endothelin-1 and Cardiovascular-Diseases

Discovered almost 40 years ago, the potent vasoconstrictor peptide endothelin-1 (ET-1) has a wide range of roles both physiologically and pathologically. In recent years, there has been a focus on the contribution of ET-1 to disease. This has led to the development of various ET receptor antagonists, some of which are approved for the treatment of pulmonary arterial hypertension, while clinical trials for other diseases have been numerous yet, for the most part, unsuccessful. However, given the vast physiological impact of ET-1, it is both surprising and disappointing that therapeutics targeting the ET-1 pathway remain limited. Strategies aimed at the pathways influencing the synthesis and release of ET-1 could provide new therapeutic avenues, yet research using cultured cells in vitro has had little follow up in intact ex vivo and in vivo preparations. This article summarises what is currently known about the synthesis, storage and release of ET-1 as well as the role of ET-1 in several diseases including cardiovascular diseases, COVID-19 and chronic pain. Unravelling the ET-1 pathway and identifying therapeutic targets has the potential to treat many diseases whether through disease prevention, slowing disease progression or reversing pathology.

Topics: Cardiovascular Diseases; Chronic Pain; COVID-19; Endothelin-1; Endothelins; Humans

Circulating plasma levels of endothelin-1 and related peptides generated during the synthesis of endothelin-1 from its precursor molecule pre-proendothelin-1 have been widely studied as potential risk markers for cardiovascular events. The associations of endothelin-1 with aging, blood pressure, lung function, and chronic kidney disease have been described, as have relations between endothelin-1 levels and evidence of cardiac remodeling, including increased left atrial diameter and increased left ventricular mass. Endothelin-1 has been studied as a predictor of and prognostic marker in coronary artery disease, myocardial infarction, and heart failure. The relationship of endothelin-1 levels to mortality in the general population has also been explored. This review examines the current state of knowledge of circulating endothelin-1 levels as they relate to cardiovascular events and prognosis, and explores future directions for research, including using endothelin-1 or related peptide levels to guide personalized treatment regimens and to select patients for primary prevention strategies.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Cardiovascular System; Clinical Decision-Making; Endothelin-1; Humans; Predictive Value of Tests; Prognosis; Risk Factors

There is substantial research on the vasoactive peptide endothelin (ET)-1 in physiology, as well as in pathology. In fact, pathologically elevated levels of ET-1 have been found in several disease states, such as various cardiovascular diseases, different cancers, some neurodegenerative disorders, as well as in diabetes. Here, we describe and discuss ET-1, its importance in different diseases, and the potential therapeutic effects of ET-traps in the treatment of these diseases. Previous in vitro and in vivo research (in the diabetes disease space) demonstrated that ET-traps potently and significantly prevent the induction of different markers of diabetes-related pathology. This included induction of extracellular matrix (ECM) proteins (collagen 4α1 and fibronectin), which are pathologically elevated in diabetes. The ET-traps prevented induction of these and brought a significant return to non-diabetic levels. We also discuss the merits of using ET-traps over the currently used endothelin receptor antagonists (ERAs) and previously used therapeutic antibodies.

Topics: Cardiovascular Diseases; Diabetes Mellitus; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Neurodegenerative Diseases; Pregnancy; Pregnancy Complications; Receptors, Endothelin

To evaluate the efficacy and safety of Tongxinluo Capsule (, TXL) for patients with cardiac syndrome X (CSX).. Randomized controlled trials (RCTs) regarding TXL in the treatment of CSX were searched in Chinese Biomedicine Literature Database, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Database, PubMed, EMBASE, Cochrane Central Register of Controlled Trial, websites of the Chinese and International Clinical Trial Registry platform up to June 30, 2015. The intervention was either TXL alone or TXL combined with conventional treatment, while the control intervention was conventional treatment with or without placebo. Data extraction, methodological quality assessment and data analyses were performed according to the Cochrane criteria. The primary outcome was a composite event of death, acute myocardial infarction (AMI), angina requiring hospitalization, revascularization, and heart failure. The secondary outcome measures were angina symptom improvement, electrocardiograph (ECG) improvement, and serum endothelin-1 (ET-1) level. The adverse events were also recorded. RevMan 5.3 software was applied for data analyses.. Twelve RCTs (696 patients) were included. Compared with conventional treatment, the addition of TXL to conventional treatment showed some benefits on relieving angina symptoms [risk ratio (RR): 1.46, 95% confidence interval (CI) (1.25, 1.71), P<0.01], and improving ECG [RR: 1.45, 95% CI (1.21, 1.74), P<0.01]. The pooled result did not support a benefit of TXL on reducing the incidence of primary outcome [RR: 0.20, 95% CI (0.02, 1.61), P=0.13]. In addition, TXL decreased serum ET-1 concentration of CSX patients [standardized mean number:-1.63, 95% CI (-2.29,-0.96), P<0.01]. No serious adverse events were reported.. TXL documents potential benefits on attenuating angina symptoms, improving ECG and decreasing serum ET-1 level for CSX patients. However, more rigorous RCTs with high quality are needed to confirm its efficacy and safety.

Topics: Capsules; Cardiovascular Diseases; Drugs, Chinese Herbal; Electrocardiography; Endothelin-1; Humans; Middle Aged; Outcome Assessment, Health Care; Publication Bias; Syndrome

Mounting evidence suggests that there is an internal molecular "clock" within the kidney to help maintain normal renal function. Disturbance of the kidney circadian rhythm may pose a threat to water and electrolyte homeostasis and blood pressure regulation, among many other problems. The identification of circadian genes facilitated a more comprehensive appreciation of the importance of "keeping the body on time"; however, our knowledge is very limited with regard to how circadian genes regulate kidney function. In this brief review, we summarize recent progress in circadian control of renal physiology, with a particular focus on aryl hydrocarbon receptor nuclear translocator-like protein (Arntl1; also called Bmal1).

Topics: Animals; ARNTL Transcription Factors; Blood Pressure; Cardiovascular Diseases; Circadian Rhythm; Endothelin-1; Humans; Kidney; Kidney Diseases; Signal Transduction; Time Factors; Water-Electrolyte Balance

Exposure to air pollution negatively impacts cardiovascular health. Studies show that increased exposure to a number of airborne pollutants increases the risk for cardiovascular disease progression, myocardial events, and cardiovascular mortality. A hypothesized mechanism linking air pollution and cardiovascular disease is the development of systemic inflammation and endothelium dysfunction, the latter of which can result from an imbalance of vasoactive factors within the vasculature. Endothelin-1 (ET-1) is a potent peptide vasoconstrictor that plays a significant role in regulating vascular homeostasis. It has been reported that the production and function of ET-1 and its receptors are upregulated in a number of disease states associated with endothelium dysfunction including hypertension and atherosclerosis. This mini-review surveys epidemiological and experimental air pollution studies focused on ET-1 dysregulation as a plausible mechanism underlying the development of cardiovascular disease. Although alterations in ET-1 system components are observed in some studies, there remains a need for future research to clarify whether these specific changes are compensatory or causally related to vascular injury and dysfunction. Moreover, further research may test the efficacy of selective ET-1 pharmacological interventions (e.g., ETA receptor inhibitors) to determine whether these treatments could impede the deleterious impact of air pollution exposure on cardiovascular health.

Topics: Air Pollutants; Air Pollution; Animals; Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Environmental Exposure; Humans; Occupational Exposure; Prognosis; Receptors, Endothelin; Risk Assessment; Risk Factors; Signal Transduction; Tobacco Smoke Pollution

Endothelin-1, (ET-1, EDN1) is an endogenous polypeptide which demonstrates dominant vasoconstriction activity and mitogenic effect. It has positive inotropic and chronotropic effects on the heart, stimulates the sympathetic and the renin-angiotensin-aldosterone systems and modifies homeostasis. The human ET-1 gene which consists of 6836 nucleotides located on chromosome 6p23-p24 produces Pre-pro-ET-1, which is consequently cleaved to big-ET-1. The mature 21-amino acid ET-1 is generated by subsequent enzymatic cleavage of the big-ET-1. A comprehensive review of the literature on the consequences of different ET-1 gene variants on ET-1 linked diseases has not been accomplished. Many variants of ET-1 gene, including transversion, transition, insertion, and repeated nucleotide polymorphisms, which influence the hereditary risk of cardiovascular and other related diseases have already been located, genotyped, and examined. Among them ten polymorphisms including transversion; -1370 (T-1370G) (rs1800541), +5665 (Lys198Asn) (rs5370), G2288T polymorphisms (rs2070699), and -974 C

Topics: Animals; Cardiovascular Diseases; Endothelin-1; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Phenotype; Polymorphism, Genetic; Vasoconstriction

Obstructive sleep apnea (OSA) is now recognized as an independent and important risk factor for cardiovascular diseases such as hypertension, coronary heart disease, heart failure and stroke. Clinical and experimental data have confirmed that intermittent hypoxia is a major contributor to these deleterious consequences. The repetitive occurrence of hypoxia-reoxygenation sequences generates significant amounts of free radicals, particularly in moderate to severe OSA patients. Moreover, in addition to hypoxia, reactive oxygen species (ROS) are potential inducers of the hypoxia inducible transcription factor-1 (HIF-1) that promotes the transcription of numerous adaptive genes some of which being deleterious for the cardiovascular system, such as the endothelin-1 gene. This review will focus on the involvement of the ROS-HIF-1-endothelin signaling pathway in OSA and intermittent hypoxia and discuss current and potential therapeutic approaches targeting this pathway to treat or prevent cardiovascular disease in moderate to severe OSA patients.

Topics: Animals; Cardiovascular Diseases; Endothelin-1; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Reactive Oxygen Species; Risk Factors; Severity of Illness Index; Signal Transduction; Sleep Apnea, Obstructive

Vascular endothelial cell (EC) dysfunction strongly induces development of cardiovascular and cerebrovascular diseases. Epidemiologic studies demonstrated a preventative effect of dietary polyphenols toward cardiovascular disease. In studies using cultured vascular ECs, polyphenols were recognized to regulate nitric oxide and endothelin-1 (ET-1) production. Furthermore, epigallocatechin-3-gallate inhibited the expression of adhesion molecules by a signaling pathway that is similar to that of high-density lipoprotein and involves induction of Ca(2+)/calmodulin-dependent kinase II, liver kinase B, and phosphatidylinositol 3-kinase expression. The effects of polyphenols on ECs include antioxidant activity and enhancement of the expression of several protective proteins, including endothelial nitric oxide synthase and paraoxonase 1. However, the observed effects of dietary polyphenols in vitro do not always translate to an in vivo setting. As such, there are many questions concerning their physiological mode of action. In this review, we discuss research on the effect of dietary polyphenols on cardiovascular disease and their protective effect on EC dysfunction.

Topics: Administration, Oral; Animals; Apigenin; Aryldialkylphosphatase; Cardiovascular Diseases; Catechin; Diet; Disease Models, Animal; Endothelial Cells; Endothelin-1; Humans; Lipoproteins, HDL; Nitric Oxide; Nitric Oxide Synthase Type III; Polyphenols; Signal Transduction; U937 Cells

Psychosocial factors (i.e., social environment and emotional factors) contribute to an increased risk of cardiovascular disease (CVD). Perturbation in a potent vasoconstrictive peptide endothelin (ET)-1 could be one of the mechanisms linking psychosocial factors to CVD. Our aim was to evaluate the literature on the relationship between plasma ET-1 and psychosocial risk factors for CVD.. MEDLINE and PsycINFO databases were searched for articles on human studies published in peer-reviewed English-language journals through September 2012.. Of the 20 studies that met the inclusion criteria, 14 were experimental studies of acute psychological/mental challenges and 6 were observational studies of psychological and social factors. The inferences drawn from this review were as follows: a) laboratory-induced acute psychological/mental stress may result in exaggerated plasma ET-1 release in those with CVD and those at risk for CVD (positive studies: 5/10); b) chronic/episodic psychosocial factors may have a positive relationship to plasma ET-1 (positive studies: 3/5); and c) race (African American), sex (male), and individual differences in autonomic and hemodynamic responses to stress (parasympathetic withdrawal and elevated blood pressure responsiveness) may moderate the relationship between psychosocial factors and plasma ET-1.. This review indicates that psychosocial risk factors for CVD are associated with elevated plasma ET-1; however, the relatively small number of studies, methodological differences, and variable assessment tools preclude definitive conclusions about the strength of the association. Specific suggestions regarding the selection of psychosocial factors, optimization of acute challenge protocols, and standardization of methods and timing of the ET-1 measures are provided.

Topics: Acute Disease; Blood Pressure; Cardiovascular Diseases; Endothelin-1; Humans; Research Design; Risk Factors; Social Class; Social Environment; Stress, Psychological; Vasoconstriction

Since the discovery of the endothelin system in 1988, it has been implicated in numerous physiological and pathological phenomena. In the cardiovascular system, endothelin-1 (ET-1) acts through intracellular pathways of two endothelin receptors (ETA and ETB) located mainly on smooth muscle and endothelial cells to regulate vascular tone and provoke mitogenic and proinflammatory reactions. The endothelin ETA receptor is believed to play a pivotal role in the pathogenesis of several cardiovascular disease including systemic hypertension, pulmonary arterial hypertension (PAH), dilated cardiomyopathy, and diabetic microvascular dysfunction. Growing evidence from recent experimental and clinical studies indicates that the blockade of endothelin receptors, particularly the ETA subtype, grasps promise in the treatment of major cardiovascular pathologies. The simultaneous blockade of endothelin ETB receptors might not be advantageous, leading possibly to vasoconstriction and salt and water retentions. This review summarizes the role of ET-1 in cardiovascular modulation and the therapeutic potential of endothelin receptor antagonism.

Topics: Animals; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin-1; Humans; Kidney; Receptor, Endothelin A

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

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathologic conditions. Recent evidence implicates endothelin-1 (ET-1) in the induction of placental ER stress in pregnancy disorders. ER stress has previously also been implicated in various other disease states, including neurodegenerative disorders, diabetes, and cardiovascular diseases, as has ET-1 in the pathophysiology of these conditions. However, to date, there has been no investigation of the link between ET-1 and the induction of ER stress in these disease states. Based on recent evidence and mechanistic insight into the role of ET-1 in the induction of placental ER stress, the following review attempts to outline the broader implications of ET-1-induced ER stress, as well as strategies for therapeutic intervention based around ET-1.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Disease; Endoplasmic Reticulum Stress; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Nerve Degeneration; Pregnancy; Pregnancy Complications

Aldosterone exerts direct effects on the vascular system by inducing oxidative stress, inflammation, hypertrophic remodeling, fibrosis, and endothelial dysfunction. Aldosterone exerts its effects through genomic and nongenomic pathways in a mineralocorticoid receptor (MR)-dependent or independent manner. Other aldosterone receptors such as GPR30 have been identified. A tight relation exists between the aldosterone and angiotensin II pathways, as well as with the endothelin-1 system. There is a correlation between plasma levels of aldosterone and cardiovascular risk. Recently, an increasing body of evidence has underlined the importance of aldosterone in cardiovascular complications associated with the metabolic syndrome, such as arterial remodeling and endothelial dysfunction. Blockade of MR is an increasingly used evidence-based therapy for many forms of cardiovascular disease, including hypertension, heart failure, chronic kidney disease, and diabetes mellitus.

Topics: Adipocytes; Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Blood Vessels; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Fibrosis; Gene Expression Regulation; Humans; Hypertension; Hypertrophy; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Muscle, Smooth, Vascular; Oxidative Stress; Receptor, Endothelin A; Receptors, Mineralocorticoid; Renin-Angiotensin System; Signal Transduction; Sodium; Vasculitis; Vasoconstriction

Endothelin-1 (ET-1) is a multifunctional hormone which regulates the physiology of the cardiovascular and renal systems. ET-1 modulates cardiac contractility, systemic and renal vascular resistance, salt and water renal reabsorption, and glomerular function. ET-1 is responsible for a variety of cellular events: contraction, proliferation, apoptosis, etc. These effects take place after the activation of the two endothelin receptors ET(A) and ET(B), which are present - among others - on cardiomyocytes, fibroblasts, smooth muscle and endothelial cells, glomerular and tubular cells of the kidney. The complex and numerous intracellular pathways, which can be contradictory in term of functional response depending on the receptor type, cell type and physiological situation, are described in this review. Many diseases share an enhanced ET-1 expression as part of the pathophysiology. However, the use of endothelin blockers is currently restricted to pulmonary arterial hypertension, and more recently to digital ulcer. The complexity of the endothelin system does not facilitate the translation of the molecular knowledge to clinical applications. Endothelin antagonists can prevent disease development but secondary undesirable effects limit their usage. Nevertheless, the increasing understanding of the effects of ET-1 on the cardiac and renal physiology maintains the endothelin system as a promising therapeutic target.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Endothelin-1; Endothelins; Humans; Kidney; Kidney Diseases; Receptor, Endothelin A; Receptor, Endothelin B

Endothelin (ET)-1 derived from endothelial cells has a much more important role in cardiovascular system regulation than the ET-2 and ET-3 isoforms. Numerous lines of evidence indicate that ET-1 possesses a number of biological activities leading to cardiovascular diseases (CVD) including hypertension and atherosclerosis. Physiological and pathophysiological responses to ET-1 in various tissues are mediated by interactions with ET(A)- and ET(B)-receptor subtypes. Both subtypes on vascular smooth muscle cells mediate vasoconstriction, whereas the ET(B)-receptor subtype on endothelial cells contributes to vasodilatation and ET-1 clearance. Although selective ET(A)- or nonselective ET(A)/ET(B)-receptor antagonisms have been assumed as potential strategies for the treatment of several CVD based on clinical and animal experiments, it remains unclear which antagonisms are suitable for individuals with CVD because upregulation of the nitric oxide system via the ET(B) receptor is responsible for vasoprotective effects such as vasodilatation and anti-cell proliferation. In this review, we have summarized the current understanding regarding the role of ET receptors, especially the ET(B) receptor, in CVD.

Topics: Animals; Cardiovascular Diseases; Endothelin-1; Humans; Receptors, Endothelin

It is well known that adverse conditions during intrauterine life, such as intrauterine growth restriction (IUGR), can result in permanent changes in the physiology and metabolism of the newborn, which in turn leads to an increased risk of disease in adulthood (fetal origin of adult disease hypothesis). In the first part of this review the epidemiological studies in which a correlation between low birth weight and chronic pathologies in adulthood was observed are reported. The second part of the review is focused on metabolomics studies that have revealed an altered metabolism in IUGR patients compared to controls. Together with more classic biomarkers of IUGR, such as endothelin-1, leptin, protein S100B and visfatin, the new holistic metabolomics approach has assumed a crescent role in the identification of disorders in the neonatal metabolic profile, determined by the interconnection of the different processes.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelin-1; Epigenomics; Female; Fetal Growth Retardation; Fetal Nutrition Disorders; Genotype; Humans; Infant, Low Birth Weight; Infant, Newborn; Leptin; Metabolomics; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Risk Factors

Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic volume overload secondary to aortocaval fistula and mitral regurgitation. Accordingly, mast cells have been implicated to have a major role in the pathophysiology of these cardiovascular disorders. In vitro studies have verified that mast cell proteases are capable of activating collagenase, gelatinases and stromelysin. Recent results have shown that with chronic ventricular volume overload, there is an elevation in mast cell density, which is associated with a concomitant increase in matrix metalloproteinase (MMP) activity and extracellular matrix degradation. However, the role of the cardiac mast cell is not one dimensional, with evidence from hypertension and cardiac transplantation studies suggesting that they can also assume a pro-fibrotic phenotype in the heart. These adverse events do not occur in mast cell deficient rodents or when cardiac mast cells are pharmacologically prevented from degranulating. This review is focused on the regulation and dual roles of cardiac mast cells in: (i) activating MMPs and causing myocardial fibrillar collagen degradation and (ii) causing fibrosis in the stressed, injured or diseased heart. Moreover, there is strong evidence that premenopausal female cardioprotection may at least partly be due to gender differences in cardiac mast cells. This too will be addressed.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Cell Differentiation; Cell Proliferation; Complement C5a; Endothelin-1; Female; Heart Failure; Heart Transplantation; Hematopoietic Stem Cells; Humans; Hypertension; In Vitro Techniques; Male; Mast Cells; Myocardial Infarction; Myocardial Reperfusion Injury; Myocarditis; Neuropeptides; Reactive Oxygen Species; Sex Characteristics; Ventricular Remodeling

Biomarkers have been intensively studied in community-acquired pneumonia (CAP) in recent years. In the context of the CAPNETZ study we had the unique opportunity to evaluate old and new biomarkers in a multicentre study with a high number of patients.. In several substudies we found the following results: procalcitonin, CRP and leukocytes show highest values in patients with typical bacterial etiology of CAP, but do not allow individual prediction of etiology. Patients without antibiotic pre-treatment show higher values of biomarkers compared to patients with antibiotic pre-treatment. New cardiovascular biomarkers are good predictors for short- and long-term mortality in CAP, superior to the inflammatory markers procalcitonin, CRP and leukocytes and at least comparable to the clinical CRB-65 score. Pro-Adrenomedullin is among the new biomarkers the one with the best prognostic value.. Biomarkers correlate with the severity of CAP but do not allow individual prediction of etiology. New cardiovascular biomarkers are suitable for the evaluation of short- and long-term prognosis in CAP. The combination of several biomarkers reflecting different pathophysiological pathways has the potential to improve management of CAP in the future.

Topics: Adolescent; Adrenomedullin; Adult; Age Distribution; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Community-Acquired Infections; Comorbidity; Endothelin-1; Female; Germany; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Pneumonia; Predictive Value of Tests; Protein Precursors; Respiratory Rate; Survival Analysis; Vasopressins; Young Adult

Mental stress is an important factor contributing to recognized mechanisms underlying cardiovascular events. Among these, stress-related endothelial dysfunction is an early risk factor that predicts future development of severe cardiovascular disorders. Acute mental stress by a variety of tests impairs endothelial function in humans, although the opposite results have been reported by some investigators. Chronic stress always deteriorates endothelial function in humans and experimental animals. Stress hormones, such as glucocorticoids and pro-inflammatory cytokines, and endothelin-1 liberated in response to mental stress participate in endothelial dysfunction possibly via downregulation of endothelial nitric oxide synthase (eNOS) expression, eNOS inactivation, decreased nitric oxide (NO) actions, and increased NO degradation, together with vasoconstriction counteracting against NO-induced vasodilatation. Catecholamines do not directly affect endothelial function but impair its function when blood pressure elevation by the amines is sustained. Endogenous opioids favorably affect endothelial function, which counteract deteriorating effects of other stress hormones and mediators. Inhibition of cortisol and endothelin-1 production, prevention of pro-inflammatory mediator accumulation, hypnotics, mirthful laughter, humor orientation, and lifestyle modification would contribute to the prevention and treatment for stress-related endothelial dysfunction and future serious cardiovascular disease.

Topics: Animals; Cardiovascular Diseases; Catecholamines; Cytokines; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide; Nitric Oxide Synthase Type III; Opioid Peptides; Risk Factors; Stress, Psychological

Vascular endothelial dysfunction refers to a loss of normal homeostatic functions in the blood vessels. It is characterized by reduced vasodilation and enhanced vasoconstriction functions and chronic prothrombotic and inflammatory activity. There is convincing evidence for endothelial dysfunction in obstructive sleep apnea (OSA): OSA is associated with alterations in vascular structures and their elastic properties, increased circulating cell-derived microparticles, reduced endothelial repair capacity, and vascular reactivity. These alterations may be related to the reduced availability of nitric oxide, which has major vasoprotective effects including vasodilation, inhibition of platelet adhesion and aggregation, inhibition of leukocyte-endothelial adhesion and inhibition of smooth muscle cell proliferation. It is unknown whether endothelial dysfunction in OSA is due to alterations in vasoconstriction mechanisms related to angiotensin II or endothelin 1. In OSA, endothelial dysfunction may be related to chronic intermittent hypoxia and to sleep loss and fragmentation. These conditions may increase the levels of various markers of inflammation and oxidative stress, as well as those of increased procoagulant and thrombotic activity. In addition, they may produce an imbalance of vasomotor function. Endothelial dysfunction contributes to the development of atherosclerosis and cardiovascular disorders associated with OSA. However, other diseases that are also associated with endothelial dysfunction are OSA comorbidities, e.g. obesity, insulin resistance, smoking habits and cardiovascular diseases such as hypertension and coronary artery disease. This makes it difficult to demonstrate a causal link between OSA and endothelial dysfunction; nevertheless, evidence for such a link has been produced by therapeutic studies. The administration of continuous positive airway pressure may reverse changes associated with endothelial dysfunction and, therefore, may decrease the risk of cardiovascular disease in OSA patients.

Topics: Adult; Angiotensin II; Apoptosis; Biomarkers; Blood Coagulation Disorders; Cardiovascular Diseases; Continuous Positive Airway Pressure; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide; Oxidative Stress; Risk Factors; Sleep Apnea, Obstructive

Endothelin (ET-1) is the polypeptide about wide spectrum of physiological effects. The results of numerous experimental and clinical investigations showed its essential role also in the pathophysiology of various cardiovascular diseases (arteriosclerosis, heart failure, pulmonary hypertension, renal failure) and some neoplastic conditions. Thus, ET-1 blocking becomes an interesting tool of modern pharmacotherapy, targeted on neurohormonal mechanisms. The article briefly describes biochemical properties of ET-1 and ET and pathophysiological role of ET-1 in selected cardiovascular diseases.

Topics: Cardiovascular Diseases; Endothelin-1; Humans

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

Factor involved in the pathogenesis of cardiovascular diseases, especially coronary heart disease is the endothelium. The balance between endothelial substances originating from the action, and narrowed the extension is the essence of vascular hemostasis. The main dish is shrinking substances endothelin-1 (ET-1). The aim of the study was to determine the role of signs ET-1 levels in the diagnosis of cardiovascular diseases, especially coronary heart disease. In numerous reports described the impact of increased blood pressure, caused by the press on blood vessels. Most authors reported higher concentrations of ET-1 in serum of patients with ischemic heart disease, particularly its unstable character. High values were observed in patients with myocardial infarction. ET-1 level in the blood is markedly increased in patients with heart failure, correlating with NYHA functional class. High concentrations of ET-1 in many disease entities, and thus its low specificity makes the need for further research on the importance of this substance in the diagnosis of cardiovascular diseases.

Topics: Biomarkers; Cardiovascular Diseases; Coronary Disease; Endothelin-1; Humans; Myocardial Infarction; Sensitivity and Specificity

Endothelium is essential for maintenance of health of the vessel wall and for the local regulation of vascular tone and structure and haemostasis. Regular physical exercise, which is known to promote a favourable cardiovascular state, may improve endothelial function via several mechanisms. Indeed, it augments blood flow and laminar shear stress, resulting in increased nitric oxide production and bioavailability. In this regard, the beneficial effects of training on endothelial function can be mediated in a number of ways, including synthesis of molecular mediators, changes in neurohormonal release and oxidant/antioxidant balance. On the other hand, physical exercise can also elicit systemic molecular pathways connected with angiogenesis and chronic anti-inflammatory action with consequent modification of the endothelial function. However, its benefit depends on the type and intensity of training performed. While strenuous exercise increases oxidative metabolism and produces a pro-oxidant environment, only regular moderate physical activity promotes an antioxidant state and preserves endothelial function. Thus, exercise may have a beneficial effect on the development of cardiovascular disease through preserving endothelial function.

Topics: Aging; Cardiovascular Diseases; Cell Adhesion Molecules; Eicosanoids; Endothelin-1; Endothelium, Vascular; Exercise; Humans; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Nitric Oxide; Oxidative Phosphorylation; Oxidative Stress; Shear Strength; Stress, Physiological; Tissue Plasminogen Activator; Vasodilation

Topics: Atherosclerosis; Brachial Artery; Cardiovascular Diseases; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Humans; Ischemic Attack, Transient; Meta-Analysis as Topic; Nitric Oxide; Risk Factors; Tunica Intima; Tunica Media

There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ET(A) receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub-arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized.

Topics: Animals; Aspartic Acid Endopeptidases; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Drug Delivery Systems; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Humans; Metalloendopeptidases; Receptors, Endothelin

Previous studies have shown that consumption of fruit and vegetables plays a role in preventing the onset of CVD. These beneficial effects have been linked to the presence of polyphenolic compounds in plant-derived foods and their antioxidant capacity. It has been hypothesised that polyphenols may also have a direct effect on vascular endothelial cell growth and the expression of genes involved in angiogenesis and other roles of the endothelium. Previous studies in this area have tended to use concentrations of polyphenols that are supraphysiological (1-100 microm). The effects of more physiological concentrations (0.1 microm) of various individual polyphenols on gene expression were therefore investigated in cultured human umbilical vein endothelial cells (HUVEC) using both microarray and quantitative RT-PCR methodologies. Treatment of HUVEC with ferulic acid, quercetin or resveratrol (0.1 microm) resulted in changes to gene expression that for the three treatments amounted to significant (>2-fold) down-regulation of the expression of 363 genes and significant (>2-fold) up-regulation of 233 genes of the 10 000 genes present on the microarray. The majority of these genes were affected by resveratrol. Quantitative RT-PCR studies indicated that resveratrol (0.1 microm) significantly increased the expression of the gene encoding endothelial NO synthase (eNOS), which synthesises the vasodilator molecule NO, and both resveratrol and quercetin decreased expression of the potent vasoconstrictor, endothelin-1 (ET-1), while ferulic acid had no effect. The effects of resveratrol (0.1 microm) were also investigated when HUVEC were under oxidative stress following treatment with H2O2 (0-50 microm), which dose-dependently increased expression of eNOS and ET-1. Resveratrol stimulated eNOS mRNA in the absence of H2O2 and still allowed the increase with H2O2, but the effects were not additive. In contrast, resveratrol blocked the stimulatory effect of H2O2 on ET-1 expression. Hence, resveratrol has potent effects at a physiological concentration (0.1 microm) that would be expected to result in vasodilation and therefore help reduce blood pressure and the risk of CVD.

Topics: Cardiovascular Diseases; Cells, Cultured; Dose-Response Relationship, Drug; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Flavonoids; Gene Expression Profiling; Gene Expression Regulation; Humans; Nitric Oxide Synthase; Oligonucleotide Array Sequence Analysis; Phenols; Polyphenols; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes; Umbilical Veins

High dietary fat intake is a major risk factor for the development of obesity, which is frequently associated with diseases such as hypertension and diabetes and thus accelerated atherosclerosis. Angiotensin II and endothelin-1 are powerful growth factors and vasoconstrictors implicated in regulating vascular tone, vascular structure, and inflammation. Reduced bioactivity of nitric oxide and increased formation of reactive oxygen species (ROS) have been associated with obesity and high dietary fat intake. This article reviews the effects of high-fat diet on vascular functional changes in rodents and humans. Changes include alterations in vasoconstrictor function and receptor expression, and modulators of endothelium-dependent vascular tone (eg, nitric oxide- or endothelium-dependent contracting factor-mediated responses). Novel vasodilator effects of ROS and the anatomic heterogeneity of vascular responses are discussed. The beneficial effects of vasoactive mediators on vascular function could play a role for susceptibility to obesity-dependent hypertension, which is present in many, but not all, obese patients.

Topics: Angiotensin II; Animals; Cardiovascular Diseases; Cardiovascular System; Dietary Fats; Endothelin-1; Humans; Nitric Oxide; Obesity; Reactive Oxygen Species; Renin-Angiotensin System; Risk Factors

Numerous vasoactive agents play an important physiological role in regulating vascular tone, reactivity and structure. In pathological conditions, alterations in the regulation of vasoactive peptides result in endothelial dysfunction, vascular remodeling and vascular inflammation, which are important processes underlying vascular damage in cardiovascular disease. Among the many vasoactive agents implicated in vascular (patho)biology, angiotensin II (Ang II), endothelin (ET), serotonin and natriuretic peptides appear to be particularly important because of their many pleiotropic actions and because they have been identified as potential therapeutic targets in cardiovascular disease. Ang II, ET-1, serotonin and natriuretic peptides mediate effects via specific receptors, which belong to the group of G-protein-coupled receptors. ET, serotonin and Ang II are primarily vasoconstrictors with growth-promoting actions, whereas natriuretic peptides, specifically atrial, brain and C-type natriuretic peptides, are vasodilators with natriuretic effects. Inhibition of vasoconstrictor actions with drugs that block peptide receptors, compounds that inhibit enzymes that generate vasoactive peptides or agents that increase levels of natriuretic peptides are potentially valuable therapeutic tools in the management of cardiovascular diseases. This review focuses on ET, natriuretic peptides and serotonin. The properties and distribution of these vasoactive agents and their receptors, mechanisms of action and implications in cardiovascular (patho)physiology will be discussed.

Topics: Cardiovascular Diseases; Endothelin-1; Heart; Humans; Natriuretic Peptides; Serotonin

Endothelin (ET)-1 is a potent vasoconstrictor peptide originally isolated from endothelial cells. Its production is stimulated in a variety of different cell types under the influence of risk factors for cardiovascular disease and during the development of cardiovascular disease. Based on these observations and the biological effects induced by ET-1, including profound vasoconstriction, pro-inflammatory actions, mitogenic and proliferative effects, stimulation of free radical formation and platelet activation, ET-1 has been implicated as an important factor in the development of vascular dysfunction and cardiovascular disease. In the following the pathogenic role of ET-1, the mechanisms underlying the involvement of ET-1 for the development of vascular dysfunction and the potentially beneficial therapeutic effects of selective ET(A) and dual ET(A)/ET(B) receptor antagonists will be discussed. In particular the changes of pathophysiological importance mediated by ET-1 in clinical studies are reviewed. These changes may be of significance for the development of various cardiovascular diseases beyond pulmonary arterial hypertension which is the currently approved indication for ET receptor antagonists.

Topics: Animals; Bosentan; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Vasoconstriction

Endothelin (ET) has been implicated in the pathogenesis of several cardiovascular disorders because of its powerful vasoconstrictor and growth-promoting properties. The ET family consists of three isoforms, ET-1, ET-2 and ET-3. ET-1 appears to be the predominant member of the family generated by vascular endothelial cells. In view of the multiple cardiovascular actions of ET-1, there has been much interest in its contribution to the pathophysiology of hypertension and arteriosclerosis. We have been investigating the roles of ET(A) and ET(B) receptors in ET-1-related cardiovascular diseases using subtype-selective ET receptor antagonists and ET(B) receptor-deficient animals. Our studies have demonstrated that ET-1 overproduction and ET(A)-mediated ET-1 actions seem to play a crucial role in the development of several types of hypertensive and post-ischemic diseases. On the other hand, ET-1 biosynthesis and release are regulated at the transcriptional level, and various endogenous substances are known to stimulate ET-1 gene expression by DNA binding of transcription factors. We and others have recently demonstrated that nuclear factor-kappaB (NF-kappaB), a transcription factor with a pivotal role in inducing genes involved in immune, inflammatory and stress responses, is responsible for endothelial ET-1 production. In in vivo studies, agents that can inhibit the NF-kappaB activation improved the development of ET-1-related cardiovascular diseases. Thus, NF-kappaB inhibition may be a pertinent treatment for ET-1 related diseases.

Topics: Acute Kidney Injury; Animals; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Humans; Hypertension; NF-kappa B; Nitric Oxide; Receptor, Endothelin A

There is now increasing evidence that endothelial dysfunction is an early event in the pathophysiology of cardiovascular diseases and can be corrected with certain therapies such as angiotensin converting enzyme inhibitors angiotensin type I receptor antagonists and stains independently of blood pressure lowering effects. Restoring endothelial function appears to be a crucial target since endothelial dysfunction predicts cardiovascular events in various situations such as coronary artery disease peripheral artery disease, or hypertension and in patients undergoing vascular surgery. Preclinical and clinical data strongly support that endothelin receptor antagonists belong to this restricted class of pharmacological agents able to act on the endothelium, and offer a potential therapeutic approach for numerous diseases associated with endothelial dysfunction. The purpose of this review will be therefore, 1) to propose mechanisms by which ET-1 can cause endothelial dysfunction; 2) to provide an overview of pathological situations associated with endothelial dysfunction related to ET-1; and 3) to assemble evidence on efficacy of endothelin receptor antagonists for improvement of endothelial function.

