endothelin-1 and Chronic-Disease

Natriuretic peptides (NPs) promote diuresis, natriuresis and vasodilation in early chronic heart failure (CHF), countering renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) overstimulation. Despite dramatic increases in circulating NP concentrations as CHF progresses, their effects become blunted. Increases in diuresis, natriuresis, and vasodilation after administration of exogenous atrial (ANP) or brain (BNP) natriuretic peptides are attenuated in patients with advanced CHF compared with controls. Several major factors may account for the reduced effectiveness of the natriuretic peptide system (NPS) in CHF. First, there is reduced availability of active forms of NPs, namely BNP. Second, target organ responsiveness becomes diminished. Third, the counter-regulatory hormones of the RAAS and SNS, and endothelin-1 become over-activated. Therefore, pharmacological approaches to enhance the functional effectiveness of the NPS in CHF have been explored in recent years. In terms of clinical outcomes, studies of synthetic BNP, or of neprilysin inhibitors alone or associated with an angiotensin converting enzyme inhibitor, have been controversial for several reasons. Recently, however, encouraging results have been obtained with the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. The available data show that treatment with sacubitril/valsartan is associated with increased levels of NPs and their intracellular mediator cyclic guanosine monophosphate, suggesting improved functional effectiveness of the NPS, in addition to beneficial effects on mortality and morbidity outcomes. Therefore, combined targeting of the NPS and RAAS with sacubitril/valsartan emerges as the current optimal approach for redressing the neurohormonal imbalance in CHF.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Atrial Natriuretic Factor; Biphenyl Compounds; Chronic Disease; Drug Combinations; Endothelin-1; Heart Failure; Humans; Natriuretic Agents; Natriuretic Peptide, Brain; Neprilysin; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System; Sympathetic Nervous System; Tetrazoles; Valsartan

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

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

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

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

The incidence of chronic kidney diseases is increasing worldwide at an alarming rate. As this is emerging as a global threat to human health, present efforts are concentrated on the identification of new treatments that slow or even reverse the progression of chronic nephropathies. Endothelin (ET)-1 is a potent vasoconstrictor peptide with proinflammatory, mitogenic, and profibrotic effects, and it contributes to both normal renal physiology and pathology. There is robust experimental and clinical evidence for the role of ET-1and its cognate receptors in many progressive renal disorders. The effectiveness of ET receptor antagonists in improving renal hemodynamics and reducing fibrosis has been largely documented in experimental animals. However, whether selective ET(A) or dual ET(A)/ET(B) receptor antagonists are preferable is still a matter of debate. Combined therapies, including ET receptor antagonists, are promising to maximize partial renoprotection achieved with blockade of the renin-angiotensin system, particularly when treatment is given in the latter phase of the disease. The focus of this review is to explore the role of ET-1 in kidney diseases and to shed light on the novel pharmacological setting in chronic nephropathies.

Topics: Animals; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Humans; Proteinuria; Receptors, Endothelin

Observational studies have shown a strong positive correlation between the severity of anemia and the risk of poor outcomes in patients with chronic kidney disease (CKD). This observation was initially taken to imply that adverse outcomes in CKD are caused by anemia. However, the assumption of causality ignores the possibility that anemia and adverse outcomes might be unrelated and that both are caused by underlying inflammation, oxidative stress and comorbid conditions. Randomized clinical trials of anemia correction have revealed an increased risk of adverse cardiovascular outcomes in patients assigned to normal, rather than subnormal, hemoglobin targets. As a result, correction of anemia is now considered potentially hazardous in patients with CKD. Notably, individuals who did not reach the target hemoglobin level in the clinical trials, despite receiving high doses of erythropoietin and iron, experienced a disproportionately large share of the adverse outcomes. These observations point to overdose of erythropoietin and iron, rather than anemia correction per se, as the likely culprit. This Review explores the reasons for the apparent contradiction between the findings of observational studies and randomized clinical trials of anemia treatment in CKD. I have focused on data from basic and translational studies, which are often overlooked in the design and interpretation of clinical studies and in the formulation of clinical guidelines.

