left ventricular failure without pulmonary hypertension. Plasma endothelin concentration was measured in pulmonary artery and capillary wedge pressure were evaluated with Swan-Ganz catheter and also peripheral and pulmonary vascular resistance were calculated. Endothelin plasma concentration in peripheral vein was compared between patients and healthy volunteers. Plasma endothelin concentration in pulmonary artery, peripheral artery and vein was higher in patients with pulmonary hypertension than in patients with chronic exacerbated left ventricular failure without pulmonary hypertension. Plasma endothelin concentration in patients with chronic exacerbated left ventricular failure without pulmonary hypertension was higher in pulmonary artery than in peripheral artery and vein. At these patients plasma endothelin concentration in the peripheral vein didn't differ significantly from the healthy volunteers.

    Topics: Adult; Aged; Chronic Disease; Endothelin-1; Endothelin-2; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Ventricular Dysfunction, Left

1999
Endothelin receptor blockade attenuates air embolization-induced pulmonary hypertension in sheep.
    European journal of pharmacology, 1999, Dec-03, Volume: 385, Issue:2-3

    We investigated the effects of two types of endothelin receptor antagonists on pulmonary hypertension induced by pulmonary air embolization in awake sheep. We prepared awake sheep with indwelling catheters inserted in blood vessels for continuous monitoring of pulmonary artery pressure, left atrial pressure and systemic arterial pressure. Cardiac output was measured every 30 min. The study consisted of two experiments, one with FR139317 (100 microg/kg/min; (R)2-[(R)-2-[(S)-2-[1-(hexahydro-1H-azepinyl)]-carbonyl]amino-4-++ +methy l-pentanoyl]amino-3-[3-(1-methyl-1H-indolyl)]propionyl)amino-3-(2-pyr idyl)propionic acid), a selective endothelin ET(A) receptor antagonist, and the other with TAK-044 (100 microg/kg/h; cyclo[D-alpha-aspartyl-3-[(4-phenylpiperazin-yl)carbonyl]-L-alanyl -L- alpha- aspartyl-D-2-(2-thienyl) glycyl-L-leucyl-D-tryptophyl] disodium salt), an endothelin ET(A) and ET(B) receptor antagonist. In the paired experiments, air was continuously (4.06 ml/min) infused into the main pulmonary artery for 3 h after the baseline pressures were stabilized. Sheep were treated or not treated with FR139317 or TAK-044. Pulmonary artery pressure was significantly higher than the baseline pressure after the start of air infusion. Both FR139317 and TAK-044 significantly attenuated the increase in pulmonary artery pressure during air embolization. Plasma endothelin -1 levels in both pulmonary and systemic arteries were equally and significantly increased after the start of air infusion. The results indicate that endothelin-1 release is attributable to the development of pulmonary hypertension during the course of air embolization in awake sheep.

    Topics: Animals; Azepines; Blood Gas Analysis; Embolism, Air; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Indoles; Peptides, Cyclic; Pulmonary Artery; Receptor, Endothelin A; Receptor, Endothelin B; Sheep

1999
Cardiac endothelin and big endothelin in right-heart hypertrophy due to monocrotaline-induced pulmonary hypertension in rat.
    Cardiovascular research, 1999, Volume: 44, Issue:1

    Recent observations suggest the existence of a myocardial endothelin (ET) system and its possible involvement in left-ventricular myocardial hypertrophy and failure. However, nothing is known about the role of myocardial ET in right-ventricular hypertrophy.. Rats (80-100 g) were given an intraperitoneal injection of saline (controls) or monocrotaline (50 mg/kg) resulting in pulmonary hypertension-induced myocardial hypertrophy (n = 11 in both groups). After 10 weeks, the animals were sacrificed and hearts perfused in vitro to determine levels of big ET-1 and ET-1 in coronary effluent, interstitial fluid and ventricular tissue homogenates; plasma levels were also determined.. In monocrotaline-treated animals, weights of right ventricles were 1.5 and of right atria 1.8-fold higher than in controls (p < 0.05), indicating substantial right-ventricular hypertrophy as also evident from greatly increased myocardial production of atrial natriuretic peptide. Left-ventricular weights were not different. Release of big ET-1 in coronary effluent, and of ET-1 in coronary effluent and interstitial transudate were similar in control and hypertrophic hearts (p > 0.05). Disruption of endothelium with collagenase reduced release of both peptides close to zero, indicating endothelial (not myocardial) origin of the peptides. Levels of big ET-1 and ET-1 were similar in left ventricles of both experimental groups, but lower in right ventricles of hypertrophic than control hearts (p < 0.05), reflecting increased tissue mass rather than reduced peptide production. On the other hand, plasma levels of both peptides and of ANP were twofold and levels of angiotensin II 1.3-fold higher in rats with right-heart hypertrophy than in controls (p < 0.05 in each case).. These data do not support a role for local cardiac ET-1 and/or big ET-1 in right-ventricular hypertrophy, but point to blood-borne endothelins as possible mediators.

    Topics: Analysis of Variance; Angiotensin II; Animals; Atrial Natriuretic Factor; Endothelin-1; Endothelins; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Monocrotaline; Myocardium; Perfusion; Poisons; Protein Precursors; Rats; Rats, Sprague-Dawley

1999
Interrelation between nitric oxide and endothelin-1 in an experimental acute hypoxia in rats and its intervention.
    Chinese medical journal, 1999, Volume: 112, Issue:4

    To study the interrelation between nitric oxide (NO) and endothelin-1 (ET1) in experimental acute hypoxic rats, and to evaluate the mechanism of acute hypoxic pulmonary hypertension affected by NO and ET1 and its intervention.. Nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemical staining method, Griess biochemical assay and radioimmune assay were applied to investigate the changes of nitric oxide syntheses (NOS), NO and ET1 in normal, hypoxic, and L-Arginine (L-Arg) and dexamethasone treated hypoxic rats.. In normal rats, the NOS stain was localized in pulmonary vascular endothelium, and in the hypoxic rats, the activity of NOS was significantly lower. The level of plasma NO was significantly lower during acute hypoxia, but L-Arg as well as dexamethasone could prevent the drop of plasma NO. The level of plasma ET1 rose up significantly in the acute hypoxic rats, but after L-Arg therapy, it was significantly reduced, however, dexamethasone could not affect plasma ET1. The level of plasma cyclic guanosine monophosphate (cGMP) was significantly lower in the acute hypoxic rats, and L-Arg could prevent the drop of plasma cGMP, but dexamethasone could not prevent the drop of plasma cGMP.. NO and ET1 may modulate hypoxic pulmonary hypertension and acute hypoxia can result in acute hypoxic pulmonary hypertension. L-Arg can reverse the acute hypoxic pulmonary hypertension. Further study is needed if dexamethasone is beneficial in acute hypoxic diseases. NO may play an important role in physiology of the lung and acute hypoxic diseases.

    Topics: Animals; Arginine; Dexamethasone; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats

1999
Extracellular matrix and pulmonary hypertension: control of vascular smooth muscle cell contractility.
    The American journal of physiology, 1998, Volume: 274, Issue:1

    Pulmonary hypertension is characterized by increased vascular resistance due to smooth muscle cell hyper-activity and excess deposition of extracellular matrix (ECM) in the vessel wall. We investigated the possibility that changes in cell-ECM interactions may play an active role in this process by modifying the contractile response of pulmonary vascular smooth muscle (PVSM) cells. Contractility was measured within individual cultured PVSM cells, when resting or stimulated with vasoactive agents, by quantitating changes in stiffness of the cytoskeleton (CSK) using magnetic twisting cytometry (N. Wang, J. P. Butler, and D. E. Ingber. Science 260: 1124-1127, 1993). Control studies confirmed that changes in CSK stiffness closely paralleled alterations in cell contraction and relaxation as measured in response to endothelin-1 (ET-1) and dibutyryl guanosine 3',5'-cyclic monophosphate (cGMP), respectively, in a collagen gel contraction assay. CSK stiffness and contractile tone in cultured PVSM cells increased in direct proportion as the density of fibronectin (FN) coating was raised from 10 to 500 ng/well in 96-well plates. Dibutyryl cGMP had no effect in cells on low FN, although it completely inhibited the FN-dependent increase in CSK stiffness on higher ECM densities. In contrast, ET-1 induced the greatest increase in CSK stiffness on the intermediate FN density (100 ng/well). The reduced sensitivity to ET-1 on high FN was not due to dysfunction of the contractile apparatus nor to changes in protein tyrosine phosphorylation. Taken together, these results show that ECM can modulate PVSM cell contractility and suggest that the changes in ECM observed in hypertensive vessels could play an important role in the etiology of this disease.

    Topics: Animals; Animals, Newborn; Cattle; Cells, Cultured; Collagen; Cytoskeleton; Dibutyryl Cyclic GMP; Endothelin-1; Extracellular Matrix; Fibronectins; Hypertension, Pulmonary; Ionomycin; Isometric Contraction; Kinetics; Muscle, Smooth, Vascular; Phosphoproteins; Phosphorylation; Phosphotyrosine; Pulmonary Artery; Stress, Mechanical

1998
Regional variability in preproEndothelin-1 gene expression in sheep pulmonary artery and lung during the onset of air-induced chronic pulmonary hypertension. Participation Of arterial smooth muscle cells.
    The Journal of clinical investigation, 1998, Mar-15, Volume: 101, Issue:6

    We investigated preproendothelin-1 (ppET-1) gene expression in the main and midregion pulmonary artery, and peripheral lung from control sheep and from animals during the development of the structural and functional changes of air-induced chronic pulmonary hypertension (CPH). Measurement of ET-1 in lung lymph (n = 7) at 1, 4, 8, and 12 d of continuous air embolization (CAE) showed a significant increase from day 4 compared with controls (n = 4). A semiquantitative reverse transcription PCR for ppET-1 gene expression was developed using ovine-specific primers. Control sheep showed strikingly fewer ppET-1 transcripts in the midregion (22.9+/-2.3 ng cDNA equivalents) than in the main pulmonary artery and lung (736.0+/-263.7 and 705.5+/-125.7, respectively). Smooth muscle cells (SMC) isolated from the main and midregion artery of control sheep confirmed these findings and showed higher levels of intracellular ET-1 synthesis in the main versus the midregion artery. Differences in gene expression persisted during CAE. In main pulmonary artery and lung, ppET-1 transcripts fell to < 1% of controls. However, transcripts in the midregion artery showed a gradual increase. Coincubation of SMC from the midregion with ET-1 plus TGF-beta resulted in an increase in intracellular big ET-1 and a decrease in SMC from the main artery. We conclude that SMC from the main and midregion pulmonary artery are phenotypically different and suggest that local synthesis of ET-1 and TGF-beta, and increased levels of ET-1 in lung lymph, regulate ppET-1 gene expression and synthesis in arterial SMC during the development of air-induced CPH.

    Topics: Animals; Cells, Cultured; DNA, Complementary; Endothelin-1; Endothelins; Gene Expression; Hemodynamics; Hypertension, Pulmonary; In Situ Hybridization; Lung; Lymph; Muscle, Smooth; Polymerase Chain Reaction; Protein Precursors; Pulmonary Artery; RNA, Messenger; Sheep; Transcription, Genetic; Transforming Growth Factor beta

1998
Influence of applied tension and nitric oxide on responses to endothelins in rat pulmonary resistance arteries: effect of chronic hypoxia.
    British journal of pharmacology, 1998, Volume: 123, Issue:5

    1. The effect of basal tension (transmural tensions 235 +/- 29 mg wt (low tension: equivalent to approximately 16 mmHg) and 305 +/- 34 mg wt (high tension: equivalent to 35 mmHg)) on rat pulmonary resistance artery responses to endothelin-1 (ET-1) and the selective ET(B)-receptor agonist sarafotoxin S6c (S6c) were studied. The effects of nitric oxide synthase inhibition with N(omega)-nitro-L-arginine methylester (L-NAME, 100 microM) on ET receptor-induced responses, as well as vasodilator responses to acetylcholine (ACh) and S6c, were also investigated. Changes with development of pulmonary hypertension, induced by two weeks of chronic hypoxia, were determined. 2. Control rat preparations showed greatest sensitivity for ET-1 when put under low tension (pEC50: 8.1 +/- 0.1) compared with at the higher tension (pEC50: 7.7 +/- 0.1) and there were significant increases in maximum contractile responses to S6c (approximately 80%) and noradrenaline (approximately 60%) when put under high tension. 3. In control pulmonary resistance arteries, both ET-1 and S6c produced potent vasoconstrictor responses. S6c was 12 fold more potent than ET-1 in vessels set at low tension (S6c pEC50: 9.2 +/- 0.1) and 200 fold more potent than ET-1 when the vessels were set at high tension (S6c pEC50: 9.0 +/- 0.1). Chronic hypoxia did not change the potencies of ET-1 and S6c but did significantly increase the maximum contractile response to ET-1 by 60% (at low tension) and 130% (at high tension). 4. In control rat vessels, L-NAME itself caused small increases in vascular tone (5-8 mg wt tension) in 33-56% of vessels. In the chronic hypoxic rats, in vessels set at high tension, L-NAME-induced tone was evident in 88% of vessels and had increased to 26.9 +/- 6.6 mg wt tension. Vasodilatation to sodium nitroprusside, in non-preconstricted vessels, was small in control rat vessels (2-6 mg wt tension) but increased significantly to 22.5 +/- 8.0 mg wt tension in chronic hypoxic vessels set at the higher tensions. Together, these results indicate an increase in endogenous tone in the vessels from the chronic hypoxic rats which is normally attenuated by nitric oxide production. 5. L-NAME increased the sensitivity to S6c 10 fold (low tension) and 6 fold (high tension) only in chronic hypoxic rat pulmonary resistance arteries. It had no effect on responses to ET-1 in any vessel studied. 6. Vasodilatation of pre-contracted vessels by ACh was markedly greater in the pulmonary resistance arteries fr