Topics: Animals; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Models, Biological; Receptors, Endothelin

Endothelial cells synthesize and release various factors that regulate angiogenesis, inflammatory responses, hemostasis, as well as vascular tone and permeability. Endothelial dysfunction has been associated with a number of pathophysiological processes. Oxidative stress appears to be a common denominator underlying endothelial dysfunction in cardiovascular diseases. However, depending on the pathology, the vascular bed studied, the stimulant, and additional factors such as age, sex, salt intake, cholesterolemia, glycemia, and hyperhomocysteinemia, the mechanisms underlying the endothelial dysfunction can be markedly different. A reduced bioavailability of nitric oxide (NO), an alteration in the production of prostanoids, including prostacyclin, thromboxane A2, and/or isoprostanes, an impairment of endothelium-dependent hyperpolarization, as well as an increased release of endothelin-1, can individually or in association contribute to endothelial dysfunction. Therapeutic interventions do not necessarily restore a proper endothelial function and, when they do, may improve only part of these variables.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Hemostasis; Humans; Hypertension; Inflammation; Nitric Oxide; Oxidative Stress; Rats; Rats, Inbred SHR; Reactive Oxygen Species

The NAD(P)H oxidase is an enzyme assembled at the cellular membrane able to produce superoxide anion from NADH or NAD(P)H (nicotinamide adenine dinucleotide phosphate). It is one of the main sources of superoxide anion in cardiovascular tissues and its role in a variety of cardiovascular disorders such as atherosclerosis, cardiac hypertrophy, and endothelial dysfunction was recently proposed. Although, many factors and receptors were shown to lead to the activation of the enzyme, particulary the type 1 angiotensin receptor, the pathways involved are still widely unknown. Despite the identification of factors such as c-Src and protein kinase C implicated in the acute activation of NAD(P)H oxidase, the signalling involved in the sustained activation of the enzyme is probably far more complex than was previously envisioned. In this review, we describe the role of endothelin-1 in NAD(P)H oxidase signalling after a sustained stimulation by angiotensin II. Since most pathologies caused by an NAD(P)H oxidase overactivation develop over a relatively long period of time, it is necessary to better understand the long-term signalling of the enzyme for the development or use of more specific therapeutic tools.

Topics: Angiotensin II; Animals; Cardiovascular Diseases; Endothelin-1; Humans; NADPH Oxidases

Topics: Animals; Binding Sites; Cardiovascular Diseases; DNA-Binding Proteins; Endothelin-1; Gene Expression Regulation; Humans; Hypertension; Hypoxia-Inducible Factor 1; Neurofibromin 1; Nuclear Proteins; Regulatory Factor X Transcription Factors; RNA, Messenger; Transcription Factors; Transcription, Genetic

Polycystic ovary syndrome (PCOS) is a good example of obesity-related cardiovascular complication affecting young women. PCOS is not only considered a reproductive problem but rather represents a complex endocrine, multifaceted syndrome with important health implications. Several evidences suggest an increased cardiovascular risk of cardiovascular disease associated with this syndrome, characterized by an impairment of heart structure and function, endothelial dysfunction and lipid abnormalities. All these features, probably linked to insulin-resistance, are often present in obese PCOS patients. Cardiovascular abnormalities represent important long-term sequelae of PCOS that need further investigations.

Topics: Biomarkers; Cardiovascular Diseases; Endothelin-1; Female; Humans; Hypertrophy, Left Ventricular; Insulin Resistance; Obesity; Plasminogen Activator Inhibitor 1; Polycystic Ovary Syndrome; Risk Assessment; Risk Factors

Both endothelin(ET)-1 and oxidative stress have been the subjects of intense investigation within the cardiovascular field over the past decade and a half, yet little is known about the precise relationship between these important modulators of vascular function. There is a firm evidence that ET-1 can stimulate the production of superoxide via NADPH oxidase activation, and at the same time, reactive oxygen species appear to stimulate ET-1 production. What is less clear is how these changes participate in the pathogenesis of vascular dysfunction. There is mixed evidence on whether oxidative stress plays a role in ET-dependent hypertension, however, a specific influence of ET-induced oxidative stress to reduce vascular reactivity is more convincing. The current review summarizes recent investigations into the relationship between ET-1 and oxidative stress and highlights several areas that require further investigation.

Topics: Animals; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Hypertension; Oxidative Stress; Superoxides

Topics: Adult; Animals; Apoptosis; Arginine; Atherosclerosis; Cardiovascular Diseases; Cells, Cultured; Child; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; GTP-Binding Proteins; Hemodynamics; Humans; Macrophages; Male; Multienzyme Complexes; Mutation; NADH, NADPH Oxidoreductases; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Pregnancy; Rats; Rats, Inbred Dahl; Reactive Oxygen Species; Risk Factors; RNA, Messenger

Although obesity is strongly associated with cardiovascular disease (CVD), the endogenous relationship between obesity and CVD is still not fully clear. Emerging evidence from both animal and human studies indicates that leptin may play an important role in obesity-related CVD. Besides modulating appetite and metabolism, leptin has also been shown to increase sympathetic nerve activity, stimulate generation of reactive oxygen species, upregulate endothelin-1 production and potentiate platelet aggregation. These effects of leptin may contribute to hypertension, endothelial dysfunction and atherosclerosis in obese individuals. Better understanding the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. These recent discoveries could lead to novel strategies for treatment of obesity-associated CVD.

Topics: Adult; Animals; Cardiovascular Diseases; Endothelin-1; Humans; Leptin; Obesity; Reactive Oxygen Species; Sympathetic Nervous System; Ventricular Remodeling

Topics: Angiotensin II; Arteriosclerosis; Cardiovascular Diseases; Cell Adhesion Molecules; Coagulants; Diabetes Mellitus; Endothelin-1; Endothelium, Vascular; Female; Humans; Pre-Eclampsia; Pregnancy; Vasoconstrictor Agents; Vasodilator Agents

The aim of the present paper is to analyze recent literature concerning the incidence of cardiovascular complications in women suffering from polycystic ovary syndrome (PCOS). The study takes into consideration all the studies that have been published to date in the international literature in order to clarify whether or not PCOS is able to determine an early onset or whether it is responsible for a higher global incidence of cardiovascular complications in adult age. The main difficulty lies in the absence of prospective studies owing to the long period of time existing between the diagnosis of PCOS and cardiovascular disease which notoriously has a long latency period. Much attention has been paid in the literature, on the other hand, to the analysis of the incidence of cardiovascular risk factors in women suffering from PCOS. Although epidemiological studies have not evidenced an increased incidence of death from cardiovascular events in women suffering from PCOS, the above conclusions might well be invalidated by a patient selection bias, by obsolete diagnostic criteria or by medical or surgical therapies that could influence the outcome of the disease and which are not considered as a confusion factor. Undoubtedly, all the data available up to the present suggest that PCOS possesses the intrinsic conditions that lead to an increased incidence of factors predisposing to cardiovascular diseases. Future longitudinal studies of a prospective nature might be useful for understanding whether the higher incidence of predisposing factors might also lead to greater expectation of cardiovascular events or whether medical therapies or other factors (improvement in endocrine symptomatology with the menopause?) may prevent the increase in the expected incidence of these events.

Topics: Biomarkers; Blood Coagulation Disorders; Cardiovascular Diseases; Carotid Stenosis; Endothelin-1; Endothelium, Vascular; Female; Humans; Hyperlipidemias; Hypertension; Incidence; Menstrual Cycle; Myocardial Ischemia; Polycystic Ovary Syndrome; Risk Factors

Topics: Amino Acid Sequence; Animals; Azepines; Cardiovascular Diseases; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Indans; Indoles; Molecular Sequence Data; Peptides, Cyclic; Pyrimidines; Receptors, Endothelin; Sulfonamides; Vasoconstriction

Topics: Animals; Aspartic Acid Endopeptidases; Bosentan; Cardiovascular Diseases; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Hemodynamics; Humans; Metalloendopeptidases; Organophosphonates; Peptides, Cyclic; Quinazolines; Receptors, Endothelin; Sulfonamides; Sulfonylurea Compounds; Tetracyclines; Tetrazoles

Three isopeptides of endothelin (ET-1, -2, and -3) exert various actions through stimulation of two sub-types of receptor (ETA and ETB). Vascular endothelial cells produce only ET-1. In addition to its powerful vasoconstrictor action, ET-1 has direct mitogenic actions on cardiovascular tissues, as well as comitogennic actions with a wide variety of growth factors and vasoactive substances. ET-1 also promotes the synthesis and secretion of growth factors and various substances, including extracellular constituents. These effects of endogenous ET-1 would naturally be thought to be concerned with the development and/or aggravation of chronic cardiovascular diseases; e.g., hypertension, pulmonary hypertension, vascular remodeling (stenosis, atherosclerosis), renal failure, and heart failure. A large number of peptide and orally active non-peptide endothelin receptor antagonists have been developed, and utilized to analyze physiological and pathophysiological roles of endogenous ET-1. These antagonists have been shown to exert excellent therapeutic effects in animal models of various kinds of diseases by either acute or chronic treatment. Therapeutic treatment of patients suffering from the above-mentioned cardiovascular diseases with ET-receptor antagonists have also been taking place, and bosentan (ETA/ETB antagonist) was recently approved by the FDA as a formal therapeutic drug for pulmonary hypertension. In this review, perspectives for therapeutic applicability of ET-receptor antagonists will be explored.

Topics: Animals; Bosentan; Cardiovascular Diseases; Chronic Disease; Clinical Trials as Topic; Disease Models, Animal; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; Growth Substances; Humans; Mitogens; Receptors, Endothelin; Sulfonamides; Vasoconstriction

The natriuretic peptides are a group of structurally related but genetically distinct peptides. Four types of natriuretic peptides have been found thus far: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and Dendroaspis natriuretic peptide (DNP). ANP and BNP are secreted mainly from the heart and function as hormones with vasodilatory and natriuretic effects. CNP originates mainly from endothelial cells with a paracrine effect to induce vasodilation. Other effects of natriuretic peptides including negative inotropy, antimitogenic and anticoagulation have been described. Three types of natriuretic peptide receptors mediate their functions, and among them two are cGMP-coupled. Clearance of natriuretic peptides is via its clearance receptor through the action of neutral endopeptidases. Natriuretic peptides interact with other vasoactive peptides including endothelin. The putative role of natriuretic peptides in the pathophysiology of various cardiovascular diseases including congestive heart failure, hypertension, ischemic heart disease, and cardiomyopathy are discussed. Natriuretic peptide plasma levels are used for the diagnosis and therapeutic follow-up of congestive heart failure patients. Increasing the levels of natriuretic peptides by natriuretic peptide mimetics and neutral endopeptidase inhibitors may provide a new therapeutic strategy for the treatment of cardiovascular diseases such as congestive heart failure and hypertension.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Cardiovascular Diseases; Elapid Venoms; Endothelin-1; Humans; Intercellular Signaling Peptides and Proteins; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Peptides; Protease Inhibitors

A proteasome-dependent proteolytic pathway serves important functions in cell cycle control and transcriptional regulation; however, its pathophysiological role in cardiovascular diseases is still unclear. We have recently obtained evidence that proteasome inhibitors are capable of preventing the development of deoxycorticosterone acetate (DOCA)-salt-induced hypertension or hypertrophy and of ischemic acute renal failure (ARF). Beneficial effects of the proteasome inhibitors were accompanied by a decrease in endothelin-1 (ET-1) content in the aorta and kidney of DOCA-salt and ischemic ARF animals, respectively. In addition, there is evidence showing that the reduction of nuclear factor-kappaB (NF-kappaB) activation is involved in the mechanisms for suppressive effects of proteasome inhibitors on ET-1 gene transcription and the consequent decrease in ET-1 mRNA expression in the cultured vascular endothelial cells. These findings suggest that a proteasome-dependent proteolytic pathway has a crucial role in the pathogenesis of ET-1-related cardiovascular diseases, probably through the activation of NF-kappaB, and also that the use of proteasome inhibitors may be a novel approach to the treatment of cardiovascular diseases.

Topics: Acute Kidney Injury; Animals; Blood Vessels; Cardiovascular Diseases; Endothelin-1; Humans; Hypertension; Hypertrophy; Ischemia; Kidney; Proteasome Endopeptidase Complex; Proteasome Inhibitors

The endothelium-derived 21 amino acid peptide endothelin-1 is one of the most potent vasoconstrictors. Endothelin-1 exerts its effects upon a variety of vascular and non-vascular cells through a direct interaction with specific receptors. Beyond its vasoconstrictive action on vascular smooth muscle cells endothelin-1 has mitogenic and pro-inflammatory properties. The present review deals with current experimental and clinical evidence for the involvement of endothelin-1 in several cardiovascular disorders with inflammatory components. We further discuss the potential clinical relevance of the endothelin system and therapeutical perspectives of anti-endothelin strategies in the treatment of cardiovascular disease.

Topics: Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Humans; Muscle, Smooth, Vascular; Raynaud Disease; Vasoconstriction

One of the two receptors by which the potent vasoactive effects of endothelin (ET)-1 are mediated is the ET(B) receptor (ET(BR)), which is found in several tissues, but, more importantly from a cardiovascular point of view, on the endothelial cell. The endothelial cell also has the unique capability of releasing ET-1, as well as other factors, such as the endothelial-derived relaxing factors and prostacyclin, which counteract the myotropic effects of the peptide. The secretory and contractile responses to ET-1 rely on G-protein-coupled ET(BR)s, as well as ET(A)-G-protein-coupled receptor-like proteins. The mitogenic properties of ET-1 via ET(A) receptors (ET(AR)s) coupled to mitogen-activated protein kinases and tyrosine kinases on the vascular smooth muscle may occur in conjunction with the anti-apoptotic characteristics of the endothelial ET(BR)s. Interestingly, most of the relevant antagonists and agonists for both ET(AR)s and ET(BR)s have been developed by the pharmaceutical industry. This highlights the therapeutical potential of compounds that act on ET receptors. In normal as well as in physiopathological conditions, the ET(BR) plays an important role in the control of vascular tone, and must be taken into account when using ET receptor antagonists for the treatment of cardiovascular diseases. For the management of congestive heart failure, renal failure and primary pulmonary hypertension, the most recent literature supports the use of selective ET(AR) antagonists rather than mixed antagonists of ET(AR)s and ET(BR)s. Nonetheless, validation of this view will have to await the first clinical trials comparing the actions of ET(A) to mixed ET(A)/ET(B) receptor antagonists.

Topics: Animals; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Humans; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

Topics: Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelin-3; Endothelins; Humans; Receptors, Endothelin

Blood pressure is controlled by a complex combination of processes that influence cardiac output and peripheral vascular resistance. Multiple genes potentially influence each parameter involved in the control of blood pressure, and individuals with the same blood pressor level do not necessarily have the same genotype at relevant loci, nor do individuals with the same genotype at particular loci necessarily have the same blood pressure. Nevertheless, pharmacogenetic studies of vascular reactivity will certainly allow the analysis of the mechanisms affected by genes, and lead to a better understanding of the epidemiologic observations seen in large groups of patients. Polymorphisms in the genes of the renin-angiotensin system allow definition of the "genetic profile" associated with a higher risk of cardiovascular disease, and can also be linked to significant changes in vascular reactivity in arteries isolated from patients carrying the polymorphisms.

Topics: Angiotensin II; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Endothelin-1; Endothelins; Genotype; Humans; Hypertension; Nitric Oxide Synthase; Polymorphism, Genetic; Protein Precursors; Renin-Angiotensin System

Endothelin (ET)-1 is an endothelium-derived peptide with potent vasoconstrictor and proliferative properties. The ET system is activated in several cardiovascular disease states associated with functional and structural vascular changes, including hypertension and heart failure. The two ET receptor subtypes are known as ET(A)R and ET(B)R. The former is located mainly on vascular smooth muscle cells and is responsible for mediating vasoconstriction and proliferation. The latter is present predominantly on endothelial cells and mediates vasorelaxation as well as ET-1 clearance. Activation of smooth muscle ET(B)R causes vasoconstriction. Selective ET(A)R antagonists as well as nonselective ET(A)R-ET(B)R antagonists have been developed. Studies with animal models and early-phase clinical trials provided strong evidence that these agents are effective in the treatment of heart failure, essential hypertension, pulmonary hypertension, and atherosclerosis. However, the complexity of biologic effects mediated by two different receptor subtypes complicates therapy with selective versus nonselective ET receptor antagonists. In addition to subtype selectivity and potency, changes in receptor subtype distribution under different pathologic conditions and different patient populations will play a crucial role in the evaluation of these potentially therapeutic drugs.

Topics: Animals; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Humans; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Cardiovascular Diseases; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelin-1; Endothelin-Converting Enzymes; Humans; Metalloendopeptidases; Neprilysin; Protease Inhibitors; Rats

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

Topics: Cardiovascular Diseases; Coronary Vessels; Endothelin-1; Endothelins; Endothelium, Vascular; Fibrinolytic Agents; Free Radical Scavengers; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Muscle, Smooth, Vascular; Neutrophil Infiltration; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Protein Precursors; Simvastatin

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

Endothelin (ET)-1, a 21-amino acid peptide, is the predominant isoform of the endothelin peptide family. ET-1 is ubiquitously expressed and stimulates vasoconstriction and cell proliferation. Enzymes such as endothelin converting enzymes (ECE), chymases, and non-ECE metalloproteinases contribute to the synthesis of ET-1, which is regulated in an autocrine fashion in vascular and nonvascular cells. Endothelin ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are involved in the clearance of ET-1, inhibition of endothelial apoptosis, release of nitric oxide and prostacyclin, and inhibition of ECE-1 expression. Most cardiovascular diseases, such as arterial hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, pulmonary hypertension, and renal failure are associated with local activation of the endothelin system. Experimental studies and first clinical trials suggest that ET-1 is importantly involved in the functional and structural changes in the cardiovascular system, and that many of the actions of ET-1 are mediated through pressure-independent mechanisms. Endothelin antagonists promise to be successful as a new class of drugs for the treatment of cardiovascular diseases.

Topics: Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Humans; Receptors, Endothelin

Endothelin-1 was first identified by Yanagisawa in 1988 and shown to be a potent and sustained vasoconstrictor and pressure peptide. Endothelial cells line all blood vessels and are capable of generating endothelin-1; receptors for the endothelins are widely expressed, particularly in tissues involved in cardiovascular regulation, including the heart, blood vessels, kidney and brain. Endothelin-1 has potent vasoconstrictor properties and the coronary, renal and cerebral blood vessels appear particularly sensitive. Moreover, endothelin-1 has activity as co-mitogen, interacts with the sympathetic nervous and renin-angiotensin system. These properties indicate a likelihood that the endothelin system is of functional importance in human cardiovascular physiology and may play a role in the pathophysiology of cardiovascular disease. It is possible that endothelin antagonists might be effective in the treatment of diseases associated with intermittent or sustained vasoconstriction.

Topics: Cardiovascular Diseases; Endothelin-1; Endothelins; Humans; Receptors, Endothelin; Vasoconstriction

Topics: Animals; Cardiovascular Diseases; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; GTP-Binding Proteins; Humans; Oligopeptides; Peptides, Cyclic; Piperidines; Receptors, Endothelin; Signal Transduction

1. Brachial artery infusion of endothelin (ET)-1 causes transient vasodilatation followed by sustained vasoconstriction of the forearm vascular bed, whereas ET-1 antagonists cause sustained vasodilatation. These data suggest that ET-1 contributes to basal vascular tone. 2. Systemic infusion of ET-1 increases blood pressure and total peripheral vascular resistance and reduces heart rate and cardiac output. The renal and pulmonary circulations are particularly sensitive to the vasoconstrictor effects of ET-1. Systemic infusion of the ETA/B receptor antagonist TAK-044 reduces mean arterial pressure and peripheral vascular resistance. 3. Plasma ET-1 concentrations are not elevated in essential hypertension; however, insulin resistance may be a major determinant of plasma ET-1 concentrations. Vascular sensitivity to ET-1 is normal or may be increased in essential hypertension. 4. Plasma ET-1 concentrations are increased in moderate and severe heart failure and are correlated with clinical and haemodynamic measures of severity. Endothelin-1 contributes to increased vascular tone in cardiac failure. 5. Plasma ET-1 concentrations increase following myocardial infarction and persistent elevation predicts an increased mortality within the subsequent 12 months. 6. Preliminary data suggest that interventions that reduce the activity of the endothelin system may have a beneficial effect in heart failure and myocardial infarction.

Topics: Cardiovascular Diseases; Endothelin-1; Forearm; Heart Failure; Humans; Hypertension; Myocardial Ischemia

Endothelins are peptides released from endothelial cells. According to both their structure and receptor affinity, three isoforms may be identified. Endothelin-1 is secreted abluminally by endothelial cells, and binds ETA and ETB2 receptors expressed on vascular smooth muscle cells, and ETB1 expressed on endothelial cells. ETA and ETB2 receptors stimulation induces smooth muscle contraction and proliferation, whereas ETB1 receptors stimulation induces relaxation.. Endothelin-1 plays an important role in maintaining peripheral vascular tone and systemic blood pressure. It is recognized to have a role in various diseases associated with vasoconstriction and vascular hypertrophy.. Recent development of endothelin receptor antagonists seems promising for the treatment of heart failure and systemic hypertension, with interesting results obtained from short-term clinical trials. However, better evaluation of these drugs requires further long-term studies regarding not only the above mentioned diseases but also ischemic heart disease or pulmonary hypertension. Endothelin antagonists are therefore new therapeutic agents able to inhibit a vasoconstricting system that has been recently discovered. Results of ongoing clinical studies are awaited with interest.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Humans; Muscle, Smooth, Vascular; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

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

A series of gene targeting research have revealed novel roles of endothelins (ETs), peptides with potent vasoconstrictive and proliferative activities, in neural crest development in mammals. The phenotype of mice lacking the ET-1/ET-A receptor-mediated signalling affects cranial/cardiac neural crest-derived structures including the branchial arches and great vessels, and is highly similar to a set of the phenotypes of the avian neural crest ablation model. In contrast, mice lacking the ET-3/ET-B receptor-mediated signalling have defects in enteric neurons and melanocytes derived from trunk/vagal neural crest, resulting in megacolon and coat color spotting. Thus, both distinct pathways of the ET system seem to participate in the normal development of different neural crest lineages. Moreover, mutations in the human ET-3 and ET-B receptor genes have been identified in patients with Hirschsprung disease. As for the mechanisms involving the ET system in neural crest development, HANDs and Goosecoid, transcriptional factors essential for embryogenesis, have been suggested as key molecules downstream to the ET-mediated signalling in cranial/cardiac neural crest.

Topics: Animals; Cardiovascular Diseases; Craniofacial Abnormalities; Endothelin-1; Endothelin-3; Endothelins; Gene Expression Regulation, Developmental; Hirschsprung Disease; Humans; Mice; Mice, Knockout; Neural Crest; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

Topics: Animals; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Humans; Receptor, Endothelin A

There is convincing evidence that the prevalence of erectile dysfunction is increased among men with ischaemic heart disease. This association may be attributed to the fact that both erectile dysfunction and ischaemic heart disease share similar risk factors (e.g. hypertension, dyslipidaemia, diabetes and smoking). Nitric oxide (NO) activity is adversely affected, in penile and vascular tissue, by these risk factors. It is therefore not surprising that a defect in NO activity is thought to play a role in the pathogenesis of both erectile dysfunction and ischaemic heart disease. We consider this evidence and propose that defective NO activity provides a unifying explanation for the association between these two conditions. Further research in this area may improve our understanding of the pathogenesis of cardiovascular diseases as a whole.

Topics: Cardiovascular Diseases; Diabetes Mellitus; Endothelin-1; Humans; Hypercholesterolemia; Male; Muscle, Smooth, Vascular; Nitric Oxide; Penile Erection; Penis

An increasing body of evidence indicates that impairment of endothelial function is crucially involved in the pathogenesis of cardiovascular disease. Injury to the endothelium precipitates atherosclerosis by causing smooth-muscle cell migration and proliferation, induction of expression of growth factors, and impairment of plasma coagulation and endogenous fibrinolysis. Angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists are widely used in patients with cardiovascular disease and have beneficial vascular effects beyond blood pressure control alone. Both exhibit a synergistic hemodynamic profile. Whereas calcium antagonists dilate large conduit and resistance arteries, ACE inhibitors inhibit the renin-angiotensin system (RAS) and reduce sympathetic outflow. Certain calcium antagonists, such as verapamil and diltiazem, reduce heart rate, whereas dihydropyridines tend to increase it. In the blood vessel wall, the local vascular effects of ACE inhibitors and calcium antagonists are complementary. ACE inhibitors diminish transformation of angiotensin I (Ang I) into angiotensin II (Ang II) and prevent degradation of bradykinin [which stimulates nitric oxide (NO) and prostacyclin formation]. Calcium antagonists inhibit the effects of Ang I and endothelin-1 (ET-1) at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of NO. The resistance circulation is particularly dependent on extracellular Ca2+, thereby explaining why nifedipine and verapamil effectively inhibit ET-induced vasoconstriction in vitro and in vivo. In hypertension, ACE inhibitors and calcium antagonists markedly improve structural changes and increase the media/lumen ratio in resistance arteries. Long-term combination therapy with verapamil and trandolapril is particularly effective in reversing endothelial dysfunction in hypertensive animals. ACE inhibitors substantially reduce morbidity and mortality in patients with left ventricular dysfunction after myocardial infarction (MI). There is a strong trend indicating benefit with verapamil as well, but this is confined to patients with a normal left ventricular ejection fraction. Clinical studies have confirmed that calcium antagonists exhibit antiatherogenic properties. However, the clinical relevance of these findings has recently been disputed because short-acting dihydropyridines are reported to increase risk for MI. Because ACE inhibitors and calcium antagonists exhibit synerg

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Arteriosclerosis; Calcium Channel Blockers; Cardiovascular Diseases; Drug Therapy, Combination; Endothelin-1; Endothelium, Vascular; Humans; Muscle, Smooth, Vascular

Endothelin-1 (ET-1) is the most potent vasoconstrictor yet described. The active 21-amino-acid peptide is derived from the conversion of the inactive precursor "Big ET-1" by an enzyme called endothelin-converting enzyme. In addition to its potent action as a vasoconstrictor, endothelin promotes growth and proliferation of smooth muscle and myocardial hypertrophy. ET-1 levels are elevated in acute myocardial infarction (MI), atherosclerosis, renal failure, diabetes, pulmonary hypertension, and congestive heart failure (CHF). ET-1 levels correlate extremely well with the seriousness of the pathophysiologic condition. ET-1 levels at 72 h post MI accurately predict long-term survival. In patients with heart failure, ET-1 levels also predict long-term outcome, with the prognosis being severely compromised in patients with elevated ET-1 levels. Levels of plasma big ET-1 have been demonstrated to predict 1-year mortality and have been shown to be a better predictor of 1-year outcome than plasma atrial natriuretic peptide and norepinephrine, NYHA class, age, and echocardiographic left ventricular parameters. Although a small number of studies have reported beneficial effects of ACE inhibitors on ET-1 levels in animal models, most reports in humans have not found an effect of ACE inhibitors on ET-1 levels. Only one ACE inhibitor, fosinopril, has been shown to be effective in normalizing ET-1 levels in clinically relevant situations, such as the long-term study of patients with CHF. This observation may point to a superior role of fosinopril compared with other ACE inhibitors in CHF patients and may indicate beneficial effects of fosinopril beyond blood pressure control.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Cardiovascular Diseases; Endothelin-1; Heart Failure; Humans; Prognosis; Receptors, Endothelin

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Cardiovascular Diseases; Diabetic Nephropathies; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Hemodynamics; Humans; Kidney Failure, Chronic; Metalloendopeptidases; Renin-Angiotensin System

Topics: Aged; Aging; Animals; Cardiovascular Diseases; Endothelin-1; Female; Glycosaminoglycans; Humans; Kidney; Lipoproteins; Male; Risk Factors; Smoking

Topics: Animals; Cardiovascular Diseases; Coronary Vessels; Endothelin-1; Endothelins; Humans; Receptors, Endothelin; Vasoconstriction

Endothelin-1 is a vasoactive peptide produced by endothelial cells. Endothelin-1 exerts potent vasoconstrictory effects upon vascular smooth muscle cells, and it may play a role in the pathogenesis of several cardiovascular disorders such as atherosclerosis and ischemic conditions. Besides the investigation of its biological effects, knowledge about cellular mechanisms of the synthesis, signal transduction pathway(s) and receptor-mediated actions on target cells is mandatory for the development of pharmacological strategies in the treatment of cardiovascular disease. In this review cellular mechanisms of endothelial endothelin-1 synthesis and release are discussed.

Topics: Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Humans; Muscle, Smooth, Vascular; Receptors, Endothelin; Signal Transduction; Vasoconstriction

The endothelins are a family of potent vasoconstrictors and mitogenic agents. Since the isolation of ET-1 in 1988 the worldwide scientific research interest has mushroomed, resulting in considerable knowledge about molecular biology, biochemistry and pharmacological actions of these peptides. A body of evidence has parallelly emerged pointing to their role in some physiological phenomena as well as in the pathophysiology of cardiovascular disease. The future therapeutic use of anti-endothelin strategies may offer clinical benefit in many of these conditions.

Topics: Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Hemodynamics; Humans; Muscle, Smooth, Vascular; Receptors, Endothelin; Vasoconstriction

The endothelins (ET) are a family of contractile peptides made up of 21 amino acids. They are synthesised from larger precursors and they are expressed in different tissues. ET-1 is synthesised in endothelial cells by means of a specific endothelin converting enzyme and it is assumed that most of it is secreted into the basolateral compartment. It acts in a paracrine manner on the ETA and ETB2 receptors located on the surface of the vascular smooth muscle to elicit an increase in intracellular calcium and vasoconstriction. The circulating ET-1 can also activate endothelial ETC and ETB1 receptors releasing vascular smooth muscle relaxing factors, such as nitric oxide and prostacyclin. At present, it is generally accepted that ET-1 is a vasodilator in physiological conditions acting on endothelium ETB1 receptors. Nevertheless, in pathological situations such as hypertension, heart failure, acute myocardial infarction, acute renal failure and vasospastic conditions (Raynaud's disease and subarachnoid haemorrhage), ET-1 levels increase and it binds to the receptors present in vascular smooth muscle in such a way that its vasoconstrictor effect is manifested. Currently, experimental and clinical evidence exists to support the importance of the development of drugs that block the production or actions of ET for use in cardiovascular medicine, particularly in conditions in which these peptides are clearly implicated.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Humans; Molecular Sequence Data; Muscle, Smooth, Vascular; Receptors, Endothelin

Only 10 years ago, the vasoconstricting peptide endothelin was discovered; it is produced by endothelial cells. Different isoforms and receptors of endothelin have been identified. The effects of endothelin-I, the most important isoform, are mainly vasoconstriction and proliferation of cells. In the last few years endothelin receptor antagonists have become available, which can delineate the clinical importance of the endothelin system. Possible indications for endothelin receptor blockers are renal disease (acute and chronic renal failure) and cardiovascular disease (heart failure; restenosis after percutaneous transluminal coronary angioplasty (PTCA); pulmonary hypertension; systemic hypertension). There is also a possible role for endothelin receptor blockers in oncology (prostatic carcinoma). Currently clinical trials are being carried out to determine the efficacy of these compounds for the above-mentioned indications.

Topics: Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Female; Humans; Kidney Diseases; Male; Prostatic Neoplasms; Receptors, Endothelin

Endothelin-1, a member of a novel family of regulatory peptides, is the most potent vasoconstrictor and pressor substance known. Endothelin-1 is a 21-amino-acid endothelium-derived peptide causing uniquely sustained vasoconstriction. In addition, endothelin-1 has pronounced effects on the coronary, renal and cerebral circulations, enhances responses to other vasoconstrictors, and is comitogenic. Recent studies have shown that the endothelins are essential for normal fetal development, and that endothelin-1 plays an important physiological role in the regulation of basal vascular tone and blood pressure in healthy humans. There is now also a wealth of evidence suggesting that endothelin-1 is a key mediator in a range of cardiovascular diseases associated with sustained vasoconstriction, such as chronic heart failure, and with vasospasm, such as subarachnoid haemorrhage. In addition, endothelin-1 appears to act in opposition to nitric oxide to promote the atherosclerotic process. There are a large number of oral and intravenously active endothelin antagonists entering clinical development and a number of clinical studies, particularly with endothelin receptor antagonists, are now under way. Such studies are beginning to define the role of the endothelins in cardiovascular disease and to confirm the potential of the endothelin system as an important new therapeutic target.