Topics: Anemia; Animals; Blood Platelets; Blood Pressure; Causality; Chronic Disease; Comorbidity; Dose-Response Relationship, Drug; Drug Overdose; Endothelin-1; Erythropoietin; Hemoglobins; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Morbidity; Nitric Oxide; Oxidative Stress

The aims of the present review are to summarize and to discuss the role of hypoxia-inducible factor-1 (HIF-1) and the expression and functions of vasoactive substances in chronic hypoxemia with specific focus in the liver and the carotid body. Vascular remodelling and vasoactive substances play important functional roles in the adaptive response to chronic hypoxemia for the maintenance of oxygen homeostasis in all systems in man. HIF-1 regulates the gene expression of vasoactive substances such as vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) and enzymes for producing nitric oxide (NO). Recent studies have shown the effect of chronic hypoxia on the expression of HIF-1alpha and HIF-1-target genes in multiple organ systems including the liver and the carotid body. Results are consistent with increases in the hematocrit levels, pulmonary arterial pressure and right heart mass developed during chronic hypoxia. In addition, the carotid body is also hyperplastic and increases in organ mass with increased levels of HIF-1alpha and the vasoactive substances. These molecules increase the mitotic activity and modulate the excitability of the chemoreceptor. Intriguingly, the liver morphology, serum alanine aminotransferase and 8-isoprostane levels are within normal range in chronic hypoxia, suggesting the absence of significant oxidative stress. Yet, the HIF-1alpha is upregulated and the mRNA and protein levels of VEGF, ET-1, inducible and constitutive NO synthases are elevated in the liver during chronic hypoxia. In conclusion, the adaptive response to long-term hypoxemia involves compensatory mechanisms mediated by expressing significant levels of HIF-1alpha and vasoactive substances regulated by HIF-1.

Topics: Animals; Carotid Arteries; Chronic Disease; Endothelin-1; Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Liver; Nitric Oxide; Oxygen; Transcription Factors; Vascular Endothelial Growth Factor A

Endothelin (ET)-1 is a potent vasoconstrictor peptide with pro-inflammatory, mitogenic, and pro-fibrotic properties that is closely involved in both normal renal physiology and pathology. ET-1 exerts a wide variety of biological effects, including constriction of cortical and medullary vessels, mesangial cell contraction, stimulation of extracellular matrix production, and inhibition of sodium and water reabsorption along the collecting duct, effects that are primarily mediated in an autocrine/paracrine manner. Increasing evidence indicates that the ET system is involved in an array of renal disorders. These comprise chronic proteinuric states associated with progressive glomerular and tubulointerstitial fibrosis, including diabetic and hypertensive nephropathy, glomerulonephritis and others. In addition, ET-1 is causally linked to renal disorders characterized by increased renal vascular resistance, including acute ischaemic renal failure, calcineurin inhibitor toxicity, endotoxaemia, hepatorenal syndrome and others. Furthermore, derangement of the ET system may be involved in conditions associated with inappropriate sodium and water retention; for example, in congestive heart failure and hepatic cirrhosis. Both selective and non-selective ET receptor antagonist have been developed and tested in animal models with promising results. As key events in progressive renal injury like inflammation and fibrosis are mediated via both ET(A) and ET(B) receptors, while constrictor effects are primarily transduced by ET(A) receptors, dual ET receptor blockade may be superior over selective ET(A) antagonism. Several compounds have been developed with remarkable effects in several models of acute and progressive renal injury. Thus, clinical studies are required to assess whether these results can be confirmed in humans, hopefully leading to novel and effective therapeutic options with few side effects.

Topics: Acute Kidney Injury; Animals; Chronic Disease; Diabetic Nephropathies; Endothelin-1; Endothelins; Glomerulonephritis; Hepatorenal Syndrome; Humans; Hypertension; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Receptors, Endothelin

Topics: Angiotensin-Converting Enzyme Inhibitors; Arginine; Chronic Disease; Diagnosis, Differential; Diuretics; Drug Therapy, Combination; Endothelin-1; Heart Failure; Humans; Hypertension; Prognosis; Renin-Angiotensin System; Vasopressins

Topics: Biomarkers; Cell Adhesion; Chronic Disease; Disease Progression; Endothelin-1; Endothelium, Vascular; Humans; Leukocytes; Varicose Veins

Vascular damage caused by cerebral ischemia leads to edema, hemorrhage formation, and worsened outcomes in ischemic stroke patients. Therapeutic interventions need to be developed to provide vascular protection. The purpose of this review is to identify the pathophysiologic processes involved in vascular damage after ischemia, which may lead to strategies to provide vascular protection in ischemic stroke patients.. The pathologic processes caused by vascular injury after an occlusion of a cerebral artery can be separated into acute (hours), subacute (hours to days), and chronic (days to months). Targets for intervention can be identified for all 3 stages. Acutely, superoxide is the predominant mediator, followed by inflammatory mediators and proteases subacutely. In the chronic phase, proapoptotic gene products have been implicated.. Pharmacological agents designed to target specific pathologic and protective processes affecting the vasculature should be used in clinical trials of vascular protection after acute ischemic stroke.