    Topics: Animals; Endothelin-1; Endothelium, Vascular; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pulmonary Artery; Rats; Rats, Wistar; Vasodilator Agents; Viper Venoms

1998
Reduced pulmonary clearance of endothelin-1 in pulmonary hypertension.
    American heart journal, 1998, Volume: 135, Issue:4

    Pulmonary hypertension (PHT) is associated with increased endothelin-1 (ET-1) levels that correlate with the severity of the disease. The pulmonary circulation is an important site for ET-1 metabolism and may modulate plasma ET-1 through an increase in production, a reduction in removal, or a combination of both. We measured and compared pulmonary metabolism of circulating ET-1 in controls and in patients with PHT.. The indicator-dilution technique was combined with measurements of ET-1 levels to quantify pulmonary metabolism of ET-1 in controls (n = 13) and in patients with PHT (n = 17). ET-1 levels doubled in PHT (p < 0.05) and, although there was no difference between aortic and pulmonary artery levels in controls (0.68+/-0.09 and 0.61+/-0.08 pg/ml, respectively, p = 0.22), they tended to be higher in PHT (1.23+/-0.26 vs 1.07+/-0.19 pg/ml, p = 0.08). Pulmonary extraction of tracer iodine-125-ET-1 was reduced from 47%+/-2.0% in the controls to 34%+/-3.6% in PHT (p = 0.005) and inversely correlated with the severity of pulmonary hypertension (r = -0.524, p = 0.03). Consequently, circulating ET-1 clearance was reduced by PHT from 1424+/-77 ml/min to 892+/-119 ml/min (p < 0.001). Pulmonary production of circulating ET-1 (in picograms per minute) was not different but the quantity of ET-1 that survives passage through the lungs was increased by PHT (1860+/-359 pg/min vs 992+/-152 pg/min, p = 0.037).. PHT is associated with a reduced pulmonary clearance of ET-1 that contributes to the increase in circulating levels.

    Topics: Aorta, Thoracic; Biomarkers; Blood Pressure; Cardiac Catheterization; Echocardiography; Endothelin-1; Heart Failure; Humans; Hypertension, Pulmonary; Iodine Radioisotopes; Middle Aged; Mitral Valve Stenosis; Pulmonary Artery; Pulmonary Wedge Pressure; Severity of Illness Index; Spectrophotometry; Vascular Resistance

1998
Effect of inhaled nitric oxide in endothelin-1-induced pulmonary hypertension.
    Biology of the neonate, 1998, Volume: 73, Issue:4

    The interaction of two vasoactive substances, the vasoidilator nitric oxide (NO) and the complex-acting peptide endothelin-1 (ET-1), may help explain the pathophysiology of pulmonary hypertension, an important part of many pulmonary disorders in neonates. To understand better the interactions of inhaled NO and ET-1, we investigated the effects of ET-1 infusions with and without inhaled NO in two groups of piglets, one group pretreated with L-nitro-arginine methylester (L-NAME) and the other not pretreated. Inhaled NO (60 ppm) was administered during infusion of 1.0 microgram/kg or 2.5 micrograms/kg of ET-1. In animals not pretreated with L-NAME, the increase in PVR and in SVR induced by either dose of ET-1 was not reduced with administration of NO. The increase in systemic vascular resistance with ET-1 was greater (mean increase of 50% above baseline with 1.0 microgram/kg ET-1 and 100% with 2.5 micrograms/kg ET-1 by 5 min) than the increase in PVR, but the PVR/SVR ratio did not change during ET-1 administration. In contrast, animals pretreated with L-NAME did demonstrate inhibition of ET-1-induced increase in PVR with NO. No differences in effects on SVR were noted. We conclude that ET-1-induced increases in PVR are not diminished by 60 ppm of inhaled NO unless there has been inhibition of endogenous NO production.

    Topics: Administration, Inhalation; Animals; Drug Interactions; Endothelin-1; Enzyme Inhibitors; Female; Hypertension, Pulmonary; Lung; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Swine; Vascular Resistance

1998
Vascular remodeling and growth factor gene expression in the rat lung during hypoxia.
    Respiration physiology, 1998, Volume: 111, Issue:2

    Recent studies suggest that the vasoactive peptides endothelin-1 and -3 and the mitogens VEGF and PDGF-A and -B could be involved in the pathogenesis of hypoxic pulmonary hypertension. We were interested to investigate whether these peptides could also be involved in the vascular remodeling occurring during chronic hypoxia (10% oxygen; 1 and 3 weeks) in the rat. Hypoxia increased significantly systolic right ventricular pressure and typical morphological signs of vascular remodeling were found. This was accompanied by increased ET-1 and the ET-3 mRNA expression after acute (6 h; P < 0.05) and chronic hypoxia of 1 (P < 0.05) and 3 weeks (P < 0.05). In contrast, we found no effects of hypoxia on the gene expression of VEGF and PDGF-A and -B in the lung. Our findings indicate that ET-3 in addition to ET-1 could be involved in the process of hypoxia-induced vascular remodeling, whereas it appears less likely that the mitogens VEGF and PDGF-A and -B are essentially involved in the pathogenesis of hypoxic pulmonary hypertension.

    Topics: Animals; Endothelial Growth Factors; Endothelin-1; Endothelin-3; Gene Expression; Growth Substances; Hypertension, Pulmonary; Hypoxia; Lung; Lymphokines; Male; Platelet-Derived Growth Factor; Pulmonary Circulation; Rats; Rats, Wistar; RNA, Messenger; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

1998
Increased lung preproET-1 and decreased ETB-receptor gene expression in fetal pulmonary hypertension.
    The American journal of physiology, 1998, Volume: 274, Issue:4

    Endothelin (ET)-1, a potent vasoconstrictor and smooth muscle mitogen, is produced from its precursor, preproET-1, by endothelin-converting enzyme (ECE)-1 activity. ET-1 may bind to two receptors, ETA and ETB, that mediate vasoconstriction and vasodilation in the ovine fetal lung, respectively. ET-1 contributes to high pulmonary vascular resistance in experimental perinatal pulmonary hypertension induced by ligation of the ductus arteriosus in the fetal lamb. Physiological studies in this model have demonstrated enhanced ETA- and diminished ETB-receptor activities and a threefold increase in lung immunoreactive ET-1 protein content. We hypothesized that increased ET production and an imbalance in receptor expression would favor vasoconstriction and smooth muscle cell hypertrophy in pulmonary hypertension and may be partially due to alterations in gene expression. To test this hypothesis, we studied lung mRNA expression of preproET-1, ECE-1, and the ETA and ETB receptors in normal and hypertensive fetal lambs. Total RNA was isolated from whole lung tissue in normal late-gestation fetuses (135 +/- 3 days; 147 days = term) and from animals with pulmonary hypertension after ductus arteriosus ligation for 8 days (134 +/- 4 days). Ductus arteriosus ligation increased right ventricular hypertrophy [control 0.56 +/- 0.02 vs. hypertension 0.85 +/- 0.05; right ventricle/(left ventricle + septum); P < 0.05]. Northern blot analysis was performed using cDNA probes and was normalized to the signal for 18S rRNA. We found a 71 +/- 24% increase in steady-state preproET-1 mRNA (P < 0.05) and a 62 +/- 5% decrease in ETB mRNA (P < 0.05) expression in ductus arteriosus ligation. ECE-1 and ETA-receptor mRNA expression did not change. We conclude that chronic intrauterine pulmonary hypertension after ductus arteriosus ligation increases steady-state preproET-1 mRNA and decreases ETB-receptor mRNA without changing ECE-1 mRNA or ETA-receptor mRNA expression. These findings suggest that increased ET-1 production and decreased ETB-receptor expression may contribute to increased vasoconstrictor tone in this experimental model of neonatal pulmonary hypertension.

    Topics: Animals; Blotting, Northern; Endothelin-1; Endothelins; Fetal Diseases; Gene Expression; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Protein Precursors; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Sheep

1998
Efficacy of CI-1020, an endothelin-A receptor antagonist, in hypoxic pulmonary hypertension.
    Journal of cardiovascular pharmacology, 1998, Volume: 31 Suppl 1

    We previously showed that CI-1020, an endothelin (ET)-A-selective receptor antagonist, dose-dependently blocked acute hypoxic pulmonary hypertension (PH) in rats. In this study we show that CI-1020 can reverse existing PH and prevent progression of right ventricular hypertrophy (RVH) in rats exposed to chronic hypoxia. Male Sprague-Dawley rats were exposed to 20 days of hypoxia (10% O2) with CI-1020 treatment (20 or 40 mg/kg/day) starting on day 10. On day 20 of hypoxia, the rats were instrumented under anesthesia with a pulmonary artery cannula and allowed to recover to consciousness before measurement of mean pulmonary arterial pressure (MPAP). Blood samples were then collected for plasma ET-1 measurements, the rats killed, and their hearts dissected, dried, and weighed. RV/LV + septum ratio (g/g) was used as an index of RVH (RVHi). Normoxic rats and rats exposed to hypoxia for only 10 days were also evaluated as controls. Normoxic rats had MPAPs of 13 +/- 1 mm Hg, plasma ET-1 levels of 2.1 +/- 0.1 pg/ml, and an average RVHi of 0.29 +/- 0.03. Rats exposed to 10 or 20 days of hypoxia had MPAPs of 33 +/- 2 and 44 +/- 0 mm Hg, plasma ET-1 levels of 4.2 +/- 0.8 and 4.6 +/- 0.8 pg/ml, and average RVHis of 0.47 +/- 0.05 and 0.52 +/- 0.03, respectively. In comparison, rats treated with CI-1020 had MPAPs that were 37% (20 mg/kg/day) and 44% (40 mg/kg/day) lower than untreated 20-day hypoxic rats. Furthermore, rats dosed with 40 mg/kg/day of CI-1020 had MPAPs that were significantly lower (24%) than control 10-day hypoxic rats, indicating a significant reversal of PH. Along with this reversal in PH, their average RVHi was 23% lower (p < 0.05) relative to untreated 20-day hypoxic rats.

    Topics: Animals; Blood Pressure; Cardiomegaly; Chronic Disease; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

1998
Endothelin-1, atrial natriuretic peptide and pathophysiology of pulmonary hypertension in porcine meconium aspiration.
    Acta paediatrica (Oslo, Norway : 1992), 1998, Volume: 87, Issue:4

    To evaluate the role of endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) in the development of meconium aspiration-induced pulmonary hypertension, plasma ET-1 and ANP levels were measured serially for 6h after meconium instillation in juvenile pigs. Eleven 10-week-old, anaesthetized and catheterized pigs received intratracheally a bolus of 3 ml kg(-1) 20% human meconium, and five of them were premedicated with 30 mg kg(-1) methylprednisolone i.v. Another six pigs served as controls and were given 3 ml kg(-1) sterile saline intratracheally. Meconium instillation resulted in an increase in plasma ET-1 levels with a significant correlation to the simultaneously increasing PVR (r = 0.72). Methylprednisolone had no effect on the early (0-1 h) ET-1 increase, but prevented significantly the second phase (1-6 h) rise with a concomitant attenuation of the progressive pulmonary hypertension. ANP concentrations were higher in the meconium than in the control group throughout the study and further increased after steroid treatment with a good correlation to ET-1 (r = 0.86). Thus, the postinjury rise in circulating vasoactive peptides, together with the pulmonary hypertensive response, and modulation of the peptide balance and pressor reaction by steroids, suggest a contributory role for ET-1 and ANP in the development of pulmonary hypertension after meconium aspiration.

    Topics: Animals; Anti-Inflammatory Agents; Atrial Natriuretic Factor; Endothelin-1; Humans; Hypertension, Pulmonary; Infant, Newborn; Meconium Aspiration Syndrome; Methylprednisolone; Swine

1998
Type V phosphodiesterase inhibition modulates endogenous immunoreactivities of endothelin-1 and endothelial nitric oxide synthase in pulmonary arteries in rats with monocrotaline-induced pulmonary hypertension.
    Research in experimental medicine. Zeitschrift fur die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie, 1998, Volume: 197, Issue:6

    We evaluated the effects of oral administration of E4021 (100 mg/kg/day), a type V phosphodiesterase inhibitor, on immunoreactivities of endothelin-1, endothelin receptors, and nitric oxide synthases in pulmonary arteries in a rat model of pulmonary hypertension. Immunoreactivities of endothelin-1 and endothelial nitric oxide synthase were observed significantly less frequently, together with significant reduction of right ventricular overload and medial thickening in rats treated with E4021 than in the control with monocrotaline on day 28. The levels of plasma endothelin-1 and serum nitrite and nitrate were significantly lower in rats that received E4021 than in the control with monocrotaline. Oral administration of E4021 modulates endogenous immunoreactivities of endothelin-1 and endothelial nitric oxide synthase with the improvement or right ventricular overload and medial thickening.

    Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Immunohistochemistry; Male; Monocrotaline; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperidines; Pulmonary Artery; Quinazolines; Rats; Rats, Wistar; Receptors, Endothelin

1998
The ETA receptor antagonist, BMS-182874, reduces acute hypoxic pulmonary hypertension in pigs in vivo.
    Cardiovascular research, 1998, Volume: 37, Issue:3

    Elevated levels of the potent vasoactive peptide endothelin (ET), have been found in pathophysiological conditions associated with pulmonary hypertension. In this study, we have investigated the effects of the ETA receptor antagonist, BMS-182874, on hypoxic pulmonary hypertension in pigs.. Pigs were subjected to acute, intermittent 15-min periods of hypoxia (FiO2 0.1). Following a first hypoxia establishing hypoxic baseline values, vehicle or BMS-182874 (10 or 30 mg/kg) was administered i.v. before a second hypoxic period. In separate groups of animals, the effects of the nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NNA) in combination with BMS-182874 (10 mg) during repeated hypoxia were investigated. The ET-1-blocking properties of BMS-182874 were studied in vivo by infusion of ET-1 during normoxia and in vitro using isolated porcine pulmonary arteries.. The hypoxia-evoked increase in mean pulmonary artery pressure was reduced by administration of BMS-182874 (10 mg/kg i.v.; from 42 +/- 8 to 34 +/- 4 mmHg, P < 0.05 and 30 mg/kg i.v.; from 38 +/- 4 to 30 +/- 5 mmHg, P < 0.05). In addition, BMS-182874 at 30 mg/kg reduced the pulmonary vascular resistance during hypoxia (from 7.4 +/- 1.5 to 5.3 +/- 1.1 mmHg.min.l-1 P < 0.05). The hemodynamic response to repeated hypoxia was reproducible in control animals and unaffected by the cyclo-oxygenase inhibitor diclophenac (3 mg/kg). Infusion of L-NNA alone resulted in an augmented pulmonary vasoconstriction during hypoxia; pulmonary arterial pressure from 35 +/- 6 to 43 +/- 9 mmHg; P < 0.05 and vascular resistance from 7.2 +/- 1.1 to 9.9 +/- 1.8 mmHg.min.l-1; P < 0.05. L-NNA in combination with BMS-182874 (10 mg/kg) resulted in a hypoxic pulmonary vasoconstriction of similar magnitude as hypoxic baseline. In addition, BMS-182874 reduced the hemodynamic response to ET-1 in normoxic pigs and competitively antagonized the vasoconstrictor effect of ET-1 in isolated porcine pulmonary arteries.. The non-peptide, selective ETA receptor antagonist, BMS-182874, reduces hypoxic pulmonary vasoconstriction in pigs. The reduction in pulmonary vascular response to hypoxia following BMS-182874 is at least partly independent of nitric oxide.

    Topics: Animals; Antihypertensive Agents; Dansyl Compounds; Drug Synergism; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Nitric Oxide Synthase; Nitroarginine; Pulmonary Artery; Swine

1998
Effects of chronic hypoxia and altered hemodynamics on endothelial nitric oxide synthase and preproendothelin-1 expression in the adult rat lung.
    Chest, 1998, Volume: 114, Issue:1 Suppl

    Topics: Animals; Chronic Disease; Endothelin-1; Endothelins; Endothelium, Vascular; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Protein Precursors; Rats

1998
Chronic intrauterine pulmonary hypertension increases preproendothelin-1 and decreases endothelin B receptor mRNA expression in the ovine fetal lung.
    Chest, 1998, Volume: 114, Issue:1 Suppl

    Topics: Animals; Chronic Disease; Disease Models, Animal; Endothelin-1; Endothelins; Fetal Diseases; Hypertension, Pulmonary; Lung; Protein Precursors; Receptors, Endothelin; RNA, Messenger; Sheep; Vasoconstriction

1998
Role of vasoactive mediators in primary and secondary pulmonary hypertension.
    The American journal of cardiology, 1998, Jul-15, Volume: 82, Issue:2

    The role of vasoactive mediators, such as endothelin-1, nitric oxide, prostacyclin, and thromboxane, in pulmonary hypertension remains undefined. This study investigated the circulating levels and transpulmonary gradients of these vasoactive mediators in patients with primary and secondary pulmonary hypertension to define whether there is increased production or decreased clearance of these substances in the lung vasculature.

    Topics: Adult; Antihypertensive Agents; Endothelin-1; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Thromboxane A2; Vasodilation

1998
The role of endothelin-1 as a mediator of the pressure response after air embolism in blood perfused lungs.
    Intensive care medicine, 1998, Volume: 24, Issue:6

    It is well known that lung embolism is associated with an increase in pulmonary vascular resistance. Since the mechanisms of pulmonary vascular reactions during embolism are still unclear, the aim of this study was to investigate the potential involvement of endothelin-1 (ET-1) and thromboxane A2 (TXA2) as mediators of the pulmonary artery pressure (PAP) increase after embolism using the selective ETA receptor antagonist LU135252 [1], the ETB receptor antagonist BQ788 [2], and the cyclooxygenase inhibitor diclofenac.. Prospective experimental study in rabbits.. Experimental laboratory in a university teaching hospital.. 36 adult rabbits of either sex.. The experiments were performed in 36 isolated and ventilated rabbit lungs which were perfused with a buffer solution containing 10% of autologous blood. Embolism was induced by the injection of 0.75 ml air into the pulmonary artery.. PAP and lung weight, reflecting edema formation, were continuously recorded. Perfusate samples were drawn intermittently to determine TXA2 and ET-1 concentrations. Air injection resulted in an immediate increase in PAP up to 22.8 +/- 1.4 mm Hg at 2.5 min (control, n = 6), which was parallelled by an enhanced generation of TXA2. No relevant edema formation occurred during the observation period. Pretreatment with the ETA receptor antagonist LU135252 significantly reduced the pressure reaction after air embolism (p < 0.001) whereas the ETB receptor antagonist BQ788 (n = 6) was without marked effects. The administration of diclofenac (n = 6) did not alter the PAP increase 2.5 min after embolism, but significantly reduced the pressure reaction during the further observation period (p < 0.001). The application of LU135252 and diclofenac together (n = 6) also significantly reduced the PAP increase from 2.5 min during the total observation period (p < 0.001).. The acute pressure reaction after air embolism is mainly mediated via ET-1 by an ETA receptor related mechanism. TXA2 seems to maintain this reaction for a longer time.

    Topics: Analysis of Variance; Animals; Cyclooxygenase Inhibitors; Diclofenac; Disease Models, Animal; Embolism, Air; Endothelin Receptor Antagonists; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Hypertension, Pulmonary; In Vitro Techniques; Oligopeptides; Perfusion; Phenylpropionates; Piperidines; Pulmonary Artery; Pulmonary Embolism; Pyrimidines; Rabbits; Radioimmunoassay; Thromboxane A2; Time Factors; Vascular Resistance

1998
Endothelin-1 pulmonary vasoconstriction in rats with diaphragmatic hernia.
    The Journal of surgical research, 1998, Volume: 76, Issue:1

    Pulmonary hypertension is an important cause of mortality in infants with congenital diaphragmatic hernia (CDH). Endothelin-1 has been implicated as a mediator of pulmonary hypertension. ET-A receptors are increased in the nitrofen model of CDH in rats. We hypothesized that vasoconstrictor responses to endothelin-1 are increased in pulmonary arterioles of rats with nitrofen-induced CDH.. CDH was induced in fetal rats by feeding nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether) to pregnant rats at midgestation. Third-generation pulmonary arterioles were isolated on the final day of gestation. Arterioles were cannulated and perfused at constant pressure with a physiologic salt solution. Diameters of arterioles from control animals (n = 8), CDH animals (n = 5), and animals exposed to nitrofen but without CDH (n = 4) were measured. Responses to endothelin-1 concentrations of 10(-12) to 10(-8) M were compared by Student's t test.. CDH arterioles constricted more than controls in response to endothelin-1 at concentrations of 10(-11) M (29 +/- 11% vs 5 +/- 3%, P = 0.02) and 10(-10) M (40 +/- 14% vs 9 +/- 6%, P = 0.04). The log concentration of endothelin-1 that induced half-maximal response (ED50) was lower for CDH arterioles than for control arterioles (-10.3 +/- 0.6 vs -9.1 +/- 0.2, P = 0.03). Responses of arterioles from animals exposed to nitrofen but without CDH were not different from controls (P > or = 0.05).. Exaggerated vasoconstrictor responses to endothelin-1 may contribute to pulmonary hypertension in CDH.

    Topics: Animals; Arterioles; Disease Models, Animal; Endothelin-1; Female; Herbicides; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Lung; Phenyl Ethers; Pregnancy; Prenatal Exposure Delayed Effects; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vasoconstriction

1998
Pulmonary responses to 5-hydroxytryptamine and endothelin-1 in a rabbit model of left ventricular dysfunction.
    Cardiovascular research, 1998, Volume: 38, Issue:2

    To determine whether pulmonary hypertension developed in a coronary artery-ligated rabbit model of left ventricular dysfunction (LVD) and to examine the effects of i.v. 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) on pulmonary arterial pressure (PAP).. Eight weeks after experimental coronary artery ligation or sham operation, ejection fractions were assessed by echocardiography. The rabbits were later anaesthetised and pulmonary arterial pressure was measured via a catheter inserted into the pulmonary artery via the right external jugular vein. 5-HT (1-400 micrograms/kg) and ET-1 (0.001-4 nmol/kg) were administered i.v.. Ejection fraction was significantly decreased from 76.6 +/- 1.4% in sham-operated to 42.2 +/- 1.3% in coronary artery-ligated rabbits (n = 9 in each group; P < 0.001), consistent with LVD. Baseline mean pulmonary arterial pressure was significantly increased in the coronary artery-ligated group compared to the shams, (16.5 +/- 0.5 vs. 11.5 +/- 0.8 mmHg; P < 0.001). A significant degree of right ventricular hypertrophy was found in the coronary artery-ligated rabbits (0.70 +/- 0.04 g/kg final body weight (f.b.wt.), n = 8 cf. 0.48 +/- 0.02 g/kg f.b.wt. in sham-operated controls, n = 8; P < 0.001). There was a significant increase in the percentage of muscularised pulmonary vessels adjacent to alveolar ducts and alveoli < 60 microns i.d. in the LVD rabbits compared with their sham-operated controls (8.5 +/- 0.4 cf. 20 +/- 0.5%; P < 0.0005). 5-HT produced a greater response in the coronary artery-ligated rabbits (a maximum increase of 8.7 +/- 1.0 mmHg in mean pulmonary artery pressure vs. 4.6 +/- 1.5 mmHg for sham-operated controls; P < 0.05). ET-1 did not have any effect on pulmonary arterial pressure in either group.. In the rabbit, LVD secondary to coronary artery ligation, causes right ventricular hypertrophy, pulmonary vascular remodelling, and an increased PAP consistent with the onset of pulmonary hypertension (PHT). The greater PAP response to i.v. 5-HT in the PHT group supports the hypothesis that this substance could be involved in the development of PHT. A role for ET-1 cannot be excluded, despite its lack of effect on PAP when intravenously administered in either group.

    Topics: Animals; Echocardiography; Endothelin-1; Hypertension, Pulmonary; Male; Rabbits; Regression Analysis; Serotonin; Ventricular Dysfunction, Left

1998
Update on endothelin.
    The Canadian journal of cardiology, 1998, Volume: 14 Suppl D

    Endothelin is a very potent vasoconstrictor peptide produced by the vascular endothelium. Several studies have shown that the endothelin system is activated in various cardiovascular conditions, including myocardial infarction, heart failure and pulmonary hypertension. The known actions of the endothelin-1 isoform suggest that it may be an important mediator in several of the pathophysiological manifestations of heart failure. Data on the potential value of endothelin antagonists in heart failure are reviewed.

    Topics: Endothelin-1; Endothelins; Endothelium, Vascular; Heart Failure; Humans; Hypertension, Pulmonary; Myocardial Infarction

1998
Adrenomedullin in patients at high risk for pulmonary hypertension.
    The Annals of thoracic surgery, 1998, Volume: 66, Issue:2

    Adrenomedullin is a newly identified peptide with profound hypotensive effects. We investigated perioperative adrenomedullin levels among patients with congenital heart disease with and without pulmonary hypertension.. Levels of plasma adrenomedullin, endothelin-1, and nitric oxide metabolites were measured in three groups: (1) low pulmonary flow (n=11); (2) high flow/low pulmonary arterial pressure (less than 60% systemic pressure) (n=9); and (3) high flow/high pressure (n=10). Samples were obtained preoperatively, on and off pump, and 3, 6, and 12 hours after bypass.. Adrenomedullin levels were highest in the low pulmonary flow group (189.7+/-15 pg/mL low flow versus 103.1+/-9.5 pg/mL high flow/low pulmonary and 139+/-17.5 pg/mL high flow/high pressure at 12 hours; p < or = 0.05). The arterial pressure/systemic pressure remained significantly lower in the high flow/low pulmonary pressure compared with the high flow/high pressure group (0.37+/-0.08 versus 0.62+/-0.11; p < 0.005). Perioperative endothelin-1 and nitric oxide levels remained low in the low pulmonary flow group but increased progressively in both high flow groups.. Circulating plasma adrenomedullin appears to affect baseline vascular tone in patients with intact endothelial function. It may interact with nitric oxide and endothelin-1 to help regulate blood pressure perioperatively in patients with congenital heart disease.