Topics: Amino Acid Sequence; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Endothelin-1; Humans; Molecular Sequence Data; Vasoconstriction

The endothelin family of peptides are extremely potent endogenous vasoconstrictor and pressor agents. Of the 3 isoforms, endothelin-1 is the major isoform produced by the vascular endothelium and is, therefore, likely to be of most importance for regulation of vascular function. Two endothelin receptor subtypes have so far been cloned in mammalian species; ET A, and ET B. Both receptor subtypes are found on smooth muscle cells and mediate the vasoconstrictor and pressor actions of endothelin. The ET B receptor is also found on vascular endothelial cells and mediates endothelin-dependent vasodilatation through release of nitric oxide and prostacyclin. Since their discovery in 1988, the endothelins have been the subject of intense research on their physiological function and potential pathophysiological role in cardiovascular disease. There is now good evidence that endothelin regulates vascular tone and blood pressure, and studies to support the development of endothelin receptor antagonists in conditions associated with chronic vasoconstriction, such as hypertension and heart failure, as well as in vasospastic disorders, such as subarachnoid haemorrhage and Raynaud's disease. There are now a number of selective ET A and combined ET A/B receptor antagonists available for preclinical studies. However, it is still not clear which of these will prove to be of most therapeutic value. Some of these agents are currently being assessed in early phase clinical trials. Endothelin receptor antagonists represent a novel therapeutic approach to a fundamental and newly discovered endogenous vasoconstrictor mechanism. The results of the current clinical trials are awaited with considerable interest.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Coronary Disease; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension; Migraine Disorders; Raynaud Disease; Subarachnoid Hemorrhage

SURROGATE END-POINTS: Pharmacotherapy of cardiovascular disease has been increasingly validated in large interventional trials to assess its efficacy, safety and costs. As endpoints, morbidity and mortality are evaluated. More recently, surrogate end-points have been included in interventional trials, both to increase our understanding of pathogenic mechanisms and for their potential use as markers of risk in patients.. The endothelium lies in a strategic anatomical position between the circulating blood and vascular smooth muscle and hence is a major local mediator of cardiovascular function. Also, endothelial cells are a target for mechanical forces and cardiovascular risk factors in the circulation. Thus, it is not surprising that their function becomes impaired at an early stage in the disease process. The cells are able to produce numerous proteins and mediators. This review focuses on nitric oxide and endothelin-1, which are endothelium-derived relaxing and constrictor factors, respectively. Nitric oxide also prevents platelet adhesion and aggregation and the adhesion of monocytes. Both substances also affect vascular structure in that nitric oxide inhibits while endothelin stimulates vascular smooth muscle proliferation and migration.. Endothelial function and the effects of nitric oxide and endothelin in particular can be evaluated in the coronary circulation by quantitative coronary angiography and Doppler flow wire, and in the peripheral circulation with plethysmography and new ultrasound/Doppler devices. In these experimental set-ups, lipid-lowering drugs and angiotensin converting enzyme (ACE) inhibitors have been evaluated. Lipid-lowering drugs improve endothelium-dependent vasodilation in the coronary and forearm circulation of patients with hyperlipidemia and atherosclerosis. Similarly, ACE inhibitors improve coronary vasomotion in patients with coronary artery disease and normal lipid levels. In hypertension, ACE inhibitors have failed to improve endothelium-dependent vasodilation, while studies with other drugs are planned.. Endothelial function can now be assessed precisely in patients in vivo, in both the coronary and the peripheral circulation. Tests can detect early dysfunction in patients with a risk of cardiovascular disease and the possible effects of drugs on endothelial function. Large interventional trials are needed to establish how far endothelial dysfunction can or cannot predict clinical outcome.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Hypolipidemic Agents; Nitric Oxide

Endothelin (ET)-1, an endothelium-derived peptide, is the most potent vasoconstrictor agent described to date. ET-1 also has positive inotropic and chronotropic effects in the heart and is a co-mitogen in both cardiac and vascular myocytes. The major elements of the system involved in formation of ET-1 and its isopeptides, as well as the receptors mediating their effects, have been cloned and characterised. Antagonists of the ET receptors are now available, and selective inhibitors of the ET-converting enzymes are being developed. Early studies using receptor antagonists support the involvement of ET-1 in the pathophysiology of several cardiovascular diseases. The relative merits of ET-converting enzyme inhibitors and receptor antagonists for the treatment of cardiovascular disease are discussed.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Endothelin-1; Humans; Molecular Sequence Data; Receptors, Endothelin

Cardiovascular disease is a complication of systemic inflammatory diseases including anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). The mechanisms of cardiovascular morbidity in AAV are poorly understood, and risk-reduction strategies are lacking. Therefore, in a series of double-blind, randomized case-control forearm plethysmography and crossover systemic interventional studies, we examined arterial stiffness and endothelial function in patients with AAV in long-term disease remission and in matched healthy volunteers (32 each group). The primary outcome for the case-control study was the difference in endothelium-dependent vasodilation between health and AAV, and for the crossover study was the difference in pulse wave velocity (PWV) between treatment with placebo and selective endothelin-A receptor antagonism. Parallel in vitro studies of circulating monocytes and platelets explored mechanisms. Compared to healthy volunteers, patients with AAV had 30% reduced endothelium-dependent vasodilation and 50% reduced acute release of endothelial active tissue plasminogen activator (tPA), both significant in the case-control study. Patients with AAV had significantly increased arterial stiffness (PWV: 7.3 versus 6.4 m/s). Plasma endothelin-1 was two-fold higher in AAV and independently predicted PWV and tPA release. Compared to placebo, both selective endothelin-A and dual endothelin-A/B receptor blockade reduced PWV and increased tPA release in AAV in the crossover study. Mechanistically, patients with AAV had increased platelet activation, more platelet-monocyte aggregates, and altered monocyte endothelin receptor function, reflecting reduced endothelin-1 clearance. Patients with AAV in long-term remission have elevated cardiovascular risk and endothelin-1 contributes to this. Thus, our data support a role for endothelin-blockers to reduce cardiovascular risk by reducing arterial stiffness and increasing circulating tPA activity.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Cardiovascular Diseases; Case-Control Studies; Cross-Over Studies; Endothelin-1; Fibrinolysis; Heart Disease Risk Factors; Humans; Pulse Wave Analysis; Receptors, Endothelin; Risk Factors; Tissue Plasminogen Activator; Vascular Stiffness

Polycystic ovary syndrome (PCOS) is a complex syndrome with cardiovascular risk factors, including obesity and insulin resistance. PCOS is also associated with high androgens, increases the risk of cardiovascular dysfunction in women. Due to the complexity of PCOS, had it has been challenging to isolate specific causes of the cardiovascular dysfunction. Our measure of cardiovascular dysfunction (endothelial dysfunction) was most profound in lean women with PCOS. The endothelin-1-induced vasodilation in these PCOS subject, was dependent on the ET. Endothelin-1 (ET-1) is an indicator of endothelial injury and dysfunction and is elevated in women with androgen excess polycystic ovary syndrome (AE-PCOS). The endothelin B receptor (ET

Topics: Adult; Androgens; Cardiovascular Diseases; Dihydrotestosterone; Endothelin-1; Endothelium, Vascular; Estrogens; Ethinyl Estradiol; Female; Glucose Tolerance Test; Humans; Microvessels; Nitric Oxide; Obesity; Polycystic Ovary Syndrome; Receptor, Endothelin B; Skin; Vascular Endothelial Growth Factor A; Vasodilation; Young Adult

Obesity and increased arterial stiffness are independent risk factors for cardiovascular disease. Arterial stiffness is increased in obese individuals than in age-matched nonobese individuals. We demonstrated that dietary modification and exercise training are effective in reducing arterial stiffness in obese persons. However, the differences in the effect on arterial stiffness between dietary modification and exercise training are unknown. The purpose of the current study was to compare the effect of dietary modification and aerobic exercise training on arterial stiffness and endothelial function in overweight and obese persons. Forty-five overweight and obese men (48 ± 1 year) completed either a dietary modification (well-balanced nutrient, 1680 kcal/day) or an exercise-training program (walking, 40-60 min/day, 3 days/week) for 12 weeks. Before and after the intervention, all participants underwent anthropometric measurements. Arterial stiffness was measured based on carotid arterial compliance, brachial-ankle pulse wave velocity (baPWV), and endothelial function was determined by circulating level of endothelin-1 (ET-1) and nitric oxide metabolite (nitrites/nitrate as metabolite: NOx). Body mass and waist circumference significantly decreased after both intervention programs. Weight loss was greater after dietary modification than after exercise training (-10.1 ± 0.6 kg vs. -3.6 ± 0.5 kg, p < .01). Although arterial stiffness and the plasma levels of ET-1 and NOx were improved after dietary modification or exercise training, there were no differences in those improvements between the 2 types of interventions. Exercise training improves arterial function in obese men without as much weight loss as after dietary modification.

Topics: Adult; Body Mass Index; Cardiovascular Diseases; Diet Records; Diet, Reducing; Endothelin-1; Endothelium, Vascular; Exercise; Humans; Japan; Life Style; Male; Middle Aged; Nitric Oxide; Obesity; Overweight; Oxygen Consumption; Risk Factors; Vascular Stiffness; Waist Circumference; Walking; Weight Loss

Prospective cohort studies showed inverse associations between the intake of flavonoid-rich foods (cocoa and tea) and cardiovascular disease (CVD). Intervention studies showed protective effects on intermediate markers of CVD. This may be due to the protective effects of the flavonoids epicatechin (in cocoa and tea) and quercetin (in tea).. We investigated the effects of supplementation of pure epicatechin and quercetin on vascular function and cardiometabolic health.. Thirty-seven apparently healthy men and women aged 40-80 y with a systolic blood pressure (BP) between 125 and 160 mm Hg at screening were enrolled in a randomized, double-blind, placebo-controlled, crossover trial. CVD risk factors were measured before and after 4 wk of daily flavonoid supplementation. Participants received (-)-epicatechin (100 mg/d), quercetin-3-glucoside (160 mg/d), or placebo capsules for 4 wk in random order. The primary outcome was the change in flow-mediated dilation from pre- to postintervention. Secondary outcomes included other markers of CVD risk and vascular function.. Epicatechin supplementation did not change flow-mediated dilation significantly (1.1% absolute; 95% CI: -0.1%, 2.3%; P = 0.07). Epicatechin supplementation improved fasting plasma insulin (Δ insulin: -1.46 mU/L; 95% CI: -2.74, -0.18 mU/L; P = 0.03) and insulin resistance (Δ homeostasis model assessment of insulin resistance: -0.38; 95% CI: -0.74, -0.01; P = 0.04) and had no effect on fasting plasma glucose. Epicatechin did not change BP (office BP and 24-h ambulatory BP), arterial stiffness, nitric oxide, endothelin 1, or blood lipid profile. Quercetin-3-glucoside supplementation had no effect on flow-mediated dilation, insulin resistance, or other CVD risk factors.. Our results suggest that epicatechin may in part contribute to the cardioprotective effects of cocoa and tea by improving insulin resistance. It is unlikely that quercetin plays an important role in the cardioprotective effects of tea. This study was registered at clinicaltrials.gov as NCT01691404.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Cacao; Cardiovascular Diseases; Catechin; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Female; Healthy Volunteers; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Nitric Oxide; Quercetin; Tea; Triglycerides; Vascular Stiffness

To demonstrate the efficacy of exenatide versus insulin glargine on endothelial functions and cardiovascular risk markers.. Thirty-four insulin and incretin-naive patients with type 2 diabetes mellitus (body mass index 25-45 kg/m(2)) who received metformin for at least two months were randomized to exenatide or insulin glargine treatment arms and followed-up for 26 weeks. Measurements of endothelial functions were done by ultrasonography, cardiovascular risk markers by serum enzyme-linked immunosorbent assay, and total body fat mass by bioimpedance.. Levels of high sensitivity-C-reactive protein and endothelin-1 decreased (27.5% and 18.75%, respectively) in the exenatide arm. However, in the insulin glargine arm, fibrinogen, monocyte chemoattractant protein-1, leptin and endothelin-1 levels (13.4, 30.2, 47.5, and 80%, respectively) increased. Post-treatment flow mediated dilatation and endothelium independent vascular responses were significantly higher in both arms (p=0.0001, p=0.0001). Positive correlation was observed between the changes in body weight and endothelium-independent vasodilatation, leptin, plasminogen activator inhibitor type 1 and endothelin-1 in both arms (r=0.376, r=0.507, r=0.490, r=0.362, respectively).. Insulin glargine improved endothelial functions, without leading to positive changes in cardiovascular risk markers. Exenatide treatment of 26 weeks resulted in reduced body weight and improvement in certain cardiovascular risk markers and endothelial functions.

Topics: Biomarkers; Blood Glucose; Brachial Artery; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Peptides; Prognosis; Risk Factors; Ultrasonography; Vasodilation; Venoms

The experimental aim of this study was to determine whether ET-1-mediated vasoconstrictor tone is elevated in adult humans with impaired fasting blood glucose concentrations, independent of other cardiovascular risk factors.. Forearm blood flow (FBF: plethysmography) responses to intra-arterial infusion of selective ETA receptor blockade (BQ-123: 100 nmol/min for 60 min) and non-selective ETA/B blockade (BQ-123 + BQ-788: 50 nmol/min for 60 min) were determined in 28 middle-aged, sedentary adults (17 M/11 F): 14 with normal fasting blood glucose (age: 57 ± 2 yr; 6 F/8 M; BMI: 29.2 ± 0.9 kg/m(2); glucose: 4.9 ± 0.1 mmol/L) and 14 impaired fasting blood glucose (58 ± 1 yr; 5 F/9 M; 29.6 ± 1.1 kg/m(2); 5.8 ± 0.1 mmol/L) concentrations.. Selective ETA receptor blockade elicited a significantly greater (∼20%) increase in FBF in the impaired fasting glucose adults compared with the normoglycemia controls. ETA/B blockade resulted in a further 2-fold increase (P < 0.05) in FBF above that elicited by ETA receptor antagonism in the impaired fasting glucose but not normal fasting glucose adults. There was a positive correlation between fasting blood glucose levels and the peak vascular responses to ETA (r = 0.44; P < 0.05) and ETA/B (r = 0.62; P < 0.05) blockade. No other anthropometric, hemodynamic or metabolic variable was correlated with the blood flow responses to ET-1 receptor blockade.. ET-1-mediated vasoconstrictor tone is elevated in adults with impaired fasting blood glucose concentrations, independent of other cardiometabolic risk factors. Enhanced ET-1 system activity may underlie endothelial vasomotor dysfunction and increased cardiovascular risk in adults with impaired fasting blood glucose concentrations.

Topics: Antihypertensive Agents; Blood Glucose; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Fasting; Female; Glucose Intolerance; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Plethysmography; Risk Factors; Sedentary Behavior; Vasoconstriction

Arterial stiffness and impaired nitric oxide (NO) bioavailability contribute to the high risk for cardiovascular disease in CKD. Both asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, and endothelin-1 (ET-1) oppose the actions of NO, suggesting that ET-1 receptor antagonists may have a role in cardiovascular protection in CKD. We conducted a randomized, double-blind, three-way crossover study in 27 patients with proteinuric CKD to compare the effects of the ET(A) receptor antagonist sitaxentan, nifedipine, and placebo on proteinuria, BP, arterial stiffness, and various cardiovascular biomarkers. After 6 weeks of treatment, placebo and nifedipine did not affect plasma urate, ADMA, or urine ET-1/creatinine, which reflects renal ET-1 production; in contrast, sitaxentan led to statistically significant reductions in all three of these biomarkers. No treatment affected plasma ET-1. Reductions in proteinuria and BP after sitaxentan treatment was associated with increases in urine ET-1/creatinine, whereas reduction in pulse-wave velocity, a measure of arterial stiffness, was associated with a decrease in ADMA. Taken together, these data suggest that ET(A) receptor antagonism may modify risk factors for cardiovascular disease in CKD.

Topics: Adult; Biomarkers; Blood Pressure; Cardiovascular Diseases; Cross-Over Studies; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Isoxazoles; Male; Middle Aged; Nifedipine; Proteinuria; Pulse Wave Analysis; Renal Insufficiency, Chronic; Thiophenes; Vascular Stiffness; Vasodilator Agents

Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy.. We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin, in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker). These 3 biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of ≥2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36-0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74-1.59; P(interaction)=0.012).. In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy.

Topics: Adrenomedullin; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Coronary Disease; Death; Endothelin-1; Female; Glycopeptides; Heart Failure; Humans; Indoles; Male; Middle Aged; Peptide Fragments; Prognosis; Protein Precursors; Risk; Stress, Physiological; Stroke Volume

To provide scientific evidence supporting the efficacy of forest bathing as a natural therapy for human hypertension.. Twenty-four elderly patients with essential hypertension were randomly divided into two groups of 12. One group was sent to a broad-leaved evergreen forest to experience a 7-day/7-night trip, and the other was sent to a city area in Hangzhou for control. Blood pressure indicators, cardiovascular disease-related pathological factors including endothelin-1, homocysteine, renin, angiotensinogen, angiotensin II, angiotensin II type 1 receptor, angiotensin II type 2 receptor as well as inflammatory cytokines interleukin-6 and tumor necrosis factor α were detected. Meanwhile, profile of mood states (POMS) evaluation was used to assess the change of mood state of subjects. In addition, the air quality in the two experimental sites was monitored during the 7-day duration, simultaneously.. The baselines of the indicators of the subjects were not significantly different. Little alteration in the detected indicators in the city group was observed after the experiment. While subjects exposed to the forest environment showed a significant reduction in blood pressure in comparison to that of the city group. The values for the bio-indicators in subjects exposed to the forest environment were also lower than those in the urban control group and the baseline levels of themselves. POMS evaluation showed that the scores in the negative subscales were lowered after exposure to the forest environment. Besides, the air quality in the forest environment was much better than that of the urban area evidenced by the quantitative detection of negative ions and PM10 (particulate matter < 10 μm in aerodynamic diameter).. Our results provided direct evidence that forest bathing has therapeutic effects on human hypertension and induces inhibition of the renin-angiotensin system and inflammation, and thus inspiring its preventive efficacy against cardiovascular disorders.

Topics: Affect; Aged; Blood Pressure; Cardiovascular Diseases; Cities; Endothelin-1; Environment; Homocysteine; Humans; Hypertension; Inflammation; Interleukin-6; Middle Aged; Renin-Angiotensin System; Treatment Outcome; Trees; Tumor Necrosis Factor-alpha

To study the effect of exenatide on body composition and circulating cardiovascular risk biomarkers.. Metformin-treated patients with type 2 diabetes (N = 69) were randomized to exenatide or insulin glargine and treated for 1 year. Body composition was evaluated by dual-energy X-ray absorptiometry. Additionally, body weight, waist circumference, and cardiovascular biomarkers were measured.. Treatment with exenatide for 1 year significantly reduced body weight, waist circumference, and total body and trunkal fat mass by 6, 5, 11, and 13%, respectively. In addition, exenatide increased total adiponectin by 12% and reduced high-sensitivity C-reactive protein by 61%. Insulin glargine significantly reduced endothelin-1 by 7%. These changes were statistically independent of the change in total body fat mass and body weight.. Exenatide treatment for 1 year reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk. No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels.

Topics: Absorptiometry, Photon; Adiponectin; Body Composition; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Endothelin-1; Exenatide; Female; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Peptides; Risk Factors; Venoms; Waist Circumference

Polyunsaturated fatty acids (PUFA) have beneficial effects on cardiovascular risk, although the mechanisms are incompletely understood. In a previous article, we showed significant reductions in low-density lipoprotein cholesterol and several markers of inflammation with increasing intake of alpha-linolenic acid (ALA) from walnuts and flax.. To examine effects of ALA on cardiovascular responses to acute stress, flow-mediated dilation (FMD) of the brachial artery, and blood concentrations of endothelin-1 and arginine-vasopressin (AVP).. Using a randomized, crossover study design, cardiovascular responses to acute stress were assessed in 20 hypercholesterolemic subjects, a subset of whom also underwent FMD testing (n  =  12). Participants were fed an average American diet (AAD) and 2 experimental diets that varied in the amount of ALA and linoleic acid (LA) that they contained. The AAD provided 8.7% energy from PUFA (7.7% LA, 0.8% ALA). On the LA diet, saturated fat was reduced, and PUFA from walnuts and walnut oil provided 16.4% of energy (12.6% LA, 3.6% ALA). On the ALA diet, walnuts, walnut oil, and flax oil provided 17% energy from PUFA (10.5% LA, 6.5% ALA).. The ALA and LA diets significantly reduced diastolic blood pressure (-2 to -3 mm Hg) and total peripheral resistance (-4%), and this effect was evident at rest and during stress (main effect of diet, p < 0.02). FMD increased (+34%) on the diet containing additional ALA. AVP also increased by 20%, and endothelin-1 was unchanged.. These results suggest novel mechanisms for the cardioprotective effects of walnuts and flax, and further work is needed to identify the bioactives responsible for these effects.

Topics: alpha-Linolenic Acid; Biomarkers; Blood Pressure; Cardiovascular Diseases; Cholesterol, LDL; Cross-Over Studies; Diet; Endothelin-1; Flax; Humans; Hypercholesterolemia; Juglans; Linoleic Acid; Middle Aged; Nuts; Plant Oils; Risk Factors; Stress, Psychological; Vascular Resistance

To compare the short-term effects of two oral continuous combined oestrogen-progestogen treatment regimens on blood concentrations of several cardiovascular risk markers in healthy postmenopausal women.. In a 12-week randomised controlled study, 48 healthy non-hysterectomised postmenopausal women, aged 41-58 years, received either no treatment (control group; n=16), or daily oral continuous combined treatment with 1 mg micronised 17beta-oestradiol plus 5 mg dydrogesterone (E/D group; n=18) or 0.625 mg conjugated equine oestrogens plus 5 mg medroxyprogesterone acetate (CEE/MPA group; n=14). Fasting blood sampling was performed at baseline and after 12 weeks of follow-up.. Compared with the control group, 12-week treatment with E/D or CEE/MPA reduced fibrinogen (-7.7%, p=0.004 and -3.3%, p=0.083, respectively), factor VII-act (-8.7%, p=0.14 and -9.7%, p=0.06, respectively), homocysteine (-20.5%, p=0.02 and -26.7%, p=0.005, respectively), and IGF-1 (-27.9%, p<0.001 and -18.1%, p=0.002, respectively), but increased factor VII-ag (+10.1%, p=0.03 and +4.4%, p=0.46, respectively), endothelin-1 (+15.2%, p=0.12 and +20.0%, p=0.13, respectively) and C-reactive protein (+88.8%, p=0.18 and +71.0%, p=0.44, respectively). Fibrinolytic factors were not affected by either hormone therapy (HT).. Short-term oral continuous combined therapy with oestradiol/dydrogesterone and conjugated equine oestrogens/medroxyprogesterone acetate had comparable effects on the investigated cardiovascular risk markers.

Topics: Adult; alpha-2-Antiplasmin; Antigens; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Drug Combinations; Dydrogesterone; Endothelin-1; Estradiol; Estrogen Replacement Therapy; Factor VII; Female; Fibrinogen; Fibrinolysin; Homocysteine; Humans; Insulin-Like Growth Factor I; Medroxyprogesterone Acetate; Middle Aged; Plasminogen Activator Inhibitor 1; Postmenopause; Risk Factors; Time Factors; Tissue Plasminogen Activator

Patients with T2DM have an increased risk of CVD. Prevention of CVD represents the major goal of all treatment of T2DM, and early intervention in those patients at particularly high risk is important.We measured the insulin sensitivity and plasma biomarkers of CVD to determine whether a home-based exercise training program improves biomarker levels and insulin sensitivity. Patients with T2DM (n=12), IGT (n=4) and healthy control subjects (n=9) were studied before and after eight weeks of exercise training by rowing ergometry at 65-70% of peak oxygen uptake.. 1) patients with T2DM have elevated plasma concentrations of CVD biomarkers compared to the matched control and IGT groups; 2) a moderate to vigorous intensity home-based training program did not reduce plasma concentrations of these CVD markers; 3) insulin sensitivity improved as a result of exercise training in the control group, but not in the T2DM group.

Topics: Biomarkers; Blood Glucose; Body Composition; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelin-1; Exercise Therapy; Glucose Tolerance Test; Glycated Hemoglobin; Home Care Services; Humans; Insulin; Intercellular Adhesion Molecule-1; Male; Middle Aged; Oxygen Consumption; Program Evaluation; Time Factors; Treatment Outcome; Vascular Cell Adhesion Molecule-1; von Willebrand Factor

Patients with type 2 diabetes are at considerable risk of excessive morbidity and mortality from cardiovascular disease (CVD). We investigated the clinical effectiveness of Pycnogenol, a flavonoid-rich dietary supplement, in reducing antihypertensive medication use and CVD risk factors in subjects with type 2 diabetes. Forty-eight individuals were enrolled in a randomized, double-blind, placebo-controlled trial with parallel-group design. Patients were diagnosed with both type 2 diabetes and mild to moderate hypertension and were undergoing treatment with angiotensin-converting enzyme (ACE) inhibitors. Subjects were randomly assigned to receive either Pycnogenol pill (125 mg daily) or matched placebo for 12 weeks. According to the values of blood pressure (BP) measured at 2-week intervals, the pretrial ACE inhibitor dosage was left unchanged, reduced by 50%, or brought back to the pretrial dosage until a stable BP was obtained. Fasting plasma glucose, low-density lipoprotein (LDL) cholesterol, glycosylated hemoglobin (HbA1c), serum endothelin-1, and urinary albumin were evaluated monthly. Pycnogenol treatment achieved BP control in 58.3% of subjects at the end of the 12 weeks with 50% reduction in individual pretrial dose of ACE-inhibitors (P <.05). Plasma endothelin-1 decreased by 3.9 pg/mL in Pycnogenol-treated group vs 0.5 pg/mL increase in control group (P < .001). Mean HbA1c dropped by 0.8% in Pycnogenol-treated group (P < .05), whereas it decreased by 0.1% in control group. Fasting plasma glucose declined by 23.7 mg/dL in Pycnogenol-treated group vs 5.7 mg/dL in control group (P < .0001). Low-density lipoprotein cholesterol improved significantly in Pycnogenol-treated group, declining by 12.7 mg/dL (P < .001). A significant decrease in urinary albumin level was observed at week 8 compared with the control group (P < .05). However, this reduction was not significant at 12th week. After 12 weeks of supplementation, Pycnogenol resulted in improved diabetes control, lowered CVD risk factors, and reduced antihypertensive medicine use vs controls.

Topics: Aged; Albumins; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Blood Glucose; Cardiovascular Diseases; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Endothelin-1; Female; Flavonoids; Glycated Hemoglobin; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Phytotherapy; Pinus; Plant Bark; Plant Extracts

The authors present remodelling mechanisms of distal peripheral vessels in vibration disease, caused by endothelium functions disorder (lower NO, increased endothelin-1 and Villebrandt factor), stressed oxidative metabolism in neutrophils, intensified lipid peroxidation, depressed antioxidant defence, activated anti-inflammatory cytokines (TNF-alpha, IL-1beta) and hyperhomocysteinemia. Degree of the changes increases with combination of vibration disease and arterial hypertension. The data justify application of Telmisartan improving functional state of endothelium.

Topics: Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Benzoates; Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Humans; Male; Middle Aged; Nitric Oxide; Peripheral Vascular Diseases; Telmisartan; Vibration

This study sought to determine whether combined continuous ethinyl estradiol and norethindrone acetate, a postmenopausal hormone therapy (HT) combination designed to have fewer side effects than cyclical therapies and therapies using medroxyprogesterone acetate (MPA), could improve vascular endothelial function in postmenopausal women with risk factors for cardiovascular disease (CVD).. Eighteen postmenopausal women (mean age 62 +/- 11 years) participated in a randomized, placebo-controlled, crossover design trial of 10 microg estradiol/1 mg norethindrone acetate given once daily for 3 months, with a 1-month washout period between placebo and active treatment phases. Vascular reactivity was assessed at each phase of the study using high-frequency brachial artery ultrasound in response to flow-mediated hyperemia, cold pressor testing, and sublingual nitroglycerin. Markers of cardiovascular risk, including cholesterol levels, inflammatory markers, fibrinolytic markers, and solubilized adhesion molecules, were also measured at each phase.. We found no significant difference in vascular reactivity measurements during active treatment with ethinyl estradiol/norethindrone acetate vs. placebo. C-reactive protein (CRP) levels increased significantly during active treatment, and high-density lipoprotein (HDL) levels decreased significantly. Vascular cell adhesion molecule-1 (VCAM-1) levels declined during active treatment. Plasminogen activator inhibitor-1 (PAI-1) levels were inversely correlated with flow-mediated hyperemic vascular reactivity, independent of active treatment or placebo phases.. In this older postmenopausal population with at least one cardiovascular risk factor, treatment with combined continuous ethinyl estradiol and norethindrone acetate failed to improve vascular endothelial function. The agent's proinflammatory effect or subclinical atherosclerosis in this population may have contributed to this finding.

Topics: Aged; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Endothelin-1; Estrogen Replacement Therapy; Ethinyl Estradiol; Female; Forearm; Humans; Middle Aged; Norethindrone; Pilot Projects; Plasminogen Activator Inhibitor 1; Postmenopause; Regional Blood Flow; Treatment Outcome; Vascular Cell Adhesion Molecule-1; Women's Health

Menopause is associated with an increased cardiovascular risk and with a decrease in endothelial function. Hormone replacement therapy (HRT) improves endothelial function in post-menopausal women (PMW) without established atherosclerosis. New alternative treatments, among which tibolone (T) and DHEAS have been suggested to reduce postmenopausal cardiovascular risk. Although, in vitro animal studies have suggested that T and DHEAS improve endothelial function, their effect in humans has never been tested. The aim of the present study was to compare the effects of HRT (continuous combined 0.625 mg conjugated equine estrogen plus 2.5 mg/d medoxyprogesterone) DHEAS and T on endothelium-dependent flow-mediated vasodilatation (FMD), plasma nitrite, nitrate and endothelin-1 levels in 16 PMW with increased cardiovascular risk in a double-blinded, double-crossover study. Women were randomized and treated for 4 weeks with HRT, T or DHEAS. Brachial artery diameter, FMD, endothelin-1 and plasma nitrite and nitrate levels were measured at baseline and after each treatment phase. Brachial artery diameters remained unchanged after each treatment phase. HRT significantly improved FMD compared to both baseline and to T and DHEAS therapies while no effect of T or DHEAS on FMD was noted. In conclusion, HRT, but neither T nor DHEAS, improves endothelial function and reduces plasma levels of endothelin-1 in PMW at risk of CAD.

Topics: Brachial Artery; Cardiovascular Diseases; Cross-Over Studies; Dehydroepiandrosterone; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Forearm; Humans; Medroxyprogesterone; Middle Aged; Nitrates; Nitrites; Nitroglycerin; Norpregnenes; Postmenopause; Pulsatile Flow; Regional Blood Flow; Treatment Outcome; Vasodilation

Hormone replacement therapy (HRT) improves endothelial function in postmenopausal women while the effects of raloxifene, a selective estrogen receptor modulator, are still under debate. The aim of this study was to evaluate endothelium-dependent flow-mediated vasodilatation in the brachial artery and plasma levels of nitrite, nitrate and endothelin-1 in 20 postmenopausal women with increased cardiovascular risk treated with either HRT or raloxifene for 4 weeks in a randomized double-blind single cross-over study. Patients had an endothelium-dependent flow-mediated dilatation of 4% prior to initiation of the study. Treatment with HRT resulted in a 67% increase in dilatation compared with baseline (from a 7.4% increase to a 12.4% increase, p < 0.01). Raloxifene treatment resulted in no change in vasodilatation from baseline. Endothelium-dependent dilatation was significantly improved by HRT compared with raloxifene treatment (12.4+/-0.6% vs. 6.1+/-2.0%; p < 0.01). Compared with baseline values, nitrate plus nitrite levels increased significantly (p < 0.05) with HRT but not with raloxifene. Similarly, endothelin-1 decreased from baseline with both treatments, but only the HRT-induced decrease was statistically significant (p < 0.05). In conclusion, HRT improved endothelial function and reduced plasma levels of endothelin-1 in postmenopausal women at risk of coronary artery disease. These beneficial effects were not shared by raloxifene.

Topics: Aged; Brachial Artery; Cardiovascular Diseases; Cross-Over Studies; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Humans; Medroxyprogesterone Acetate; Middle Aged; Nitrates; Nitrites; Postmenopause; Pulsatile Flow; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Treatment Outcome; Vasodilation

To evaluate whether in healthy postmenopausal women endothelial substances such as endothelin-1 (ET-1) and nitric oxide are related to cardiovascular risk factors and can be influenced by estradiol replacement.. A cross-sectional evaluation and a randomized, double-blind, placebo-controlled study with cross-over.. In 20 healthy postmenopausal women it was investigated the relation of ET-1 and NOx with age, BMI, 24-h blood pressure, lipid and glucose metabolism, and coagulation parameters. In addition, in the same women, the role played by estrogens on circulating ET-1 and stable derivatives of nitric oxide (nitrite/nitrates) was investigated by administering for 2 months transdermal estradiol (50 microg/day) vs. placebo.. ET-1 and NOx were inversely related to each other (r=0.458; P=0.016). Multivariate analysis of regression showed that ET-1 levels were related directly to LDL-cholesterol (r=0.585; P=0.0005) and protein C (r=0.516; P=0.0008), and inversely to insulin (r=0.488; P=0.0065). The ratio NOx/ET-1 was directly related to HDL-cholesterol (r=0.441; P=0.005). The above relations were not influenced by estradiol. Indeed, in comparison to placebo, transdermal estradiol, besides reducing nocturnal systolic (P=0.002) and diastolic (P=0.03) blood pressure, did not modify ET-1 or NOx levels, as well as, any of the parameters considered.. The relation of several cardiovascular risk factors with ET-1 and NOx/ET-1 suggests a primary role for these endothelial products in the determination of the cardiovascular risk of women. The present data do not support a role for transdermal estradiol in modifying ET-1 or NOx levels of healthy postmenopausal women.

Topics: Administration, Cutaneous; Blood Pressure; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Cross-Sectional Studies; Double-Blind Method; Endothelin-1; Estradiol; Estrogen Replacement Therapy; Female; Humans; Insulin; Middle Aged; Nitric Oxide; Postmenopause; Protein C; Treatment Outcome

Recently the pathophysiological role of endothelin (ET) has been presumed in a number of adrenal disorders such as primary hyperaldosteronism, pheochromocytoma and adrenocortical insufficiency.. The aim of the present study was to evaluate circulating ET-1 levels in patients with endogenous Cushing's syndrome.. Plasma ET-1 levels were determined by highly sensitive RIA. Thirteen untreated subjects with Cushing's syndrome were studied: eight women and five men of mean age 44.2+/-9.5 Years (s.d.). In ten of them, Cushing's disease had been diagnosed and three had adrenal adenomas. ET-1 was 3-fold higher in the patient group than in age-matched healthy controls (n=13): 1.59+/-0.78 vs 0.46+/-0.20 pmol/l respectively, P<0.001. In adrenal adenoma patients, ET-1 was not significantly higher than in the Cushing's disease subjects (1.84+/-0.67 vs 1.51+/-0.83 pmol/l respectively, P>0.05). In three patients who died of severe cardiovascular complications, plasma ET-1 was significantly higher than in the remaining patients (2.34+/-0.35 pmol/l, P<0.05). A positive correlation was found between the total cholesterol (6.94+/-1.75 mmol/l) and ET-1 levels in the patients with Cushing's syndrome: r=+0.73, P<0.02. No correlation was observed, however, between the levels of ET-1 and blood pressure (183+/-37/106+/-18 mmHg), plasma cortisol levels (455.2+/-74.5 nmol/l) or urinary cortisol excretion (1463+/-726 nmol/24 h). The successful treatment and correction of hypercortisolism in seven patients led to insignificant reduction in plasma ET from 1.34+/-0.69 to 0.73+/-0.53 pmol/l, P>0.05.. Our results clearly demonstrate that the ET system is activated in Cushing's syndrome. Elevated plasma ET-1 levels probably play a role in the pathogenesis of accelerated and early atherosclerosis development in this disorder.

Topics: Adenoma; Adrenal Gland Neoplasms; Adult; Cardiovascular Diseases; Cushing Syndrome; Endothelin-1; Female; Humans; Hydrocortisone; Male; Matched-Pair Analysis; Middle Aged; Reference Values; Risk Factors

This randomized double-blind study was conducted to investigate the effects of 17 beta-estradiol plus norethisterone acetate, and raloxifene, on nitric oxide (NO), prostacyclin (PGI2) and endothelin-1 (ET-1) serum levels in postmenopausal women. Treatment was initiated after a 28-50 day placebo period. Fourteen women were treated daily with 17 beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2 + NETA), and 14 with raloxifene HCl 60 mg for a period of 6 months. Serum NO, PGI2 and ET-1 levels were estimated at baseline, after placebo, and at months 3 and 6. E2 + NETA decreased NO levels significantly, while raloxifene did not cause any appreciable change. Both regimens decreased PGI2 levels and ET-1 levels significantly. Finally, E2 + NETA and raloxifene increased the NO/ET-1 ratio by 61.4% and 81.1%, respectively. In conclusion, both regimens may exert a cardio-protective effect by decreasing ET-1 levels and increasing the NO/ET-1 ratio. In contrast, both regimens had a negative influence on PGI2 levels.

Topics: Cardiovascular Diseases; Double-Blind Method; Endothelin-1; Epoprostenol; Estradiol; Estrogen Replacement Therapy; Female; Humans; Middle Aged; Nitric Oxide; Norethindrone; Norethindrone Acetate; Placebos; Postmenopause; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators

The phytoestrogen genistein improves endothelial dysfunction in ovariectomized rats through a nitric oxide-dependent mechanism. We investigated whether genistein alters the balance between the nitric oxide products and endothelin-1 and influences endothelium-dependent vasodilation in postmenopausal women. Sixty healthy postmenopausal women were enrolled in the study. A double-blind, placebo controlled, randomized design was employed. After a 4-week stabilization on a standard fat-reduced diet, participants to the study were randomly assigned to receive either genistein (n=30; 54 mg/day) or placebo (n=30). Flow-mediated, endothelium-dependent vasodilation of the brachial artery, plasma nitric oxide breakdown products and endothelin-1 levels were measured at baseline and after 6 months of genistein therapy. The mean baseline level of nitrites/nitrates was 22+/-10 micromol/l and increased to 41+/-10 micromol/ml after 6 months of treatment. The mean baseline plasma endothelin-1 level was 14+/-4 pg/ml and decreased to 7+/-1 pg/ml following 6 months of treatment with genistein. The mean baseline ratio of nitric oxide to endothelin also significantly increased at the end of treatment. Flow-mediated, endothelium-dependent vasodilation of the brachial artery was 3.9+/-0.8 mm at baseline and increased to 4.4+/-0.7 mm after 6 months of treatment. Placebo-treated women showed no changes in plasma nitrites/nitrates, endothelin-1 levels and flow-mediated vasodilation. Genistein therapy improves flow-mediated endothelium dependent vasodilation in healthy postmenopausal women. This improvement may be mediated by a direct effect of genistein on the vascular function and could be the result of an increased ratio of nitric oxide to endothelin.

Topics: Brachial Artery; Cardiovascular Diseases; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Estrogens, Non-Steroidal; Female; Genistein; Humans; Isoflavones; Middle Aged; Nitric Oxide; Phytoestrogens; Plant Preparations; Postmenopause; Vasodilation

To establish levels of plasma endothelin-1 in postmenopausal women with increased CV risk as compared with healthy premenopausal women and to measure the effects of different forms of estrogen replacement on plasma endothelin-1.. Prospective randomized study.. University of Southern California Medical Center.. We studied 18 postmenopausal women (mean age 53.4 +/- 4.9 years) with total cholesterol levels > 240 mg/dL divided into those with and without hypertension as well as in 10 healthy premenopausal women.. The postmenopausal women were randomized to receive oral estrone sulfate, transdermal E2, or placebo for 30 days.. We measured the endothelin-1 levels and total cholesterol at baseline and after 30 days of estrogen treatment.. In the postmenopausal women, endothelin-1 was higher (4.58 +/- 0.46 pg/mL) compared with premenopausal levels (2.80 +/- 0.46 pg/mL). In hypertensive postmenopausal women, endothelin-1 was 5.56 +/- 0.44 pg/mL. After estrogen, plasma endothelin-1 values decreased from 5.38 +/- 0.66 to 4.82 +/- 0.9 pg/mL with oral estrone sulfate, 4.84 +/- 0.25 to 4.54 +/- 0.49 pg/mL with transdermal E2, and did not change after placebo 4.76 +/- 0.71 to 4.81 +/- 0.46 pg/mL. In evaluating hypertensive women alone with estrogen therapy, plasma endothelin-1 showed the greatest decrement from 5.39 +/- 0.49 to 4.4 +/- 0.59 pg/mL (18.4%). The decrease in endothelin-1 with estrogen, which was statistically significant for the entire group, did appear to be influenced by the route of administration. Baseline plasma endothelin-1 levels were correlated positively to plasma cholesterol levels with a correlation coefficient of 0.632.. These data provide another potential mechanism explaining the cardioprotective effects of hormone replacement therapy.