Topics: Acute Disease; Angiopoietins; Angiotensin II; Antioxidants; Apoptosis; Blood-Brain Barrier; Brain Edema; Brain Ischemia; Cerebral Arteries; Cerebral Hemorrhage; Chronic Disease; Endothelin-1; Endothelium, Vascular; Humans; Inflammation Mediators; Matrix Metalloproteinases; Neuroprotective Agents; Neutrophils; Oxidative Stress; Reactive Oxygen Species; Vascular Endothelial Growth Factor A; Vasculitis

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 aims of this review are to describe recent data focusing on the anatomical, functional and molecular changes of the carotid body during chronic hypoxemia, and to summarize current views in the literature relevant to the topic. The carotid body is the major peripheral sensor for detecting chemicals in the arterial blood. In acute hypoxia, carotid chemoreceptors transduce the signal to the brain for triggering reflexive responses of the cardiopulmonary system. The carotid body enlarges and changes its hypoxic sensitivity in humans and animals living at high altitude or subject to long-term hypoxemia associated with chronic cardiopulmonary diseases or hematological disorders. Recently, a surge of new evidence suggests that a heterodimeric transcriptional factor directly induced by severe tissue or cellular hypoxia, namely hypoxia-inducible factor-1 (HIF-1), is a key controller for the transcriptional regulation of the gene expression of a spectrum of proteins for the cellular response to hypoxia. These proteins, such as endothelin-1, type II nitric oxide synthase and vascular endothelial growth factor, play important physiological roles in the control of vascular tone and angiogenesis. In the carotid body, chronic hypoxemia induces remodeling of the vasculature, stimulates proliferation of the chemosensitive cells, and changes their excitability and sensitivity to chemical signals. In addition, HIF-1-targeted genes are expressed in the carotid body and the expression is modulated by chronic hypoxemia, suggesting an active role for HIF-1 in moderate levels of hypoxic stress.

Topics: Animals; Carotid Body; Chronic Disease; DNA-Binding Proteins; Endothelin-1; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Nitric Oxide; Nitric Oxide Synthase; Nuclear Proteins; Receptors, Endothelin; Receptors, Vascular Endothelial Growth Factor; Transcription Factors; Vascular Endothelial Growth Factor A

In the pulmonary circulation, a decrease in oxygen tension results in the development of hypoxic pulmonary vasoconstriction (HPV), although the exact mechanism by which HPV occurs remains unclear. Evidence gathered from many laboratories suggests that while pulmonary arterial smooth muscle cells (PASMCs) can sense and respond to changes in oxygen tension, full expression of HPV requires modulating influences from the endothelium. In this review, we propose a model of HPV, based on recent studies from our laboratory, in which endothelin-1 (ET-1), a vasoactive peptide released from the endothelium, plays a central role and discuss how this model may be involved in the long-term adaptation to hypoxia.

Topics: Acute Disease; Animals; Chronic Disease; Endothelin-1; Hypoxia; Pulmonary Circulation; Vasoconstriction

Both ET(A) selective and dual, ET(A/B), receptor antagonists have favourable short- and longer-term haemodynamic actions in patients with acute and chronic heart failure. Their effect on neurohumoral measures is not yet fully determined. Two moderately large, medium-duration studies have examined the effect of dual ET(A/B) receptor antagonists on clinical status, reaching conflicting conclusions. One large scale, long-term, morbidity mortality evaluation is underway with bosentan.