    Topics: Adrenomedullin; Blood Pressure; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Peptides; Pulmonary Circulation; Risk Factors

1998
Nitric oxide and endothelin-1 in pulmonary hypertension.
    Chest, 1998, Volume: 114, Issue:3 Suppl

    We have shown previously increased expression of the potent vasoconstrictor peptide endothelin-1 (ET-1) in the pulmonary arteries of patients with pulmonary hypertension. We also demonstrated diminished expression of endothelial nitric oxide synthase, the enzyme responsible for generating nitric oxide (NO), in patients with the same disease.. To determine the expression of neuronal nitric oxide synthase (NOS-I) and endothelin-converting enzyme-1 (ECE-1) in lungs of patients with pulmonary hypertension.. Immunohistochemistry with avidin-biotin-peroxidase method.. There was little immunostaining for NOS-I in the pulmonary arteries of normal control or diseased lungs. Moderate diffuse staining was seen in the airway epithelium and nerve bundles. Immunoreactivity for ECE-1 was seen in the airway epithelium, smooth muscle cells, and scattered macrophages of both normal and diseased lungs. Strong immunoreactivity for ECE-1 was seen in the endothelium of diseased pulmonary arteries of patients with pulmonary hypertension.. We conclude that expression of NOS-I appears to be similar in normal and diseased lungs, while abundant expression of ECE-1 is present in diseased vessels, which may contribute to the pathogenesis of arteriopathy in pulmonary hypertension.

    Topics: Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Humans; Hypertension, Pulmonary; Immunoenzyme Techniques; Metalloendopeptidases; Microcirculation; Nitric Oxide; Nitric Oxide Synthase; Pulmonary Artery

1998
Plasma endothelin 1 concentrations in children with congenital heart defects.
    Minerva pediatrica, 1998, Volume: 50, Issue:4

    To investigate the changes in plasma endothelin-1 (ET-1) concentrations in patients with congenital heart defects.. Plasma ET-1 concentrations were measured by using radio-immunoassay in 50 patients in a prospective study. In 35 patients with ventricular septal defect, 20 cases had pulmonary hypertension (group 1) and 15 cases had normal pulmonary artery pressure (group 2). The other 15 patients with atrial septal defect had normal pulmonary artery pressure (group 3). Blood samples were obtained from pulmonary artery, aorta and radial artery.. Plasma ET-1 concentration in group 1 was significantly higher than those in group 2 and group 3 at all sampling sites and all different times (p < 0.01), and plasma ET-1 concentration was slightly higher in group 3 than in group 2 (p > 0.05). Plasma ET-1 concentration at aorta were also significantly higher than that at pulmonary artery in group 1 (p < 0.01). In patients with ventricular septal detect, pulmonary blood flow had a linear positive correlation with plasma ET-1 concentration (r = 0.75, p < 0.01) and there was also a significant positive correlation between plasma ET-1 concentration and pulmonary artery pressure (r = 0.68, p < 0.05). After surgical repair of the defects, plasma ET-1 concentration decreased except for 6 cases with the pulmonary resistance more than 800 dyne.sec.cm-5.. Plasma ET-1 concentrations are elevated in patients with congenital heart defect associated with left-to-right shunt and may have an important role in the pathogenesis of pulmonary hypertension.

    Topics: Child; Child, Preschool; Data Interpretation, Statistical; Endothelin-1; Female; Heart Defects, Congenital; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Infant; Male; Prospective Studies; Radioimmunoassay

1998
Hypoxia enhances cellular proliferation and inositol 1,4, 5-triphosphate generation in fibroblasts from bovine pulmonary artery but not from mesenteric artery.
    American journal of respiratory and critical care medicine, 1998, Volume: 158, Issue:6

    When pulmonary hypertension occurs in the face of hypoxia there is remodeling of all three layers of the pulmonary vessels, but in particular, there is an increase in number of adventitial fibroblasts. Hypoxia causes vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. We hypothesized that there are fundamental differences in oxygen sensing and cell signaling between systemic and pulmonary artery cells in response to hypoxia. Here, we determined the effect of hypoxia either alone or in combination with known growth factors such as serum, endothelin-1 (ET-1), and platelet-derived growth factor (PDGF) on the proliferative responses of bovine pulmonary artery and mesenteric artery fibroblasts. Fibroblasts were obtained from primary cultures. Growth was assessed by [3H]thymidine incorporation. Inositol 1,4,5-triphosphate (IP3) generation was measured using a competitive binding assay. Hypoxia alone increased proliferation of pulmonary artery fibroblasts (611 +/- 24%), but not in those from the mesentery. Furthermore, hypoxia had the effect of increasing the replicative response of pulmonary fibroblasts to serum and PDGF, but no change was observed in the mesenteric cells. ET-1 had no effect on growth of either cell type. PDGF gave rise to a significant elevation in IP3 production under hypoxic conditions in the pulmonary artery cells (234%), but not in the mesenteric cells. ET-1 caused no change in IP3 production in any cell type. These data suggest that hypoxia sensitizes pulmonary artery fibroblasts to the proliferative effect of mitogens through a pathway that is not present, or is present but repressed, in the mesenteric cells.

    Topics: Analysis of Variance; Animals; Blood; Cattle; Cell Communication; Cell Division; Cells, Cultured; Elastic Tissue; Endothelin-1; Fibroblasts; Hypertension, Pulmonary; Hypoxia; Inositol 1,4,5-Trisphosphate; Mesenteric Arteries; Mitogens; Platelet-Derived Growth Factor; Pulmonary Artery; Radiopharmaceuticals; Thymidine; Tritium; Vasoconstriction; Vasodilation

1998
[Cromakalim inhibits endothelin-1 induced pulmonary hypertension in rats].
    Hua xi yi ke da xue xue bao = Journal of West China University of Medical Sciences = Huaxi yike daxue xuebao, 1998, Volume: 29, Issue:1

    There is evidence that endothelin-1 (ET-1) and potassium channel may play an important role in the development of pulmonary hypertension. To evaluate the effect of ATP-sensitive K+ channel opener on pulmonary hypertension induced by ET-1, catheter was inserted into the pulmonary artery in ten male Wistar rats which had had pulmonary hypertension established by infusion of ET-1 (1.5 micrograms/kg), and then cromakalim were injected with a dose of 150 micrograms/kg. The mean pulmonary arterial pressure (mPAP), cardiac output (CO) monitored before and after infusion of ET-1, and 1 min, 5 min, 10 min after cromakalim injection, and pulmonary vascular resistance (PVR) were calculated. It was found that the mPAP was significantly increased, from 2.36 +/- 0.24 kPa to 3.32 +/- 0.49 kPa(P < 0.01), and PVR also increased, by infusion of ET-1. After cromakalim injection, mPAP were decreased to 2.50 +/- 0.62 kPa in 1 min, 1.14 +/- 0.18 kPa in 5 min and 2.33 +/- 0.52 kPa in 10 min, PVR decreased significantly. It is suggested that there is interaction between ET-1 and potassium Channel, and Cromakalim decreases mPAP in part by inhibiting the response of pulmonary artery to ET-1.

    Topics: Animals; Antihypertensive Agents; Blood Pressure; Cardiac Output; Cromakalim; Endothelin-1; Hypertension, Pulmonary; Male; Potassium Channels; Pulmonary Artery; Rats; Rats, Wistar; Vascular Resistance

1998
[Relationship between plasma endothelin, nitric oxide, calcitonin gene-related peptide levels and pulmonary hemodynamics in patients with chronic cor pulmonale].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 1998, Volume: 21, Issue:7

    To explore the relationship between plasma endothlin-1 (ET-1), nitric oxide (NO), calcitonin gene-related peptide (CGRP) levels and hypoxic pulmonary hypertension.. Cardiac catheterization was performed in 55 cases of chronic cor pulmonale to monitor the changes of their hemodynamic indices and to determine the levels of pulmonary arterial plasma ET-1, NO and CGRP.. The plasma ET-1 level of patients with pulmonary hypertension (Group A) was significantly higher than that of patients without pulmonary hypertension (Group B) and controls. The plasma NO level of group A was significantly lower than that of Group B and controls. The plasma CGRP level of ET-1 had a significantly negative correlation with PaO2 and positive correlation with pulmonary arterial pressure. The levels of NO and CGRP had significantly positive correlation with PaO2 and negative correlation with pulmonary arterial pressure. After 60-min oxygenation with 30% oxygen inhalation, the level of ET-1 decreased remarkably, but the levels of NO and CGRP went up notably.. These results demonstrate that hypoxia affects plasma ET-1, NO, CGRP levels in patients with chronic cor pulmonale. ET-1, NO, CGRP play synergistic roles in regulation of pulmonary arterial pressure.

    Topics: Adult; Aged; Calcitonin Gene-Related Peptide; Endothelin-1; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Middle Aged; Nitric Oxide; Pulmonary Heart Disease

1998
Nonpeptide endothelin receptor antagonists. VIII: attentuation of acute hypoxia-induced pulmonary hypertension in the dog.
    The Journal of pharmacology and experimental therapeutics, 1997, Volume: 280, Issue:2

    It has been proposed that endothelin-1 (ET-1), a potent endogenous vasoactive peptide, may play an important role in the regulation of pulmonary blood flow. The purpose of the present study was to characterize the effects of ET-1 and a nonpeptide mixed ET(A) and ET(B) receptor antagonist, SB 209670, in isolated segments of the canine pulmonary artery and to examine the effects of SB 209670 in a canine model of acute hypoxia-induced pulmonary hypertension. In isolated segments of the pulmonary artery, SB 209670 (3-300 nM) produced a concentration-dependent antagonism of contraction elicited by ET-1 (pA2 = 8.9; slope = 0.9) and had no effect on phenylephrine responses. In addition, SB 209670 antagonized the small, endothelium-dependent relaxation induced by sarafotoxin 6c in phenylephrine (10 microM)-precontracted vessels (pKB = 8.6). In anesthetized dogs, the driving pressure across the pulmonary circulation increased approximately 100% during the hypoxic period (area under the curve [AUC] = 267.1 +/- 25.3 mm Hg x min). SB 209670 treatment (3 and 30 microg/kg/min i.v.) reduced pulmonary vascular resistance and produced a profound dose-related inhibition of hypoxia-induced pulmonary hypertension (AUC = 158.3 +/- 22.7 mm Hg x min and 50.1 +/- 4.9 mm Hg x min, respectively). None of the other hemodynamic or arterial blood gas parameters differed significantly in the vehicle and treatment groups. In addition, SB 209670 produced a significant reversal of hypoxia-induced pulmonary hypertension (AUC = 267.1 +/- 25.3 mm Hg x min vs. 167.8 +/- 23.4 mm Hg x min) when administered at the plateau of the hypoxic response. It was found that SB 209670 administration significantly elevated plasma levels of ET-1-LI (> or = 25-fold). These results suggest that ET-1 is an important mediator of hypoxia-induced pulmonary hypertension in the dog and that SB 209670, a potent and selective mixed ET(A) and ET(B)receptor antagonist in the pulmonary circulation, may represent an important therapeutic approach to the treatment of pulmonary hypertension.

    Topics: Animals; Blood Pressure; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Heart Rate; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Indans; Male; Muscle Contraction; Muscle, Smooth, Vascular; Phenylephrine; Pulmonary Artery; Vasoconstrictor Agents; Viper Venoms

1997
Post-cardiopulmonary bypass pulmonary hypertension in lambs with increased pulmonary blood flow. A role for endothelin 1.
    Circulation, 1997, Feb-18, Volume: 95, Issue:4

    After cardiopulmonary bypass (CPB), pulmonary hypertension and its associated increased vascular reactivity are a major source of morbidity, particularly for children with increased pulmonary blood flow. Although post-CPB pulmonary hypertension is well described, its mechanisms remain incompletely understood. Plasma levels of endothelin 1. a potent vasoactive substance implicated in pulmonary hypertension, are increased after CPB. The purpose of the present study was threefold: to characterize the changes in pulmonary vascular resistance and vascular reactivity induced by hypothermic CPB; to investigate the effects of preexisting increased pulmonary blood flow on these changes; and to better define the role of endothelin 1 in the pathogenesis of post-CPB pulmonary hypertension.. Vascular pressures and blood flows were monitored in 14 1-month-old lambs with increased pulmonary blood flow (after in utero placement of an aortopulmonary shunt) and 6 age-matched control lambs. During the 2-hour study period after 105.3 +/- 20.6 minutes of hypothermic CPB the increase in pulmonary vascular resistance was significantly augmented in lambs with increased pulmonary blood flow compared with control lambs (P < .05). Pretreatment with PD 145065 (a nonselective endothelin receptor blocker; 50 micrograms.kg-1.min-1) completely blocked this increase in pulmonary vascular resistance and blocked the increase in pulmonary vascular resistance in response to acute alveolar hypoxia after CPB (96.3 +/- 88.5% versus -9.7 +/- 16.4%; P < .05). Plasma endothelin 1 levels increased after CPB in all lambs.. Preexisting increased pulmonary blood flow alters the response of the pulmonary circulation to hypothermic CPB; the increase in pulmonary vascular resistance induced by CPB is augmented in lambs with increased pulmonary blood flow. Pretreatment with endothelin 1 receptor blockers eliminated the increase in pulmonary vascular resistance and the pulmonary vasoconstricting response to alveolar hypoxia, suggesting a role for endothelin 1 in post-CPB pulmonary hypertension. Endothelin 1 receptor blockers may decrease morbidity in children at risk for pulmonary hypertension after surgical repair with CPB and warrants further study.