Topics: Administration, Cutaneous; Administration, Oral; Adult; Cardiovascular Diseases; Cholesterol; Endothelin-1; Estrogen Replacement Therapy; Estrogens; Estrone; Female; Humans; Hypertension; Middle Aged; Postmenopause; Premenopause; Prospective Studies; Reference Values; Risk Factors

Fourteen patients undergoing cardiac or great vessel surgery using cardiopulmonary bypass (ECC) were divided into two groups. Group A of 7 patients received 2 x 10(6) units of aprotinin (apr) 15 min before ECC and 0.5 x 10(6) unit immediately after the ECC. Group B of 7 patients received 0.5 x 10(6) unit of aprotinin 15 min before ECC and 2 x 10(6) units immediately after the ECC. Several physiological parameters were measured two hours before ECC, immediately after the cessation of the ECC and 4 hours thereafter. No difference was noted in coagulation time, which remained within normal range, and postoperative hemorrhage between the groups after ECC. Although thrombomodulin, ELAM-1 and ICAM-1 tended to decrease slightly in the two groups immediately after ECC, recovery of the thrombomodulin was much more rapid in the A group than in the B group. On the other hand, blood endothelin level and von Willebrand factor activity were elevated progressively after the ECC. Blood granulocyte-elastase activity and IL-8 increased markedly immediately after the ECC and then tended to decrease. These data indicate that no marked damage would be caused on the endothelial cells during ECC which was carried out using a relatively small dose of apr. However, the protective effect of apr remained to be clarified in the future.

Topics: Adult; Aged; Aprotinin; Cardiopulmonary Bypass; Cardiovascular Diseases; Dose-Response Relationship, Drug; E-Selectin; Endothelin-1; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Postoperative Hemorrhage; Thrombomodulin; von Willebrand Factor

Endothelin system comprises three endogenous 21-amino-acid peptide ligands endothelin-1, -2, and -3 (ET-1/2/3), and two G protein-coupled receptor (GPCR) subtypes-endothelin receptor A (ET

Topics: Amino Acids; Cardiovascular Diseases; Cryoelectron Microscopy; Endothelin-1; Humans; Peptides; Receptor, Endothelin A

Endothelin-1 and its prohormone C-terminal pro-endothelin-1 (CT-proET-1) have been linked to metabolic alterations, inflammatory responses and cardiovascular events in selected study populations. We analyzed the association of CT-proET-1 with cardiovascular events and mortality, carotid intima-media-thickness as surrogate for early atherosclerotic lesions, biomarkers of subclinical inflammation and adipokines in a population-based study.. The cross-sectional and prospective analyses used data from the KORA F4 study with a median follow-up time of 9.1 (8.8-9.4) years. Data on CT-proET-1 and mortality were available for 1554 participants, data on the other outcomes in subgroups (n = 596-1554). The associations were estimated using multivariable linear regression and Cox proportional hazard models adjusted for sex, age, body mass index, estimated glomerular filtration rate, arterial hypertension, diabetes, low-density and high-density lipoprotein cholesterol, current and former smoking and physical activity. The Bonferroni method was used to correct for multiple testing.. In the fully adjusted model, CT-proET-1 was associated with cardiovascular (hazard ratio (HR) per standard deviation increase: 1.66; 95% confidence interval (CI): 1.10-2.51; p = 0.017) and all-cause mortality (HR: 2.03; 95% CI 1.55-2.67; p < 0.001), but not with cardiovascular events, and was inversely associated with the intima-media thickness (β: -0.09 ± 0.03; p = 0.001). CT-proET-1 was positively associated with five out of ten biomarkers of subclinical inflammation and with two out of five adipokines after correction for multiple testing. After inclusion of biomarkers of subclinical inflammation in the Cox proportional hazard model, the association of CT-proET-1 with all-cause mortality persisted (p < 0.001).. These results emphasize the complexity of endothelin-1 actions and/or indicator functions of CT-proET-1. CT-proET-1 is a risk marker for all-cause mortality, which is likely independent of vascular endothelin-1 actions, cardiovascular disease and inflammation.

Topics: Adipokines; Biomarkers; Cardiovascular Diseases; Carotid Intima-Media Thickness; Cross-Sectional Studies; Endothelin-1; Humans; Inflammation; Mortality; Peptide Fragments; Prospective Studies

Aging is a risk factor for many chronic noncommunicable diseases, including chronic obstructive pulmonary disease (COPD), which is often associated with cardiovascular disease (CVD). Moreover, aging is associated with a mild form of systemic inflammation. The aim of our study was to analyze the relationship between age, systemic and vascular inflammation, and the presence of CVD comorbidities in a stable COPD population. Forty COPD patients were divided into 2 age groups (<65 and ≥65 years of age), from which we collected the following inflammatory biomarkers: C-reactive protein, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and endothelin-1 (ET-1). Elderly COPD patients had more frequent exacerbation events per year (2 vs 1, P = .06), a higher prevalence of CVD (3 vs 2, P = .04), more limited exercise tolerance (6-minute walking test distance, 343 [283-403] vs 434 [384-484]; P = .02), and mild systemic inflammation (TNF-α, 9.02 [7.08-10.96] vs 6.48 [5.21-7.76]; P = .03; ET-1, 2.24 [1.76-2.71] vs 1.67 [1.36-1.98] pg/mL; P = .04). A weak correlation between age and ET-1 (r = 0.32, P = .04) was observed. Mild systemic inflammation, characterized by a slightly increased level of TNF-α, and endothelial dysfunction, marked by elevated ET-1, could be liaisons between aging, COPD, and CVD comorbidities.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Endothelin-1; Humans; Inflammation; Lung; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha; Vascular Diseases

Preeclampsia affects ∼2-8% of pregnancies worldwide. It is associated with increased long-term maternal cardiovascular disease risk. This study assesses the effect of the vasoconstrictor N(ω)-nitro-L-arginine methyl ester (L-NAME) in modelling preeclampsia in mice, and its long-term effects on maternal cardiovascular health. In this study, we found that L-NAME administration mimicked key characteristics of preeclampsia, including elevated blood pressure, impaired fetal and placental growth, and increased circulating endothelin-1 (vasoconstrictor), soluble fms-like tyrosine kinase-1 (anti-angiogenic factor), and C-reactive protein (inflammatory marker). Post-delivery, mice that received L-NAME in pregnancy recovered, with no discernible changes in measured cardiovascular indices at 1-, 2-, and 4-wk post-delivery, compared with matched controls. At 10-wk post-delivery, arteries collected from the L-NAME mice constricted significantly more to phenylephrine than controls. In addition, these mice had increased kidney

Topics: Animals; C-Reactive Protein; Cardiovascular Diseases; Disease Models, Animal; Endothelin-1; Female; Matrix Metalloproteinase 9; Mice; NG-Nitroarginine Methyl Ester; Phenylephrine; Placenta; Pre-Eclampsia; Pregnancy; RNA, Messenger; Vascular Endothelial Growth Factor Receptor-1; Vasoconstrictor Agents

Sedentary behavior or physical inactivity is considered a foremost contributor to the rise in obesity and overweight and a risk factor for several non-communicable diseases. However, its effect on the etiopathogenesis of some diseases is underestimated in both developed and developing countries worldwide. The present study designed a novel sedentary cage with a view to achieving sedentariness in rats, and also investigated the effectiveness of the cage in achieving sedentariness by assessing some markers of cardiometabolic risks in Wistar rats.. Adult male Wistar rats were divided into 3 groups of six rats. Rats in Group 1 were the control. The sedentary groups were 4-hr. sedentary and 8-hr. sedentary. The sedentary rats were subjected to restrained movements for 4 and 8 hours daily in the sedentary cage for 3 months. Anthropometric indices, food consumption and blood pressure parameters of the rats were measured. Microalbuminuria and serum glucose, uric acid, albumin, nitric oxide, endothelin-1, insulin, inflammatory markers were also Measured.. Results indicated significant increases in body weight, BMI, Lee index, food consumption, systolic and diastolic pressure and decrease in serum nitric oxide bioavailability in the 8-hr sedentary rats. There were also significant increases in serum glucose, uric acid, endothelin-1, insulin, CRP and microalbuminuria in the 8-hr. sedentary rats in comparison with the control. The interleukin-6 and TNF-α also revealed a significant increase in the 8-hr. sedentary rats compared with the control. However, there was no significant difference in cortisol level across all the groups.. We concluded that the novel sedentary cage successfully caused sedentariness in the rats as evident by the alteration in the cardiometabolic health in the rats, especially the group that were made sedentary for 8 h.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Endothelin-1; Glucose; Insulin; Male; Nitric Oxide; Rats; Rats, Wistar; Uric Acid

Overdose of stimulant drugs has been associated with increased risk of adverse cardiovascular events (ACVE), some of which may be ascribed to endothelial dysfunction. The aims of this study were to evaluate biomarkers of endothelial dysfunction in emergency department (ED) patients with acute cocaine overdose and to assess the association between in-hospital ACVE in ED patients with any acute drug overdose. This was a prospective consecutive cohort study over 9 months (2015-2016) at two urban, tertiary-care hospital EDs. Consecutive adults (≥18 years) presenting with suspected acute drug overdose were eligible and separated into three groups: cocaine (n = 47), other drugs (n = 128), and controls (n = 11). Data were obtained from medical records and linked to waste serum specimens, sent as part of routine clinical care, for biomarker analysis. Serum specimens were collected and analyzed using enzyme-linked immunosorbent assay kit for three biomarkers of endothelial dysfunction: (a) endothelin-1 (ET-1), (b) regulated upon activation normal T cell expressed and secreted (RANTES), and (c) soluble intercellular adhesion molecule-1 (siCAM-1). Mean siCAM was elevated for cocaine compared with controls and other drugs (p < .01); however, mean RANTES and ET-1 levels were not significantly different for any drug exposure groups. Receiver operating characteristics curve analysis for prediction of in-hospital ACVE revealed excellent performance of siCAM-1 (area under curve, 0.86; p < .001) but lack of predictive utility for either RANTES or ET-1. These results suggest that serum siCAM-1 is a viable biomarker for acute cocaine overdose and that endothelial dysfunction may be an important surrogate for adverse cardiovascular events following any drug overdose.

Topics: Adult; Biomarkers; Cardiovascular Diseases; Chemokine CCL5; Cocaine; Drug Overdose; Emergency Service, Hospital; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; Prospective Studies; Risk Factors; ROC Curve; Tertiary Care Centers

The search of biochemical markers of endothelial dysfunction: lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)-involved in atherosclerotic plaques formation-and endothelin-1 (ET-1)-potent vasoconstrictor-might help in detecting obstructive sleep apnea (OSA) patients at high risk of cardiovascular diseases.. In 71 OSA patients (apnoea/hypopnoea index, AHI 28.2 ± 17.9/hour) and in 21 healthy controls the serum levels of LOX-1 and ET-1 were measured.. There were increased levels of ET-1 (1.58 ± 0.65 vs. 1.09 ± 0.38 pg/mL;. There is endothelial dysfunction in OSA patients as indicated by increased serum levels of ET-1 and possibly endothelial dysfunction in diabetic OSA patients as indicated by increased serum levels of LOX-1 and its correlation with fasting glucose levels.

Topics: Biomarkers; Cardiovascular Diseases; Endothelin-1; Humans; Scavenger Receptors, Class E; Sleep Apnea, Obstructive

Airborne particulate matter (PM) is associated with an increased risk for cardiovascular diseases. Although the goal of thermal remediation is to eliminate organic wastes through combustion, when incomplete combustion occurs, organics chemisorb to transition metals to generate PM-containing environmentally persistent free radicals (EPFRs). Similar EPFR species have been detected in PM found in diesel and gasoline exhaust, woodsmoke, and urban air. Prior in vivo studies demonstrated that EPFRs reduce cardiac function secondary to elevations in pulmonary arterial pressures. In vitro studies showed that EPFRs increase ROS and cytokines in pulmonary epithelial cells. We thus hypothesized that EPFR inhalation would promote lung inflammation and oxidative stress, leading to systemic inflammation, vascular endothelial injury, and a decline in vascular function. Mice were exposed to EPFRs for either 4 h or for 4 h/day for 10 days and lung and vascular function were assessed. After a 4-h exposure, plasma nitric oxide (NO) was reduced while endothelin-1 (ET-1) was increased, however lung function was not altered. After 10 day, plasma NO and ET-1 levels were again altered and lung tidal volume was reduced. These time course studies suggested the vasculature may be an early target of injury. To test this hypothesis, an intermediate time point of 3 days was selected. Though the mice exhibited no marked inflammation in either the lung or the blood, we did note significantly reduced endothelial function concurrent with a reduction in lung tidal volume and an elevation in annexin V protein levels in the lung. Although vascular dysfunction was not dependent upon inflammation, it may be associated with an injury at the air-blood interface. Gene expression analysis suggested roles for oxidative stress and aryl hydrocarbon receptor (Ahr) signaling. Studies probing the relationship between pulmonary oxidative stress and AhR signaling at the air-blood interface with vascular dysfunction seem warranted.

Topics: Animals; Aorta; Basic Helix-Loop-Helix Transcription Factors; Cardiovascular Diseases; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Environmental Pollutants; Free Radicals; Gene Expression Regulation; Inhalation Exposure; Lung; Male; Mice, Inbred C57BL; Nitric Oxide; Oxidative Stress; Particulate Matter; Pneumonia; Receptors, Aryl Hydrocarbon; Tidal Volume; Time Factors

Hyperthyroidism promotes the development and progression of cardiovascular diseases (CVD). Aldosterone, a key mediator of myocardial inflammation, oxidative stress and fibrosis, may be activated in hyperthyroidism.. To assess the impact of hyperthyroidism on aldosterone levels and myocardial oxidative status, inflammatory and fibrotic markers in hyperthyroid rats, and to test if the use of spironolactone (an aldosterone antagonist) attenuates these changes.. Adult Wistar rats were randomly distributed into 4 groups; controls, spironolactone treated rats (Spir, 50mg/kg/day), hyperthyroid rats (Hyper, daily intraperitoneal levothyroxine 0.3mg/kg/day), and spironolactone treated hyperthyroid rats (Hyper+Spir) for 4 weeks. Blood pressure (Bp), and levels of serum and myocardial aldosterone, oxidants/antioxidants, inflammatory and fibrotic markers were measured.. Levothyroxine increased serum thyroid hormones and increased Bp, heart rate and heart to bodyweight ratio. Relative to control, serum aldosterone levels were increased in Hyper and Hyper+ Spir groups. In parallel, cardiac lipid peroxides and serum endothelin-1 were increased whereas cardiac superoxide dismutase, catalase, glutathione, and matrix metalloproteinase -2 were reduced in the Hyper group. Spironolactone decreased serum thyroid hormones and improved cardiac lipid peroxides and metalloproteinase -2 levels. The use of spironolactone decreased serum nitrite levels and increased cardiac SOD and glutathione. Cardiac levels of aldosterone, endothelin-1, transforming growth factor-beta and nitrite were similar among all groups.. Hyperthyroid status was associated with an increase in aldosterone and oxidant/ inflammatory biomarkers. The use of spironolactone enhanced antioxidant defenses. Aldosterone antagonists may serve as potential drugs to attenuate the development of cardiac disease in hyperthyroidism.

Topics: Aldosterone; Animals; Antioxidants; Biomarkers; Blood Pressure; Body Weight; Cardiovascular Diseases; Endothelin-1; Heart; Heart Rate; Hyperthyroidism; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Nitrites; Organ Size; Oxidative Stress; Random Allocation; Rats; Spironolactone; Thyroid Hormones; Thyroxine; Transforming Growth Factor beta

Elevated levels of endothelin-1 (ET-1) were recorded in sera of scorpion sting patients. However, no studies focused on the mechanism of ET-1 involvement in the pathogenesis of scorpion envenomation, particularly in the cardiovascular system which is seriously affected in severe cases of scorpion stings. Inflammation induced by

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Diseases; Cardiovascular System; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Inflammation; Inflammation Mediators; Male; Mice; Peptides, Cyclic; Receptor, Endothelin A; Scorpion Stings; Scorpion Venoms; Signal Transduction

Ageing is considered to be the major and non-modifiable risk factor for the development of hypertension and cardiovascular diseases. During ageing, the vascular system undergoes structural and functional alterations, including endothelial dysfunction, thickening of the vascular wall, reduced distensibility and increased arterial stiffness. Vascular rigidity results from fibrosis and remodelling of the extracellular matrix, processes that are associated with ageing and are amplified in hypertension. These events may be induced by vasoactive agents, such as angiotensin II, endothelin-1, and aldosterone, which are increased in the vasculature during aging and hypertension. Complex interaction between the process of ageing and prohypertensive factors results in accelerated vascular remodelling and fibrosis, as well as increased arterial stiffness. Hypertension accelerates and augments age-related vascular remodelling and dysfunction, and ageing may impact on the severity of vascular damage in hypertension, thus strongly suggesting close interactions between biological ageing and blood pressure elevation. Molecular and cellular mechanisms underlying vascular alterations in ageing and hypertension are common and include aberrant signal transduction, oxidative stress and activation of pro-inflammatory and pro-fibrotic transcription factors. Strategies to suppress age-associated vascular changes can ameliorate vascular damage associated with hypertension. This article looks into vascular alterations occurring during ageing and hypertension, focussing particularly on arterial stiffness and vascular remodelling, also emphasizing the importance of diagnostic methods.. Старение считается основным и немодифицируемым фактором риска развития гипертонической болезни и сердечно-сосудистых заболеваний. В процессе старения сосудистая система подвергается структурным и функциональным изменениям, включающим эндотелиальную дисфункцию, утолщение сосудистой стенки, снижение растяжимости и повышение артериальной жесткости. Сосудистая жесткость является результатом фиброза и ремоделирования внеклеточного матрикса, процессами которые ассоциированы со старением и усиливающимися при гипертонии. Эти события могут быть индуцированы вазоактивными агентами, такими как ангиотензин II, эндотелин–1 и альдостерон, увеличивающимися в сосудистой системе в процессе старения и развития гипертонической болезни. Комплексное взаимодействие между процессом старения и прогипертензивными факторами приводит к ускоренному сосудистому ремоделированию и фиброзу, а также к повышению артериальной жесткости. Гипертония ускоряет и увеличивает возрастное сосудистое ремоделирование и дисфункцию, а старение может влиять на тяжесть сосудистого повреждения при гипертонии, указывая на тесное взаимодействие между биологическим старением и повышением кровяного давления. Молекулярные и клеточные механизмы, лежащие в основе сосудистых изменений при старении и гипертонии, являются общими и включают аберрантную трансдукцию сигнала, окислительный стресс и активацию провоспалительных и профибротических факторов транскрипции. Стратегии подавления возрастных сосудистых изменений могут улучшить состояние сосудистых повреждений, связанных с гипертонией. В данной статье рассмотрены сосудистые изменения в процессе старения и при гипертонии, уделено особое внимание артериальной жесткости и сосудистому ремоделированию. Также подчеркивается важное значение методов диагностики.

Topics: Aging; Cardiovascular Diseases; Endothelin-1; Humans; Hypertension; Vascular Stiffness

Topics: Cardiovascular Diseases; Cardiovascular System; Endothelin-1; Endothelins; Humans; Primary Prevention

Topics: Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Receptor, Endothelin A

Obesity is a state of chronic low-level inflammation closely associated with oxidative stress. Childhood obesity is associated with endothelial dysfunction, inflammation, and oxidative stress markers individually. This study was aimed at determining the association between the biomarkers of inflammation, oxidative stress, and endothelial dysfunction in urine samples of healthy, overweight, and obese children. Eighty-eight elementary school children aged between 6 and 10 years participated in this study. Anthropometric measurements were measured using WHO recommendations. The biomarkers of low-grade inflammation such as C-reactive protein (CRP), interleukin-6 (IL-6), and

Topics: Biomarkers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Child; Dinoprost; Early Diagnosis; Endothelial Cells; Endothelin-1; Female; Humans; Inflammation; Male; Oxidative Stress; Pediatric Obesity

Soluble urokinase-type plasminogen activator receptor (suPAR) is upregulated by inflammation and plays a role in the pathogenesis of atherosclerosis. Chronic obstructive pulmonary disease (COPD) is associated with enhanced systemic inflammation and increased risk for atherosclerosis, however, studies analysing the circulating suPAR levels in COPD are contradictory. The aim of the study was to investigate plasma suPAR concentrations together with markers of arterial stiffness in COPD.. Twenty-four patients with COPD and 18 non-COPD, control subjects participated in the study. Plasma suPAR was measured, together with lung volumes, symptom burden, exacerbation history, markers of arterial stiffness and soluble inflammatory biomarkers, such as endothelin-1, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6).. Plasma suPAR levels are elevated in COPD and relate to arterial stiffness. Our results suggest that suPAR may be a potential link between COPD and atherosclerosis.

Topics: Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Female; Forced Expiratory Volume; Humans; Interleukin-6; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Receptors, Urokinase Plasminogen Activator; Severity of Illness Index; Up-Regulation; Vascular Stiffness; Vital Capacity

In human pericardial resistance arteries, effects of the endothelium-dependent vasodilator bradykinin are mediated by NO during contraction induced by K

Topics: Aged; Cardiovascular Diseases; Coronary Vessels; Endothelin-1; Endothelium, Vascular; Female; Humans; Hydrogen Peroxide; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Pericardium; Vasodilation; Vasodilator Agents

In a recent issue of Clinical Science, Stanhewicz et al. investigated persistent microvascular dysfunction in women up to 16 months postpartum. The authors found sensitivity to the pressor effects of endothelin-1 (ET-1) was enhanced when compared with women who had a normotensive pregnancy. Importantly, the authors demonstrated that this effect was mediated via the endothelin type B (ET

Topics: Cardiovascular Diseases; Endothelin-1; Endothelins; Female; Humans; Pre-Eclampsia; Pregnancy; Receptor, Endothelin B

Preeclampsia (PE), associates with long-term increased risk for cardiovascular disease in women, suggesting that PE is not an isolated disease of pregnancy. It is not known if increased risk for long-term diseases is due to PE-specific factors or to prepregnancy renal and cardiovascular risk factors. We used a mouse model in which a WT female with normal prepregnancy health develops PE to investigate if preeclampsia causes long-term cardiovascular consequences after pregnancy for mothers and offspring. Mothers exhibited endothelial dysfunction and hypertension after PE and had glomerular injury that not only persisted but deteriorated, leading to fibrosis. Left ventricular (LV) remodeling characterized by increased collagen deposition and MMP-9 expression and enlarged cardiomyocytes were also detected after PE. Increased LV internal wall thickness and mass, increased end diastolic and end systolic volumes, and increased stroke volume were observed after PE in the mothers. Placenta-derived bioactive factors that modulate vascular function, markers of metabolic disease, vasoconstrictor isoprostane-8, and proinflammatory mediators were increased in sera during and after a preeclamptic pregnancy in the mother. Offspring of PE mice developed endothelial dysfunction, hypertension, and signs of metabolic disease. Microglia activation was increased in the neonatal brains after PE, suggesting neurogenic hypertension in offspring. Prevention of placental insufficiency with pravastatin prevented PE-associated cardiovascular complications in both mothers and offspring. In conclusion, factors that develop during PE have long-term, cardiovascular effects in the mother and offspring independent of prepregnancy risk factors.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Endothelin-1; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Male; Mice; Mice, Inbred C57BL; Placenta; Pravastatin; Pre-Eclampsia; Pregnancy; Risk Factors; Vascular Remodeling

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

The current study addressed the hypothesis that the local decrease in endothelin-1 (ET-1) bioavailability during sustained flow increases contributes to endothelium-dependent, flow-mediated dilatation (FMD) of conduit arteries and is altered in presence of cardiovascular risk factors.. In nine young healthy individuals, the decrease in local ET-1 plasma levels and radial artery FMD in response to hand skin heating (from 34 to 44 °C) was not affected by endothelin type A (ETA) receptor blockade, achieved using the brachial infusion of BQ-123 (100 nmol/min per l of forearm), as compared with physiological saline (0.9% NaCl) infusion. In contrast, endothelin type B (ETB) receptor blockade with BQ-788 (10 nmol/min per l) suppressed the decrease in plasma ET-1 during heating and reduced FMD, without altering nitric oxide release. The coinfusion of BQ-123 did not affect the inhibitory effect of ETB receptor blockade on the decrease in ET-1 plasma levels during heating but prevented the reduction in FMD. Basal radial artery parameters, systemic hemodynamics, and endothelium-independent dilatation to glyceryl trinitrate were not modified by ETA and/or ETB blockade. In a general population of 40 participants without treatment or major cardiovascular diseases, including the nine healthy individuals, the reduction in endothelin-1 level during heating was correlated with FMD (r = -0.55, P < 0.001) and decreased with increased age (r = 0.49, P = 0.001), mean arterial blood pressure (r = 0.48, P = 0.002), and total cholesterol level (r = 0.37, P = 0.024).. The uptake of endothelin-1 by ETB receptors contributes to conduit artery FMD, preventing its vasoconstrictor action mediated by ETA receptors. The alteration of this mechanism by cardiovascular risk factors may contribute to endothelial dysfunction.

Topics: Adult; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Female; Hemodynamics; Humans; Male; Nitric Oxide; Oligopeptides; Peptides, Cyclic; Piperidines; Risk Factors; Vasodilation; Young Adult

Evidence points to activation of pro-inflammatory and pro-thrombotic stimuli during the haemodialysis process in end-stage renal disease (ESRD) with potential to predispose to cardiovascular events. Diabetes is associated with a higher incidence of cardiovascular disease in haemodialysis patients. We tested the hypothesis that a range of mediators and markers that modulate cardiovascular risk are elevated in haemodialysis patients with diabetes compared to those without.. Men and women with diabetes (n = 6) and without diabetes (n = 6) aged 18-90 years receiving haemodialysis were recruited. Blood samples were collected and analysed pre- and post-haemodialysis sessions for (platelet-monocyte conjugates (PMC), oxidised LDL (Ox-LDL), endothelin 1 (ET-1) and vascular endothelial growth factor (VEGF-A).. PMC levels significantly increased after haemodialysis in both groups (diabetes p = 0.047; non-diabetes p = 0.005). Baseline VEGF-A was significantly higher in people with diabetes (p = 0.009) and post-dialysis levels were significantly reduced in both groups (P = 0.002). Ox-LDL and CRP concentrations were not significantly different between groups nor affected in either group post-dialysis. Similarly, ET-1 concentrations were comparable in all patients at baseline, with no change post-dialysis in either group.. In this pilot study, we have confirmed that circulating PMCs are increased following dialysis irrespective of diabetes status. This is likely to be a mechanistic process and offers a potential explanation for high rates of vascular events associated with haemodialysis. The higher VEGF-A concentrations between patients with and without diabetes is a previously unreported finding in diabetic ESRD. Further research is merited to establish whether VEGF-A is a marker or mediator (or both) of cardiovascular risk in haemodialysis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Cholesterol, LDL; Diabetes Complications; Endothelin-1; Female; Humans; Hypoxia; Kidney Failure, Chronic; Male; Middle Aged; Pilot Projects; Renal Dialysis; Risk; Vascular Endothelial Growth Factor A; Young Adult

South Africans are at high risk for developing cardiovascular disease. Endothelin-1 is known for its vasoconstrictive properties and its ability to contribute to vascular structural changes. In this study we investigated the association of change in endothelin-1 levels and change in markers implicated in vascular remodelling after 3 years. Serum endothelin-1 levels and markers of vascular remodelling such as carotid intima-media thickness, carotid cross-sectional wall area (CSWA) and arterial compliance were measured. Participants were divided into two groups according to an increase (n=185) and a decrease (n=152) in plasma endothelin-1 levels after 3 years. In partial regression analysis, the extent of endothelin-1 increase correlated positively with a change in pulse pressure and inversely with the change in arterial compliance in the group with increased endothelin-1 levels after 3 years. In the group with decreased endothelin-1 levels, the extent of decreased endothelin-1 correlated inversely with a change in CSWA. In multiple regression analysis, after splitting for race, the increase in endothelin-1 levels associated positively with the change in pulse pressure (Adj. R

Topics: Age of Onset; Biomarkers; Black People; Blood Pressure; Cardiovascular Diseases; Carotid Intima-Media Thickness; Endothelin-1; Female; Humans; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Risk Factors; South Africa; Time Factors; Up-Regulation; Vascular Remodeling; Vascular Stiffness; White People

The relation between testosterone (T) plasma concentration and cardiovascular (CV) risk is unclear, with evidence supporting increased risk in men with low and high T levels. Few studies have assessed CV risk as a function of plasma T levels using objective biomarkers.. To determine the relation between T levels and high-sensitivity CV risk biomarkers.. Ten thousand forty-one male patients were identified in the database of a commercial clinical laboratory performing biomarker testing. Patients were grouped by total T concentration and associations with the following biomarkers were determined: cardiac troponin I (cTnI), endothelin-1 (ET-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-17A, N-terminal pro-B-type natriuretic peptide (NTproBNP), high-density lipoprotein (HDL) cholesterol, high-sensitivity C-reactive protein (hs-CRP), hemoglobin A. Association of CV risk markers with levels of T in men.. Men with low T levels could be at increased risk for increased CV disease as seen by increased CV risk markers.. This study was performed in a group of 10,041 men and is the first study to examine CV risk associated with circulating T levels using a large panel of 10 objective biomarkers. This study is limited by an absence of clinical data indicating whether men had pre-existing CV disease or other CV risk factors.. Men with low plasma T levels exhibit increases in CV risk markers, consistent with a potential increased risk of CV disease. Pastuszak AW, Kohn TP, Estis J, Lipshultz LI. Low Plasma Testosterone Is Associated With Elevated Cardiovascular Disease Biomarkers. J Sex Med 2017;14:1095-1103.

Topics: Aged; Biomarkers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Endothelin-1; Humans; Interleukin-17; Interleukin-6; Lipoproteins, HDL; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Risk Assessment; Testosterone; Tumor Necrosis Factor-alpha

Cardiovascular (CV) complications are the main cause of death in end-stage renal disease (ESRD) patients. The high CV risks are attributable to the additive effects of multiple factors. Endothelin (EDN) is a potent vasoconstrictor and plays a role in regulating vascular homeostasis. However, whether variants of the EDN gene are associated with risks of CV events is not known. We conducted a study to investigate associations of variants of the EDN gene with CV events in ESRD patients.. A cohort of 190 ESRD patients was recruited, and 19 tagged single-nucleotide polymorphisms within the EDN gene family were selected for genotyping through a TaqMan assay. Data on clinical characteristics and hospitalizations for CV events were collected. Associations of genetic variants of the EDN gene with CV events were analyzed.. In this cohort, 62% (n = 118) of patients were hospitalized for a CV event. The EDN1 rs4714384 (CC/TC vs. TT) polymorphism was associated with an increased risk of a CV event after multiple testing (p < 0.001). Further functional exploration showed that it was a quantitative trait locus which may significantly alter gene expression in the tibial artery.. EDN1 rs4714384 is very likely an important biomarker of CV events in ESRD patients.

Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Cohort Studies; Endothelin-1; Female; Genetic Association Studies; Genetic Variation; Humans; Kidney Failure, Chronic; Male; Middle Aged

The aim of the study was to evaluate exhaled nitric oxide (eNO) derived from different areas of airway in obstructive sleep apnea hypopnea syndrome (OSAHS) patients with NO exchange model and investigate the potential application and interpretation of eNO in clinical setting.. This study was divided into two parts. Firstly, we performed a case control study in 32 OSAHS patients and 27 non-OSAHS participants. Fractional eNO (FeNO) and eNO from the central airway (J'awNO) and from alveoli (CANO) were compared in OSAHS and control groups. Also, correlation of eNO to severity of OSAHS was analyzed. Secondly, a prospective study was conducted in 30 severe OSAHS patients who received a short-term nasal continuous positive airway pressure (nCPAP) treatment. We evaluated eNO, plasma ET-1 concentration, and echocardiography during the treatment process and explored the potential relationship among them.. FeNO and J'awNO were higher in OSAHS and associated with disease severity, while CANO was relatively lower. After nCPAP treatment in severe OSAHS patients, FeNO and J'awNO decreased and CANO increased significantly. Substantial agreement was shown between the elevation of CANO and the decrease of plasma ET-1 concentration after nCPAP by Kappa analysis for consistency. Tei index, which is considered indicative of global right ventricular function, might be predicted by plasma ET-1 levels in severe OSAHS patients.. NO exchange model provides us with more information of eNO derived from different areas. eNO is not only confirmed to be an effective method for airway inflammation evaluation in the follow-up of OSAHS, CANO may also serve as a useful marker in monitoring endothelial function, resistance of pulmonary circulation, and right ventricular function for clinical implication.

Topics: Breath Tests; Bronchi; Cardiovascular Diseases; Case-Control Studies; Comorbidity; Continuous Positive Airway Pressure; Endothelin-1; Endothelium; Exhalation; Female; Humans; Male; Middle Aged; Nitric Oxide; Pulmonary Alveoli; Reference Values; Sleep Apnea, Obstructive; Statistics as Topic; Ventricular Function, Right

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a "vascular disease-like" phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes.

Topics: Aged; Aged, 80 and over; Animals; Aorta; Blotting, Western; Cardiovascular Diseases; Carotid Arteries; Case-Control Studies; Coronary Vessels; Cyclic AMP Response Element-Binding Protein; Diabetes Mellitus, Type 2; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Gastric Inhibitory Polypeptide; Humans; Immunohistochemistry; Male; Mice; Mice, Knockout; Microscopy, Confocal; Microvessels; Middle Aged; Myocytes, Smooth Muscle; Osteopontin; Peripheral Arterial Disease; Plaque, Atherosclerotic; Polymorphism, Single Nucleotide; Rats; Rats, Inbred WKY; Real-Time Polymerase Chain Reaction; Receptors, Gastrointestinal Hormone; RNA, Messenger; Stroke; Sus scrofa; Swine

The elevation of bradykinin (BK) level during attacks of hereditary angioedema due to C1-Inhibitor deficiency (C1-INH-HAE) is well known. We previously demonstrated that endothelin-1 (ET-1) level also increases during C1-INH-HAE attacks. Although BK and ET-1 are both potent vasoactive peptides, the vasoregulatory aspect of the pathomechanism of C1-INH-HAE has not yet been investigated. Hence we studied the levels of vasoactive peptides in controls and in C1-INH-HAE patients, as well as evaluated their changes during C1-INH-HAE attacks. The levels of arginine vasopressin (AVP), adrenomedullin (ADM) and ET-1 were measured in the plasma of 100 C1-INH-HAE patients in inter-attack periods and of 111 control subjects, using BRAHMS Kryptor technologies. In 18 of the 100 C1-INH-HAE patients, the levels of vasoactive peptides were compared in blood samples obtained during attacks, or in inter-attack periods. AVP, ADM and ET-1 levels were similar in inter-attack samples from C1-INH-HAE patients and in the samples of controls, although cardiovascular risk has an effect on the levels of vasoactive peptides in both groups. The levels of all three vasoactive peptides increased during C1-INH-HAE attacks. Moreover, the levels of ET-1 and ADM as well as their changes during attacks were significantly correlated. This study demonstrated that vascular regulation by vasoactive peptides is affected during C1-INH-HAE attacks. Our results suggest that the cooperation of several vasoactive peptides may be necessary to counterbalance the actions of excess BK, and to terminate the attacks. This may reveal a novel pathophysiological aspect of C1-INH-HAE.