Topics: Chronic Disease; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Middle Aged; Receptors, Endothelin

A role of the potent and long-acting vasoconstrictor peptide endothelin-1 and the pathophysiology of chronic human heart failure has been postulated based upon indirect evidence such as elevated plasma endothelin-1 levels and their with the degree of hemodynamic impairment. The advent of specific of endothelin-1 receptor antagonists has provided the opportunity not only to directly evaluate its pathophysiological role but also to assess its potential role as a new approach to heart failure therapy. This brief review summarizes the evidence linking endothelin-1 to the pathophysiology of chronic heart failure and the clinical results obtained in patients during acute, intravenous and more prolonged, oral administration with bosentan, a mixed ET(A)/ET(B)-receptor antagonist. Bosentan acutely and during short-term oral therapy markedly improved hemodynamics in patients in addition to standard heart failure therapy, including an ACE-inhibitor. These effects were associated with a reduced responsiveness of the renin-angiotensin system to diuretic therapy and reduced basal plasma aldosterone levels. Although the hemodynamic and neurohumoral profile of short-term bosentan therapy looks promising for the treatment of patients with chronic heart failure appropriate trials will have to be performed to document clinical benefit during long-term therapy. Finally, the question remains open whether mixed endothelin-1 receptor antagonists like bosentan will have similar effects as compared to antagonists which block the ET(A) receptor only.

Topics: Bosentan; Chronic Disease; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Receptors, Endothelin; Sulfonamides

There is now considerable evidence to support a role for the endothelin (ET) system in the pathogenesis and progression of chronic heart failure (CHF). As such, the potential exists for this system to be useful in both diagnosis (by measurement of peptide levels in plasma and other body fluids) and treatment (by pharmacological blockade) of this condition. Plasma levels of endothelin-1 (ET-1) are elevated in CHF and the magnitude of elevation correlates with disease severity. ET-1 levels in plasma predict subsequent mortality in patients with CHF. ET-1 may also contribute to symptoms associated with CHF, such as exercise intolerance. In the diagnosis of CHF, plasma levels of ET-1 appear to be a less powerful discriminator between patients with mild disease and control subjects with normal ventricular function on multivariate analyses, compared to brain natriuretic peptide (BNP), or its N-terminal fragment. ET-1 concentrations are also elevated in the saliva of patients with CHF and may represent an alternative approach to assessment of the status of the ET system in these patients. Specific ET receptor antagonists (both mixed and ET(A)-selective) have been developed. Studies with these agents in animal models of CHF have demonstrated beneficial effects via both haemodynamic and non-haemodynamic pathways. A number of short-term clinical studies have been performed demonstrating improvements in haemodynamic parameters without neurohormonal activation. Long-term clinical studies with ET receptor antagonists are currently underway to definitively test the impact of blockade of this system on mortality and major cardiovascular endpoints. Endothelin converting enzyme (ECE) inhibitors represent an alternative strategy of ET blockade, and early data from animal models suggest these agents may be of clinical utility, either alone or, more likely, in combination with other zinc metallopeptidases.

Topics: Animals; Chronic Disease; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Receptors, Endothelin

Sympatho-excitation is a hallmark of the chronic heart failure (CHF) state. It has long been assumed that this sympatho-excitation is mediated by a reduction in sensory input from cardiopulmonary and arterial baroreceptors. However, recent data suggest that these reflexes may only be important in the initiation of the sympatho-excitatory state and may not be necessary for the sustained increase in sympathetic nerve activity (SNA) in CHF. Two humoral factors that can influence SNA are nitric oxide (NO) and angiotensin II (AngII). Animals with CHF exhibit a downregulation in central gene expression for the neuronal isoform of nitric oxide synthase (nNOS). In addition, blockade of AngII receptors in combination with NO donation reduces SNA in animals with CHF, while NO donation alone has no effect on SNA. Chronic exercise training (EX) reduces both plasma AngII and SNA in rabbits with CHF while improving baroreflex function. Blockade of AT1 receptors enhances baroreflex function in non-EX CHF rabbits, but has little effect in EX CHF rabbits. These data suggest that the sympatho-excitatory state that is typical of CHF is, in part, due to changes in AngII and NO. Depressed baroreflex function and the elevated SNA can be improved by EX in animals with CHF.

Topics: Angiotensin II; Animals; Cardiac Output, Low; Chronic Disease; Endothelin-1; Nitric Oxide; Physical Conditioning, Animal; Sympathetic Nervous System

There is now considerable evidence to suggest that neurohormonal and immune mechanisms may play a central role in the pathogenesis of chronic heart failure (CHF), which is likely to have important implications for the management of this condition. It has been proposed that CHF is a state of immune activation with inflammatory cytokines contributing to both the central and the peripheral manifestations of this syndrome. The immune system is the body's natural defence mechanism against infection and other stresses, which has several different components that interact with each other in a complex manner. The main components which are thought to be relevant to the pathogenesis of CHF are: cytokines, adhesion molecules, autoantibodies, nitric oxide, and endothelin-1, and this review will concentrate on these factors. This article will also discuss the potential role of anti-cytokine therapies in the treatment of CHF.