    Topics: Animals; Blood Pressure; Cardiopulmonary Bypass; Child; Endothelin-1; Female; Fetus; Heart Rate; Hemodynamics; Humans; Hypertension, Pulmonary; Oligopeptides; Postoperative Complications; Pregnancy; Pulmonary Artery; Pulmonary Circulation; Sheep; Vascular Resistance

1997
Endothelin-1 in the lungs of patients with pulmonary hypertension.
    Cardiovascular research, 1997, Volume: 33, Issue:1

    Pulmonary hypertension (PH) is characterized by an increase in vascular tone and an abnormal proliferation of muscle cells in the walls of pulmonary arteries. Recent studies have found high plasma endothelin-1 (ET-1) concentrations in patients with PH. This study was conducted to assess whether elevated circulating ET-1 levels in PH really reflect excessive local pulmonary production.. We prospectively studied ET-1 concentration in lung specimens from 6 control subjects and 13 patients with severe PH referred for lung or heart-lung transplantation (6 patients had primary PH and 7 PH secondary to congenital heart defect). Endothelin-like immunoreactivity (ET-LI) was measured in plasma and lung tissue, using a radioimmunoassay, after ET-1 extraction. Reverse-phase high-performance liquid chromatography was also performed.. Peripheral venous plasma ET-LI concentrations in patients with PH, whatever the cause, were greater than those in controls (10.7 +/- 0.8 vs 5.3 +/- 0.7 pg/ml; P < 0.0005). Pulmonary ET-LI was significantly higher in patients with PH, irrespective of its cause, than in controls (25.2 +/- 5.1 vs 8.1 +/- 1.1 pg/mg, P < 0.03). ET-LI pulmonary concentrations were slightly higher in Eisenmenger than in primary PH, but this was not significant (27.1 +/- 8.6 vs 22.8 +/- 5.4 pg/mg). Linear regression analysis indicated a small but significant correlation between ET-LI pulmonary concentrations and pulmonary vascular resistance in the patients with PH (r = 0.38; P = 0.047). In each case, HPLC separation of ET indicated that most of the immuno-reactivity was detected in the same fraction as ET-1.. The striking increase in ET-1 pulmonary concentration provides new evidence that excessive local pulmonary ET-1 production may contribute to the vascular abnormalities of pulmonary hypertension.

    Topics: Adult; Aged; Chromatography, High Pressure Liquid; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Prospective Studies; Radioimmunoassay

1997
Time course of endothelin-1 and nitrate anion levels after cardiopulmonary bypass in congenital heart defects.
    The Annals of thoracic surgery, 1997, Volume: 63, Issue:3

    The endothelium-derived vasoconstrictor endothelin-1 (ET-1) may be involved in pulmonary hypertension (PH), but production of the endothelium-derived vasodilator nitric oxide (NO) after cardiopulmonary bypass (CPB) in congenital heart disease is unclear.. Twenty patients (age, 4 months to 12 years) were divided into three groups: severe PH (mean pulmonary-to-systemic arterial pressure ratio > 0.5) and high pulmonary flow (n = 8), mild PH (mean pulmonary-to-systemic arterial pressure ratio < 0.35) and high pulmonary flow (n = 6), and no PH and low pulmonary flow (n = 6). The mean pulmonary-to-systemic arterial pressure ratio was calculated and blood samples were taken, and NO3-, an NO metabolite, was measured.. Levels of ET-1 in the group with severe PH and high pulmonary flow were higher than in the other groups until 6 hours after CPB, and NO3- was not changed significantly in the group with severe PH and high pulmonary flow and or the group with mild PH and high pulmonary flow during CPB. Endothelin-1 in the group with no PH and low pulmonary flow was higher than in the group with mild PH and high pulmonary flow after CPB, and NO3- in the group with no PH and low pulmonary flow significantly decreased after CPB. A positive correlation was obtained between mean pulmonary-to-systemic arterial pressure ratio and ET-1 (r = 0.742 before CPB; r = 0.689 after CPB).. Imbalance between increased ET-1 and constant NO after CPB in the group with severe PH and high pulmonary flow could contribute to dominant effects of ET-1, which may injure the lung. The increased ET-1 and the decreased NO after CPB in the group with no PH and low pulmonary flow may induce a mechanism of protective vasoconstriction against an acute increase in pulmonary flow.

    Topics: Cardiopulmonary Bypass; Case-Control Studies; Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Nitrates; Nitric Oxide; Pulmonary Circulation; Time Factors

1997
Endothelin causes portal and pulmonary hypertension in porcine endotoxemic shock.
    The American journal of physiology, 1997, Volume: 272, Issue:3 Pt 2

    A porcine model of endotoxemic shock was used to test the hypothesis that endothelins (ET) mediate the sustained increases in portal and pulmonary vascular resistances. Anesthetized pigs (n = 18) were instrumented and pretreated with 1) saline as a control; 2) indomethacin (Idm), a cyclooxygenase (Cox) inhibitor; or 3) Idm + bosentan (Bos), a mixed ET-receptor antagonist, and then were treated with endotoxin to produce shock and followed for 240 min. Global and regional hemodynamic parameters and plasma levels of ET-1 and thromboxane B2 were measured. The results show that 1) ET is independently responsible for the sustained increase in pulmonary vascular resistance; 2) ET and Cox products combine to increase portal venous resistance; 3) ET independently reduces cardiac output and attenuates or negates global systemic arterial vasodilation (presumptively mediated by nitric oxide) and exhibits regional differences, having little if any influence on the gut arterial bed. When considered with our prior study of nitric oxide regulation of the same beds in endotoxemic shock (N. Brienza, T. Ayuse, J. P. Revelly, C. P. O'Donnell, and J. L. Robotham, J. Appl. Physiol. 78: 784-792, 1995), the similarities between the portal venous and pulmonary arterial beds suggest that these two beds reflect phenomena occurring in microvascular and/or venous beds in multiple organs. The overall results suggest that a dynamic balance exists between NO and ET regulating arterial and microvascular and/or venous vasomotor activity during the evolution of endotoxemic shock.

    Topics: Analysis of Variance; Animals; Bosentan; Cyclooxygenase Inhibitors; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endotoxemia; Hemodynamics; Hypertension, Portal; Hypertension, Pulmonary; Indomethacin; Liver Circulation; Portal System; Pulmonary Artery; Pulmonary Circulation; Regional Blood Flow; Shock, Septic; Sulfonamides; Swine; Thromboxane B2; Vascular Resistance

1997
Cardiopulmonary bypass and circulatory arrest increase endothelin-1 production and receptor expression in the lung.
    The Journal of thoracic and cardiovascular surgery, 1997, Volume: 113, Issue:4

    Endothelin-1 has been shown to be a mediator of pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circulatory arrest. It is not known whether the mechanism is increased production of endothelin-1 or alterations in expression of endothelin-1 receptors in the lung. This study was designed to test the hypothesis that circulatory arrest increases endothelin-1 mRNA levels and endothelin-1 receptor expression in the lung.. Twenty-four piglets (7 to 30 days old) were studied randomly either at baseline (controls, n = 12) or after cardiopulmonary bypass with 30 minutes of circulatory arrest (deep hypothermic circulatory arrest, n = 12). Lungs and pulmonary arteries were harvested immediately after hemodynamic data collection. Deep hypothermic circulatory arrest significantly increased pulmonary vascular resistance (p < 0.01). Deep hypothermic circulatory arrest also produced a significant increase in endothelin-1 mRNA levels in the pulmonary arteries (149 +/- 55 pg vs 547 +/- 111 pg, p = 0.007). There was no significant change in the pulmonary parenchymal endothelin-1 mRNA levels (4102 +/- 379 pg vs 4623 +/- 308 pg, p = 0.32). Ligand binding studies of the lung parenchyma revealed a single specific endothelin-1 binding site with an EC50 value (effective concentration causing 50% of the maximum response) of about 1 x 10(-8) mol/L, consistent with the endothelin B subtype. Deep hypothermic circulatory arrest resulted in a significant increase in the number of endothelin-1 receptors in the lung (109 +/- 6 fmol/mg total protein to 135 +/- 9 fmol/mg total protein, p = 0.02).. Deep hypothermic circulatory arrest increases production of endothelin-1 by the pulmonary vascular endothelium. Endothelin-1 production in the pulmonary parenchyma does not change. Expression of endothelin B receptors in the pulmonary parenchyma also increases after cardiopulmonary bypass with deep hypothermic circulatory arrest. This study supports the hypothesis that deep hypothermic circulatory arrest results in pulmonary vascular endothelial activation with increased endothelin-1 mRNA production.

    Topics: Animals; Cardiopulmonary Bypass; Endothelin-1; Gene Expression Regulation; Heart Arrest, Induced; Hemodynamics; Hypertension, Pulmonary; Lung; Random Allocation; Receptors, Endothelin; RNA, Messenger; Swine

1997
Cardiopulmonary dysfunction during porcine endotoxin shock is effectively counteracted by the endothelin receptor antagonist bosentan.
    Shock (Augusta, Ga.), 1997, Volume: 7, Issue:5

    In a porcine endotoxin shock model, the mixed nonpeptide endothelin receptor antagonist bosentan was administered 2 h after onset of endotoxemia (n = 8). Cardiopulmonary vascular changes, oxygen-related variables, and plasma levels of endothelin-1-like immunoreactivity were compared with a control group that received only endotoxin (n = 8). Bosentan abolished the progressive increase in mean pulmonary artery pressure and pulmonary vascular resistance seen in controls. Possible mechanisms include blockade of vasoconstrictive endothelin receptors, and a lesser degree of edema and inflammation indicated by less alveolar protein and a lower inflammatory cell count observed in bronchoalveolar lavage. Further, bosentan restored cardiac index to the pre-endotoxin level by an increase in stroke volume index, improved systemic oxygen delivery, and acid base balance. Because mean arterial blood pressure was unaffected, bosentan reduced systemic vascular resistance. Endotoxemia resulted in an increase in tumor necrosis factor-alpha and endothelin-1-like immunoreactivity plasma levels, the latter being further increased by bosentan. In conclusion, in porcine endotoxemia, treatment with the endothelin receptor antagonist bosentan, administered during fulminate shock, abolished pulmonary hypertension and restored cardiac index. These findings suggest that bosentan could be an effective treatment for reversing a deteriorated cardiopulmonary state during septic shock.

    Topics: Acid-Base Imbalance; Animals; Bosentan; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Female; Hemoglobins; Hypertension, Pulmonary; Lactic Acid; Male; Oxygen Consumption; Shock, Septic; Sulfonamides; Swine; Treatment Outcome; Tumor Necrosis Factor-alpha

1997
Endothelin-1 mediates nitro-L-arginine vasoconstriction of hypertensive rat lungs.
    The American journal of physiology, 1997, Volume: 272, Issue:5 Pt 1

    Inhibition of endothelium-derived nitric oxide (NO) synthesis by L-arginine analogs such as nitro-L-arginine (L-NNA) elicits marked precapillary vasoconstriction in lungs from rats with chronic hypoxia-induced pulmonary hypertension. To investigate the role of endogenous endothelin (ET)-1 in L-NNA-induced vasoconstriction, we tested, in salt solution-perfused hypertensive lungs isolated from chronically hypoxic (3-4 wk at barometric pressure = 410 mmHg) adult male rats, if the pressor responses to L-NNA and exogenous ET-1 were inhibited by either separate or combined ETA and ETB receptor blockade. Whereas only combined pretreatment with 5 microM BQ-123 (selective ETA receptor blocker) and 5 microM BQ-788 (selective ETB receptor blocker) inhibited the response to 100 microM L-NNA, the response to 10 nM ET-1 was reduced by both BQ-123 alone and the combined blockers. Because exogenous ET-1 causes postcapillary vasoconstriction in salt solution-but not blood-perfused normotensive rat lungs, we next compared effects of ETA and ETB receptor blockade on L-NNA and ET-1 vasoconstrictions in blood-perfused hypertensive lungs. In this case, the combined but not the separate effects of BQ-123 and BQ-788 inhibited the responses to both L-NNA and ET-1. The last experiment showed that the use of BQ-788 to inhibit ETB receptor-mediated clearance of circulating ET-1 resulted in greater accumulation of endogenous ET-1 in the perfusate of hypertensive than of normotensive lungs. There was no difference between L-NNA-treated and vehicle control hypertensive lungs in accumulation of ET-1. These results suggest that increased endogenous levels of ET-1 acting through stimulation of both ETA and ETB receptors contribute to the vasoconstriction unmasked by inhibition of NO synthesis in hypertensive rat lungs. The increased ET-1 is apparently not due to the inhibition of NO synthesis, but, instead, its underlying stimulation of smooth muscle cell contraction is counteracted by NO activity.