Topics: Adrenomedullin; Adult; Angioedemas, Hereditary; Arginine Vasopressin; Cardiovascular Diseases; Case-Control Studies; Complement C1 Inhibitor Protein; Disease Progression; Endothelin-1; Female; Hereditary Angioedema Types I and II; Humans; Male; Middle Aged; Risk Factors; Young Adult

We tested the hypothesis that in resistance arteries from cardiovascular disease (CVD) patients, effects of an endothelium-dependent vasodilator depend on the contractile stimulus.. Arteries dissected from parietal pericardium of cardiothoracic surgery patients were studied by myography and imaging techniques. Segments were sub-maximally contracted by K(+) , the TxA2 analogue U46619 or endothelin-1 (ET-1).. Relaxing effects of Na-nitroprusside were comparable, but those of bradykinin (BK) were bigger in the presence of ET-1 compared with K(+) or U46619. BK-induced relaxation was (i) abolished by L-NAME in K(+) -contracted arteries, (ii) partly inhibited by L-NAME in the presence of U46619 and (iii) not altered by indomethacin, L-NAME plus inhibitors of small and intermediate conductance calcium-activated K(+) channels, but attenuated by catalase, in ET-1-contracted arteries. This catalase-sensitive relaxation was unaffected by inhibitors of NADPH oxidases or allopurinol. Exogenous H2 O2 caused a larger relaxation of ET-1-induced contractions than those evoked by K(+) or U46619 in the presence of inhibitors of other endothelium-derived relaxing factors. Catalase-sensitive staining of cellular ROS with CellROX Deep Red was significantly increased in the presence of both 1 μM BK and 2 nM ET-1 but not either peptide alone.. In resistance arteries from patients with CVD, exogenous ET-1 shifts the mediator of relaxing responses to the endothelium-dependent vasodilator BK from NO to H2 O2 and neither NADPH oxidases, xanthine oxidase nor NOS appear to be involved in this effect. This might have consequences for endothelial dysfunction in conditions where intra-arterial levels of ET-1 are enhanced.

Topics: Aged; Arteries; Bradykinin; Cardiovascular Diseases; Endothelin-1; Female; Humans; Hydrogen Peroxide; In Vitro Techniques; Male; Nitric Oxide

Both the lipid prostacyclin and the peptide endothelin-1 are endothelium-derived substances. Endothelin-1 is one of the most powerful endogenous vasoconstrictors, while prostacyclin is a potent antiaggregatory and vasodilator mediator upon activation of prostaglandin I2 (IP) receptors. During endothelium-dependent, prostanoid-mediated contractions/constrictions, however, prostacyclin appears to be a major endothelium-derived contracting factor (EDCF). Such cyclooxygenase-dependent responses, whether measured ex vivo or in vivo, are exacerbated by aging, obesity, diabetes, or hypertension. On the background of such cardiovascular risk factors, endothelin-1 may potentiate these contractions by promoting prostacyclin production. The latter is reduced by endothelin-A (ETA) receptor antagonists. This receptor subtype is recognized for mediating contractions of smooth muscle cells to endothelin-1. However, it is present also on endothelial cells, where its activation increases intracellular calcium concentration with subsequent initiation of phospholipase A2 that provides arachidonic acid for metabolism by cyclooxygenases. Thus, endothelin-1 favors cyclooxygenase-dependent vasoconstrictor prostanoid formation, including prostacyclin. Activation of endothelial endothelin-B (ETB) receptors promotes the release of nitric oxide, which opposes both EDCF and endothelin-1. This is less pronounced in disease promoting ETA- and smooth muscle ETB receptor-dependent as well as prostanoid-mediated contractions. In addition, the thromboxane prostanoid (TP) receptors on vascular smooth muscle cells become hyperresponsive to EDCF under pathophysiological conditions, while IP receptor responsiveness diminishes. A better understanding of the interaction between prostacyclin and endothelin-1 and the determination of the roles of the TP and IP receptors involved in prostanoid-mediated contractions in health and during disease will help to define advanced pharmacological strategies for the therapy of cardiovascular disorders.

Topics: Animals; Cardiovascular Diseases; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Receptors, Endothelin; Receptors, Thromboxane; Risk Factors; Vasoconstrictor Agents

What is the central question of this study? This study addresses the relative impact of obesity and intermittent hypoxia in the pathophysiological process of obstructive sleep apnoea by investigating the metabolic, inflammatory and cardiovascular consequences of intermittent hypoxia in lean and obese Zucker rats. What is the main finding and its importance? We found that obesity and intermittent hypoxia have mainly distinct consequences on the investigated inflammatory and cardiometabolic parameters in Zucker rats. This suggests that, for a given severity of sleep apnea, the association of obesity and obstructive sleep apnoea may not necessarily be deleterious. Obstructive sleep apnoea is associated with obesity with a high prevalence, and both co-morbidities are independent cardiovascular risk factors. Intermittent hypoxia (IH) is thought to be the main factor responsible for the obstructive sleep apnoea-related cardiometabolic alterations. The aim of this study was to assess the respective impact of obesity and IH on the inflammatory and cardiometabolic state in rats. Lean and obese Zucker rats were exposed to normoxia or chronic IH, and we assessed metabolic and inflammatory parameters, such as plasma lipids and glucose, serum leptin and adiponectin, liver cytokines, nuclear factor-κB activity and cardiac endothelin-1 levels. Myocardial infarct size was also evaluated following in vitro ischaemia-reperfusion. Circulating lipids, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin and adiponectin levels were higher in obese versus lean rats. Chronic IH did not have a significant impact on metabolic parameters in lean rats. In obese rats, IH increased glycaemia and HOMA-IR. Liver interleukin-6 and tumour necrosis factor-α levels were elevated in lean rats exposed to IH; obesity prevented the increase in interleukin-6 but not in tumour necrosis factor-α. Finally, IH exposure enhanced myocardial sensitivity to infarction in both lean and obese rats and increased cardiac endothelin-1 in lean but not obese rats. In conclusion, this study shows that the dyslipidaemia and insulin resistance induced by obesity of genetic origin does not enhance the deleterious cardiovascular response to IH and may even partly protect against IH-induced inflammation.

Topics: Adiponectin; Animals; Blood Glucose; Cardiovascular Diseases; Cytokines; Disease Models, Animal; Endothelin-1; Hypoxia; Inflammation; Insulin; Interleukin-6; Leptin; Lipids; Liver; Male; Myocardium; NF-kappa B; Obesity; Rats; Rats, Zucker; Tumor Necrosis Factor-alpha

Endothelial dysfunction is a major precursor of atherosclerosis. The aim of this study was to assess the interrelationships between plasma endothelin-1 (ET-1) levels and cardiovascular risk among young and healthy individuals.. We performed a population-based study among 2160 healthy adults aged between 25 and 41 years in the Principality of Liechtenstein. Individuals with prevalent cardiovascular disease, diabetes or a body mass index >35 kg/m(2) were excluded. Plasma ET-1 was measured using a novel high-sensitive, single-molecule counting technology. The relationships between plasma levels of ET-1 and various cardiovascular risk factors were assessed by multivariable regression analyses.. Median age of our population was 37 years. Median ET-1 levels across ET-1 quartiles were 1.86, 2.33, 2.76 and 3.48 pg/mL. After multivariable adjustment, there were significant correlations of ET-1 with systolic blood pressure (β per 1-unit increase in log transformed ET-1 2.30 (95% confidence interval (CI) 1.03; 3.58, p = 0.0004), C-reactive protein (β 0.19 (95% CI 0.03; 0.34, p = 0.021), glomerular filtration rate (β -1.73 (95% CI -3.17; -0.29, p = 0.019), and current smoking (Odds ratio 1.94 (95% CI 1.39; 2.71, p < 0.0001). We also found a highly significant association between ET-1 levels and overall cardiovascular risk estimated by the "Prospective Cardiovascular Münster" (PROCAM) and the Framingham score (β 0.18 (95% CI 0.06; 0.31, p = 0.004, and β 0.11 (95% CI 0.05; 0.16), p < 0.0001, respectively).. Plasma ET-1 levels are easily measurable in healthy adults and correlate with major cardiovascular risk factors and global cardiovascular risk.

Topics: Adult; Cardiovascular Diseases; Cohort Studies; Endothelin-1; Female; Glomerular Filtration Rate; Healthy Volunteers; Humans; Inflammation; Liechtenstein; Male; Multivariate Analysis; Phenotype; Risk Factors; Smoking; Surveys and Questionnaires; Systole; Young Adult

Healthy middle-aged postmenopausal women have higher endothelium-dependent dilation and lower vasoconstrictor activity of endothelin-1 than men. Whether these sex-specific differences extend to patients with cardiovascular risk factors has not been investigated. The current study aimed to determine whether, in patients with cardiovascular risk factors, sex-specific differences exist in endothelium-dependent dilation and endothelin-1 activity.. Forearm blood flow responses were measured by strain-gauge plethysmography during the intra-arterial infusion of acetylcholine, sodium nitroprusside, and the selective endothelin type A receptor blocker BQ-123 in 50 women and 64 men with cardiovascular risk factors.. Acetylcholine and sodium nitroprusside induced a significant vasodilation in women and men alike (p < 0.01 for both). Also BQ-123 caused a significant vasodilation (p < 0.001) in both groups. The vasodilator response to acetylcholine was greater in women compared to men; however there were no differences in the response to sodium nitroprusside and BQ-123 (p = NS for both) between the two sex groups.. Middle-aged women with cardiovascular risk factors have significantly higher endothelium-dependent dilation than middle-aged men; however, vascular endothelin 1 activity is similar in the two groups. These findings suggest that the presence of cardiovascular risk factors is associated with sex-specific effects on endothelium-dependent dilation but not on endothelin 1 activity. Further study is needed to confirm our findings and to characterize the mechanisms underlying this sex-specific regulation of endothelial function.

Topics: Acetylcholine; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Forearm; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Nitroprusside; Peptides, Cyclic; Regional Blood Flow; Risk Factors; Sex Characteristics; Vasodilation; Vasodilator Agents

Elevated levels of endothelin-1 (ET-1), a potent vasoactive peptide, are implicated as a risk factor for cardiovascular diseases by exerting vasoconstriction. The aim of this study was to address whether ET-1, at sub-vasomotor concentrations, elicits adverse effects on coronary microvascular function. Porcine coronary arterioles (50-100μm) were isolated, cannulated and pressurized without flow for in vitro study. Diameter changes were recorded using a videomicrometer. Arterioles developed basal tone (60±3μm) and dilated to the endothelium-dependent nitric oxide (NO)-mediated vasodilators serotonin (1nmol/L to 0.1μmol/L) and adenosine (1nmol/L to 10μmol/L). Treating the vessels with a clinically relevant sub-vasomotor concentration of ET-1 (10pmol/L, 60min) significantly attenuated arteriolar dilations to adenosine and serotonin but not to endothelium-independent vasodilator sodium nitroprusside. The arteriolar wall contains ETA receptors and the adverse effect of ET-1 was prevented by ETA receptor antagonist BQ123, the superoxide scavenger Tempol, the NADPH oxidase inhibitors apocynin and VAS2870, the NOX2-based NADPH oxidase inhibitor gp91 ds-tat, or the p38 kinase inhibitor SB203580. However, ETB receptor antagonist BQ788, H2O2 scavenger catalase, scrambled gp91 ds-tat, or inhibitors of xanthine oxidase (allopurinol), PKC (Gö 6983), Rho kinase (Y27632), and c-Jun N-terminal kinase (SP600125) did not protect the vessel. Immunohistochemical staining showed that ET-1 elicited Tempol-, apocynin- and SB203580-sensitive superoxide productions in the arteriolar wall. Our results indicate that exposure of coronary arterioles to a pathophysiological, sub-vasomotor concentration of ET-1 leads to vascular dysfunction by impairing endothelium-dependent NO-mediated dilation via p38 kinase-mediated production of superoxide from NADPH oxidase following ETA receptor activation.

Topics: Adenosine; Animals; Arterioles; Cardiovascular Diseases; Coronary Vessels; Endothelin-1; Endothelium, Vascular; Humans; Hydrogen Peroxide; NADPH Oxidases; Nitric Oxide; Nitroprusside; p38 Mitogen-Activated Protein Kinases; Serotonin; Swine; Vasoconstriction; Vasodilation; Vasodilator Agents

Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer.. We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint.. During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP.. Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Topics: Adrenomedullin; Aged; Asymptomatic Diseases; Atrial Natriuretic Factor; Austria; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Endothelin-1; Female; Glycopeptides; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Neoplasm Staging; Neoplasms; Peptide Fragments; Prospective Studies; Protein Precursors; Troponin T

A history of pre-eclampsia increases the risk of cardiovascular morbidity by mechanisms yet unknown. The aim of the present study was to assess whether plasma norepinephrine (NE) levels are increased 5-6 years after pre-eclamptic pregnancy and to investigate associations with pathophysiological mechanisms of cardiovascular disease: insulin sensitivity, vascular function and arterial pressure. A total of 28 women with previous pre-eclampsia and 20 controls were examined. Blood pressure (BP) and plasma levels of NE and endothelin-1 (ET-1) were measured at rest and after standing for 5 min. Insulin sensitivity was assessed with minimal model analysis and vascular function was assessed using venous occlusion plethysmography and pulse wave analysis. Twenty-four-hour BP measurements were carried out. Women with previous pre-eclampsia had higher levels of NE at rest (P=0.02), which did not associate significantly with insulin sensitivity or overall vasodilatory capacity. The 24-h mean of systolic and diastolic blood pressures (BPs) and heart rate did not differ between the groups (P=0.30, P=0.10 and P=0.46, respectively), and there was no significant association with NE levels. ET-1 levels were similar between the groups, but a positive correlation with systolic (P=0.04) and diastolic (P=0.03) BPs in the upright position was shown in the patient group. Increased levels of plasma NE are sustained in women with previous pre-eclampsia and may contribute to the increased risk for cardiovascular disease in these women.

Topics: Adult; Biomarkers; Blood Pressure; Cardiovascular Diseases; Case-Control Studies; Endothelin-1; Female; Heart Rate; Humans; Hypertension; Insulin Resistance; Norepinephrine; Postpartum Period; Pre-Eclampsia; Pregnancy; Risk Factors; Sympathetic Nervous System; Time Factors

Many studies of human subjects have demonstrated the utility of assessing serum levels of endothelin-1 (ET-1) and big ET-1 as clinical biomarkers in cardiopulmonary and neoplastic diseases. In this study we explored the feasibility of using serum big ET-1 as a reliable veterinary marker in dogs with various cardiopulmonary and neoplastic diseases.. Serum big ET-1 levels were measured by ELISA in dogs with cardiopulmonary (n=21) and neoplastic diseases (n=57). Dogs exhibiting cardiopulmonary disease were divided into two groups based on the velocity of tricuspid valve regurgitation (3.0>m/s) measured by ultrasound: without and with pulmonary hypertension. Big ET-1 levels for the dogs with the diseases were compared with levels in normal healthy dogs (n=17).. Dogs with cardiopulmonary disease (4.6±4.6 pmol/l) showed a significantly (P<0.01) higher level of big ET-1 than healthy control dogs (1.1±0.53 pmol/l). Serum levels in the dogs with pulmonary hypertension (6.2±5.3 pmol/l) were significantly (P<0.01) higher than those without pulmonary hypertension (2.0±0.6 pmol/l). Dogs with hemangiosarcoma (5.6±2.2 pmol/l), adenocarcinoma (2.0±1.8 pmol/l), histiocytic sarcoma (3.3±1.9 pmol/l), chondrosarcoma or osteosarcoma (3.0±1.6 pmol/l) and hepatocellular carcinoma (2.7±1.8 pmol/l) showed significantly (P<0.05) higher levels than healthy control dogs.. These findings point to the potential of serum big ET-1 as a clinical marker for cardiopulmonary and neoplastic diseases in dogs.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Dogs; Endothelin-1; Female; Humans; Lung Diseases; Male; Natriuretic Peptide, Brain; Neoplasms; Peptide Fragments

Exposure to pro-inflammatory cytokines, such as Angiotensin II, endothelin-1 or TNF leads to endothelial dysfunction, characterized by the reduced production of nitric oxide via endothelial nitric oxide synthase (eNOS). We recently identified the Ca(2+) binding protein S100A1 as an essential factor required for eNOS activity. Here we report that pro-inflammatory cytokines down-regulate expression of S100A1 in primary human microvascular endothelial cells (HMVECs) via induction of microRNA-138 (miR-138), in a manner that depends on the stabilization of HIF1-α. We show that loss of S100A1 in ECs reduces stimulus-induced NO production, which can be prevented by inhibition of miR-138. Our study suggests that targeting miR-138 might be beneficial for the treatment of cardiovascular disease.

Topics: Angiotensin II; Cardiovascular Diseases; Cell Line; Endothelial Cells; Endothelin-1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation Mediators; MAP Kinase Signaling System; MicroRNAs; Mitogen-Activated Protein Kinases; Nitric Oxide Synthase Type III; Phosphorylation; Protein Processing, Post-Translational; S100 Proteins; Transcriptional Activation; Tumor Necrosis Factor-alpha

Since its discovery in 1988, the endothelin system has been employed in multiple physiological and pathological roles. Endothelin-1 (ET-1) is not only a major regulator of vascular tone and cardiac contractility but also exerts mitogenic effects and is involved in inflammatory responses. ET-1 acts via two endothelin receptors located mainly on smooth muscle and endothelial cells through complex intracellular pathways differing between receptors and cell types. Polymorphisms of the endothelin receptor A have been associated not only with the risk in pulmonary arterial hypertension (PAH), systolic heart failure and systemic hypertension but are also of prognostic significance in dilated cardiomyopathy. Polymorphisms of endothelin receptors might lead to altered endothelin signaling and influence the response to endothelin receptor antagonist therapy in PAH in light of pharmacogenetics. This review will summarize the role of ET-1 within major cardiovascular pathologies and discuss endothelin receptor polymorphisms with special emphasis on potential therapeutic and screening implications.

Topics: Cardiovascular Diseases; Cardiovascular System; Endothelin-1; Humans; Mass Screening; Polymorphism, Genetic; Receptor, Endothelin A

The effects of cold air on cardiovascular and cerebrovascular diseases were investigated in an experimental study examining blood pressure and biochemical indicators. Zhangye, a city in Gansu Province, China, was selected as the experimental site. Health screening and blood tests were conducted, and finally, 30 cardiovascular disease patients and 40 healthy subjects were recruited. The experiment was performed during a cold event during 27-28 April 2013. Blood pressure, catecholamine, angiotensin II (ANG-II), cardiac troponin I (cTnI), muscle myoglobin (Mb) and endothefin-1 (ET-1) levels of the subjects were evaluated 1 day before, during the 2nd day of the cold exposure and 1 day after the cold air exposure. Our results suggest that cold air exposure increases blood pressure in cardiovascular disease patients and healthy subjects via the sympathetic nervous system (SNS) that is activated first and which augments ANG-II levels accelerating the release of the norepinephrine and stimulates the renin-angiotensin system (RAS). The combined effect of these factors leads to a rise in blood pressure. In addition, cold air exposure can cause significant metabolism and secretion of Mb, cTnI and ET-1 in subjects; taking the patient group as an example, ET-1 was 202.7 ng/L during the cold air exposure, increased 58 ng/L compared with before the cold air exposure, Mb and cTnI levels remained relatively high (2,219.5 ng/L and 613.2 ng/L, increased 642.1 ng/L and 306.5 ng/L compared with before the cold air exposure, respectively) 1-day after the cold exposure. This showed that cold air can cause damage to patients' heart cells, and the damage cannot be rapidly repaired. Some of the responses related to the biochemical markers indicated that cold exposure increased cardiovascular strain and possible myocardial injury.

Topics: Adult; Aged; Air; Angiotensin II; Biomarkers; Blood Pressure; Cardiovascular Diseases; Case-Control Studies; Catecholamines; Cerebrovascular Disorders; Cold Temperature; Endothelin-1; Female; Humans; Male; Middle Aged; Myoglobin; Troponin I

Topics: Animals; Cardiovascular Diseases; Cholesterol, HDL; Diabetic Nephropathies; Endothelin-1; Female; Humans; Male; Podocytes; Renal Insufficiency, Chronic

Heat-shock protein 60 (Hsp60) has been shown to provoke inflammation, and anti-Hsp60 may facilitate the development of atherosclerosis. In this study, we have investigated 30 patients with mixed connective tissue disease (MCTD) and assessed anti-Hsp60 and their relationship to cardiovascular diseases (CVD). Out of 30 patients with MCTD, 15 had CVDs. Anti-Hsp60 antibody was determined by enzyme-linked immunosorbent assay. Since endothelial dysfunction and accelerated atherosclerosis are characteristic to MCTD, a wide array of MCTD-, endothelial dysfunction- and CVD-associated parameters was investigated: serum lipid levels, paraoxonase activity (PON1), rich nuclear ribonucleoprotein U1 (anti-U1RNP), anti-endothelial cell antibodies, anti-cardiolipin and anti-β2-glycoprotein I antibody isotypes (anti-CL and anti-β2GPI), endothelin-1 (ET-1) levels, also intima-media thickness (IMT), a quantitative indicator of atherosclerosis. In MCTD, anti-Hsp60 antibody levels were significantly higher than in healthy individuals (p < 0.02). MCTD patients with CVD had significantly higher levels of anti-Hsp60 compared to MCTD without CVD (p = 0.001). Patients with MCTD had significantly lower high-density lipoprotein cholesterol (p = 0.02) and PON activity (p < 0.001), and significantly increased systolic (p < 0.0002) and diastolic (p < 0.001) blood pressure compared to healthy individuals. Anti-U1RNP levels (p < 0.002) and IMT were higher in patients compared to controls (p = 0.002). The CVD-positive MCTD patients had increased anti-Hsp60 (p < 0.0013), anti-CL IgG (p = 0.0005), ET-1 serum concentration (p < 0.05) and IMT levels (p < 0.001) compared to MCTD patients without CVD. Anti-Hsp60 showed a strong correlation with anti-oxLDL (r = 0.36, p = 0.01) and serum ET-1 (r = 0.62, p < 0.001) and negative correlation with PON activity (r = -0.47, p = 0.01). Anti-Hsp60 indicates endothelial injury, CVD, and can function as a novel atherosclerotic risk factor, also a valuable diagnostic marker in patients with MCTD.

Topics: Adult; Aged; Aryldialkylphosphatase; Autoantibodies; Cardiolipins; Cardiovascular Diseases; Chaperonin 60; Endothelin-1; Female; Humans; Immunoglobulin G; Lipids; Male; Middle Aged; Mixed Connective Tissue Disease

To investigate the ability of cardiovascular plasma biomarkers to identify imminent preeclampsia (PE) among pregnant women at triage.. C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1), mid-regional pro-adrenomedullin (MR-proADM), and mid-regional pro-atrial natriuretic peptide (MR-proANP) were prospectively measured in pregnant women presenting at the obstetrical triage units of the University Hospitals of Basel and Zurich, Switzerland. Logistic regression and receiver operating characteristics (ROC) analysis was used to assess and quantify the predictive ability of cardiovascular biomarkers.. Of the 147 included women, 27 (18.4%) were diagnosed at admission with PE. All biomarker levels were significantly higher in participants with PE as compared to controls. However, only MR-proANP, MR-proADM and CT-proET-1 were significant and independent predictors of PE, after taking into account the effect of various clinical confounders. The area under the ROC curve (AUC) was 0.62 (95% confidence interval 0.50-0.73) for copeptin, 0.64 (0.52-0.76) for MR-proADM, 0.71 (0.61-0.82) for CT-proET-1, and 0.83 (0.73-0.92) for MR-proANP. The combination of MR-proANP and MR-proADM resulted in the highest diagnostic performance (AUC 0.88; 0.79-0.96).. Assessment of the cardiovascular plasma biomarkers MR-proANP and MR-proADM holds promise to support diagnosis of PE at triage.

Topics: Adrenomedullin; Adult; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Endothelin-1; Epidemiologic Studies; Female; Glycopeptides; Humans; Peptide Fragments; Pre-Eclampsia; Pregnancy; Protein Precursors; Triage

The present study was designed to compare novel risk factors for cardiovascular diseases (CVD) between hemodialysis (HD) patients with or without protein-energy wasting (PEW) for determining novel risk factors for CVD in HD patients with PEW.. In this cross-sectional study, 291 HD patients were randomly selected from among 2,302 adult HD patients in Tehran hemodialysis centers. The presence of PEW in HD patients was determined by subjective global assessment. In addition, 4 mL blood was obtained before dialysis and analyzed for serum concentrations of novel risk factors for CVD, including C-reactive protein (CRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), sE-selectin, malondialdehyde (MDA), nitric oxide (NO), endothelin-1 and lipoprotein (a) [Lp (a)].. Serum CRP and sICAM-1 were significantly higher in HD patients with PEW as compared to those without PEW (P < 0.01), whereas there were no significant differences in serum sVCAM-1, sE-selectin, MDA, NO, endothelin-1 and Lp (a) between the two groups. Serum CRP and sICAM-1 were significantly higher in HD patients with PEW type IIa and IIb than in those with PEW type I (P < 0.01).. The present study indicates that serum CRP and sICAM-1, as two CVD risk factors, increase in HD patients with PEW as compared to those without PEW and these increases occur in HD patients with PEW type IIa and IIb who have inflammation.

Topics: Adolescent; Adult; Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Cross-Sectional Studies; E-Selectin; Endothelin-1; Female; Humans; Intercellular Adhesion Molecule-1; Iran; Lipoprotein(a); Male; Malondialdehyde; Middle Aged; Nitric Oxide; Protein-Energy Malnutrition; Renal Dialysis; Risk Factors; Vascular Cell Adhesion Molecule-1

Clinical and experimental evidence suggests that endothelin-1 (ET-1) plays a role in cardiac and vascular disease. In the present study, we investigated the prognostic significance of ET-1 for cerebrovascular and cardiovascular outcome, in a 20-year follow-up.. We studied 82 originally healthy individuals, referred to our Unit of Cardiovascular Prevention, to evaluate the presence of asymptomatic carotid lesions. We subdivided these individuals into two groups, according to the plasma values of ET-1 (respectively ≤ or >2.7 pg/ml). Traditional cardiovascular risk factors were investigated, and by carotid ultrasound examination, we distinguished between normal individuals and those with intima-media thickening or asymptomatic carotid plaque.. Major cardiac and cerebral events (all-cause death, myocardial infarction, revascularization procedures, fatal and nonfatal stroke) were registered in 41 individuals and significantly more in those with high vs. low ET-1 levels (95 vs. 5%; P < 0.0001). Furthermore, by logistic multivariate regression analysis, we found that among all evaluated baseline clinical and laboratory variables, hypertension [odds ratio (OR): 20.4 (3.3-127), P = 0.001], high ET-1 concentrations [OR: 1.4 (1.0-1.8), P = 0.02] and the presence of intima-media thickness or asymptomatic carotid plaque [OR: 3.7 (1.14-12.1), P = 0.02] were independent predictors of future events. Finally, integrating technical and laboratory data, high levels of ET-1 have defined a high risk of major cardiac and cerebral event and stroke at follow-up, which increased in relation to the progression of carotid atherosclerosis (P < 0.05).. ET-1 plasmatic levels significantly influence the cardiovascular and cerebrovascular risk profile, beyond traditional cardiovascular risk factors and preclinical carotid atherosclerosis.

Topics: Adult; Aged; Asymptomatic Diseases; Biomarkers; Cardiovascular Diseases; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cerebrovascular Disorders; Endothelin-1; Female; Follow-Up Studies; Humans; Male; Middle Aged; Plaque, Atherosclerotic; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Factors

To investigate the relationship between interleukin-6 (IL-6), endothelin-1 (ET-1), E-selectin and the risk of cardio-cerebrovascular events.. Based on a cohort study in which 2 589 Mongolians had been followed up for 10 years, a nested case-control study was carried out to analyze the relationship between IL-6, ET-1, E-selectin and the risk of cardio-cerebrovascular events. Logistic regression analysis was used to calculate the odds ratio (OR) and 95% confidence intervals (95%CI).. The average level of IL-6 (7.66 vs. 8.77 pg/ml), ET-1 (0.74 vs. 0.75 pg/ml) and E-selectin (17.96 vs. 18.32 ng/ml)were not significantly different between the case and the control groups (P > 0.05). Data from the logistic regression analysis showed that IL-6, ET-1 and E-selectin were not significantly associated with the risk of cardio-cerebrovascular events. The multivariable adjusted ORs (95%CI) on the risk of cardio-cerebrovascular events were 0.69 (0.41-1.16), 1.10 (0.66-1.85) and 1.19 (0.71-2.00) for the participants with IL-6>23.91 pg/ml, ET-1>1.33 pg/ml and E-selectin>24.43 ng/ml, respectively, compared with those having IL-6≤23.91 pg/ml, ET-1≤1.33 pg/ml or E-selectin≤24.43 ng/ml.. Data from our study indicated that the levels of IL-6, ET-1 and E-selectin at baseline were not significantly associated with the risk of cardio-cerebrovascular events in people from Inner Mongolia.

Topics: Cardiovascular Diseases; Case-Control Studies; Cerebrovascular Disorders; China; Cohort Studies; E-Selectin; Endothelin-1; Humans; Interleukin-6; Odds Ratio; Risk

To investigate the toxicological effects of biogenic- versus anthropogenic-source secondary organic aerosol (SOA) on the cardiovascular system, the Secondary Particulate Health Effects Research program irradiation chamber was used to expose atherosclerotic apolipoprotein E null (Apo E-/-) mice to SOA from the oxidation of either α-pinene or toluene for 7 days. SOA atmospheres were produced to yield 250-300 μg/m(3) of particulate matter and ratios of 10:1:1 α-pinene:nitrogen oxide (NOx):ammonia (NH3); 10:1:1:1 α-pinene:NOx:NH3:sulfur dioxide (SO2) or 10:1:1 toluene:NOx:NH3; and 10:1:1:1 toluene:NOx:NH3:SO2. Resulting effects on the cardiovascular system were assessed by measurement of vascular lipid peroxidation (thiobarbituric acid reactive substance (TBARS)), as well as quantification of heme-oxygenase (HO)-1, endothelin (ET)-1, and matrix metalloproteinase (MMP)-9 mRNA expression for comparison to previous program exposure results. Consistent with similar previous studies, vascular TBARS were not increased significantly with any acute SOA exposure. However, vascular HO-1, MMP-9, and ET-1 observed in Apo E-/- mice exposed to α-pinene + NOx + NH3 + SO2 increased statistically, while α-pinene + NOx + NH3 exposure to either toluene + NOx + NH3 or toluene +NOx + NH3 + SO2 resulted in a decreased expression of these vascular factors. Such findings suggest that the specific chemistry created by the presence or absence of acidic components may be important in SOA-mediated toxicity in the cardiovascular system and/or progression of cardiovascular disease.

Topics: Administration, Inhalation; Aerosols; Ammonia; Animals; Aorta; Apolipoproteins E; Bicyclic Monoterpenes; Biomarkers; Cardiovascular Diseases; Endothelin-1; Heme Oxygenase-1; Male; Matrix Metalloproteinase 9; Membrane Proteins; Mice; Mice, Knockout; Monoterpenes; Nitric Oxide; Organic Chemicals; RNA, Messenger; Thiobarbituric Acid Reactive Substances; Toluene

BACKGROUND AND OBJECTIVE. In this study, we attempted to determine whether the C/T polymorphism of the ET-1 gene was significantly associated with changes in several clinical characteristics after the 16-week combined exercise program in overweight middle-aged women. MATERIAL AND METHODS. The C/T polymorphism of the ET-1 gene was assayed using polymerase chain reaction, i.e., the TaqI restriction fragment length polymorphism method. RESULTS. The genetic variation in the ET-1 gene showed a significant association with the serum LDL cholesterol level as well as several parameters of physical fitness, including muscular endurance and power of the participants (P<0.05). In addition, this genetic variation showed a significant association with changes in muscular strength of the participants after the 16-week combined exercise program (P<0.05). CONCLUSIONS. Our data suggest that the C/T substitution on intron 4 of the ET-1 gene may be a useful genetic marker influencing muscular strength through a gene-exercise interaction and is associated with an interindividual difference of cardiovascular risk factors and parameters of physical fitness.

Topics: Asian People; Cardiovascular Diseases; Endothelin-1; Exercise; Female; Gene-Environment Interaction; Genetic Variation; Humans; Middle Aged; Muscle Strength; Republic of Korea

To investigate the effect of a short-term yoga-based lifestyle intervention on risk factors for cardiovascular disease (CVD) and markers of inflammation and endothelial function in overweight and obese men.. Nonrandomized prospective lifestyle intervention study with pre-post design. SETTING AND LOCATION: Integral Health Clinic, an outpatient facility providing yoga-based lifestyle intervention programs for prevention and management of chronic diseases.. Overweight and obese men (n=51) were enrolled in the study. Subjects who were physically unable to participate and those participating in other interventions were excluded from the study.. A pretested intervention program including asanas (physical postures), pranayama (breathing exercises), group discussions, lectures, and individualized advice.. The primary outcome measure was weight loss, and the secondary outcome measures were clinical and laboratory correlates of CVD risk, levels of interleukin-6 (IL-6), adiponectin, and endothelin-1 (ET-1).. Men (n=51, body mass index [BMI] 26.26±2.42 kg/m(2)) were enrolled and underwent a yoga-based lifestyle intervention for 10 days. Of 51 subjects, 30 completed the study. There was a significant reduction in weight from Baseline to Day 10 (74.60±7.98, 72.69±8.37 kg, p<0.001, respectively), BMI (26.26±2.42, 25.69±2.47 kg/m(2), p<0.001, respectively), and systolic BP (121.73±11.58, 116.73±9.00, p=0.042, respectively). There was a significant reduction in plasma IL-6 from Baseline to Day 10 (median 2.24 vs. 1.26 pg/mL, respectively, p=0.012). There was a significant increase in the plasma adiponectin from Baseline to Day 10 (median 4.95 vs. 6.26 μg/mL, respectively, p=0.014). Plasma ET-1 level remained unchanged.. These findings suggest that even a short-term yoga-based lifestyle intervention may be an important modality to reduce the risk for CVD as indicated by weight loss, reduction in systolic blood pressure, an increase in adiponectin, and decrease in IL-6 in overweight and obese men.

Topics: Adiponectin; Adolescent; Adult; Blood Pressure; Body Mass Index; Body Weight; Cardiovascular Diseases; Endothelin-1; Humans; Interleukin-6; Life Style; Lipoproteins; Male; Middle Aged; Obesity; Overweight; Prospective Studies; Pulse; Risk Factors; Yoga; Young Adult

1. Tanshinone IIA, one of the active components of the Radix of Salvia miltiorrhiza, is used in traditional Chinese medicine to treat cardiovascular diseases. However, the intracellular mechanism of action of tanshinone IIA remain to be determined. The aims of the present study were to test the hypothesis that tanshinone IIA alters strain-induced endothelin (ET)-1 expression and nitric oxide (NO) production, as well as to identify the putative signalling pathways involved, in human umbilical vein endothelial cells (HUVEC). 2. Cultured HUVEC were exposed to cyclic strain in the presence of 1-10 μmol/L tanshinone IIA. Expression of ET-1 was examined by reverse transcription-polymerase chain reaction and ELISA. Phosphorylation of endothelial NO synthase (eNOS) and activating transcription factor (ATF) 3 was assessed by western blot analysis. 3. Tanshinone IIA (3 and 10 μmol/L) inhibited strain-induced ET-1 expression. In contrast, NO production, eNOS phosphorylation and ATF3 expression were enhanced by tanshinone IIA. The eNOS inhibitor N(G) -nitro-L-arginine methyl ester (l-NAME; 100 μmol/L), the phosphatidylinositol 3-kinase inhibitor LY294002 (5 μmol/L) and the soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ; 10 μmol/L) inhibited tanshinone IIA-induced increases in ATF3 expression. Moreover, treatment of HUVEC with either an NO donor (3,3-bis [aminoethyl]-1-hydroxy-2-oxo-1-triazene; 500 μmol/L) or an ATF3 activator (carbobenzoxy-L-leucyl-L-leucyl-L-leucinal; 5 μmol/L) resulted in the repression of strain-induced ET-1 expression. The inhibitory effect of tanshinone IIA on strain-induced ET-1 expression was significantly attenuated by l-NAME, ODQ and the transfection of small interfering RNA for ATF3. 4. In conclusion, tanshinone IIA inhibits strain-induced ET-1 expression by increasing NO and upregulating ATF3 in HUVEC. The present study provides important new insights into the molecular pathways that may contribute to the beneficial effects of tanshinone IIA in the cardiovascular system.