Topics: Autoantibodies; Cardiac Output, Low; Cell Adhesion Molecules; Chronic Disease; Cytokines; Endothelin-1; Humans; Inflammation Mediators; Nitric Oxide; Oxidative Stress; Tumor Necrosis Factor-alpha

Despite conventional therapy, there is still much room for improvement in the prognosis of patients with chronic systolic heart failure. Evidence supports a role for endothelin-1 (ET-1), a potent vasoconstrictor, in the pathophysiology of heart failure. Given its potentially deleterious effects, the optimal treatment of heart failure may need to include efforts directed toward antagonizing this hormone. In support of this notion, the use of ET receptor antagonists produces a number of beneficial effects in heart failure, including both improvements in hemodynamics and reductions in the levels of other vasoconstricting neurohormones. There are at least 2 receptors for ET-1 (the ET-A and ET-B receptor), and the effects of ET-1 binding differ depending on the receptor involved. It is still unclear whether blockade of the ET-A receptor alone or the combined blockade of both the ET-A and ET-B receptors will be most efficacious as a therapeutic strategy. Long-term benefits have been achieved with the use of a mixed ET-A/B receptor antagonist, when added to standard triple-drug therapy, in patients with severe heart failure. We await the results of ongoing trials to determine if these agents will fulfill the promise of adding substantial incremental benefit to the treatment of the disease.

Topics: Bosentan; Carboxylic Acids; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Indans; Peptides, Cyclic; Prognosis; Pyridines; Pyrimidines; Receptors, Endothelin; Sulfonamides; Treatment Outcome

Pathogenic mechanisms of chronic systolic heart failure are constantly of great interest. In recent years the neurohumoral theory of heart failure has gained attraction. According to this theory, neurohumoral mechanisms play the main role in the pathogenesis of heart failure, especially in its progression. These mechanisms can be divided into 2 categories: vasoconstrictive, mitogenic and antinatriuretic on the one hand and vasodilative, antimitogenic and natriuretic on the other one. The former consists of sympathetic nervous system, renin-angiotensin-aldosterone system, vasopressin, endothelin, cytokines. The latter comprises natriuretic peptides, prostaglandins and nitric oxide. Undoubtedly unfavourable roles of sympathetic system and renin-angiotensin-aldosteron have been shown in the progression of heart failure. Data are being also gathered confirming harmful effects of endothelin and cytokines and possibly of neuropeptide Y and vasopressine. Extensive data exist that demonstrate beneficial influence of natriuretic peptide on heart failure. The roles of nitric oxide as well as recently discovered adrenomedullin and medullipin are far from clear.

Topics: Chronic Disease; Cytokines; Disease Progression; Endothelin-1; Heart Failure; Humans; Natriuretic Agents; Neuropeptide Y; Nitric Oxide; Renin-Angiotensin System; Sympathetic Nervous System; Vasopressins

Endothelin-1, discovered in 1988, is a 21-amino-acid peptide and currently the most potent vasoconstrictor and pressor substance known. Generated by vascular endothelial cells in response to a variety of chemical and mechanical signals, endothelin-1 is known to potentiate the actions of other vasoconstrictor substances and act as a comitogen in addition to directly causing vasoconstriction. There is evidence that endothelin-1 may contribute to the pathophysiology of conditions associated with sustained vasoconstriction, such as hypertension and heart failure, vasospastic conditions, such as subarachnoid hemorrhage, and atherogenesis. Studies using endothelin receptor antagonists show that endothelin-1 plays an important role in the maintenance of vascular tone and blood pressure in healthy humans, predominantly via an effect on the vascular smooth muscle ETA receptors. The endothelin receptor antagonist bosentan also effectively lowers blood pressure in hypertensive subjects and produces sustained and favorable effects on systemic and pulmonary hemodynamics in patients with chronic heart failure. A good side-effect profile, together with a potential for inhibition of atherogenesis, makes the endothelin receptor antagonists a potentially interesting class of novel agents for the treatment of cardiovascular disease.