    Topics: Animals; Blood; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; In Vitro Techniques; Lung; Male; Nitroarginine; Perfusion; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Sodium Chloride; Vasoconstriction

1997
The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Sprague-Dawley rats.
    Journal of cardiovascular pharmacology, 1997, Volume: 29, Issue:6

    Exposure to hypoxia is associated with increased pulmonary artery pressure and plasma endothelin (ET-1) levels and with selective enhancement of ET-1 peptide and messenger RNA (mRNA) and endothelin-A (ET-A) receptor mRNA in rat lung. Our study tested the hypothesis that A-127722, an orally active antagonist of the ET-A receptor, can prevent hypoxia-induced pulmonary hypertension and vascular remodeling in the rat. Pretreatment with A-127722 (3, 10, and 30 mg/kg/day in drinking water for 2 days) caused dose-dependent inhibition of the pulmonary vasoconstrictor response to short-term hypoxia (10% O2, 90 min). Long-term A-127722 treatment (10 mg/kg/day in drinking water for 2 weeks) instituted 48 h before hypoxic exposure attenuated the subsequent development of pulmonary hypertension, the associated right atrial hypertrophy, and pulmonary vascular remodeling. Institution of A-127722 treatment (10 mg/kg/day in drinking water for 4 weeks) after 2 weeks of hypoxia retarded the progression of established hypoxia-induced pulmonary hypertension and right atrial hypertrophy and reversed the pulmonary vascular remodeling despite continuing hypoxic exposure. These findings support the hypothesis that endogenous ET-1 plays a major role in hypoxic pulmonary vasoconstriction/hypertension, right heart hypertrophy, and pulmonary vascular remodeling and suggest that ET-A receptor blockers may be useful in the treatment and prevention of hypoxic pulmonary hypertension in humans.

    Topics: Animals; Atrasentan; Blood Pressure; Cardiomegaly; Endothelin Receptor Antagonists; Endothelin-1; Heart Rate; Hypertension, Pulmonary; Hypoxia; Male; Pulmonary Artery; Pyrrolidines; Rats; Receptor, Endothelin A

1997
Endothelin receptor changes in hypoxia-induced pulmonary hypertension in the newborn piglet.
    The American journal of physiology, 1997, Volume: 273, Issue:1 Pt 1

    Endothelin (ET)-1, a potent vasoconstrictor and mitogen, acts through ETA and ETB receptors and may be involved in the pathogenesis of persistent pulmonary hypertension of the newborn. We hypothesized that hypoxia-induced pulmonary hypertension in the newborn is associated with increased ET-1 release and modified ET receptor characteristics leading to vasoconstriction and vascular remodeling. Therefore, we studied 1-day-old piglets exposed for 3 or 14 days to hypoxia (fraction of inspired O2 = 0.10) or normoxia (controls). ET-1 circulating levels in pulmonary artery and vein were measured. Pulmonary vascular reactivity to ET-1 was evaluated using isolated-perfused lungs. ET binding characteristics were examined in microsomes from pulmonary arteries (down to 100 microns). ET-1 circulating levels are low and are not altered by hypoxia. The magnitude of the initial dilator response to ET-1 decreases after 3 days of hypoxia (P < 0.05), whereas the number of ETB receptors is reduced by 40% in the pulmonary arteries (P < 0.05). ETA receptors are predominant (65-90%) in pulmonary arteries. ETA receptors decrease by 50% after 14 days of exposure to hypoxia (P < 0.05), whereas the constrictor response to ET-1 remains unchanged. The fact that the reduction in vasodilator response parallels the decrease in ETB receptors suggests a decrease in receptor expression. We speculate that the maintenance of the vasoconstrictor response to ET-1 despite a reduction in the number of binding sites is likely due to receptor occupancy. In conclusion, in the newborn piglet pulmonary vasculature, ETA and ETB receptors may be affected differently by hypoxia.

    Topics: Animals; Animals, Newborn; Down-Regulation; Endothelin-1; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Microsomes; Pulmonary Artery; Pulmonary Circulation; Pulmonary Veins; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reference Values; Swine; Vasoconstriction; Vasodilation

1997
[Hypoxia and inflammation--causes of acute and chronic pulmonary artery hypertension].
    Pneumologie (Stuttgart, Germany), 1997, Volume: 51, Issue:5

    Topics: Cell Hypoxia; Culture Techniques; Endothelin-1; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Nitric Oxide; Nitric Oxide Synthase; Organ Culture Techniques; Pneumonia; Pseudomonas Infections; Pulmonary Heart Disease

1997
Arterial endothelin-1 level in pulmonary emphysema and interstitial lung disease. Relation with pulmonary hypertension during exercise.
    The European respiratory journal, 1997, Volume: 10, Issue:9

    This study was undertaken to assess the arterial plasma levels of endothelin-1 (ET-1) and their relationship with pulmonary haemodynamic and gas exchange variables during exercise in patients with emphysema and interstitial lung disease (ILD). Incremental cycle ergometry was performed in all patients up to maximal capacity. At rest, arterial ET-1 levels were higher in emphysema (1.86 +/- 0.35 pg.mL-1; p < 0.02) and ILD (1.75 +/- 0.25 pg.mL-1; p < 0.03) patients than in controls (1.35 +/- 0.18 pg.mL-1). Emphysema (2.08 +/- 0.26 versus 1.70 +/- 0.40 pg.mL-1) and ILD (1.98 +/- 0.21 versus 1.67 +/- 0.02 pg.mL-1) patients with pulmonary hypertension (PH) presented significantly (p < 0.05) higher arterial ET-1 levels than those without. At rest, arterial ET-1 levels were significantly correlated with mean pulmonary arterial pressure (Ppa) in both ILD (r = 0.8, p = 0.01) and emphysema (r = 0.5, p = 0.03) patients. During exercise, the arterial ET-1 levels were significantly correlated with arterial oxygen (Pa,O2) (r = -0.6, p = 0.04), alveolar-arterial oxygen difference (r = 0.8, p = 0.01), and Ppa (r = 0.6, p = 0.04) in ILD patients, but not in those with emphysema. In brief, the results of this study suggest that arterial endothelin-1 is markedly increased in interstitial lung disease and emphysema patients, and that, it is related to the exercise-induced exacerbation of pulmonary hypertension in patients with interstitial lung disease, but not in those with emphysema.

    Topics: Aged; Carbon Dioxide; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Middle Aged; Oxygen; Physical Exertion; Pulmonary Emphysema; Rest

1997
The orally active ET(A) receptor antagonist (+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphe nyl-propionic acid (LU 135252) prevents the development of pulmonary hypertension and endothelial metabolic dysfunction in monocrotaline-treated ra
    The Journal of pharmacology and experimental therapeutics, 1997, Volume: 282, Issue:3

    Pulmonary hypertension is associated with endothelial dysfunction that may mediate or contribute to the disease process; among those abnormalities is an increase in circulating endothelin-1 levels. We investigated the effect of the orally active endothelin A receptor antagonist LU 135252 (LU) on the development of monocrotaline (MCT)-induced pulmonary hypertension and endothelial metabolic dysfunction. Rats were assigned to four groups by receiving a single dose of MCT or saline, followed by once-daily gavage with LU (50 mg/kg) or saline for 3 weeks. Plasma immunoreactive endothelin-1 levels doubled after MCT and were unaffected by LU therapy. The MCT-induced increase in right ventricular systolic pressure (72.5 +/- 15.9 mmHg) and hypertrophy (right ventricle/[left ventricle plus septum weight]; 0.58 +/- 0.08) were reduced by LU to 42.7 +/- 8.5 mmHg (P < .01) and 0.42 +/- 0.05 (P < .01), respectively. LU, however, did not modify MCT-induced pulmonary artery medial hypertrophy. Pulmonary vascular endothelial metabolic activity was evaluated in isolated lungs by measuring endothelium-bound angiotensin-converting enzyme activity using a synthetic angiotensin-converting enzyme substrate, 3H-benzoyl-phenylalanly-glycyl-proline. MCT reduced fractional 3H-benzoyl-phenylalanly-glycyl-proline hydrolysis (0.488 +/- 0.051, P < .01) which was normalized by LU therapy (0.563 +/- 0.050). LU treatment alone had no significant effect on any of these parameters. We conclude that the endothelin A antagonist LU reduces MCT-induced pulmonary hypertension and right ventricular hypertrophy and restores endothelial metabolic function. These results support the development of endothelin antagonists for the treatment of pulmonary hypertension and associated endothelial metabolic abnormalities.

    Topics: Administration, Oral; Animals; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Peptidyl-Dipeptidase A; Phenylpropionates; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Ventricular Function, Right

1997
Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats.
    Journal of applied physiology (Bethesda, Md. : 1985), 1997, Volume: 83, Issue:4

    Endothelin-1 (ET-1), a potent vasoactive and mitogenic peptide, has been implicated in the pathogenesis of several forms of pulmonary hypertension. We hypothesized that nonspecific blockade of ET receptors would blunt the development of monocrotaline (MCT)-induced pulmonary hypertension in rats. A single dose of the nonspecific ET blocker bosentan (100 mg/kg) given to intact rats by gavage completely blocked the pulmonary vasoconstrictor actions of Big ET-1 and partially blunted hypoxic pulmonary vasoconstriction. After 3 wk, MCT-injected (105 mg/kg sc) rats gavaged once daily with bosentan (200 mg/kg) had lower right ventricular (RV) systolic pressure (RVSP), RV-to-body weight (RV/BW) and RV-to-left ventricular (LV) plus septal (S) weight [RV/(LV+S)] ratios and less percent medial thickness of small pulmonary arteries than control MCT-injected rats. Lower dose bosentan (100 mg/kg) had no effect on these parameters after MCT or saline injection. Bosentan raised plasma ET-1 levels but had no effect on lung ET-1 levels. Bosentan (200 mg/kg) also had no effect on wet-to-dry lung weight ratios 6 days after MCT injection. When given during the last 10 days, but not the first 11 days of a 3-wk period after MCT injection, bosentan reduced RV/(LV+S) compared with MCT-injected controls. We conclude that ET-1 contributes to the pathogenesis of MCT-induced pulmonary hypertension and acts mainly during the later inflammatory rather than the acute injury phase after injection.

    Topics: Animals; Antihypertensive Agents; Bosentan; Cardiac Output; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Male; Monocrotaline; Neovascularization, Pathologic; Organ Size; Poisons; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Sulfonamides

1997
Dynamic changes of endothelin-1, nitric oxide, and cyclic GMP in patients with congenital heart disease.
    Circulation, 1997, Nov-04, Volume: 96, Issue:9 Suppl

    Pulmonary hypertension causes major morbidity and mortality after congenital heart surgery, but its mechanism remains unclear.. Plasma endothelin-1 (ET-1), nitric oxide (NO), and cyclic GMP (cGMP) were assayed at 6 intervals in 50 children undergoing cardiopulmonary bypass (CPB): before CPB, 10 minutes into CPB, and 0, 3, 6, and 12 hours after CPB. Three groups based on pulmonary flow and pressure were analyzed: low flow (LF, n=21), high flow/low pressure (systolic pulmonary pressure/systemic pressure ratio, Pp/Ps<50%, HF-LP, n=11), and high flow/high pressure (Pp/Ps> or =50%, HF-HP, n=19). HF-HP and HF-LP received alpha-blockers (chlorpromazine and/or prazosin). HF-HP patients received nitric oxide donors (nitroglycerin/sodium nitroprusside). ET-1 peaked at 6 hours, with its highest level in the HF-HP group (P<.01, by ANOVA). ET-1 correlated significantly with Pp/Ps at 6 hours (r2=.43, P<.005). In the HF-HP group, ET-1 remained above the other groups at 12 hours (12.7+/-2.5 pg/mL versus 6.4+/-1.1 pg/mL versus 6.5+/-3.8 pg/mL P<.05 by ANOVA). NO metabolites were elevated equivalently for the HF-HP and HF-LP groups (5.7+/-2.6 micromol/L versus 0.3.5+/-2.5 micromol/L at 12 hours, P=NS) despite nitric oxide donors and the excess ET-1 in HF-HP patients. Levels of cGMP were similarly elevated in HF-HP and HF-LP patients during this study.. Endogenous NO may decrease vascular tone and maintain low pulmonary pressure in HF-LP patients. High levels of ET-1, inadequate NO production, and/or impaired responses to NO may increase pulmonary pressure in HF-HP patients.