Topics: Abietanes; Activating Transcription Factor 3; Cardiovascular Diseases; Cells, Cultured; Cellular Microenvironment; Down-Regulation; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Guanylate Cyclase; Human Umbilical Vein Endothelial Cells; Humans; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Processing, Post-Translational; Receptors, Cytoplasmic and Nuclear; RNA Interference; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Soluble Guanylyl Cyclase

Erectile dysfunction (ED) is an early manifestation of arteriosclerosis associated with endothelial damage/dysfunction and to a blunted ability of cultured mononuclear circulating cells (MNCs) to differentiate circulating angiogenic cells (CACs), putatively involved in endothelial damage repair. Here we explored effects of human serum (HS) from patients with ED and cardiovascular risk factors (VRFs) but no clinical atherosclerosis, on cultured MNCs of healthy men to differentiate CACs and to form colonies. Effect of HS on number of CACS and of colony forming units (CFUs) was correlated with circulating markers of endothelial damage and with angiogenic modulators. MNCs from healthy men were cultured in standard conditions or with 20% HS from 35 patients with ED and from 10 healthy men. CACs were identified after 7 days of culture by uptake of acetylated low-density lipoprotein with concomitant binding of Ulex europaeus agglutinin I. CFUs were counted after 5 days of culture. Enzyme-linked immunosorbent assays assessed plasmatic soluble (s) form of E-selectin, Endothelin (ET)-1, tissue type plasminogen activator (tPA), vascular endothelial growth factor (VEGF)(165) and sVEGF receptor (R)-1. The number of CACs and of CFUs from healthy men was reduced after culturing MNCs with HS compared to standard medium. The inhibitory effect was significantly higher with HS from ED patients with higher or lower VRF exposure compared to healthy men. Inhibition was positively correlated with VRFs exposure, with ED severity, with common carotid artery intima media thickness measured using B-mode ultrasound, and to a lesser extent with plasmatic sE-Selectin, sET-1 and sVEGFR-1. Dysfunction of cells involved in vascular homoeostasis is induced by soluble factors still unknown and already present in a very initial systemic vascular disease in men with ED and VRFs.

Topics: Adult; Aged; Cardiovascular Diseases; Carotid Intima-Media Thickness; E-Selectin; Endothelin-1; Endothelium, Vascular; Erectile Dysfunction; Humans; Leukocytes, Mononuclear; Lipoproteins, LDL; Male; Middle Aged; Risk Factors; Stem Cells; Tissue Plasminogen Activator; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

The aim of this study was to assess relationship of insulin resistance, oxidant-antioxidant status, endothelial dysfunction, lipid metabolism, and their contribution to the risks of cardiovascular disease in women with polycystic ovary syndrome (PCOS). Forty-five women with PCOS and 17 healthy women were included in this study. Nitric oxide (NO), endothelin-1 (ET-1), malondialdehyde (MDA), Apo A1, Apo B, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride, small, dense LDL cholesterol (sdLDL-C), large buoyant LDL cholesterol (LbLDL-C) levels, and paraoxonase 1 (PON1) activity were measured in serum/plasma obtained from study groups. Insulin resistance [homeostasis model assessment (HOMA) index] and serum sex hormone binding globulin (SHBG), total testosterone (tT), free testosterone (fT), androstenedione, and dehydroepiandrosteronsulfate (DHEAS) levels were also evaluated. Significantly decreased SHBG, NO, HDL-C levels, and PON1 activities, but increased tT, fT, androstenedione, DHEAS, HOMA index, MDA, ET-1, LDL-C, sdLDL-C, and LbLDL-C values were found in PCOS patients compared with those of controls. There was a positive correlation between MDA and fT levels; and a negative correlation between PON1 activity and fT. Our data show that insulin resistance, dyslipidemia, endothelial dysfunction, and oxidative stress might contribute to the excess risk of cardiovascular disease reported in PCOS patients.

Topics: Adolescent; Apolipoprotein A-I; Apolipoproteins B; Aryldialkylphosphatase; Cardiovascular Diseases; Dyslipidemias; Endothelin-1; Endothelium, Vascular; Female; Humans; Insulin Resistance; Lipoproteins, LDL; Malondialdehyde; Nitric Oxide; Oxidative Stress; Polycystic Ovary Syndrome; Risk Factors; Testosterone; Turkey; Young Adult

The aim of this study was to investigate the association between plasma COOH-terminal proendothelin-1 (CT-proET-1) and fatal cardiovascular events, all-cause mortality, and new-onset albuminuria in patients with type 2 diabetes.. A total of 1,225 patients with type 2 diabetes participated in this prospective observational study of two combined cohorts. Three clinical end points were studied: fatal cardiovascular events, all-cause mortality, and new-onset albuminuria. After a median follow-up of 3 or 10 years, Cox proportional hazard modeling was used to investigate the association between CT-proET-1 and the end points. Harrell C statistic, the Groennesby and Borgan test, the integrated discrimination improvement (IDI), and the net reclassification improvement (NRI) were used to evaluate whether CT-proET-1 is of additional value compared with classic cardiovascular and renal risk factors.. During follow-up, 364 (30%) patients died, 150 (42%) of whom died of cardiovascular disease; 182 (26.7%) of 688 patients with normoalbuminuria at baseline developed albuminuria. CT-proET-1 was associated with fatal cardiovascular events, all-cause mortality, and new-onset albuminuria with hazard ratios of 1.59 (95% CI 1.15-2.20), 1.41 (95% CI 1.14-1.74), and 1.48 (95% CI 1.10-2.01), respectively. Addition of CT-proET-1 to a model containing traditional risk factors leads only to improved prediction of fatal cardiovascular events. The IDI appeared significant for fatal cardiovascular events (0.82 [0.1-1.54]) and all-cause mortality (0.4 [0.05-0.92]), but not for new-onset albuminuria.. CT-proET-1 has additional value for the prediction of fatal cardiovascular events and new-onset albuminuria in patients with type 2 diabetes, compared with conventional risk factors, but not for all-cause mortality.

Topics: Adult; Albuminuria; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelin-1; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Peptide Fragments; Prospective Studies; Young Adult

Exposure to particulate matter (PM) increases the incidence of cardiovascular disease, but the underlying mechanisms remain unclear. To characterise ambient PM collected from a coach station in an urban area, particulate polycyclic aromatic hydrocarbons (PAHs) and trace metals were evaluated, and diagnostic ratios were then used to determine the sources based on the PAHs identified in PM. To elucidate the mechanism of PM-induced vascular toxicology, human coronary artery endothelial cells (HCAECs) were exposed to PM, PM-free supernatant and residual PM, and the associations between PAHs and trace metals, nitric oxide (NO), endothelin-1 (ET-1) and interleukin-6 (IL-6) were investigated. Petrogenic-related particulate emissions, such as vehicle exhaust, accounted for 68.75% and 75.00% of mass in the 0.1-1-μm PM (PM(0.1-1)) and <0.1-μm PM (PM(0.1)) size fractions, respectively. Vehicle exhaust particles (VEPs) caused significant NO suppression and increase in ET-1 and IL-6, whereas residual PM caused an increase in NO, ET-1 and IL-6 compared with the effects of the corresponding supernatants. PAHs in PM, particularly those with 4-6 rings, were associated with NO suppression, and ET-1 and IL-6 were positively correlated with the amount of trace metal compounds. These findings suggest that chemical components affect the regulation of vasoactive function and inflammation.

Topics: Cardiovascular Diseases; Cell Line; Dose-Response Relationship, Drug; Endothelial Cells; Endothelin-1; Humans; Inflammation; Interleukin-6; Nitric Oxide; Particulate Matter; Polycyclic Aromatic Hydrocarbons; Statistics, Nonparametric; Trace Elements; Vehicle Emissions

Endothelin-1 (ET-1) is a potent vasoconstrictor and an elevated plasma level is a prognostic marker in patients with cardiovascular diseases and/or malignancies. We hypothesized that an elevated plasma level might be a prognostic marker even in subjects without apparent cardiovascular disease or malignancy at baseline.. We measured plasma ET-1 levels in 1,440 healthy subjects over 40 years of age (580 men, 860 women) who were periodically followed for 10 years. The follow-up rate was 96.8%. Baseline plasma ET-1 levels were categorized into quartiles. Baseline plasma ET-1 levels were significantly associated with age, blood pressure, high-density lipoprotein-cholesterol, renal function, uric acid and all-cause death, but not with cardiovascular or cancer death. Kaplan-Meier curves demonstrated that all-cause mortality was significantly higher in the highest quartile of ET-1 than in the lowest quartile. Cox proportional hazards regression analysis demonstrated that ET-1 was an independent predictor of all-cause death [hazard ratio: 1.11, 95% confidence interval (CI) 1.01-1.23 per 1 pg/ml difference]. The hazard ratio of all-cause death in the highest quartile of plasma ET-1 (≥5.9 pg/ml) vs. the lowest quartile after adjusting for confounding factors was 1.54 (95% CI 1.09-2.20).. The plasma ET-1 level may be a predictor of all-cause death in a healthy population.

Topics: Aged; Asian People; Biomarkers; Cardiovascular Diseases; Cause of Death; Chi-Square Distribution; Confounding Factors, Epidemiologic; Endothelin-1; Female; Follow-Up Studies; Health Surveys; Humans; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Neoplasms; Prognosis; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Up-Regulation

The objective of this study was to evaluate the effects of supplemental selenium (Se) on expression of endothelin-1 (ET-1) and its receptors in cultured chick embryos pulmonary microvascular endothelial cells (PMVECs). To accomplish this, PMVECs were treated in Se-deficient or Se-supplement (12, 24, 50, 100 ng/ml) culture medium for 48 h. Low Se medium was achieved by reducing serum concentrations and the essential growth factors were added. After the incubation, the effects of supplemental Se on ET-1 and its receptors gene expression were assessed by quantitative real-time PCR (qRT-PCR). Compared with the control group, our results showed that among the different concentrations of Se supplement, the levels of ET-1 gene expression treated with both the moderate Se doses (24, 50 ng/ml, P < 0.01, P < 0.01, respectively) and the high doses (100 ng/ml, P < 0.05) were noticeably decreased, the low-dose group (12 ng/ml), which showed no changes. Meanwhile, Se supplement (24, 50, 100 ng/ml) was found to be effective in reducing the expression levels of ETA (P < 0.01, P < 0.05, P < 0.05, respectively) in cultured PMVECs grown in low Se medium. However, there were no significant changes (P > 0.05) in ETB mRNA levels during the cell proliferation. These observations indicated that Se may play both direct and indirect role in the regulation of ET-1 and its receptors gene expression and their production in avian PMVECs. Se supplement decreases in ET-1 and ETA production in Se-deficient PMVECs may partly explain the mechanism of the protective effects of the Se on the cardiovascular system.

Topics: Animals; Avian Proteins; Cardiovascular Diseases; Cell Survival; Cells, Cultured; Chick Embryo; Down-Regulation; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation, Developmental; Lung; Microvessels; Osmolar Concentration; Protective Agents; Receptor, Endothelin A; Receptor, Endothelin B; Reproducibility of Results; RNA, Messenger; Selenium; Sodium Selenite

The purpose was to investigate the effects of artificial cold air on cardiovascular risk in hypertensive subjects. An artificial cold air was simulated with hourly ambient temperature data of a real moderate cold air in China. Twenty-four male SHR rats were randomly divided into the minimum temperature (Tmin) group, the rewarming temperature (Tr) group and two concurrent control groups with six rats in each (Tmin and Tr represent two cold air time points, respectively). Tmin and Tr groups were exposed to the cold air that was stopped at Tmin and Tr, respectively. After cold air exposure, blood pressure, heart rate and body weight were monitored, blood was collected for the detection of some indexes like fibrinogen, total cholesterol and uric acid. Results demonstrated that blood pressure, whole blood viscosity, blood fibrinogen, total cholesterol and uric acid increased significantly both in the Tmin and Tr groups; low density lipoprotein/high density lipoprotein increased significantly only in Tr group; there was higher level of blood fibrinogen in the Tr group than the Tmin group; higher levels of creatine kinase-MB was found in both the Tmin and Tr groups. These results suggest that cold air may increase the cardiovascular risks in hypertensive subjects indirectly through its effects on the sympathetic nervous system and renin angiotensin system, blood pressure and atherosclerosis risk factors like blood viscosity and fibrinogen, lipids and uric acid in the blood.

Topics: Angiotensin II; Animals; Blood Chemical Analysis; Blood Pressure; Blood Viscosity; Body Weight; Cardiovascular Diseases; Cold Temperature; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Epinephrine; Fibrinogen; Heart Rate; Lipids; Male; Norepinephrine; Rats; Rats, Inbred SHR; Risk Factors; Vasoconstrictor Agents

Glycosylation with β-N-acetylglucosamine (O-GlcNAcylation) is one of the most complex post-translational modifications. The cycling of O-GlcNAc is controlled by two enzymes: UDP-NAc transferase (OGT) and O-GlcNAcase (OGA). We recently reported that endothelin-1 (ET-1) augments vascular levels of O-GlcNAcylated proteins. Here we tested the hypothesis that O-GlcNAcylation contributes to the vascular effects of ET-1 via activation of the RhoA/Rho-kinase pathway.. Incubation of vascular smooth muscle cells (VSMCs) with ET-1 (0.1 μM) produces a time-dependent increase in O-GlcNAc levels. ET-1-induced O-GlcNAcylation is not observed when VSMCs are previously transfected with OGT siRNA, treated with ST045849 (OGT inhibitor) or atrasentan (ET(A) antagonist). ET-1 as well as PugNAc (OGA inhibitor) augmented contractions to phenylephrine in endothelium-denuded rat aortas, an effect that was abolished by the Rho kinase inhibitor Y-27632. Incubation of VSMCs with ET-1 increased expression of the phosphorylated forms of myosin phosphatase target subunit 1 (MYPT-1), protein kinase C-potentiated protein phosphatase 1 inhibitor protein (protein kinase C-potentiated phosphatase inhibitor-17), and myosin light chain (MLC) and RhoA expression and activity, and this effect was abolished by both OGT siRNA transfection or OGT inhibition and atrasentan. ET-1 also augmented expression of PDZ-Rho GEF (guanine nucleotide exchange factor) and p115-Rho GEF in VSMCs and this was prevented by OGT siRNA, ST045849, and atrasentan.. We suggest that ET-1 augments O-GlcNAcylation and this modification contributes to increased vascular contractile responses via activation of the RhoA/Rho-kinase pathway.

Topics: Acetylglucosamine; Acylation; Animals; Aorta, Thoracic; Cardiovascular Diseases; Cells, Cultured; Endothelin-1; Male; Muscle, Smooth, Vascular; Phosphorylation; Rats; Rats, Wistar; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Vasoconstriction

Topics: Acetylglucosamine; Acylation; Animals; Cardiovascular Diseases; Endothelin-1; Humans; rho-Associated Kinases

Obstructive sleep apnea (OSA) causes endothelial dysfunction and is an independent risk factor for hypertension and cardiovascular diseases. Although vasoactive agents and sympathoexcitation have been implicated and operational in the pathogenesis of hypertension associated with OSA the exact mechanisms underlying hypertension have not been established. Soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) are released under hypoxic stress and cause endothelial dysfunction and hypertension in humans and animals. The present study was conducted to investigate the role of these antiangiogenic proteins in OSA and to determine their clinical significance.. In 22 untreated OSA patients with apnea-hypopnea index ≥30 events/h (11 with hypertension and 11 without hypertension) we measured plasma concentrations of endothelin-1, epinephrine, norepinephrine, nitric oxide metabolites, sFlt-1 and sEng.. The apnea-hypopnea indices were 81±11 and 76±9 events/h (P=ns) and the sleep times with SaO(2)<90% were 42±13 and 39±13 min (P=ns) for normotensives and hypertensives, respectively. Both groups had similarly elevated levels of catecholamines with normal endothelin-1 levels. Nitric oxide metabolites were depressed in both groups with no inter-group differences. On the other hand, both sFlt-1 (90.0±4.6 pg/ml vs. 74.0±4.4 pg/ml, P=0. 018) and sEng (4.9±0.34 ng/ml vs. 3.50±0.42 ng/ml, P=0.016) were significantly elevated in the hypertensive patients compared to the normotensive subjects.. These data show that sFlt-1 and sEng are increased in the circulation of patients with OSA and hypertension and suggest that they may be involved in the pathogenesis of hypertension.

Topics: Antigens, CD; Cardiovascular Diseases; Endoglin; Endothelin-1; Endothelium, Vascular; Epinephrine; Female; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Norepinephrine; Polysomnography; Receptors, Cell Surface; Risk Factors; Sleep Apnea, Obstructive; Vascular Endothelial Growth Factor Receptor-1

This study, in optimally treated CAD patients with newly diagnosed OSA, focused on (1) The relationships between OSA and serum biomarkers of four potential pathways of cardiovascular injury in OSA: high-sensitivity C-reactive protein (hs-CRP), endothelin-1 (ET-1), N terminal pro B type natriuretic peptide (NT-proBNP) and fibrinogen; and (2) The effect of continuous positive airway pressure (CPAP) therapy on these markers. 151 Chinese patients with proven CAD and standard medication were enrolled. After polysomnography, patients were classified into four groups according to apnea-hypopnea index (AHI): no OSA (n = 25); mild OSA (n = 50); moderate OSA (n = 43); severe OSA (n = 33). Morning levels of hs-CRP, ET-1, NT-proBNP and fibrinogen were assayed and repeated in severe OSA patients after 3-months CPAP treatment. Hs-CRP was greater in patients with severe OSA than those with no OSA or mild OSA (P = 0.001, P = 0.003; respectively). After adjustment for confounders, the hs-CRP levels correlated most strongly with AHI and oxygen desturation index (ODI) (r = 0.439, P < 0.001; r = 0.445, P < 0.001; respectively). In stepwise multiple linear regressions, the strongest predictor of hs-CRP levels was ODI (P < 0.001). After 3 months of CPAP treatment, the hs-CRP levels deceased (P = 0.005) in CAD patients with severe OSA. In CAD patients on current optimal medications, hs-CRP is significantly correlated with the severity of OSA, and the elevated hs-CRP levels can be decreased by CPAP. This suggests that OSA could activate vascular inflammation in CAD patients despite current best practice medications.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Continuous Positive Airway Pressure; Cross-Sectional Studies; Endothelin-1; Female; Fibrinogen; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Polysomnography; Sleep Apnea, Obstructive

Hypertension is more prevalent among HIV-infected individuals than in the general population and contributes to increased cardiovascular risk. The angiotensin II receptor blocker telmisartan is also a partial peroxisome proliferator activated receptor-γ agonist with documented effects on glucose and lipid homeostasis. The aim of this study was to evaluate the antihypertensive and metabolic effects of telmisartan in hypertensive HIV-positive patients.. A total of 18 HIV-positive men treated with antiretroviral therapy and recently diagnosed with hypertension were administered 80 mg telmisartan daily. Systolic blood pressure (SBP) and diastolic blood pressure (DBP), viroimmunological and metabolic parameters, insulin resistance, C-reactive protein, microalbuminuria, cystatin C and plasma levels of interleukin-18 and endothelin-1 were measured at baseline (T0), 1 month (T1), 3 months (T3) and 6 months (T6).. Treatment with telmisartan not only decreased SBP and DBP levels, but also improved insulin resistance and microalbuminuria by T1. Levels of triglycerides significantly decreased and high-density lipoprotein cholesterol increased at T1, whereas total and low-density lipoprotein cholesterol levels were statistically reduced at T3 and T6. Cystatin C and endothelin-1 showed a significant reduction at T1, whereas interleukin-18 decreased at both T3 and T6.. Telmisartan was effective in reducing blood pressure and improving lipid metabolism and renal function. Reduction of endothelin-1 might be related to an endothelial protective effect. On the basis of these findings, and because of properties unrelated to blood pressure lowering, telmisartan might be the first choice antihypertensive drug for the treatment of HIV-positive patients.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Cystatin C; Endothelin-1; HIV Seropositivity; Humans; Hypertension; Insulin Resistance; Interleukin-18; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; PPAR gamma; Risk Factors; Telmisartan; Triglycerides

Endothelin-1 is elevated in women with polycystic ovary syndrome (PCOS), and may play a role in the endothelial dysfunction associated with PCOS. Endothelin-1 binds two receptor subtypes, endothelin A (ET-A) and endothelin B (ET-B). We hypothesized that ET-A mediates vasoconstriction in the cutaneous microvasculature in women with and without PCOS. We further hypothesized that while the ET-B receptors mediate vasodilatation in both groups of women, this response would be blunted in women with PCOS. During local skin warming, we used laser Doppler flowmetry combined with intradermal microdialysis to measure skin blood flow (SkBF) during graded ET-A (BQ-123) and ET-B (BQ-788) antagonist infusions in women with (n = 6) and without (n = 8) PCOS. In both groups, SkBF increased during local heating. The percentage of maximal SkBF-[BQ123] sigmoidal dose-response curve indicated a vasodilatory response as the concentration of the antagonist increased (Hill slope 4.96 ± 4.77, 4.74 ± 5.01; logED(50) 2.53 ± 0.09, 2.49 ± 0.09 nm, for PCOS and Control, respectively). In contrast, the % max SkBF-[BQ788] curve indicated a vasoconstrictive response (Hill slope -4.69 ± 3.85, -4.03 ± 3.85; logED(50), 2.56 ± 0.09, 2.41 ± 0.12 nm, in PCOS and Control). Moreover, the SkBF-[BQ788] curve shifted to the right in women with PCOS, suggesting attenuated ET-B receptor mediated vasodilatation during local skin warming compared to Controls. Thus, the endothelium located ET-B receptors function similarly in women with and without PCOS, although with blunted responsiveness in women with PCOS. Our studies suggest that the lower ET-B receptor responsiveness associated with PCOS may reflect lower endothelial-mediated vasodilatation independent of generally lower vascular reactivity.

Topics: Adult; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelium, Vascular; Female; Humans; Microcirculation; Microvessels; Oligopeptides; Peptides, Cyclic; Piperidines; Polycystic Ovary Syndrome; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; Skin; Vasoconstriction; Vasodilation; Young Adult

We sought to verify if an oral contraceptive (OC) containing drospirenone affects the cardiovascular risk of patients with polycystic ovary syndrome (PCOS).. A total of 28 women with PCOS (16 lean [group A] and 12 overweight [group B]) were assessed at baseline and after 6 months therapy with an OC. Leptin, homocysteine, endothelin-1, and flow-mediated dilatation of brachial artery were measured.. The brachial artery diameter and the pulsatility index, after the reactive hyperemia, did not change in group A; it improved significantly in group B after 6 months of treatment. At baseline and after therapy the plasma levels of homocysteine and endothelin-1 did not differ among the groups. Leptin was significantly lower at baseline in group A compared to group B.. The OC containing drospirenone does not seem to affect the surrogate markers of cardiovascular risk in lean patients with PCOS.

Topics: Adolescent; Adult; Androstenes; Brachial Artery; Cardiovascular Diseases; Contraceptives, Oral; Endothelin-1; Female; Homocysteine; Humans; Insulin; Insulin Resistance; Leptin; Mineralocorticoid Receptor Antagonists; Obesity; Pilot Projects; Polycystic Ovary Syndrome

Cardiovascular diseases are the leading cause of morbidity and mortality in the world. Aging is associated with an increased incidence of cardiovascular disease. Premenopausal women are relatively protected from vascular alterations compared with age-matched men, likely due to higher levels of the female sex hormones. However, these vasoprotective effects in women are attenuated after menopause. Thus, the vascular system in aging women is affected by both the aging process as well as loss of hormonal protection, positioning women of this age group at a high risk for cardiovascular diseases such as hypertension, myocardial infarction, and stroke. The endothelin system in general and endothelin-1 (ET-1) in particular plays an important role in the pathogenesis of vascular dysfunction associated with aging. Evidence suggests that the female sex steroids can interfere with the vascular expression and actions of ET-1 via several mechanisms, which may further contribute to pathological processes in the vasculature of aging women. In this review, we have summarized hormone-dependent vascular pathways whereby ET-1 may mediate the deleterious effects of aging in postmenopausal females.

Topics: Aged; Aging; Animals; Cardiovascular Diseases; Endothelin-1; Estrogens; Female; Humans; Vasculitis; Vasoconstriction

to refine a role of free radical oxidation (FRO), anemia, and endothelial dysfunction in the development of cardiovascular events in patients with chronic renal failure (CRF) at diferent stages of the disease.. Eighty-six patients, including 46 (53%) women and 40 (47%) men with Stages II-IV CRF, were examined. The patients' mean age was 43.6 +/- 14 years. Echocardiography, measurements of the blood levels of hemoglobin, albumin, cholesterol, and uric acid, and determination of blood electrolytic composition were made. Blood creatinine concentrations in the group averaged 0.3 mmol/l. Glomerular filtration rate (GFR) calculated from the Cockroft-Goult formula averaged 33.96 +/- 13 ml/min; the duration of CRF was 9.3 +/- 1.6 years. Anemia was detected in 46 (53%) patients. Iron metabolism was estimated from serum ferritin levels. Special studies involved determination of FRO--malondialdehyde (MDA) and the activities of catalase and superoxide dismutase (SOD) in plasma and serum. The plasma concentrations of endohelin-1 (ET-1), thromboxane A2, and prostacyclin were measured by radioimmunoassay. Results. The higher concentrations of MDA and the decreased activities of catalase and SOD, i.e., FRO, correlated with the progression of renal failure. There were also increases in the levels of ET-1 and thromboxane A, and a reduction in the concentration of prostacyclin as blood creatinine levels elevated. Left ventricular hypertrophy was found in 43 (50%) of the 86 patients. Its severity depended on the decrease of creatine phosphokinase and the severity of anemia and arterial hypertension. There was a stable correlation between the changes in left ventricular myocardial mass, MDA levels, and catalase and SOD activities.. The higher level of MDA and the lower activities of catalase and SOD in patients with CRF, which correlate with diminished renal function, confirm that the disease is closely associated with FRO, that, by aggravating anemia and endothelial dysfunction, affects the magnitude of morphological and functional changes in the cardiovascular system in patients with CRF patients.

Topics: Adult; Cardiovascular Diseases; Catalase; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Follow-Up Studies; Free Radical Scavengers; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Malondialdehyde; Oxidative Stress; Prognosis; Superoxide Dismutase; Thromboxane A2

The endothelin (ET)-system is composed of three endothelins, two receptors and two enzymes. The study of this system presents a great interest to understand the cardiovascular physiopathology. The ET-system is involved in cardiac organogenesis, angiogenesis and vascular tone homeostasis. Its role in arterial pulmonary hypertension, arterial hypertension and atherosclerosis has been shown. The numerous ET-system's targets suggest that it could be involved in pathologies which bring together various cardiovascular disorders such as the obstructive sleep apnoea syndrome. Thus, the ET-system generates today a lively interest for experimental and clinical trials.

Topics: Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Clinical Trials as Topic; Endothelin-1; Endothelins; Humans; Organogenesis; Sleep Apnea, Obstructive

Several new biomarkers are related to mortality in community-acquired pneumonia (CAP).. Aim of this study was to compare new biomarkers for the prediction of short- and long-term all-cause mortality in CAP.. We enrolled 728 patients (59.0 ± 18.2 yr) with CAP. Midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), proarginin-vasopressin (copeptin), proendothelin-1 (CT-proET-1), procalcitonin (PCT), C-reactive protein, white blood cell (WBC) count, and clinical confusion, respiratory rate, blood pressure, and age over 65 years (CRB-65) score were determined on admission. Patients were followed up for 180 days.. In patients who died of any cause within 28 and 180 days (2.5 and 5.1%, respectively), MR-proADM, MR-proANP, copeptin, CT-proET-1 and PCT as well as CRB-65 were significantly higher compared with survivors. MR-proADM had the best performance for 28 days (HR 3.67) and 180 days (HR 2.84) survival. The C index of MR-proADM for 28-day survival (0.85) was superior to MR-proANP (0.81), copeptin (0.78), CT-proET-1 (0.79), and CRB-65 (0.72) for the prediction of mortality. For prediction of mortality at 180 days, the C index of MR-proADM (0.78) was higher than that for MR-proANP (0.74), copeptin (0.73), CT-proET-1 (0.76), PCT, C-reactive protein, and white blood cells. MR-proADM was independent of CRB-65, and added prognostic information for short- and long-term mortality. MR-proADM was an independent and strong predictor of short- and long-term mortality.. All new biomarkers were good predictors of short- and long-term all-cause mortality, superior to inflammatory markers, and at least comparable to CRB-65 score. MR-proADM showed the best performance. A combination of CRB-65 with MR-proADM might be the best predictor for mortality.

Topics: Adolescent; Adrenomedullin; Adult; Age Distribution; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Community-Acquired Infections; Comorbidity; Endothelin-1; Female; Germany; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Pneumonia; Predictive Value of Tests; Protein Precursors; Respiratory Rate; Survival Analysis; Vasopressins; Young Adult

Smoking is a significant independent risk factor for cardiovascular disease. Among the chemicals present in the cigarette smoke, nicotine is responsible for much of the damage; it induces marked vessel morphological dysfunction and vasoconstriction. Unfortunately, pharmacological or behavioural treatment is not useful against cigarette smoking. The purpose of this study is to test, in experimental conditions, the therapeutic ability of exogenous melatonin administered after smoking-induced vasculopathy and to evaluate the targets of its effects.. Nicotine was orally administered for 28 days. Thereafter, the rats were orally treated with melatonin for another 28 days. Vessel damage, an important vasoconstrictor peptide (endothelin-1) and the oxidative stress markers were analysed.. Nicotine treatment induced marked endothelial damage and an obvious vasoconstriction in the aorta as evaluated by an increased endothelin-1 (ET-1) expression. These alterations were correlated with a reduction of endothelial nitric oxide synthase (eNOS) and superoxide dismutase (SOD) and with increases of heat shock protein (Hsp70) and inducible nitric oxide synthase (iNOS) activities. Melatonin not only improved the impairment of endothelial-dependent relaxation, but also induced the increase of eNOS and SOD and the reduction of iNOS and Hsp70.. The findings indicate that nicotine is associated with an elevated synthesis of the vasoconstrictor peptide (ET-1); it also induces a reduction of nitric oxide-mediated vasodilatation (eNOS) and promotes oxidative stress in the vessel wall. We propose that melatonin should be considered as a therapeutic intervention for smokers since it reduces vasoconstriction and oxidative stress and improves endothelial physiology.

Topics: Animals; Aorta; Biomarkers; Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; HSP70 Heat-Shock Proteins; Male; Melatonin; Nicotine; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Random Allocation; Rats; Rats, Wistar; Smoking; Up-Regulation; Vasoconstriction; Vasodilation

Cardiovascular (CV) diseases are a leading cause of mortality and they are frequent in patients with the obstructive sleep apnea syndrome (OSAS).. In this study we investigated if OSAS influences CV function independently of other CV risk factors frequently present in these patients (e.g. obesity, high blood pressure).. We compared plasma markers of endothelial dysfunction, asymmetric dimethylarginine (ADMA) and endothelin-1 (ET-1), and atherosclerosis progression (soluble fraction of the CD40 ligand, sCD40L) in OSAS patients with (n = 23) and without (n = 18) concurrent CV risk factors, as well as in healthy subjects (n = 23).. Plasma ADMA (p < 0.01) and sCD40L (p < 0.05) were abnormally increased in patients with OSAS versus healthy controls, but they were not influenced by the presence or absence of CV risk factors in OSAS. ET-1 levels were not different between the three groups of subjects studied.. OSAS is associated with endothelial injury and atherosclerosis progression independently of other CV risk factors.

Topics: Adult; Arginine; Atherosclerosis; Cardiovascular Diseases; Case-Control Studies; CD40 Ligand; Endothelin-1; Humans; Male; Middle Aged; Risk Factors; Sleep Apnea, Obstructive

The objective of this study was to evaluate traditional risk factors for cardiovascular disease (CVD) and endothelin-1 (ET-1) levels in Takayasu arteritis (TA) patients. Twenty-two TA patients and 37 controls were evaluated. TA patients had a higher prevalence of hypertension (63.6% vs. 21.6%, p=0.001) and higher levels of triglycerides (129.5 mg/dL+/-70.8 vs. 88.4 mg/dL+/-60.8, p=0.017) than controls. Mean number of CVD risk factors was 1.64+/-1.22 in TA patients and 1.03+/-1.44 among controls, p=0.030. More TA patients presented at least one CVD risk factor when compared to controls (77.2% vs. 51.3%, p=0.048). ET-1 levels were higher in patients than in controls (1.49 pg/mL+/-0.45 vs. 1.27 pg/mL+/-0.32, p=0.034), however no significant difference was found between patients with active and inactive disease. In this study, TA patients presented a higher prevalence of hypertension, higher levels of triglycerides, and ET-1 than controls.

Topics: Adult; Atherosclerosis; Cardiovascular Diseases; Endothelin-1; Female; Humans; Hypertension; Inflammation; Male; Middle Aged; Risk Factors; Takayasu Arteritis; Treatment Outcome; Triglycerides

Endothelin (ET)-1 is a vasoconstrictor involved in cardiovascular diseases. Connective tissue growth factor/CCN2 (CTGF) is a fibrotic mediator overexpressed in human atherosclerotic lesions, myocardial infarction, and hypertension. In different cell types CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation and plays important roles in angiogenesis, chondrogenesis, osteogenesis, tissue repair, cancer and fibrosis. In the present study, we investigated the ET-1 signaling which triggers CTGF expression in cultured adult mouse atrial-muscle HL-1 cells used as a model system. ET-1 activated the CTGF promoter and induced CTGF expression at both mRNA and protein levels. Real-time PCR analysis revealed CTGF induction also in isolated rat heart preparations perfused with ET-1. Several intracellular signals elicited by ET-1 via ET receptors and even Epidermal Growth Factor Receptor (EGFR) contributed to the up-regulation of CTGF, including ERK activation and induction of the AP-1 components c-fos and c-jun, as also evaluated by ChIP analysis. Moreover, in cells treated with ET-1 the expression of ECM component decorin was abolished by CTGF silencing, indicating that CTGF is involved in ET-1 induced ECM accumulation not only in a direct manner but also through downstream effectors. Collectively, our data indicate that CTGF could be a mediator of the profibrotic effects of ET-1 in cardiomyocytes. CTGF inhibitors should be considered in setting a comprehensive pharmacological approach towards ET-1 induced cardiovascular diseases.

Topics: Animals; Apoptosis; Cardiovascular Diseases; Cell Line; Cell Movement; Cell Proliferation; Connective Tissue Growth Factor; Decorin; Endothelin-1; Enzyme Activation; ErbB Receptors; Extracellular Matrix Proteins; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Humans; Male; Mice; Models, Biological; Muscle Proteins; Myocytes, Cardiac; Proteoglycans; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Rats, Wistar; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction

In acromegalic patients, cardiovascular and metabolic comorbidities contribute to enhance mortality. Available data on the lipoprotein profile of these patients are controversial. Our aim was to characterize the lipoprotein profile and emergent biomarkers of cardiovascular disease in active acromegalic patients in comparison with sex- and age-matched healthy controls.. Eighteen patients with active acromegaly and 18 controls were studied.. Glucose levels, hormonal status, lipoprotein profile and C reactive protein (CRP) were evaluated by standardized methods. Cholesteryl ester transfer protein (CETP) and lipoprotein-associated phospholipase A(2 )(Lp-PLA(2)) were measured by radiometric techniques, endothelin-1 and vascular cell adhesion molecule (VCAM)-1 by enzyme-linked immunosorbent assay, and leucocytes CD18, CD49d and CD54 by flow cytometry.. After adjusting for body mass index (BMI), acromegalic patients presented a more atherogenic lipoprotein profile, consisting of higher levels of triglycerides and apolipoprotein B and alterations in the ratios which estimate insulin resistance and atherogenic risk. CETP activity was significantly increased in acromegalic patients as compared to controls (168 +/- 17 vs. 141 +/- 30% per ml h, respectively; P < 0.05). Endothelin-1 levels evidenced an increase in the patients' group (0.9 +/- 0.2 vs. 0.7 +/- 0.2 ng/l, respectively; P < 0.01) and showed positive and significant correlations with GH, IGF-1 and IGFBP-3 (r = 0.45, 0.42 and 0.44, respectively; P < 0.01 for all of them; with BMI as a fixed variable). Lymphocytes from acromegalic patients showed increased CD49d content (282 +/- 59 vs. 246 +/- 48 arbitrary units, respectively; P < 0.05).. Taken together, the alterations described seem to contribute to constituting a state of higher propensity for the development of atherosclerotic cardiovascular disease, which adds to the presence of specific cardiomyopathy.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acromegaly; Adult; Aged; Biomarkers; Blood Glucose; C-Reactive Protein; Cardiovascular Diseases; CD18 Antigens; Cholesterol Ester Transfer Proteins; Endothelin-1; Female; Humans; Integrin alpha4; Intercellular Adhesion Molecule-1; Lipoproteins; Male; Middle Aged; Triglycerides; Vascular Cell Adhesion Molecule-1

To assess the utility of B-type natriuretic peptide (BNP) and C-terminal-pro-endothelin-1 (CT-proET-1) to predict a severely impaired peak oxygen consumption (peak VO(2), < 14 mL kg(-1) min(-1)) in patients referred for cardiopulmonary exercise testing.. Cross-sectional study.. Tertiary care center.. Peak VO(2), BNP and CT-proET-1 were assessed in 141 consecutive patients referred for cardiopulmonary exercise testing.. B-type natriuretic peptide [median (interquartile range) 48 (38-319) vs. 33 (15-86) pg mL(-1); P = 0.002] and CT-proET-1 [87 (76-95) vs. 60 (52-74) pmol L(-1); P < 0.001] were higher in patients with a peak VO(2) < 14 mL kg(-1) min(-1) (n = 30) than in those with a peak VO(2) > or = 14 mL kg(-1) min(-1) (n = 111). CT-pro-ET-1 had a higher area under the receiver-operator-characteristics curve (AUC) to predict a peak VO(2) < 14 mL kg(-1) min(-1) than BNP (0.79 vs. 0.68; P = 0.04). The optimal BNP cut-off of 37.2 pg mL(-1) had a sensitivity of 80% and a specificity of 56%. The optimal CT-proET-1 cut-off of 74.4 pmol L(-1) had a sensitivity of 80% and specificity of 76%. A five-item score composed of body mass index, diabetes, forced expiratory volume within the first second, alveolo-arterial oxygen pressure difference, and BNP had an AUC of 0.88 to predict a peak VO(2) < 14 mL kg(-1) min(-1). Adding CT-proET-1 to the score resulted in an AUC of 0.92.. C-terminal-pro-endothelin-1 is superior to BNP for the prediction of a peak VO(2) < 14 mL kg(-1) min(-1) in patients referred for CPET. A score incorporating body mass index, diabetes status, spirometry, blood gases, BNP and CT-proET-1 improves the prediction of a peak VO(2) < 14 mL kg(-1) min(-1) based on single biomarkers.