Topics: Amino Acid Sequence; Animals; Cardiac Output, Low; Cardiovascular Physiological Phenomena; Cardiovascular System; Chronic Disease; Endothelin-1; Endothelins; Humans; Hypertension

Myocardial ischemia results in myocardial dysfunction. Recovery may be delayed ("stunning"), or persistent if perfusion remains reduced ("hibernation") and ischemia may go on to necrosis, thus, contributing to chronic heart failure. In addition, myocardium not directly affected by ischemia may undergo adaptive processes like hypertrophy and dilatation, which may result in chronic left heart failure. This process is characterized by hemodynamic, neurohumoral, and progressive morphologic changes of the heart which are closely interrelated. Hemodynamic changes basically consist of an increase in left ventricular filling pressure and a decrease in global ejection fraction, and, in most cases years after myocardial infarction, in an increase in systemic vascular resistance and right atrial pressure. Neurohumoral changes consist of an increase in plasma catecholamines, atrial natriuretic factor and vasopressin, and in an activation of the renin-angiotensin-system. Plasma endothelin-1 was recently reported to be increased in patients with heart failure, and prognosis was related to endothelin levels. Diminished response of vessels to endothelium (EDRF/NO) dependent vasodilatation suggests impairment of vascular endothelium in heart failure. Local changes of cardiac neurohumoral systems could contribute to structural changes of the heart, e.g., systemic activation to hemodynamic changes. Structural changes of the heart are characterized by an increase in volume and thickness of surviving myocardium and an expansion of ischemic and necrotic myocardium. Molecular control of these processes which include various cell types, such as cardiomyocytes and cardiofibroblasts, are currently an issue of intense research and could result in specific therapeutic importance.

Topics: Chronic Disease; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; Humans; Myocardial Ischemia; Myocardial Stunning; Myocardium; Necrosis; Nitric Oxide

The endothelins are a family of three structurally related peptides. Endothelin-1 (ET-1) is formed from the big endothelin by the action of the endothelin converting enzyme. It acts on two types of receptor, ETA and ETB. ET-1 is a powerful vasoconstrictor but also has a number of other effects: positive inotropism and stimulation of cell growth, for example. Endothelin is found in the general circulation but its role is mainly local in maintaining vascular tone. The endothelin system is activated in cardiac failure and increased concentrations of plasma endothelin increased, ET-1 converting enzyme and increased density of endothelin receptors are observed. The action of the endothelin system and its relationships with other neuro-hormonal systems activated in cardiac failure are not fully understood but research is under way which should clarify these mechanisms in the next few years. In view of the properties of endothelin, inhibition of its action might be particularly useful in patients with cardiac failure. Its action can be blocked either by preventing its synthesis by inhibiting the endothelin converting enzyme or by blocking the endothelin receptor. Endothelin receptor blockade is associated with beneficial haemodynamic changes, an action on ventricular remodelling and possibly an improved prognosis. Many substances, either selective for ETA receptors or mixed ETA and ETB receptor blockers, are under development. The benefits of these products will require confirmation by large scale clinical trials.

Topics: Cardiac Output, Low; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Glycopeptides; Humans; Metalloendopeptidases

To define the role of single or serial measurement of endothelin 1 (ET-1) for prognostication beyond traditional and modern markers of risk in heart failure (HF).. In total, 115 patients with chronic systolic HF were followed for 10 months. Clinical assessment and ET-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP), highly sensitive troponin I (hsTnI), soluble ST2 (sST2), and galectin 3 were measured at each visit.. Elevated ET-1 was associated with worse HF, lower right ventricular function, higher pulmonary pressure, and higher left atrial volume index despite similar left ventricular function. ET-1 correlated with angiotensin-converting enzyme inhibitor use. A model containing traditional risk factors, ET-1, NT-proBNP, hsTnI, and sST2 best predicted cardiovascular events, and ET-1 improved reclassification. In an adjusted time-integrated model, percent time spent with ET-1 of 5.90 pg/mL or less was predictive of fewer cardiovascular events (odds ratio, 0.75; 95% confidence interval, 0.62-0.91). ET-1 reduction over time was associated with a lower rate of cardiovascular events compared with increasing or stable ET-1 (24.4% vs 50.0%).. ET-1 may be a unique predictor of HF prognosis, complementing other biomarkers in a multimarker profile. Serial measurement of ET-1 may provide additional prognostic information.