    Topics: Blood Pressure; Cardiopulmonary Bypass; Child, Preschool; Cyclic GMP; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Nitric Oxide; Postoperative Complications

1997
Cyclooxygenase products contribute to endothelin-induced pulmonary hypertension and altered lung mechanics in sheep.
    Pulmonary pharmacology & therapeutics, 1997, Volume: 10, Issue:2

    Endothelins have potent biological effect in vivo which may, in part, be mediated by stimulation of cyclooxygenase metabolism of arachidonic acid. We administered endothelins (ETs) intravenously to chronically instrumented awake sheep with and without pretreatment with meclofenamate (n = 8). 30 micrograms doses of ET-1, ET-2, and ET-3 caused similar degrees of acute elevation of pulmonary artery pressure (PPA), reduction of the dynamic compliance of the lungs (Cdyn), and increases in lung lymph flow. Pretreatment with meclofenamate inhibited the rise in PPA and reduction in Cdyn, but had no effect on lung lymph flow. We conclude that the biological effects of the endothelins on PPA and Cdyn, but not lung fluid balance, are mediated in part by cyclooxygenase products of arachidonic acid metabolism.

    Topics: Animals; Blood Pressure; Cyclooxygenase Inhibitors; Endothelin-1; Endothelin-2; Endothelin-3; Endothelins; Female; Hypertension, Pulmonary; Lung; Lung Compliance; Lymph; Male; Meclofenamic Acid; Sheep

1997
Change of level and expression of endothelin-1 in the lungs of rats with hypoxic pulmonary hypertension.
    Chinese medical journal, 1997, Volume: 110, Issue:2

    To determine whether mRNA for endothelin-1 was present and changed in the lungs of rats exposed to chronic hypoxia.. cRNA probes for rat ET-1 and c-fos were labelled by in vitro transcription with digoxigenin-UTP for in situ hybridization. Endothelin-1 like immunoreactivity (ET-1-LI) in plasma as well as in lung homogenate was measured by radioimmunoassay.. The vascular endothelial cells of pulmonary arteries and the bronchiolar epithelial cells were strongly positive for the ET-1 probe. The perivascular and peribronchiolar smooth muscle were positive for the c-fos probe, primarily. There was little expression of ET-1 and c-fos in the rat lungs in controls. There was significant increase of ET-1-LI levels in rats exposed to hypoxia for 3 weeks, the concentration ET-1-LI in venous samples was 3.85 +/- 1.52 ng/L (P < 0.05 as compared with the control groups), in arterial sample was 4.72 +/- 1.66 ng/L (P < 0.05) and in lung was 2.06 +/- 0.68 ng/g wet lung weight (P < 0.05).. Chronic hypoxia elevated the mean pulmonary arterial pressure, caused vessel remodelling and the right ventricular hypertrophy. These changes were accompanied by an increase of ET-1 in plasma and lung homogenate. The expression and production of ET-1 were localized to endothelium and airway epithelium in the lungs.

    Topics: Animals; Endothelin-1; Gene Expression; Hypertension, Pulmonary; Hypoxia; Lung; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; RNA, Messenger

1997
[The changes of plasma endothelin concentration and its clinical significance in pulmonary hypertension associated with congenital heart defects].
    Hunan yi ke da xue xue bao = Hunan yike daxue xuebao = Bulletin of Hunan Medical University, 1997, Volume: 22, Issue:5

    Plasma endothelin (ET) concentration was measured by means of radioimmunoassay in 38 patients with congeital heart defects among whom 15 patients with pulmonary hypertension (PH) and 23 patients without pulmonary hypertension (non-PH). Blood samples were obtained separately from the femoral vein, right atrium, right ventricle, main pulmonary artery and the femoral artery during catherization. Plasma ET concentration in the PH group was significantly higher than that in the non-PH group at all four sampling sites. In the PH group plasma ET concentration in the pulmonary artery showed higher than that of the right ventricle and the femoral artery, which was significantly in positive correlation with pulmonary artery pressure. It is considered that the elevation of ET plays an important physiological role in the formation of pulmonary hypertension.

    Topics: Adolescent; Adult; Child; Child, Preschool; Double Outlet Right Ventricle; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male

1997
Overexpression of endothelin-1 and enhanced growth of pulmonary artery smooth muscle cells from fawn-hooded rats.
    The American journal of physiology, 1996, Volume: 270, Issue:1 Pt 1

    Increased production of endothelin-1 (ET-1) has been detected in lungs of fawn-hooded rats (FHR) with idiopathic pulmonary hypertension. Accelerated pulmonary artery (PA) smooth muscle cell (SMC) proliferation contributes to vascular remodeling in these rats. We hypothesized that PA SMC would be an important site of enhanced ET-1 expression in FHR lung, that these SMC would have increased growth compared with cells from a normotensive strain, and that this locally produced ET-1 would contribute to the increased growth of these cells. We found that isolated FHR PASMC overexpressed preproET-1 mRNA and produced more ET-1 peptide compared with cells from normotensive Sprague-Dawley control rats (SDR). PA SMC from FHR had increased growth compared with control cells under conditions of serum withdrawal (0.1%), submaximal serum stimulation (0.3%; a condition previously found to be required for detection of growth in response to the comitogen, ET-1), and maximal serum stimulation (10%). Enhanced growth of FHR PA SMC in the presence of 0.3% serum, but not under the other test conditions, was inhibited by the ETA receptor antagonist, BQ-123. In summary, PA SMC from rats with idiopathic pulmonary hypertension overproduce ET-1. This overproduction contributes to the enhanced growth of FHR PA SMC in the presence of 0.3% serum. These cells also possess other unique growth characteristics that are independent of ET-1. Together, these ET-1-dependent and -independent growth properties likely contribute to the hyperplasia of FHR PA SMC found in vivo.

    Topics: Animals; Blood Physiological Phenomena; Cell Division; Endothelin-1; Endothelins; Female; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Protein Precursors; Pulmonary Artery; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; RNA, Messenger; Thymidine

1996
Endothelin plasma levels during heart surgery: influence on pulmonary artery pressure?
    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 1996, Volume: 10, Issue:7

    Some studies found endothelin-1 to be a trigger for pulmonary hypertension. Endothelin-1 is an endothelial derived substance with generally vasoconstrictive properties, but probably vasodilatory effects on pulmonary arteries. The aim of the present study was to look for influences of endothelin-1 plasma values on pulmonary artery pressure.. Endothelin-1 levels during and after cardiac surgery and correlations to pulmonary artery pressure were tested in 10 control patients and 21 patients with pulmonary hypertension (mean pulmonary arterial pressure > 20 mmHg, systolic pulmonary arterial pressure > 30 mmHg).. According to endothelin-1 values before anaesthesia (normal value below 4 pg/ml) patients with pulmonary hypertension could be divided into a "high endothelin-1" (10 patients, mean 8.25 +/- 2.06 pg/ml) and a "normal endothelin-1" (11 patients, mean 2.13 +/- 0.86 pg/ml) subgroup (p < 0.01). Values of the "high endothelin-1" group decreased until end of operation (from 7.58 +/- 2.35 to 2.95 +/- 1.44 pg/ml, n = 6) when pulmonary artery pressure returned to normal. Otherwise they slightly increased (from 9.43 +/- 2.24 to 11.07 +/- 1.96 pg/ml, n = 4). Levels of the "normal endothelin-1" group increased (to 2.55 pg/ml). Endothelin-1 values peaked on the intensive care unit (ICU) in all patients. Baseline endothelin-1 and systolic pulmonary artery pressure values correlated well with each other (r = 0.73, p < 0.001). Endothelin-1 decreased after extracorporeal circulation in all patients in whom pulmonary artery pressure tended to normalise, whereas no rise in pulmonary artery pressure paralleled the marked increase in endothelin-1 on the ICU. Vasodilatory effects of endothelin on pulmonary arteries can attribute to this course.. Endothelin-1 seems not to trigger pulmonary hypertension but rather to vasodilate pulmonary vasculature.

    Topics: Aged; Blood Pressure; Cardiac Surgical Procedures; Endothelin-1; Extracorporeal Circulation; Humans; Hypertension, Pulmonary; Middle Aged; Pulmonary Artery

1996
Endothelin-1 and interleukin-8 in high altitude pulmonary oedema.
    The European respiratory journal, 1996, Volume: 9, Issue:9

    We present a case of high altitude pulmonary oedema (HAPE) with pulmonary hypertension and polymorphonuclear leucocyte (PMN) accumulation in bronchoalveolar lavage fluid (BALF), which occurred in a 21 year old man. Plasma endothelin-1 (ET-1) and interleukin-8 (IL-8) concentration in BALF were elevated on admission, and returned to normal level at recovery, when the pulmonary artery pressure and the PMN counts in BALF were normal. In addition, E-selectin and intercellular adhesion molecule-1 (ICAM-1) in BALF were also slightly increased on admission. These findings suggest that endothelin-1 is a vasoconstrictor which contributes to the pulmonary hypertension in high altitude pulmonary oedema, and that some of the inflammatory mediators play an important role in chemotaxis and accumulation of polymorphonuclear leucocytes in the development of high altitude pulmonary oedema.

    Topics: Adult; Altitude Sickness; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; E-Selectin; Endothelin-1; Humans; Hypertension, Pulmonary; Intercellular Adhesion Molecule-1; Interleukin-8; Leukocyte Count; Male; Mountaineering; Neutrophils; Pulmonary Edema; Pulmonary Wedge Pressure; Vasoconstrictor Agents

1996
Lipopolysaccharide and interleukin 1 augment the effects of hypoxia and inflammation in human pulmonary arterial tissue.
    Proceedings of the National Academy of Sciences of the United States of America, 1996, Oct-29, Volume: 93, Issue:22

    The combined effects of hypoxia and interleukin 1, lipopolysaccharide, or tumor necrosis factor alpha on the expression of genes encoding endothelial constitutive and inducible nitric oxide synthases, endothelin 1, interleukin 6, and interleukin 8 were investigated in human primary pulmonary endothelial cells and whole pulmonary artery organoid cultures. Hypoxia decreased the expression of constitutive endothelial nitric oxide synthase (NOS-3) mRNA and NOS-3 protein as compared with normoxic conditions. The inhibition of expression of NOS-3 corresponded with a reduced production of NO. A combination of hypoxia with bacterial lipopolysaccharide, interleukin 1 beta, or tumor necrosis factor alpha augmented both effects. In contrast, the combination of hypoxia and the inflammatory mediators superinduced the expression of endothelin 1, interleukin 6, and interleukin 8. Here, we have shown that inflammatory mediators aggravate the effect of hypoxia on the down-regulation of NOS-3 and increase the expression of proinflammatory cytokines in human pulmonary endothelial cells and whole pulmonary artery organoid cultures.

    Topics: Blotting, Northern; Blotting, Western; Cell Hypoxia; Endothelin-1; Endothelium, Vascular; Enzyme Induction; Gene Expression Regulation, Enzymologic; Humans; Hypertension, Pulmonary; Interleukin-1; Interleukin-6; Interleukin-8; Isoenzymes; Lipopolysaccharides; Nitric Oxide; Nitric Oxide Synthase; Pulmonary Artery; RNA, Messenger; Vasculitis

1996
Pulmonary hypertension caused by congestive heart failure is ameliorated by long-term application of an endothelin receptor antagonist. Increased expression of endothelin-1 messenger ribonucleic acid and endothelin-1-like immunoreactivity in the lung in c
    Journal of the American College of Cardiology, 1996, Nov-15, Volume: 28, Issue:6

    The purpose of this study was to investigate whether 1) endothelin-1, a potent vasoconstrictor peptide, is involved in progression of pulmonary hypertension caused by congestive heart failure (CHF); and 2) whether long-term treatment with BQ-123, an endothelin receptor antagonist, ameliorates pulmonary hypertension caused by CHF.. Congestive heart failure accompanies pulmonary hypertension, and the severity of pulmonary hypertension is an important determinant of prognosis. Although we reported that production of endothelin-1 is increased in the failing heart in rats with CHF, it is not known whether production of endothelin-1 in the lung is altered by CHF.. Congestive heart failure was induced by coronary artery ligation in rats. Expression of preproendothelin-1 messenger ribonucleic acid (mRNA) in the lung and kidney was determined. Endothelin-1 staining (immunoreactivity) in the lung was studied by immunohistochemical analysis. Effects of long-term BQ-123 treatment on the rats were studied.. Two weeks postoperatively, CHF accompanied by pulmonary hypertension developed in the rats (CHF rats). Expression of preproendothelin-1 mRNA in the lung was markedly higher in the CHF rats than in the sham-operated rats, whereas that in the kidney did not differ between the two groups. Endothelin-1 staining on the pulmonary vascular endothelial cells was more intense in the CHF rats. BQ-123 treatment over a 2-week period in the CHF rats greatly reduced right ventricular systolic pressure and central venous pressure, but it did not affect blood pressure or left ventricular contractility (peak positive first derivative of left ventricular pressure) in these rats.. Long-term BQ-123 treatment greatly ameliorated pulmonary hypertension in the CHF rats. The present study suggests that endothelin-1 plays an important role in the progression of pulmonary hypertension caused by CHF and that an endothelin receptor antagonist may be a new therapeutic agent for CHF-induced pulmonary hypertension.

    Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Hemodynamics; Hypertension, Pulmonary; Immunohistochemistry; Kidney; Lung; Peptides, Cyclic; Protein Precursors; Rats; RNA, Messenger

1996
ETB receptor mediating pulmonary hypertension and bronchoconstriction induced by endothelin-1 in the guinea pig.
    Acta physiologica Hungarica, 1996, Volume: 84, Issue:3

    Endothelin (ET-1) caused dose-related contraction of isolated superfused bronchus and pulmonary artery and bronchoconstriction and pulmonary vascular hypertension of the heart lung preparation (HLP) of guinea pig. The specific ETA receptor antagonist BQ 123 completely blocked the responses of the pulmonary artery, but failed to affect those of bronchus and of HLPs. The specific ETB receptor agonist Sarafotoxin S6c caused contractions of bronchus, but not of pulmonary artery, and bronchoconstriction and pulmonary hypertension in HLPs. It is concluded that non-ETA subtype receptors, perhaps ETB, appear to be the main responsible for the potent pulmonary hypertensive effects of ET-1.

    Topics: Animals; Bronchi; Bronchial Spasm; Endothelin-1; Guinea Pigs; Hypertension, Pulmonary; In Vitro Techniques; Male; Pulmonary Artery; Receptor, Endothelin B; Receptors, Endothelin; Vasoconstrictor Agents; Viper Venoms

1996
[Mechanism of plasma endothelin-1 level elevation and its relation with pulmonary hypertension in chronic cor pulmonale].
    Zhonghua nei ke za zhi, 1996, Volume: 35, Issue:2

    To explore the mechanism of plasma endothelin-1 (ET-1) level elevation and its relation with pulmonary hypertension in chronic cor pulmonale, plasma ET-1 level was measured by using radioimmunoassay in 21 cases of chronic cor pulmonale with acute exacerbation and cardiac catheterization was performed simultaneously. Results, Peripheral venous plasma ET-1 level of the patients was significantly higher than that of controls and also higher than that of peripheral arterial and pulmonary arterial plasma ET-1 level of the patients themselves. The plasma ET-1 level of patients had a significant negative correlation with PaO2 and SaO2 and positive correlation with mean pulmonary arterial pressure (PAPM) and pulmonary vascular resistance index (PVRI). 9 of the patients were treated with mechanical ventilation. After ventilation, PaO2 went up notably and plasma ET-1 level decreased remarkably, PAPM and PVRI also reduced simultaneously.. The causes of plasma ET-1 level elevation in cor pulmonale may be as follows, Firstly, pulmonary alveolar hypoxia increases the release of ET-1 in lungs; Secondly, the ability of the lungs to clean ET-1 decreases because of pulmonary abnormality. High level of plasma ET-1 may induce pulmonary hypertension. The level of plasma ET-1 can be lowered by correcting hypoxic status of the patients and the resulting improvement of pulmonary hemodynamics.

    Topics: Aged; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Artery; Pulmonary Heart Disease; Respiration, Artificial; Vascular Resistance

1996
[Effects of L-arginine on acute hypoxic pulmonary hypertension and production of endothelin-1 in vivo and in cultured endothelial cells].
    Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae, 1996, Volume: 18, Issue:3

    This study is aimed to investigate the effects of L-arginine, a precursor of the formation of nitric oxide, on acute hypoxic pulmonary hypertension in vivo and on production of endothelin-1 both in vivo and in cultured endothelial cells. In mechanically ventilated anesthetized dogs (n = 7), L-arginine (0.5 g/kg) reduced the mean pulmonary arterial pressure and femoral arterial pressure during hypoxic ventilation and its action lasted for about 30 minutes. Meanwhile, plasma endothelin-1 in the pulmonary and femoral artery had no remarkable change. In cultured endothelial cells from umbilical veins, different concentrations of L-arginine had no influence on endothelin-1 level of culture medium in 4 or 24 hours after the addition of L-arginine. These results indicate that L arginine can decrease the pulmonary arterial pressure during acute hypoxia, which may be associated with the increase of nitric oxide production.

    Topics: Animals; Arginine; Blood Pressure; Cells, Cultured; Dogs; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male

1996
[Changes on level and expression of endothelin-1 in the lungs of rats with hypoxic pulmonary hypertension].
    Zhonghua nei ke za zhi, 1996, Volume: 35, Issue:11

    The aim of the present study was to determine whether mRNA for endothelin-1 (ET-1) was present and changed in the lungs of rats exposed to chronic hypoxia, cRNA probes for rat ET-1 and c-fos were labelled by in vitro transcription with digoxigenin-UTP for in situ hybridization. Endothelin-1 like immunoactivity (ET-1-LI) in plasma as well as in lung homogenate was measured by radio-immunoassay. The results showed that the vascular endothelia cells of pulmonary artelics and the bronchiolar epithelial cells were strongly positive for the ET-1 probe. The perivascular and peribronchiolar smooth muscle were positive for the c-fos probe primarily. Whereas, there were little expression of ET-1 and c-fos in the rat lungs in controls. There were significant increase of ET-1-LI levels in rats exposed to hypoxia for 3 weeks, the concentration in venous samples was 3.85 +/- 1.52ng/L (P < 0.05 as compared with the control groups), in arterial sample was 4.72 +/- 1.66ng/L (P < 0.05) and in lung tissue was 2.06 +/- 0.68ng/g wet lung weight (P < 0.05). It is suggested that chronic hypoxia elevated the mean pulmonary arterial pressure, caused vessel remodelling and right ventricular hypertrophy. These changes were accompanied by an increase of ET-1 in plasma and lung homogenate. The expression and production of ET-1 were localized to endothelium and airway epithelium in the lungs.

    Topics: Animals; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Lung; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; RNA, Messenger

1996
[Plasma endothelin-1 and pulmonary hemodynamics at pre-or post exercise in chronic obstructive pulmonary disease].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 1996, Volume: 19, Issue:4

    To investigate whether plasma endothelin-1 (ET-1) affects the pathologic physiologic process of pulmonary hypertension (PH) secondary to chronic obstructive pulmonary disease (COPD).. Forty-six patients with COPD who underwent right float-assisted cardiac cather examination and a supine ergometer exercise test were classified into 3 groups, that is, group A with PH, group B with latent PH and group C without PH.. (1) There was a marked higher ET-1 level in femoral arterial plasma than in pulmonary arterial plasma from group A at pre-or post-exercise or group B at post-exercise. (2) Plasma ET-1 levels of A and B groups post-exercise are higher that that in group B post-exercise than that in group C. (3) ET-1 level is also higher in group B post-exercise than that in group C. (4) There was significant correlation between the ET-1 level and mPAP, PVR, PaO2 of group A at pre- and post-exercise or group B at post-exercise.. These finding suggest a role for ET-1 in regulating pulmonary circulation of PH secondary to COPD).

    Topics: Aged; Blood Gas Analysis; Endothelin-1; Exercise Test; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Middle Aged; Pulmonary Circulation

1996
Physiologic characterization of endothelin A and B receptor activity in the ovine fetal pulmonary circulation.
    The Journal of clinical investigation, 1994, Volume: 93, Issue:5

    To determine the potential contribution of endothelin (ET) to modulation of high pulmonary vascular resistance in the normal fetus, we studied the effects of BQ 123, a selective ET-A receptor antagonist, and sarafoxotoxin S6c (SFX), a selective ET-B receptor agonist, in 31 chronically prepared late gestation fetal lambs. Brief intrapulmonary infusions of BQ 123 (0.1-1.0 mcg/min for 10 min) caused sustained increases in left pulmonary artery flow (Qp) without changing main pulmonary artery (MPA) and aortic (Ao) pressures. In contrast, BQ 123 did not change vascular resistance in a regional systemic circulation (the fetal hindlimb). To determine whether big-endothelin-1 (big-ET-1)-induced pulmonary vasoconstriction is mediated by ET-A receptor stimulation, we studied the effects of big-ET-1 with or without pretreatment with BQ 123. BQ 123 (0.5 mcg/min for 10 min) blocked the rise in total pulmonary resistance caused by big-ET-1. CGS 27830 (100 mcg/min for 10 min), an ET-A and -B receptor antagonist, did not change basal tone but blocked big-ET-1-induced pulmonary vasoconstriction. Brief and prolonged intrapulmonary infusion of SFX (0.1 mcg/min for 10 min) increased Qp twofold without changing MPA or Ao pressures. Nitro-L-arginine (L-NA), a selective endothelium-derived nitric oxide (EDNO) antagonist, blocked vasodilation caused by BQ 123 and SFX. We conclude that: (a) BQ 123 causes sustained fetal pulmonary vasodilation, but did not change vascular resistance in the fetal hindlimb; (b) Big-ET-1-induced pulmonary vasoconstriction may be mediated through ET-A receptor stimulation; and (c) ET-B receptor stimulation causes pulmonary vasodilation through EDNO release. These findings support the hypothesis that endothelin may play a role in modulation of high basal pulmonary vascular resistance in the normal fetus.

    Topics: Animals; Arginine; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Fetus; Hypertension, Pulmonary; Muscle Tonus; Nitric Oxide; Nitroarginine; Peptides, Cyclic; Perfusion; Protein Precursors; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sheep; Vascular Resistance; Viper Venoms

1994
Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension.
    Circulation research, 1993, Volume: 73, Issue:5

    Endothelin-1 (ET-1) is known to have potent contractile and proliferative effects on vascular smooth muscle cells and is known to induce myocardial cell hypertrophy. We studied the pathophysiological role of endogenous ET-1 in rats with monocrotaline-induced pulmonary hypertension. Four-week-old rats were given a single subcutaneous injection of 60 mg/kg monocrotaline (MCT rats) or saline (control rats) and were killed after 6, 10, 14, 18, and 25 days. In the MCT rats, right ventricular systolic pressure progressively increased and right ventricular hypertrophy developed in a parallel fashion. The venous plasma ET-1 concentration also progressively increased, and this increase preceded the development of pulmonary hypertension. The isolated pulmonary artery exhibited a significantly weaker response to ET-1 in the MCT rats on day 25 but not on days 6 and 14. In the MCT rats, the expression of prepro ET-1 mRNA as measured by Northern blot analysis significantly increased in the heart on days 18 and 25, whereas it gradually decreased in the lungs. The peptide level of ET-1 in the lungs also significantly decreased in the pulmonary hypertensive stage. The expression of prepro ET-1 mRNA had increased by day 6 only in the kidneys. Continuous infusion of BQ-123, a selective ETA receptor antagonist, by an osmotic minipump (14.3 mg per day per rat for 18 days) significantly inhibited the progression of both pulmonary hypertension (right ventricular systolic pressure, 77.8 +/- 4.2 [mean +/- SEM] mm Hg [n = 10] versus 52.3 +/- 2.4 mm Hg [n = 7]; P < .01) and right ventricular hypertrophy (right ventricle/[left ventricle +/- septum], 0.56 +/- 0.03 [n = 10] versus 0.41 +/- 0.02 [n = 7]; P < .01). Histological examination revealed that BQ-123 also effectively prevented pulmonary arterial medial thickening. The inhibition of right ventricular hypertrophy by BQ-123 may be partly ascribed to the blockade of excessive stimulation of the heart by ET-1, in addition to the prevention of pulmonary hypertension. The present findings suggest that endogenous ET-1 contributes to the progression of cardiopulmonary alterations in rats with MCT-induced pulmonary hypertension.

    Topics: Animals; Endothelin-1; Endothelins; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; In Vitro Techniques; Lung; Male; Monocrotaline; Peptides, Cyclic; Protein Precursors; Pulmonary Artery; Rats; Rats, Wistar; RNA, Messenger; Vasoconstriction

1993
Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension.
    The American journal of physiology, 1992, Volume: 262, Issue:5 Pt 1

    The role of endogenous circulating or locally produced endothelin-1 (ET-1) in pulmonary hypertensive states is unknown. To investigate this we measured ET-1 levels and preproendothelin-1 (prepro-ET-1) mRNA expression at various ages in control Sprague-Dawley (SDR) rats and in fawn-hooded rats (FHR), a strain which develops idiopathic pulmonary hypertension. Although serum ET-1 levels were similar in SDR and FHR, we found twofold increases in FHR whole lung homogenate ET-1 levels by radioimmunoassay. Coexisting threefold increases in preproET-1 mRNA expression were found in FHR lungs by densitometric analysis of Northern blots and by filter hybridization, suggesting the increase in lung ET-1 was due to enhanced intrapulmonary production of the peptide. To test whether the increase in lung preproET-1 mRNA was primary or secondary to established pulmonary hypertension, we compared preproET-1 mRNA expression prior to development of pulmonary hypertension in fetal (19 day gestation) and neonatal (5 day old) FHR and SDR. Despite similar right ventricular size in SDR and FHR, preproET-1 mRNA was already elevated in neonatal FHR lungs. Furthermore, we found no increase in lung preproET-1 mRNA or ET-1 levels in adult SDR with an equivalent degree of pulmonary hypertension due to chronic hypoxia, implying that the increases in ET-1 production in FHR were not a common consequence of all pulmonary hypertensive states. The functional significance of these observations remains unclear but raises the possibility of a role for ET-1 in the pathophysiology of pulmonary hypertension in the FHR.

    Topics: Animals; Cardiomegaly; Cell Nucleus; Chronic Disease; Endothelin-1; Endothelins; Hemodynamics; Hypertension, Pulmonary; Lung; Peptide Chain Elongation, Translational; Protein Precursors; Radioimmunoassay; Rats; Rats, Inbred Strains; RNA, Messenger; Transcription, Genetic

1992