Topics: Aged; Area Under Curve; Biomarkers; Body Mass Index; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Complications; Endothelin-1; Exercise Test; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen; Oxygen Consumption; Peptide Fragments; Protein Precursors; Risk Assessment; Sensitivity and Specificity

Topics: Antihypertensive Agents; Biomarkers; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Humans

Topics: Animals; Cardiovascular Diseases; Endothelin-1; Humans; Rats; Sleep Apnea, Obstructive

Ethnic disparities in cardiovascular disease (CVD) may partially reflect differences in chronic stress burden that vary by social class and exposure to ethnic discrimination. Stress is associated with increased endothelin-1 (ET-1). This study examined the relationship of ET-1 to socioeconomic status (SES) and to perceived ethnic discrimination among black (n = 51) and white (n = 65) adults (mean age 36.5).. The Perceived Discrimination subscale of the Scale of Ethnic Experience measured exposure to discrimination and the Hollingshead Two-Factor Index of Social Position assessed SES. Plasma ET-1 was sampled upon awakening after an overnight admission.. SES and ET-1 levels were similar across ethnic groups, but mean discrimination scores were higher among blacks than whites (P < 0.001). Multiple regressions found that the SES x ethnicity interaction was associated with ET-1 (P < 0.05), after adjustment for gender, resting mean arterial pressure (MAP), body mass index (BMI), and exercise frequency. Regressions stratified by ethnicity revealed that lower SES correlated with higher ET-1 in whites (P < 0.001), but not blacks, and accounted for 21% of the variance. Another series of regressions revealed an interaction effect of ethnicity by discrimination on ET-1 (P < 0.05). Increased discrimination correlated with increased ET-1 among blacks (P < 0.05), but not whites, and explained 11% of the variance after adjustment for SES, gender, exercise frequency, and socially desirable response bias.. Thus, ET-1 levels increased in association with different psychosocial burdens in blacks and whites. Plasma ET-1 was higher among whites with lower SES and among blacks with higher levels of perceived ethnic discrimination, regardless of SES.

Topics: Adult; Black or African American; Black People; Cardiovascular Diseases; Endothelin-1; Female; Humans; Male; Prejudice; Risk Factors; Social Class; Stress, Psychological; White People

Nitric oxide (NO) is an important regulatory molecule for the host defense that plays a fundamental role in the cardiovascular, immune, and nervous systems. NO is synthesized through the conversion of L-arginine to L-citrulline by the enzyme NO synthase (NOS), which is found in three isoforms classified as neuronal (nNOS), inducible (iNOS), and endothelial (eNOS). Recent evidence supports the theory that this bioactive molecule has an influential role in the disruption of normal brain and vascular homeostasis, a condition known to elucidate chronic hypoperfusion which ultimately causes the development of brain lesions and the pathology that typify Alzheimer disease (AD). In addition, vascular NO activity appears to be a major contributor to this pathology before any overexpression of NOS isoforms is observed in the neuron, glia, and microglia of the brain tree, where the overexpression the NOS isoforms causes the formation of a large amount of NO. We hypothesize that since an imbalance between the NOS isoforms and endothelin-1 (ET-1), a human gene that encodes for blood vessel constriction, can cause antioxidant system insufficiency; by using pharmacological intervention with NO donors and/or NO suppressors, the brain lesions and the downstream progression of brain pathology and dementia in AD should be delayed or minimized.

Topics: Alzheimer Disease; Animals; Brain; Brain Injuries; Cardiovascular Diseases; Disease Progression; Endothelin-1; Humans; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Protein Isoforms

Air pollutant levels positively correlate with increases in both acute and chronic cardiovascular disease. The pollutant diesel exhaust (DE) increases endothelin (ET) levels, suggesting that this peptide may contribute to DE-induced cardiovascular disease. We hypothesized that acute exposure to DE also enhances ET-1-mediated coronary artery constrictor sensitivity. Constrictor responses to KCl, U-46619, and ET-1 were recorded by videomicroscopy in pressurized intraseptal coronary arteries from rats exposed for 5 h to DE (300 microg/m(3)) or filtered air (Air). ET-1 constriction was augmented in arteries from DE-exposed rats. Nitric oxide synthase (NOS) inhibition [N(omega)-nitro-L-arginine (L-NNA), 100 microM] and endothelium inactivation augmented ET-1 responses in arteries from Air but not DE rats so that after either treatment responses were not different between groups. DE exposure did not affect KCl and U-46619 constrictor responses, while NOS inhibition augmented KCl constriction equally in both groups. Thus basal NOS activity does not appear to be affected by DE exposure. The endothelin type B (ET(B)) receptor antagonist BQ-788 (10 microM) inhibited ET-1 constriction in DE but not Air arteries, and constriction in the presence of the antagonist was not different between groups. Cytokine levels were not different in plasma from DE and AIR rats, suggesting that acute exposure to DE does not cause an immediate inflammatory response. In summary, a 5-h DE exposure selectively increases constrictor sensitivity to ET-1. This augmentation is endothelium-, NOS-, and ET(B) receptor dependent. These data suggest that DE exposure diminishes ET(B) receptor activation of endothelial NOS and augments ET(B)-dependent vasoconstriction. This augmented coronary vasoreactivity to ET-1 after DE, coupled with previous reports that DE induces production of ET-1, suggests that ET-1 may contribute to the increased incidence of cardiac events during acute increases in air pollution levels.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Air Pollutants; Animals; Cardiovascular Diseases; Coronary Vessels; Cytokines; Dose-Response Relationship, Drug; Endothelin-1; Enzyme Inhibitors; Inflammation Mediators; Inhalation Exposure; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oligopeptides; Particulate Matter; Piperidines; Potassium Chloride; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Time Factors; Vasoconstriction; Vasoconstrictor Agents; Vehicle Emissions

The increased cardiovascular risk in diabetes has been linked to endothelial and renal dysfunction. The aim of this study was to investigate the role of stable fragments of the precursors of adrenomedullin, endothelin-1, vasopressin, and atrial natriuretic peptide in progression of cardiovascular disease in patients with diabetes.. This was a prospective, observational study design with a composite end point (death or unexpected admission to hospital due to a cardiovascular event) on 781 patients with type 2 diabetes (54 events, median duration of observation 15 months). The four stable precursor peptides midregional adrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), COOH-terminal proendothelin-1 (CT-proET-1), and COOH-terminal provasopressin or copeptin (CT-proAVP) were determined at baseline, and their association to renal function and cardiovascular events was studied using stepwise linear and Cox logistic regression analysis and receiver operating characteristic analysis, respectively.. MR-proADM, CT-proET-1, CT-proAVP, and MR-proANP were all elevated in patients with future cardiovascular events and independently correlated to serum creatinine. MR-proADM and MR-proANP were significant predictors of a future cardiovascular event, with MR-proANP being the stronger (area under the curve 0.802 +/- 0.034, sensitivity 0.833, specificity 0.576, positive predictive value 0.132, and negative predictive value 0.978 with a cutoff value of 75 pmol/l).. The four serum markers of vasoactive and natriuretic peptides are related to both kidney function and cardiovascular events, thus linking two major complications of diabetes, diabetic nephropathy and cardiovascular disease.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 2; Endothelin-1; Female; Glycopeptides; Humans; Kidney; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Protein Precursors

The aim of the present study was to evaluate the plasma endothelin-1 (ET-1) and total homocysteine (tHcy) levels as biochemical markers of endothelial dysfunction and atherosclerosis in patients with active and cured acromegaly in order to assess the relationship between the secretory status of growth hormone (GH)/insulin-like growth factor I (IGF-I) and ET-1/tHcy levels. The patients were divided in two subgroups: 1) patients with active disease (n = 30); and 2) patients with nonactive cured acromegaly (n = 21). Plasma ET-1 levels were directly determined by a highly sensitive enzyme immunoassay and plasma tHcy concentrations were measured by a fluorescence polarization immunoassay. In active acromegaly subjects, plasma ET-1 levels were 1.24 +/- 0.2 pmol/L, significantly higher than in both nonactive acromegalics (0.39 +/- 0.1 pmol/L) and age-matched healthy controls (0.49 +/- 0.2 pmol/L) (P < 0.001). Plasma tHcy concentrations, however, did not differ significantly in all studied groups: nonactive acromegalics: 9.54 +/- 4.42 micromol/L; active acromegalics: 9.0 +/- 3.14 micromol/L; and control subjects: 9.96 +/- 2.95 micromol/L (P > 0.05). In conclusion, our study demonstrated that elevated ET-1 levels probably contributed to premature atherosclerosis and cardiovascular disease and represent a new risk factor for endothelial dysfunction and early vascular complications in acromegaly. We propose that GH and IGF-I secretory status are important determinants of plasma ET-1 but not tHcy levels.

Topics: Aged; Biomarkers; Blood Pressure; Cardiomegaly; Cardiovascular Diseases; Cholesterol; Endothelin-1; Endothelium, Vascular; Female; Homocysteine; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Risk Assessment; Triglycerides

Cardiovascular disease (CVD) is the leading cause of death among postmenopausal women. Changes in endothelial function play an important role in the pathophysiology of atherosclerosis, and evidence suggests that interventions to improve endothelial function could modify the rates of progression and the risk of cardiovascular events. In addition, a positive association between markers of endothelial dysfunction and androgenicity has been described in women with polycystic ovary syndrome, suggesting a correlation with the early-onset endothelial dysfunction found in these patients. We performed a cross-sectional study to verify whether endogenous testosterone levels are correlated with markers of inflammation and endothelial function and with anthropometric and metabolic profile in 53 postmenopausal women. Serum testosterone, sex hormone-binding globulin, C-reactive protein (CRP), fibrinogen, and plasma endothelin-1 (ET-1) were determined. Patients were stratified into 2 groups (higher or lower than the mean testosterone levels of the studied sample). Mean age was 55 years (+/-5), and median time since menopause was 5.5 years (interquartile range, 3-8 years). Body mass index and waist circumference were significantly higher in the group with testosterone levels >or=0.49 ng/mL. Median CRP levels were greater in the group with higher testosterone levels (1.17 [0.17-2.36] vs 0.17 [0.17-0.61] mg/L, P = .039). Median ET-1 levels were also higher in women with greater testosterone levels (0.84 [0.81-0.97] vs 0.81 [0.74-0.84] pg/mL, P = .023). An association of testosterone with CRP (r = 0.416, P = .004) and ET-1 (r = 0.323, P = .031) was observed. This association was dependent on homeostasis model assessment index for ET-1 but not CRP. Testosterone was also associated with waist circumference and blood pressure (P = .001). These data suggest that endogenous testosterone levels in recently postmenopausal women may be part of a proatherogenic profile. Longitudinal studies are needed to assess if androgenicity represents a risk factor for cardiovascular disease and the clinical relevance of its association with ET-1 and CRP in this population.

Topics: Anthropometry; Biomarkers; Blood Glucose; Blood Pressure; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Cross-Sectional Studies; Endothelin-1; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Middle Aged; Postmenopause; Risk; Testosterone; Triglycerides; Waist-Hip Ratio

The presence of several cardiovascular risk factors is observed in women with polycystic ovary syndrome (PCOS). On the other hand, the QTc interval duration, which is related to cardiac arrhythmia and sudden death, has not been investigated thoroughly in PCOS population.. To investigate QTc interval duration and its relation to testosterone in women with PCOS.. Cross sectional case-control study.. Outpatient setting, tertiary university medical centre.. We enrolled 119 consecutive patients in whom PCOS was diagnosed based on oligomenorrhea, infertility (>2 yr), ineffective ovarian stimulation, and ultrasonographic criteria. The control group (controls) included 64 age-matched healthy women without clinical or laboratory evidence of PCOS.. In all participants we measured QTc interval duration on a standard electrocardiogram and determined plasma levels of high sensitivity C-reactive protein (hsCRP), endothelin-1 (ET-1), insulin, and testosterone.. Shorter QTc interval duration in PCOS patients.. When compared to controls, PCOS patients displayed higher values of hsCRP (2.35+/-2.14 mg/l vs 1.18+/-1.24 mg/l; p=0.01), ET-1 (23.6+/-10.3 ng/l vs 12.9+/-20.7 ng/l; p=0.03), insulin (18.5+/-7.8 mIU/l vs 10.7+/-9.1 mIU/l; p=0.02), and testosterone (2.7+/-2.1 nmol/l vs 1.4+/-1.7 nmol/l; p=0.01). QTc interval in PCOS patients was significantly shorter than in controls (401+/-61 msec vs 467+/-61 msec; p=0.007), and inversely related to the plasma levels of testosterone (Spearman -0.45, p=0.005).. QTc interval in PCOS patients is short, and inversely associated with increased levels of testosterone. QTc interval duration is not part of an adverse cardiac risk profile in PCOS.

Topics: Adult; C-Reactive Protein; Cardiovascular Diseases; Electrocardiography; Endothelin-1; Female; Heart Conduction System; Humans; Insulin; Polycystic Ovary Syndrome; Risk Factors; Testosterone

Up-regulation of vascular endothelin type A (ET(A)) and type B (ET(B)) receptors are implicated in the pathogenesis of cardiovascular disease. Culture of arteries has been shown to induce similar receptor alterations and has therefore been suggested as a suitable method for in detail delineation of the regulation of endothelin receptors. We hypothesize that protein kinase C (PKC) and mitogen-activated kinases (MAPK) are involved in the regulation of endothelin receptors. Porcine coronary arteries were studied before and after 24 h of culture, using in vitro pharmacology, real-time PCR and immunofluorescence techniques. Sarafotoxin 6c and endothelin ET-1 were used to examine the endothelin ET(A) and ET(B) receptor effects. The involvement of PKC and MAPK in the receptor regulation was examined by culture in the presence of antagonists. Organ culture resulted in increased sarafotoxin 6c and endothelin-1 contractions, endothelin ET(A) and ET(B) receptor immunofluorescence staining intensities and endothelin ET(B), but not ET(A), receptor mRNA levels. The general PKC inhibitors, bisindolylmaleimide I (10 microM) or Ro-32-0432 (10 microM), inhibited these effects. Also, the increase in sarafotoxin 6c contraction, endothelin ET(B) receptor and mRNA levels and endothelin ET(A) and ET(B) immunofluorescence staining intensities were inhibited by MAPK inhibitors for extracellular signal related kinases 1 and 2 (ERK1/2), PD98059 (10 microM), C-jun terminal kinase (JNK), SP600125 (10 microM), but not by p38 MAPK, SB203580 (10 microM). In conclusion, PKC and MAPK seem to be involved in the regulation of endothelin receptor expression in porcine coronary arteries. Inhibiting these intracellular signal transduction pathways may provide a future therapeutic target for hindering the development of vascular endothelin receptor changes in cardiovascular disease.

Topics: Animals; Cardiovascular Diseases; Coronary Vessels; Endothelin-1; Female; Male; Mitogen-Activated Protein Kinases; Organ Culture Techniques; Protein Kinase C; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Signal Transduction; Swine; Up-Regulation; Viper Venoms

The present study aimed to show whether long-term moderate magnesium (Mg)-deficient (150 mg/kg) and Mg-supplemented (3200 mg/kg) diets (versus control diet: 800 mg/kg), modified the occurrence of cardiovascular risk induced by aging in the rat.. Cardiovascular and arterial functions were determined by a systemic hemodynamic study and by ex vivo measurements of vasoconstriction and endothelium dependent-vasorelaxation. Arterial wall structure was determined using pressure myograph chamber and histomorphometric methods.. The main changes observed in old rats (96 weeks old) fed a control diet, in comparison to adult rats (16 weeks old) were increased pulse pressure, a loss of aortic endothelium-dependent relaxation, increased aortic wall thickness and a decrease of the aortic wall elastin/collagen ratio. Long-term moderate Mg deficiency progressively increased systolic blood pressure. Intra-arterial pulse pressure was higher in Mg-deficient old rats than in age-matched control rats. Histological examination showed that Mg deficiency increased the age-induced deleterious effects on composition and structure of aorta (media thickness, increased collagen content and reduction in the elastin/collagen ratio), which lead to large artery rigidity. Hypertension and increased pulse pressure may have contributed to the increase in the mortality rate observed in the hypertensive Mg-deficient group. Although the long-term Mg-supplemented diet lowered blood pressure and decreased the mortality rate, it had no significant effect on aortic wall thickening and stiffening.. It is suggested that a long-term and moderate Mg-deficient diet increases age-induced arterial thickness and stiffness in rats, and thus increases the cardiovascular risks incurred by aging.

Topics: Acetylcholine; Aging; Animals; Aorta; Blood Pressure; Cardiovascular Diseases; Dietary Supplements; Endothelin-1; Food, Formulated; Magnesium; Magnesium Deficiency; Male; Nitroprusside; Norepinephrine; Organ Culture Techniques; Rats; Rats, Sprague-Dawley; Risk Factors; Survival Rate; Time; Vasoconstrictor Agents; Vasodilator Agents; Vasomotor System

The contribution of endothelin-1 (ET-1) to vascular hyper-reactivity associated with chronic ethanol intake, a major risk factor in several cardiovascular diseases, remains to be investigated.. The biphasic haemodynamic responses to ET-1 (0.01-0.1 nmol kg(-1), i.v.) or to the selective ETB agonist, IRL1620 (0.001-1.0 nmol kg(-1), i.v.), with or without ETA or ETB antagonists (BQ123 (c(DTrp-Dasp-Pro-Dval-Leu)) at 1 and 2.5 mg kg(-1) and BQ788 (N-cis-2,6-dimethyl-piperidinocarbonyl-L-gamma-methylleucyl1-D-1methoxycarbonyltryptophanyl-D-norleucine) at 0.25 mg kg(-1), respectively) were tested in anaesthetized rats, after 2 weeks' chronic ethanol treatment. Hepatic parameters and ET receptor protein levels were also determined.. The initial hypotensive responses to ET-1 or IRL1620 were unaffected by chronic ethanol intake, whereas the subsequent pressor effects induced by ET-1, but not by IRL1620, were potentiated. BQ123 at 2.5 but not 1 mg kg(-1) reduced the pressor responses to ET-1 in ethanol-treated rats. Conversely, BQ788 (0.25 mg kg(-1)) potentiated ET-1-induced increases in mean arterial blood pressure in control as well as in ethanol-treated rats. Interestingly, in the latter group, increases in heart rate, induced by ET-1 at a dose of 0.025 mg kg(-1) were enhanced following ETB receptor blockade. Finally, we observed higher levels of ETA receptor in the heart and mesenteric artery and a reduction of ETB receptor protein levels in the aorta and kidney from rats chronically treated with ethanol.. Increased vascular reactivity to ET-1 and altered protein levels of ETA and ETB receptors could play a role in the pathogenesis of cardiovascular complications associated with chronic ethanol consumption.

Topics: Acetylcholine; Alcohol Drinking; Animals; Aorta; Blood Pressure; Cardiovascular Diseases; Endothelin-1; Endothelins; Ethanol; Heart Rate; Kidney; Liver; Male; Mesenteric Arteries; Myocardium; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Phenylephrine; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Self Administration; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

We have been examining the role of heat shock factor 1 (HSF1) in the pleiotropic effects of statins. In parallel studies, we found that statin induces the nuclear translocation of HSF1 and that a decoy oligonucleotide encoding the heat shock element inhibits the statin-induced expression of heat shock protein 70, endothelial nitric oxide synthase (eNOS) and thrombomodulin. Also, in vascular endothelial cells, increases in the expression of human HSF1 corresponded with elevated steady-state levels of eNOS and thrombomodulin and reduced levels of endothelin-1 and plasminogen activator inhibitor-1. We also found that heat shock proteins induced eNOS and thrombomodulin expression and reduced PAI-1 and ET-1 expression. In particular, a combination of HSP70 and HSP90 strongly induced eNOS expression and reduced PAI-1 expression. In the current studies, we generated a constitutively active form of HSF1 and found that it is more effective than the wild-type HSF at inducing thrombomodulin and eNOS expression and decreasing endothelin-1 and plasminogen activator inhibitor-1 expression. These results show that the wild-type and constitutively active forms of HSF1 induce anticoagulation and relaxation factors in vascular endothelial cells and could therefore be used to treat cardiovascular disease.

Topics: Aorta; Blotting, Northern; Cardiovascular Diseases; DNA Primers; DNA-Binding Proteins; Endothelin-1; Endothelium, Vascular; Heat Shock Transcription Factors; Heat-Shock Proteins; Heme Oxygenase-1; Humans; Polymerase Chain Reaction; Transcription Factors

The effect of chronic cigarette smoking on endothelin modulation of vascular contraction, and CYP enzyme levels was studied in 20 male Sprague-Dawley rats. The animals were divided equally into smoking and non-smoking groups. The smoking group was exposed to 6 research cigarettes per rat per day 5 days a week for 16 weeks. The control group was sham smoked. Functional contractile studies were performed in aortas and carotid arteries to determine the regulation of vascular tone by basal release of endothelin. Liver samples were analyzed for CYP1A1 and CYP1A2 gene expression by RT-PCR. Plasma samples were assessed for endothelin-1 (ET-1) level by enzyme immuno assay (EIA). Treatment of aortas and carotid arteries with bosentan, the dual endothelin receptor antagonist, caused a significant reduction in constrictor responses of smoking rats, indicating, increase greater regulation of tone by endothelin in smoker rats compared to controls. There was a greater expression of the cytochrome P450-liver enzymes (CYP1A1 and CYP1A2) in smoker rats. Body weight gain was also significantly decreased in smoker rats. We conclude that increased endothelin release in smoker rats significantly contributes to increased arterial tone and so contribute to the cardiovascular pathophysiology associated with cigarette smoking, such as increased vascular muscularization, increased contraction, decreased dilation and possibly vasospasm.

Topics: Animals; Aorta, Thoracic; Bosentan; Cardiovascular Diseases; Carotid Arteries; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Cytochromes; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Induction; Liver; Male; Models, Animal; Nicotiana; Nitric Oxide; Random Allocation; Rats; Rats, Sprague-Dawley; Smoke; Smoking; Sulfonamides; Time Factors; Vasoconstriction; Weight Gain

Inflammation is a major contributor to atherosclerotic vascular disease. Inflammatory parameters such as C-reactive protein (CRP) and Interleukin-6 (IL-6) have been shown to be strong predictors of cardiovascular events. The association between preoperative inflammatory parameters and early graft occlusion as well as cardiovascular events after coronary artery bypass grafting (CABG) has not, however, been fully elucidated. The aims of the present study were to prospectively investigate the prognostic value of the inflammatory parameters IL-6, CRP, and endothelin (ET-1) to predict early graft occlusion as well as late cardiovascular events after CABG.. In the present study 99 patients undergoing CABG because of stable angina pectoris due to significant coronary artery disease were prospectively included. Coronary angiography was repeated 3 months after CABG in 81 patients in order to evaluate early graft occlusion. Blood samples were collected before CABG in all patients. Patients were followed up for a median of 5 (3-7) years after CABG.. Twenty-five patients (31%) had one or more occluded grafts at the 3-month control coronary angiography. The patients with occluded grafts had higher preoperative CRP and IL-6 levels in plasma [CRP 2.22 (1.11-4.47) mg/L vs. 1.23 (0.71-2.27) mg/L P=0.03] and [IL-6 2.88 (1.91-5.94) pg/mL vs. 2.15 (1.54-3.14) pg/mL P=0.006]. There were 23 late cardiovascular events among the 99 patients during the follow-up. Patients experiencing late cardiovascular events had higher preoperative IL-6 levels than those without late cardiovascular events [4.13 (1.83-5.87) pg/mL vs. 2.08 (1.53-2.29) pg/mL, P=0.002] whereas CRP levels did not differ significantly between the two groups [1.5 (0.79-4.41) mg/L vs. 1.33 (0.74-2.48) mg/L, P=0.41]. Looking at IL-6, a cut off value more than 3.8 pg/ml was associated with a significant higher risk for an early graft occlusion (P=0.04) and late cardiovascular events (P=0.00003). Preoperative endothelin-1 did not predict early graft occlusions or late cardiovascular events.. Raised preoperative IL-6 levels are predictors of both early graft occlusion and late cardiovascular events after CABG. Elevated preoperative CRP levels can predict early graft occlusion after CABG. Endothelin did not differ between the two groups.

Topics: Aged; C-Reactive Protein; Cardiovascular Diseases; Cohort Studies; Coronary Artery Bypass; Coronary Artery Disease; Endothelin-1; Female; Graft Occlusion, Vascular; Humans; Interleukin-6; Male; Middle Aged; Predictive Value of Tests; Time Factors; Treatment Outcome

Topics: Adult; Aged; Aging; Animals; Biomarkers; Blood Vessels; Cardiovascular Diseases; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Exercise; Female; Humans; Hypertension; Life Style; Male; Middle Aged; Prognosis; Rats; Rats, Inbred SHR; Risk Assessment; Tunica Media; Vascular Resistance

This study aimed to determine whether there is an adrenomedullin (AM)-mediated protective effect of postmenopausal estrogen/progestin therapy (HRT) against cardiovascular disorders.. A total of 22 post-menopausal women without hysterectomy undergoing postmenopausal symptoms (aged 43-52) were treated with conjugated equine estrogen (0.625 mg/die) plus medroxyprogesterone acetate (2.5 mg/die) for six months. The flow velocity of the right middle cerebral artery [measured as resistance index (RI) and pulsatility index (PI)], plasma levels of adrenomedullin and endothelin- 1 (ET-1), mean baseline ratio of AM to ET-1, and lipid profiles were assessed before and after HRT.. A statistically significant difference was found for triglycerides, total cholesterol, AM/ET-1 ratio and right middle cerebral artery PI (p<0.05), without any significant differences in HDL, LDL, AM, ET-1, systolic blood pressure, diastolic blood pressure, a right middle cerebral artery RI (p>0.05) between pre- and post- HRT.. Adrenomedullin may be added to other vasoactive peptides as a new potential candidate for HRT-mediated vascular protection. The ratio of AM/ET-1 vs AM or ET-1 alone may be a useful biological marker of this protection.

Topics: Adrenomedullin; Blood Pressure; Cardiovascular Diseases; Cerebrovascular Circulation; Endothelin-1; Estrogen Replacement Therapy; Female; Humans; Lipids; Middle Aged

To analyze the relationship between QTc interval and cardiovascular risk factors in women with polycystic ovary syndrome (PCOS).. Study group included 119 PCOS women (age: 32.2+/-5.2 years) and the control group 64 age-matched healthy women; they all underwent QT interval measurement, and plasma levels of high-sensitivity CRP (hsCRP), endothelin-1 (ET1), insulin, and testosterone determinations.. In PCOS women hsCRP (2.35+/-2.14 mg/L vs. 1.01+/-1.28 mg/L; P=0.04), ET1 (23.6+/-10.3 ng/L vs. 7.7+/-15.9 ng/L; P=0.01), and insulin (16.5+/-7.8 mIU/L vs. 11.8+/-10.7 mIU/L; P=0.03) levels were significantly higher, and QTc interval significantly shorter than in controls (401+/-61 ms vs. 467+/-61 ms; P=0.007). In 67 (56%) PCOS patients with a short QTc interval (<400 ms), plasma testosterone levels were significantly higher than in PCOS women with normal QTc interval (2.3+/-2.1 nmol/L vs. 1.4+/-1.7 nmol/L; P=0.02).. In patients with polycystic ovary syndrome increased testosterone levels may attenuate the effects of coronary risk factors.

Topics: Adult; C-Reactive Protein; Cardiovascular Diseases; Endothelin-1; Female; Heart Conduction System; Humans; Polycystic Ovary Syndrome; Risk Factors; Testosterone

Psychosocial factors, associated with elevated corticotropin releasing hormone (CRH) concentrations, have been reported to be independently associated with coronary heart disease.. Endothelin-1 and NO release of human endothelial cells were quantified via ELISA or fluorometrically after treatment with CRH. CRH-receptor subtype 2 (CRH-R2) was visualized on endothelial cells by immunohistochemistry and confirmed by polymerase chain reaction using CRH-R2 primers.. CRH induced a significant increase of ET-1 release, and the effect was abolished by the CRH-receptor antagonist astressin. The effect was mediated by CRH-R2. In contrast, NO release was not affected.. CRH-R2 is expressed on human endothelial cells, mediating the CRH-induced stimulation of ET-1 release, whereas NO release is not affected. Thus, peripherally circulating CRH may offset the balance between endothelial vasoconstrictor and vasodilator release with unopposed vasoconstriction. Our data may provide a new concept on how CRH-receptor antagonists may prevent CRH-induced disorders of vascular biology.

Topics: Cardiovascular Diseases; Coronary Vessels; Corticotropin-Releasing Hormone; DNA Primers; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Humans; Immunohistochemistry; Nitric Oxide; Receptors, Corticotropin-Releasing Hormone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stress, Psychological

Oxidative stress is involved in the pathogenesis of diabetes and its cardiovascular complications. Metallothionein (MT), a stress-response protein, is significantly increased in the liver and kidney of diabetic animals. We examined whether diabetes also induces cardiac MT synthesis through oxidative damage and whether MT overexpression protects the heart from injury. Diabetes was induced in mice by single injection of streptozotocin (STZ), and cardiac MT mRNA and protein levels were measured 2 weeks and 2 months after STZ treatment. Diabetes significantly increased cardiac MT synthesis 2 weeks and 2 months after STZ treatment, with no change in cardiac metals including zinc, copper, and iron. Serum and cardiac vasopeptide endothelin and inflammatory cytokine tumor necrosis factor-alpha were also significantly increased in diabetic hearts, as were the ratio of oxidized to reduced glutathione and the immunohistochemical staining of 3-nitrotyrosine and 4-hydroxynonenal. To explore the biological importance of increased MT synthesis in the heart, MT-overexpressing transgenic mice were treated with STZ and then examined 2 months later. A loss of inotropic reserve, uncovered during beta-adrenergic stimulation, and the presence of cardiac fibrosis, shown by increased Sirius red staining of collagen, were evident in the wild-type diabetic mice but not in the MT-overexpressing transgenic diabetic mice. These results suggest that diabetes-induced cardiac MT expression likely associates with systemic increases in endothelin-1 and tumor necrosis factor-alpha and the resulting cardiac oxidative stress. Overexpressing cardiac MT significantly protects the heart from diabetes-induced injury.

Topics: Aldehydes; Animals; Blotting, Northern; Blotting, Western; Cardiovascular Diseases; Copper; Diabetes Mellitus, Experimental; Endothelin-1; Glutathione; Immunohistochemistry; Interleukin-6; Iron; Metallothionein; Mice; Mice, Transgenic; Myocardium; Oxidative Stress; RNA, Messenger; Tumor Necrosis Factor-alpha; Tyrosine; Zinc

Recent data indicate that women affected by the polycystic ovary syndrome (PCOS) are at greater risk for cardiovascular disease and that metformin may improve the metabolic alterations in these patients.. The objective of this study was to evaluate the effects of 6 months of metformin administration on endothelial structure and function in women with PCOS.. This was a prospective, baseline-controlled, clinical study.. The study was performed at University Federico II (Naples, Italy).. Thirty young normal-weight women with PCOS without additional metabolic or cardiovascular diseases were studied.. Metformin (850 mg daily) was administered for 6 months.. The main outcome measures were complete hormonal profile, including total testosterone, SHBG, dehydroepiandrosterone sulfate, prolactin, and gonadotropin levels; serum insulin and glucose levels during a 75-g 2-h oral glucose tolerance test; plasma endothelin-1 concentrations (picomoles per liter +/- sd); serum lipid profile; brachial artery baseline diameter (millimeters +/- sd), diameter after reactive hyperemia (millimeters +/- sd), and flow-mediated dilation (percentage +/- sd); and the intima media thickness (millimeters +/- sd) on both common carotid arteries.. After treatment, SHBG levels and the free androgen index changed significantly (P < 0.001). High-density lipoproteins and the area under curve for glucose/area under curve for insulin ratio also significantly (P < 0.001) increased, whereas low-density lipoproteins and plasma endothelin-1 levels were significantly (P < 0.001) reduced. No other change was found in any of the biochemical parameters evaluated. A significant difference was observed in brachial artery baseline diameter (3.24 +/- 0.30 vs. 3.0 +/- 0.30), flow-mediated dilation (14.30 +/- 1.90 vs. 15.70 +/- 1.50) (P < 0.01, each), diameter after reactive hyperemia (3.70 +/- 0.30 vs. 3.55 +/- 0.10) (P < 0.05), and intima media thickness (0.53 +/- 0.09 vs. 0.40 +/- 0.07) (P < 0.001) after metformin treatment in comparison with baseline values.. A 6-month course of metformin improves endothelial structure and function in young, normal-weight women with PCOS.

Topics: Area Under Curve; Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Metformin; Polycystic Ovary Syndrome; Prospective Studies

Tacrolimus and cyclosporin A (CsA), the mainstay of preventive therapy for solid organ rejection, may cause various side-effects, such as hypertension and nephrotoxicity. Furthermore, tacrolimus is associated with cardiac hypertrophy. In the immediate post-transplant period, both drugs raise the levels of Endothelin-1 (ET), a potent vasoconstrictor; and of B-type Natriuretic Peptide (BNP), a sensitive marker of left ventricular volume overload, which may precede echocardiographic changes of cardiac dysfunction. The aim of the study was to investigate the presence of cardiac damage, by echocardiography and by the biochemical markers BNP and ET, in post-orthotopic liver transplantation (OLT) children, receiving long-term immunosuppressive therapy. ET (ELISA) and BNP (RIA) were measured in plasma of 18 children, post-OLT and 18 healthy controls. Children post-OLT were echocardiographically assessed for left ventricular mass (interventricular septum and posterior wall dimensions), systolic function (ejection fraction, fractional shortening) and diastolic parameters (mitral valve E and A waves, deceleration time, isovolumic relaxation time). None of the post-transplant recipients had a history or physical examination consistent with cardiac disease and all recipients were normotensive. Echocardiography revealed no systolic or diastolic dysfunction in any of the recipients. The mean ET and BNP levels tended to be higher among children post-liver transplant, compared with healthy controls (ET: 4.22 +/- 5.35 pg/mL vs. 2.1 +/- 2.0 pg/mL; BNP: 7.05 +/- 4.4 pg/mL vs. 5.87 +/- 2.0 pg/mL, respectively, mean +/- s.d.) although differences did not reach statistical significance. Three children (17%) had elevated BNP and/or ET levels. A strong correlation was observed between ET and BNP levels in post-OLT children (r = 0.79, p < or = 0.05). No correlation was found between ET or BNP levels and echocardiographic findings. In children receiving long-term immunosuppressive therapy post-OLT, although cardiac function is grossly preserved, ET and BNP levels tend to be higher than in healthy, age-matched children. Thus, elevated levels of BNP and/or ET may identify patients with early cardiac damage.