Topics: Aged; Biomarkers; Chronic Disease; Echocardiography; Endothelin-1; Female; Heart Failure, Systolic; Humans; Immunoassay; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models

Concomitant renin-angiotensin-aldosterone system blockade and natriuretic peptide system enhancement may provide unique therapeutic benefits to patients with heart failure and reduced ejection fraction (HFrEF). This study assessed the pharmacodynamics and pharmacokinetics of LCZ696 in patients with HFrEF.. This was an open-label, noncontrolled single-sequence study. After a 24-h run-in period, patients (n = 30) with HFrEF (EF ≤ 40%; NYHA class II-IV) received LCZ696 100 mg twice daily (bid) for 7 days and 200 mg bid for 14 days, along with standard treatment for heart failure (HF) (except angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]).. On Day 21, significant increases were observed in the plasma biomarkers indicative of neprilysin and RAAS inhibition (ratio-to-baseline: cyclic guanosine monophosphate [cGMP], 1.38; renin concentration and activity, 3.50 and 2.27, respectively; all, P < 0.05). Plasma NT-proBNP levels significantly decreased at all the time points on Days 7 and 21; plasma aldosterone and endothelin-1 levels significantly decreased on Day 21 (all, P < 0.05). Following administration of LCZ696, the Cmax of sacubitril (neprilysin inhibitor prodrug), LBQ657 (active neprilysin inhibitor), and valsartan were reached within 0.5, 2.5, and 2 h. Between 100- and 200-mg doses, the Cmax and AUC0-12 h for sacubitril and LBQ657 were approximately dose-proportional while that of valsartan was less than dose-proportional.. Treatment with LCZ696 for 21 days was well tolerated and resulted in plasma biomarker changes indicative of neprilysin and RAAS inhibition in patients with HF. The pharmacokinetic exposure of the LCZ696 analytes in patients with HF observed in this study is comparable to that observed in the pivotal Phase III study.

Topics: Aged; Aldosterone; Aminobutyrates; Angiotensin Receptor Antagonists; Area Under Curve; Biomarkers; Biphenyl Compounds; Chronic Disease; Drug Administration Schedule; Drug Combinations; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neprilysin; Peptide Fragments; Renin-Angiotensin System; Russia; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan; Ventricular Function, Left

Topics: Biomarkers; Body Mass Index; Cachexia; Chronic Disease; Echocardiography; Endothelin-1; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Risk Factors; Time Factors; Troponin I; Weight Loss

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

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

A limited number of studies have demonstrated that some modulators of inflammation can be altered by the consumption of sweet cherries. We have taken a proteomics approach to determine the effects of dietary cherries on targeted gene expression. The purpose was then to determine changes caused by cherry consumption in the plasma concentrations of multiple biomarkers for several chronic inflammatory diseases in healthy humans with modestly elevated C-reactive protein (CRP; range, 1-14 mg/L; mean, 3.5 mg/L; normal, <1.0 mg/L). Eighteen men and women (45-61 y) supplemented their diets with Bing sweet cherries (280 g/d) for 28 d. Fasting blood samples were taken before the start of consuming the cherries (study d 7), 28 d after the initiation of cherry supplementation (d 35), and 28 d after the discontinuation (d 63). Of the 89 biomarkers assessed, cherry consumption for 28 d altered concentrations of 9, did not change those of 67, and the other 13 were below the detection limits. Cherry consumption decreased (P < 0.05) plasma concentrations of extracellular newly identified ligand for the receptor for advanced glycation end products (29.0%), CRP (20.1%), ferritin (20.3%), plasminogen activator inhibitor-1 (19.9%), endothelin-1 (13.7%), epidermal growth factor (13.2%), and IL-18 (8.1%) and increased that of IL-1 receptor antagonist (27.9%) compared with corresponding values on study d 7. The ferritin concentration continued to decrease between d 35 and 63 and it was significantly lower on d 63 than on d 7. Because the participants in this study were healthy, no clinical pathology end points were measured. However, results from the present study demonstrate that cherry consumption selectively reduced several biomarkers associated with inflammatory diseases.