Topics: Adolescent; Biomarkers; Cardiovascular Diseases; Child; Child, Preschool; Echocardiography; Endothelin-1; Female; Follow-Up Studies; Heart Function Tests; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Natriuretic Peptide, Brain; Postoperative Complications; Time Factors

Although obesity is strongly associated with cardiovascular disease (CVD), the endogenous relationship between obesity and CVD is still not fully clear. Emerging evidence from both animal and human studies indicates that leptin may play an important role in obesity-related CVD. Besides modulating appetite and metabolism, leptin has also been shown to increase sympathetic nerve activity, stimulate generation of reactive oxygen species, upregulate endothelin-1 production and potentiate platelet aggregation. These effects of leptin may contribute to hypertension, endothelial dysfunction and atherosclerosis in obese individuals. Better understanding the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. These recent discoveries could lead to novel strategies for treatment of obesity-associated CVD.

Topics: Animals; Cardiovascular Diseases; Endothelin-1; Humans; Hypertension; Leptin; Obesity; Reactive Oxygen Species

This study was designed to examine the association between adiponectin and C-reactive protein (CRP), interleukin-6 (IL-6) and endothelin-1, (ET-1) and their possible role in prediction of type-2 diabetes and development of diabetes and macrovascular complications. Forty subjects were studied. They were classified into four equal groups: Control, newly diagnosed type-2 diabetes, diabetics with old myocardial infarction (OMI) and acute myocardial infarction (AMI) groups. They were matched for body mass index (BMI), age, and sex. Adiponectin and IL-6 were determined by ELISA technique, CRP was determined by immunonephlometry and ET-1 was determined by radioimmunoassay. Adiponectin was found to be decreased in newly diagnosed diabetics (6.64 +/- 2.3 microg/ml), OMI (4.7 +/- 1.05 microg/ml) and AMI (4.23 +/- 0.73 microg/ml) when compared to controls (9.81 +/- 2.2 microg/ml), whereas CRP, IL- 6 and ET-1 were significantly elevated in AMI (18.6 +/- 5.3 mg/l, 12.6 +/- 4.2 pg/ml and 36.8 +/- 10.4 fmol/ml, respectively). The changes were marked in AMI group compared to other diabetic groups. Only adiponectin significantly decreased in newly diagnosed type-2 diabetics, but CRP, IL-6 and ET-1 did not significantly altered in newly diagnosed diabetics (4.9 +/- 1.6 mg/l, 6.9 +/- 2.3 pg/ml and 22.1 +/- 8.6 fmol/ml, respectively) compared to control. Adiponectin correlated negatively with CRP, IL-6 and ET-1, BMI and HbA1c, whereas inflammatory and vascular markers correlated positively with each other and with BMI and HbA1c. In conclusions, adiponectin may be implicated in the development of type-2 diabetes and macrovascular complications and can be used as an early predictor of type-2 diabetes. Whereas, none of the inflammatory and vascular markers can predict diabetes, but can be used as markers of acute vascular events and in follow up of these cases. Immunomodulation of adiponectin may help prevention and treatment of type-2 diabetes and its complications.

Topics: Adiponectin; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Female; Humans; Interleukin-2; Male; Middle Aged

There is little information whether cardiac capillary supply is deranged in diabetes. Hyperglycaemia is a potent stimulus for endothelin-1 (ET-1) production. We therefore hypothesised that increased ET-1 production in Streptozotocin-induced Type 1 diabetes causes abnormalities of cardiac capillaries and the aorta. To this end we compared the effects of an ET receptor A blocker (ETA-RB) with that of an ACE-inhibitor (ACE-i) or their combination in rats with Streptozotocin (STZ) diabetes.. Sprague Dawley rats were injected with 65 mg STZ i.v. and subsequently developed diabetes. Rats were left untreated or received daily either the ACE-i Trandolapril, the ETA-RB Darusentan or a combination of both. After 6 months the experiment was terminated and the heart and the aorta were investigated using quantitative morphological techniques.. ACE-i but not ETA-RB lowered blood pressure in STZ Type 1 diabetic rats. Capillary length density was lower in untreated STZ diabetic rats (2932+/-128 mm/mm3) compared to non-diabetic control rats (3410+/-252 mm/mm3). Treatment with ACE-i (3568+/-431 mm/mm3), but not with ETA-RB (2893+/-192 mm/mm3), prevented the decrease in capillary supply. Volume density of the myocardial interstitium was higher in untreated STZ diabetic rats (0.86+/-0.04%) compared to non-diabetic control rats (0.36+/-0.06%). In all three intervention groups the values were lower (ACE-i: 0.53+/-0.05%, ETA-RB: 0.7+/-0.08% and combination: 0.69+/-0.1).. Our study identifies a capillary defect of the heart in STZ diabetes, i.e. decreased capillary supply. This abnormality was reversed by ACE-i, but not by ETA-R blockade. A similar trend, although not complete normalisation, was seen in cardiac fibrosis.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Arterioles; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Collagen Type IV; Coronary Vessels; Diabetes Mellitus, Experimental; Endothelin A Receptor Antagonists; Endothelin-1; Fibrosis; Gene Expression; Heart; Immunohistochemistry; In Situ Hybridization; Indoles; Male; Myocardium; Phenylpropionates; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Transforming Growth Factor beta

Topics: Adult; Arrhythmias, Cardiac; Cardiovascular Diseases; Child; Comorbidity; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Epidemiologic Studies; Genetic Predisposition to Disease; Heart Failure; Humans; Hypertension; Male; Obesity; Risk Factors; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Thrombophilia

Endothelial dysfunction is one of the earliest events in the pathogenesis of cardiovascular disease (CVD). Studies involving healthy adults have found endothelial function, measured via flow mediated dilation (FMD), to be impaired in African Americans (AAs) compared to European Americans (EAs). The purpose of this study was to determine whether ethnic differences exist in FMD in a group of healthy teenagers and young adults, and to examine separately, by ethnic group, the relationships between FMD and several measures of adverse cardiovascular prognoses.. Subjects underwent measurement of various anthropometric, hemodynamic, and echocardiographic variables.. Measurements were made in a laboratory setting.. Subjects were 159 12- to 26-year-old AAs and EAs.. FMD, endothelin-1 (ET-1) levels, at rest and in response to stress, and measures of cardiac structure and function.. Ethnic differences were not observed in FMD. Only pre-occlusion arterial diameter was significantly related to FMD in EAs (P < .001); whereas, among AAs, FMD was negatively correlated (all Ps < .03) with gender, pre-occlusion arterial diameter, relative wall thickness (RWT), resting plasma ET-1, and ET-1 increases, related to a behavioral stressor. Multiple linear regressions for AAs revealed that gender and RWT each explained a unique variation in FMD (Total model R2 = .36, P < .0001).. Ethnic differences in FMD are not in evidence for subjects in this age range. The inverse relationships observed in AAs between FMD and measures of altered endothelial system function, and ventricular structure and function, provide additional evidence for early clustering of measures of adverse cardiovascular prognoses in this group.

Topics: Adolescent; Adult; Black or African American; Blood Pressure; Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Female; Femoral Artery; Georgia; Humans; Male; Prognosis; Regression Analysis; Risk Factors; Sex Factors; Ventricular Function, Left; White People

The evaluation of big-endothelin (ET)-1 plasmatic concentrations may serve as another noninvasive marker in patients with cardiovascular diseases, based on the assumption that it may reflect endothelin overproduction more accurately than circulating ET-1. For this reason the analytical performance of an immunoenzimatic assay for plasma Big-ET-1, with or without a preliminary step of extraction, was evaluated.. Sensitivity for direct assay was 0.15+/-0.010 fmol/ml (n=27), inter-assay variability, evaluated at 2 different concentrations, resulted 2.5+/-0.062, CV%=5.6 (n=5) and 1.47+/-0.09 fmol/ml, CV%=12.8 (n=4), respectively, while intra-assay variability was 0.89+/-0.022 fmol/ml, CV%=5.6. Sensitivity for the assay with extraction resulted 0.71+/-0.104 (n=6) fmol/ml and intra-assay variability was 3.6+/-0.13 fmol/ml, CV=7.4% (n=4). The comparison between the 2 procedures, performed on 107 plasma samples at different peptide concentrations, showed a close agreement between the results of the 2 procedures for Big-ET-1 values higher than 1 fmol/ml.. The main limitation of the direct assay is due to possible interference effects while the correct evaluation of extraction yield of the individual samples is the main drawback of the procedure with extraction. These effects become important when assaying samples with low levels of analyte. The direct assay of plasma Big-ET-1, easier to perform, more rapid and less expensive, could be the choice method.

Topics: Biomarkers; Cardiovascular Diseases; Endothelin-1; Humans; Immunoenzyme Techniques; Predictive Value of Tests; Sensitivity and Specificity

Circulating endothelin-1 (ET-1) levels have been reported to be associated with vascular complications and endothelial dysfunction in nontransplanted patients. The aim of this study was to investigate the relationship between ET-1 levels and major cardiovascular (CV) risk factors in renal transplant (RTX) patients with stable graft function.. ET-1 levels were determined in 156 RTX patients and the relationship between circulating ET-1 levels and CV risk factors including age, gender, kidney function, blood lipids, diabetes, and hypertension was studied.. Circulating ET-1 levels were found to be positively correlated with creatinine (r = 0.25, p < 0.01) and systolic blood pressure (r = 0.20, p < 0.05) and inversely correlated with high-density lipoprotein cholesterol (HDL-C) levels (r = -0.27, p < 0.01). Patients with high and intermediate total cholesterol/HDL-C ratios (TC/HDL-C) had significantly higher ET-1 levels when compared to patients with low ratios (7.02 +/- 3.74, 6.79 +/- 2.67, and 5.37 +/- 3.04 pg/ml, respectively, p < 0.002). Only creatinine, HDL-C, and age >40 years were shown to be independent correlates for ET-1 levels according to multivariate analyses. Interestingly, ET-1 levels were significantly higher (+26%, p < 0.03) in RTX patients with documented CV disease, as compared to those without, when matched for age, gender, and presence of diabetes.. Increased circulating ET-1 levels are associated with low HDL-C and documented CV disease in RTX. This is likely a reflection of vascular endothelial damage and dysfunction and therefore may represent an increased risk for atherosclerosis.

Topics: Adult; Aged; Blood Pressure Determination; Cardiovascular Diseases; Cholesterol, HDL; Creatinine; Diabetes Complications; Endothelin-1; Humans; Hypertension; Kidney Function Tests; Kidney Transplantation; Lipids; Middle Aged; Risk Factors

Cardiovascular complications are the central feature of type 2 diabetes mellitus, and insulin resistance is an early clinical manifestation of type 2 diabetes mellitus. Calcium channel blockers are widely used to treat cardiovascular diseases in diabetic patients; however, it remains unknown how endothelin-1 (ET-1) is altered and associated with cardiac lesions at the insulin-resistant early stage of type 2 diabetes mellitus, and, if so, whether calcium channel blockers can reverse such alterations. We examined plasma and cardiac expression of ET-1 in male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a spontaneous model of human type 2 diabetes mellitus. At 8 weeks of age, OLETF rats were treated for 12 weeks with a long acting calcium channel blocker, benidipine (3 mg/kg per day p.o.) (BEN, n = 15), or with vehicle (OLETF, n = 15), and age-matched genetic control, male Long-Evans Tokushima Otsuka (LETO) rats were also used (n = 15). Blood pressure was significantly higher in OLETF than LETO rats, and benidipine treatment of OLETF rats for 12 weeks did not reduce their blood pressure significantly. Plasma and cardiac levels of ET-1 were significantly higher in OLETF compared with LETO rats (both P < 0.01), and were reversed after benidipine treatment. Our results suggest that ET-1 plays a pivotal role in the pathogenesis of cardiac complications at the insulin-resistant stage of diabetes mellitus, and that benidipine treatment may have a beneficial effect on these complications.

Topics: Age Factors; Animals; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Disease Models, Animal; Down-Regulation; Endothelin-1; Insulin Resistance; Male; Myocardium; Rats; Rats, Inbred OLETF; Rats, Long-Evans

Thrombin (Thromb), activated as part of the clotting cascade, dilates conduit arteries through an endothelial pertussis toxin (PTX)-sensitive G-protein receptor and releases nitric oxide (NO). Thromb also acts on downstream microvessels. Therefore, we examined whether Thromb dilates human coronary arterioles (HCA). HCA from right atrial appendages were constricted by 30-50% with endothelin-1. Dilation to Thromb (10(-4)-1 U/ml) was assessed before and after inhibitors with videomicroscopy. There was no tachyphylaxis to Thromb dilation (maximum dilation = 87.0%, ED(50) = 1.49 x 10(-2)). Dilation to Thromb was abolished with either hirudin or denudation but was not affected by PTX. Neither N(omega)-nitro-l-arginine methyl ester (n = 7), indomethacin (n = 9), (1)H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (n = 6), tetraethylammonium chloride (n = 5), nor iberiotoxin (n = 4) reduced dilation to Thromb. However, KCl (maximum dilation = 89 +/- 5 vs. 20 +/- 10%; P < 0.05; n = 7), tetrabutylammonium chloride (maximum dilation = 79 +/- 7 vs. 21 +/- 4%; P < 0.05; n = 5), and charybdotoxin (maximum dilation = 89 +/- 4 vs. 10 +/- 2%; P < 0.05; n = 4) attenuated dilation to Thromb. In contrast to animal models, Thromb-induced dilation in human arterioles is independent of G(i)-protein activation and NO release. However, Thromb dilation is endothelium dependent, is maintained on consecutive applications, and involves activation of K(+) channels. We speculate that an endothelium-derived hyperpolarizing factor contributes to Thromb-induced dilation in HCA.

Topics: Adult; Aged; Arterioles; Cardiovascular Diseases; Charybdotoxin; Chlorates; Coronary Vessels; Endothelin-1; Endothelium, Vascular; Female; GTP-Binding Protein alpha Subunits, Gi-Go; Hirudins; Humans; In Vitro Techniques; Male; Microscopy, Video; Middle Aged; Nitric Oxide; Pertussis Toxin; Potassium Chloride; Quaternary Ammonium Compounds; Risk Factors; Thrombin; Vasodilation

To assess risk factors for cardiovascular disease in healthy postmenopausal women who had been uninterruptedly on menopausal hormone replacement therapy (HRT) for at least 5 years or who had not received any HRT.. Cross-sectional study.. The Royal Free Hospital and The Middlesex Hospital.. A total of 256 healthy postmenopausal women were analyzed: 73 were taking tibolone, 60 were taking transdermal E(2), 58 were taking conjugated equine estrogens (E), and 65 were not taking any menopausal therapy.. Cardiovascular disease risk factors measurement.. Total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, lipoprotein(a), insulin, glycated hemoglobin, high sensitivity C-reactive protein, fibrinogen, total antioxidants, and endothelin-1.. The different types of HRT induced disparate changes in the various markers of cardiovascular disease. Significantly higher high sensitivity C-reactive protein concentrations were found in women receiving conjugated equine E and tibolone than in women who were not taking any therapy. Glycated hemoglobin was significantly lower in women receiving transdermal E(2) and tibolone compared to women not on HRT. Women on tibolone had significantly higher systolic blood pressure.. Because high sensitivity C-reactive protein has recently emerged as an important predictor of cardiovascular disease, the higher high sensitivity C-reactive protein levels observed in women on conjugated equine estrogens and on tibolone have potential important clinical implications.

Topics: Administration, Cutaneous; Aged; Antioxidants; C-Reactive Protein; Cardiovascular Diseases; Cross-Sectional Studies; Endothelin-1; Estradiol; Estrogen Receptor Modulators; Estrogen Replacement Therapy; Estrogens; Estrogens, Conjugated (USP); Female; Fibrinogen; Glycated Hemoglobin; Humans; Insulin; Lipids; Middle Aged; Norpregnenes; Postmenopause; Risk Factors

Brain natriuretic peptide (BNP) gene expression accompanies cardiac hypertrophy and heart failure. The vasoconstrictor endothelin-1 (ET) may be involved in the development of these diseases. ET has also been shown to activate phospholipase A(2) (PLA(2)), and the resulting metabolites are important second messengers. We studied how ET and PLA(2) metabolites regulate BNP gene expression. The human BNP (hBNP) promoter (from -1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal ventricular myocytes (NVMs), and luciferase activity was measured as an index of promoter activity. ET induced BNP mRNA in NVMs as assessed by Northern blot. It also stimulated the hBNP promoter, an effect completely inhibited by actinomycin D. To test the involvement of different PLA(2) isoforms, transfected cells were treated with various PLA(2) inhibitors before stimulation with ET. Only Ca(2+)-independent PLA(2) blockade prevented ET-stimulated hBNP promoter activity. The PLA(2) metabolite lysophosphatidic acid (LPA) also activated the hBNP promoter, but arachidonic acid itself did not. ET regulation of the hBNP promoter is pertussis toxin-sensitive. The nonreceptor tyrosine kinase Src and the small GTPase Rac mediate the effects of both ET and LPA in stimulation of the hBNP promoter. We studied the involvement of cis elements in ET-stimulated hBNP promoter activity. Deletion of BNP promoter sequences from -1818 to -408 and from -408 to -40 reduced the effect of ET by 60% and 80%, respectively. Moreover, ET-stimulated luciferase activity was reduced by 50% when the proximal GATA element was mutated. These data suggest that (1) ET activates the hBNP promoter through a transcriptional mechanism; (2) LPA, perhaps generated by iPLA(2), is involved in the effect of ET; (3) Src and Rac mediate ET and LPA stimulation of the hBNP promoter; and (4) ET regulation of the hBNP promoter targets both distal and proximal cis elements.

Topics: Animals; Brain; Cardiovascular Diseases; Cells, Cultured; Endothelin-1; Enzyme Inhibitors; Gene Expression Regulation; Humans; Luciferases; Myocardium; Natriuretic Peptide, Brain; Phosphatidic Acids; Phospholipases A; Promoter Regions, Genetic; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transfection; Ventricular Dysfunction, Left

In 76 patients with heart failure (HF) (New York Heart Association [NYHA] classes I through IV) and in 15 control subjects, cardiac angiotensin II (Ang II) generation and its relationship with left ventricular function were investigated by measuring aorta-coronary sinus concentration gradients of endogenous angiotensins and in a part of patients by studying (125)I-labeled Ang I kinetics. Gene expression and cellular localization of the cardiac renin-angiotensin system components, the density of AT(1) and AT(2) on membranes and isolated myocytes, and the capacity of isolated myocytes for synthesizing the hypertrophying growth factors insulin-like growth factor-I (IGF-I) and endothelin (ET)-1 were also investigated on 22 HF explanted hearts (NYHA classes III and IV) and 7 nonfailing (NF) donor hearts. Ang II generation increased with progression of HF, and end-systolic wall stress was the only independent predictor of Ang II formation. Angiotensinogen and angiotensin-converting enzyme mRNA levels were elevated in HF hearts, whereas chymase levels were not, and mRNAs were almost exclusively expressed on nonmyocyte cells. Ang II was immunohistochemically detectable both on myocytes and interstitial cells. Binding studies showed that AT(1) density on failing myocytes did not differ from that of NF myocytes, with preserved AT(1)/AT(2) ratio. Conversely, AT(1) density was lower in failing membranes than in NF ones. Ang II induced IGF-I and ET-1 synthesis by isolated NF myocytes, whereas failing myocytes were unable to respond to Ang II stimulation. This study demonstrates that (1) the clinical course of HF is associated with progressive increase in cardiac Ang II formation, (2) AT(1) density does not change on failing myocytes, and (3) failing myocytes are unable to synthesize IGF-I and ET-1 in response to Ang II stimulation.

Topics: Analysis of Variance; Angiotensin I; Angiotensin II; Angiotensinogen; Cardiomyopathy, Dilated; Cardiovascular Diseases; Chymases; Endothelin-1; Gene Expression; Gene Expression Regulation; Heart Ventricles; Immunohistochemistry; In Situ Hybridization; Insulin-Like Growth Factor I; Iodine Radioisotopes; Myocardial Ischemia; Myocardium; Peptidyl-Dipeptidase A; Platelet-Derived Growth Factor; Protein Precursors; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Serine Endopeptidases; Ventricular Function, Left

This paper aims to demonstrate that there is currently sufficient evidence to suggest that endothelin-1 (ET-1) may play a role in angina and be associated with myocardial ischaemia. In order to demonstrate the potential role of ET-1 in angina, this paper examines three main factors: (i) that endothelin-1 can cause the pathophysiological states associated with myocardial ischaemia and angina; (ii) that ET-1 is over-expressed in humans and in animal models of myocardial ischaemia, which is associated with angina; and (iii) that modification of the ET-1 system is associated with an improvement in myocardial ischaemia and angina.

Topics: Angina Pectoris; Animals; Cardiovascular Diseases; Cyclic GMP; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Myocardial Ischemia

The results of the Randomized Aldactone Evaluation Study (RALES) and of several experimental studies have indicated that excess aldosterone detrimentally affects cardiovascular morbidity and mortality by acting through both classical and non-classical mineralocorticoid receptors. The effects mediated through classical mineralocorticoid receptors entail enhanced sodium and water reabsorption, potassium loss and hypokalaemia, congestion, increased vascular resistance and hypertension. Those occurring through non-classical mineralocorticoid receptors located on myofibroblasts comprise cardiac hypertrophy and fibrosis, which may be due to a direct effect of aldosterone on collagen synthesis. Data obtained in primary aldosteronism patients demonstrated left ventricular hypertrophy, as well as changes in left ventricular filling that can be accounted for by cardiac fibrosis. Available clinical data indicate that in a considerable proportion of congestive heart failure (CHF) patients treated with angiotensin converting enzyme (ACE) inhibitors, aldosterone secretion can escape from blockade of the renin-angiotensin system, thus suggesting that additional mechanisms, besides angiotensin II, can play an important role in the regulation of aldosterone secretion. Compelling evidence indicates that endothelin (ET)-1 is overtly increased in severe CHF and thus is a likely candidate for the aldosterone 'escape' phenomenon in CHF. Endothelin-1 is expressed in the adrenal cortex, together with its receptor subtypes A (ETA) and B (ETB), and directly stimulates aldosterone secretion in different species, in humans by acting via both ETA and ETB receptor subtypes. Moreover, we have recently found that the novel endothelin peptide ET-1 (1-31), by acting as an ETA agonist, can also be involved in the regulation of growth of the adrenal cortex, as well as in the pathogenesis of Conn's adenoma. In this paper, we review the findings suggesting a relationship between activation of the ET-1 system, enhanced aldosterone secretion and cardiac fibrosis and discuss the implications of endothelin antagonism for cardiovascular disease.

Topics: Adrenal Cortex; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Collagen; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Morbidity; Randomized Controlled Trials as Topic; Receptor, Endothelin A; Receptor, Endothelin B; Renin-Angiotensin System; Spironolactone

The use of the estrogen ethinylestradiol is associated with an increased cardiovascular risk. It is not known whether this might be caused by an influence of ethinylestradiol on endothelium-derived factors or on the cardiovascular risk factor homocysteine. Our aim was to evaluate whether a short-term treatment with ethinylestradiol results in changes of nitric oxide (NO), endothelin-1 and homocysteine. Participants were ten healthy women with regular menstrual cycles. NO, homocysteine, endothelin-1, estradiol and progesterone were measured during one cycle and before and after treatment with ethinylestradiol at 50 microg/day. Homocysteine and NO did not change significantly during the menstrual cycle or after treatment. However, endothelin-1 levels decreased during the cycle (from 3.89 ng/l to 2.93 ng/l p < 0.05) and after ethinylestradiol (from 2.94 ng/l to 2.26 ng/l p<0.03). Analysis of the pretreatment data showed a positive correlation between homocysteine and NO and between NO and endothelin-1. Treatment with ethinylestradiol caused a shift in the balance between NO and endothelin-1 in the direction of vasodilatation. This finding is one factor concerning the effects of ethinylestradiol on the vascular system but does not explain the cardiovascular risk of this substance.

Topics: Adult; Cardiovascular Diseases; Endothelin-1; Ethinyl Estradiol; Female; Homocysteine; Humans; Menstrual Cycle; Nitric Oxide; Risk Factors; Vasodilation

The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)-protein-coupled receptors. ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1. ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.

Topics: Aspartic Acid Endopeptidases; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Humans; Metalloendopeptidases

Topics: Cardiovascular Diseases; Endothelin-1; Humans; Sleep Apnea Syndromes

Topics: Cardiovascular Diseases; Endothelin-1; Endothelin-3; Hemodynamics; Humans; Receptor, Endothelin B; Receptors, Endothelin; Systole; Vasoconstriction; Ventricular Dysfunction, Left; Ventricular Function, Left

Lipid-lowering statin treatment reduces cardiovascular morbidity and mortality and improves endothelial function in patients with hypercholesterolemia. The aim of the present study was to evaluate plasma levels of fibrinogen, factor VII, and the macrophage-derived inflammatory mediator neopterin during lipid lowering. In addition, the endothelial production of platelet antiaggregatory and vasodilatory factors such as nitric oxide and prostacyclin, and vasoconstrictive factors such as endothelin-1, was assessed. Plasma fibrinogen, factor VII, endothelin-1, and the neopterin and intraplatelet nitric oxide and prostacyclin mediators cyclic 3'-5'guanosine monophosphate (cGMP) and cyclic 3'-5'adenosine monophosphate (cAMP) were measured before and 6 months after the institution of treatment with fluvastatin in 17 patients (eight men and nine women, median age 60 years) with vascular disease and previously untreated hypercholesterolemia. After 6 months, a decrease of 1.62 mmol/l [1.26-2.18 (19%); P < 0.01] was noted in levels of total cholesterol, and a decrease of 1.70 mmol/l [1.52-2.30 (28%); P < 0.01] in levels of low-density lipoprotein cholesterol. Plasma levels of fibrinogen had increased [from 4.81 g/l (4.26-5.27) to 5.17 g/l (4.81-5.67); P < 0.05], whereas no significant changes had occurred in intraplatelet levels of cGMP [decrease by 0.05 pmol/10(9) platelets (-0.17 to 0.24); NS], cAMP [decrease by 0.13 pmol/10(9) platelets (-0.37 to 0.86); NS], plasma endothelin-1 [decrease by 0.05 pg/ml (-0.60 to 0.70); NS], plasma factor VII [from 1.14 IE/ml (0.58-1.38) to 1.22 IE/ml (0.96-1.46); NS], or plasma neopterin [from 8.6 nmol/l (7.1-11.5) to 8.7 nmol/l (7.9-11.3); NS]. In conclusion, during cholesterol-lowering treatment with fluvastatin, plasma levels of fibrinogen increased whereas intraplatelet cyclic nucleotide levels and plasma endothelin-1, factor VII and neopterin levels were unchanged.

Topics: Aged; Anticholesteremic Agents; Blood Platelets; Cardiovascular Diseases; Cholesterol; Endothelin-1; Factor VII; Fatty Acids, Monounsaturated; Female; Fibrinogen; Fluvastatin; Humans; Hypercholesterolemia; Indoles; Male; Middle Aged; Neopterin; Nucleotides, Cyclic

Since its discovery in 1988, endothelin (ET) has been widely implicated in the pathophysiology of cardiovascular disease. ET antagonists have favourable effects in experimental models of these conditions and have proved useful in elucidating the role of the ET system. Orally acting ET antagonists appear very promising in clinical trials, particularly in patients with chronic heart failure and hypertension, but more information on the roles of the ET receptor subtypes in health and disease is required so that an informed choice can be made between the use of endothelin-A (ET-A) receptor-selective and nonselective receptor antagonists.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Drugs, Investigational; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Hypertension; Receptors, Endothelin

To investigate changes in plasma lipoprotein profile, hemostatic factors, platelet aggregation, endothelin-1, and cardiac function during postmenopausal sequential 6-month hormone replacement therapy (HRT).. Open longitudinal prospective study.. Gynecologic department of a medical center.. Twenty-one healthy hysterectomized postmenopausal women.. Oral E2 valerate (2 mg/d) combined with medroxyprogesterone acetate (MPA) (10 mg/d) during the last 10 days of each 21-day cycle. The treatment period was 6 months.. Plasma lipoprotein profile, hemostatic parameters, platelet aggregation, endothelin-1, and left ventricular function.. After 6 months of treatment, total cholesterol, triglyceride, and low density lipoprotein (LDL) cholesterol were significantly progressively reduced. Atherogenic indices of total cholesterol-to-high-density lipoprotein (HDL) cholesterol and LDL-to-HDL cholesterols also showed a significant progressive decline. The concentrations of antithrombin III were significantly increased. The maximum aggregation and slope of platelet aggregation were significantly reduced, but all parameters were more pronounced at 1 month of HRT than at 3 or 6 months. The concentrations of endothelin-1 were significantly reduced (by 16.1%). In the evaluation of left ventricular function, only peak atrial diastolic velocity was significantly reduced.. Combined HRT had favorable effects on lipids and lipoproteins, hemostatic factors, platelet aggregation, endothelin-1, and left ventricular function. However, further study is needed to evaluate the long-term effects of combined HRT, especially on platelet aggregation and cardiac function.

Topics: Blood Coagulation Factors; Cardiovascular Diseases; Electrocardiography; Endothelin-1; Estradiol; Estrogen Replacement Therapy; Female; Hemostasis; Humans; Lipoproteins; Longitudinal Studies; Medroxyprogesterone Acetate; Middle Aged; Platelet Aggregation; Postmenopause; Prospective Studies; Risk Factors; Ventricular Function, Left

This fifth international conference on ET serves to underline the rapid pace of development of our understanding of the very versatile ET system. On the one hand, the body uses ETs at several stages in embryonic development, in normal postnatal growth, and in cardiovascular homeostasis under healthy conditions. On the other hand, overwhelming evidence now exists that ET-1 plays important pathophysiological roles in conditions of decompensated vascular homeostasis. Indeed, in CHF this evidence is sufficient to justify the large-scale studies of morbidity and mortality needed to market ET antagonists as medicines. Other potentially important cardiovascular indications for ET antagonists are still emerging--including hypertension, stroke, subarachnoid haemorrhage and renal failure--and all are likely to be the subject of clinical trials over the next few years. As yet, there has been little work outside the cardiovascular and renal fields, but other areas, such as cancer treatment, may also prove promising. New molecules with increasing selectivity (ETA and ETB) continue to emerge and may be valuable. Inhibition of ECE-1 remains as an alternative approach and nonpeptide ECE inhibitors now exist. There appears to be a consensus that ETA blockade is beneficial in cardiovascular and renal disease. However, several strands of work presented at the meeting--the hypertensive salt-sensitive phenotype of rescued ETB knockout mice, the sustained and progressive hypertensive effects of ETB-selective antagonism in rats, ETB-mediated vasodilatation and natriuresis in dogs, and nitric oxide-dependent ETB-mediated vasodilatation in humans--all suggest that ETB-mediated vascular and renal responses may be protective. The development of selective ETA antagonists, therefore, now seems fully justified. In the future, direct comparisons in animal models, and patients, of ETA and ETA/B antagonists will be important in determining the value of additional ETB receptor blockade in individual diseases.

Topics: Animals; Animals, Genetically Modified; Aspartic Acid Endopeptidases; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Humans; Kidney Diseases; Lung Diseases; Metalloendopeptidases; Mice; Mice, Knockout; Promoter Regions, Genetic

To determine the effect of chronic cigarette smoking on renal function, a cross-sectional study was carried out with 30 subjects who had no known vascular disease risk factor other than cigarette smoking, and 24 age- and sex-matched controls without any vascular risk factor including cigarette smoking. Renal function by radionuclide studies of renal plasma flow, GFR, and plasma endothelin-1 concentration was determined. Compared with nonsmokers, smokers had a renal function impairment characterized by a normal GFR and a significant reduction in renal plasma flow as reflected by MAG3 clearance (199.20 +/- 58.85 ml/min per 1.73 m2 versus 256.54 +/- 60.14 ml/min per 1.73 m2; t = 3.52, P < 0.001). MAG3 clearance was significantly correlated with age and smoking. The renal dysfunction was associated with an increase in plasma endothelin-1 concentration (21.56 +/- 1.15 pmol/L versus 25.01 +/- 3.21 pmol/L; t = 5.00, P < 0.001). Former smokers as well had similar, although milder, abnormalities. In conclusion, cigarette smokers manifest an impairment of renal function, suggesting that smoke may have a detrimental effect on renal function.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Female; Glomerular Filtration Rate; Glycine; Humans; Incidence; Kidney Diseases; Male; Middle Aged; Multivariate Analysis; Peripheral Vascular Diseases; Regression Analysis; Renal Circulation; Risk Factors; Smoking; Time Factors

Topics: Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide; Tissue Plasminogen Activator

Topics: Cardiovascular Diseases; Endothelin-1; Endothelins; Humans; Immunoenzyme Techniques; Protein Precursors

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Drug Design; Endothelin-1; Humans; Ligands; Models, Molecular; Receptors, Cell Surface

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

Increased levels of endothelin (ET-1), a potent endothelium-derived vasoconstrictive peptide, have been found in plasma from non-insulin dependent diabetic (NIDDM) patients, suggesting that ET-1 might represent a new marker of diabetes-related vascular damage. To elucidate this topic, circulating ET-1 levels were evaluated in 16 NIDDM patients in good metabolic control without either cardiovascular risk factors (obesity, hypertension, smoking, hyperdislipidaemia, etc.) or diabetes-related damage of other districts and in 12 healthy subjects. Retinopathy was assessed by ophthalmological evaluation and its severity determined by Klein criteria. Resulting data showed higher levels of plasma ET-1 in NIDDM patients than in control subjects (0.80 +/- 0.13 vs 0.60 +/- 0.12 pg/mL, p < 0.001). Plasma ET-1 levels were directly correlated with retinopathy degrees in NIDDM patients affected by retinopathy (n = 10; r = 0.368; p = 0.02), and were significantly higher in these latter (n = 10) than in those without retinopathy (n = 6) (0.89 +/- 0.13 vs 0.71 +/- 0.19 pg/mL, p < 0.05). The increased levels of ET-1 could contribute to retinopathy development or, more probably, represent a marker of this diabetes-related complication.

Topics: Adult; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Endothelin-1; Humans; Male; Middle Aged; Reference Values; Risk Factors

Plasma ET-1 was measured around the clock on different calendar dates in healthy subjects and in subjects with diabetes and/or with high blood pressure and/or a history of vascular complications (HVDR). A transverse approach, with each subject contributing a single 24-h mean, assessed any about-weekly or half-weekly variation in ET-1. A circasemiseptan component resolved by single cosinor for nondiabetic (but not for diabetic) HVDR subjects (p = 0.010) differs in its timing of overall high values (p < 0.050) from that found in healthy subjects (p = 0.006). The results are aligned with circasemiseptan patterns in other circulatory variables and morbidity/mortality statistics.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Cardiovascular Diseases; Circadian Rhythm; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endothelin-1; Female; Humans; Longitudinal Studies; Male; Middle Aged; Periodicity; Risk Factors; Vascular Diseases

To elucidate the pathophysiologic significance of the family of endothelin (ET) peptides, we have investigated plasma and urinary immunoreactive (ir-) ET levels and its molecular forms in normal and pathological conditions. Plasma and urine ET were extracted with an Amprep C2 column. The molecular form of ET was determined by a combination of radioimmunoassay and reverse-phase high-performance liquid chromatography. Although plasma ir-ET was composed mainly of big ET and endothelin-1 (ET-1) in normal subjects, that in acute myocardial infarction, chronic renal failure (CRF), essential hypertension, and vasospastic angina pectoris was characterized by an increase of high molecular ir-ET in addition to increases in big ET and ET-1. Urinary ir-ET in both normal subjects and patients with CRF was composed mainly of a high molecular form in addition to big ET and ET-1. These results suggest that the biosynthetic and/or degradation process of ET under pathological conditions appears to be different from that under normal conditions.

Topics: Angina Pectoris; Cardiovascular Diseases; Endothelin-1; Endothelins; Humans; Hypertension; Kidney Diseases; Myocardial Infarction; Protein Precursors