Topics: Biomarkers; C-Reactive Protein; Chronic Disease; Diet; Dietary Supplements; Endothelin-1; Epidermal Growth Factor; Female; Ferritins; Fruit; Humans; Inflammation; Inflammation Mediators; Interleukin-18; Male; Middle Aged; Phytotherapy; Plant Preparations; Plasminogen Activator Inhibitor 1; Proteomics; Prunus; Receptors, Interleukin-1; Reference Values

Neurohormonal activation is a pathophysiological hallmark of acute and chronic heart failure (HF). The clinical significance of more recently discovered endogenous vasoactive hormones has not been well-characterized.. In 154 subjects with stable, chronic systolic HF (New York Heart Association Class I-IV, left ventricular [LV] ejection fraction or=12.1 pM (HR: 2.02, 95% CI: 1.08-3.93, P = .029) and ET-1 >or=2.29 pM (HR: 2.52, 95% CI: 1.24-5.03, P = .011) remained significant independent risk factors for adverse clinical events.. Higher levels of plasma levels of UCN-1 and ET-1 but not UT-II were associated with worse LV diastolic performance and poorer long-term clinical outcomes in patients with chronic systolic HF.

Topics: Adult; Aged; Biomarkers; Chronic Disease; Cohort Studies; Corticotropin-Releasing Hormone; Endothelin-1; Female; Heart Failure, Systolic; Humans; Male; Middle Aged; Prospective Studies; Urocortins

Mechanisms responsible for anti-ischemic benefits of enhanced external counterpulsation (EECP) remain unknown. This was the first randomized sham-controlled study to investigate the extracardiac effects of EECP on peripheral artery flow-mediated dilation.. Forty-two symptomatic patients with coronary artery disease were randomized (2:1 ratio) to thirty-five 1-hour sessions of either EECP (n=28) or sham EECP (n=14). Flow-mediated dilation of the brachial and femoral arteries was performed with the use of ultrasound. Plasma levels of nitrate and nitrite, 6-keto-prostaglandin F(1α), endothelin-1, asymmetrical dimethylarginine, tumor necrosis factor-α, monocyte chemoattractant protein-1, soluble vascular cell adhesion molecule, high-sensitivity C-reactive protein, and 8-isoprostane were measured. EECP increased brachial (+51% versus +2%) and femoral (+30% versus +3%) artery flow-mediated dilation, the nitric oxide turnover/production markers nitrate and nitrite (+36% versus +2%), and 6-keto-prostaglandin F(1α) (+71% versus +1%), whereas it decreased endothelin-1 (-25% versus +5%) and the nitric oxide synthase inhibitor asymmetrical dimethylarginine (-28% versus +0.2%) in treatment versus sham groups, respectively (all P<0.05). EECP decreased the proinflammatory cytokines tumor necrosis factor-α (-16% versus +12%), monocyte chemoattractant protein-1 (-13% versus +0.2%), soluble vascular cell adhesion molecule-1 (-6% versus +1%), high-sensitivity C-reactive protein (-32% versus +5%), and the lipid peroxidation marker 8-isoprostane (-21% versus +1.3%) in treatment versus sham groups, respectively (all P<0.05). EECP reduced angina classification (-62% versus 0%; P<0.001) in treatment versus sham groups, respectively.. Our findings provide novel mechanistic evidence that EECP has a beneficial effect on peripheral artery flow-mediated dilation and endothelial-derived vasoactive agents in patients with symptomatic coronary artery disease.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Angina Pectoris; Blood Pressure; Brachial Artery; C-Reactive Protein; Chronic Disease; Counterpulsation; Cytokines; Endothelin-1; Exercise Tolerance; Femoral Artery; Humans; Middle Aged; Nitric Oxide; Oxygen Consumption; Regional Blood Flow; Tumor Necrosis Factor-alpha; Vasodilation

Evidence suggests that urinary excretion of endothelin-1 (ET-1) reflects renal ET-1 production and is independent of systemic ET-1 activity. The influence of ET receptors on urinary ET-1 excretion has not been studied in humans, yet peritubular ETB receptors are abundant within the kidney. We have studied the effects of acute ETA and ETB receptor blockade with BQ-123 and BQ-788, respectively, on urinary ET-1 excretion in a randomized, placebo-controlled, double-blind study in 16 subjects with a wide range of GFRs (15-152 ml/min). Plasma ET-1 concentrations (pET-1) and urinary ET-1 excretion rate (uET-1) at baseline correlated inversely with GFR (R2 = 0.18 and 0.36, respectively, P < 0.01). However, changes in pET-1 after ET receptor antagonism were not related to changes in uET-1 (R2 = 0.007, P = 0.18). pET-1 increased only after BQ-788, alone or in combination with BQ-123, consistent with ETB receptor-mediated clearance of ET-1 from the circulation. uET-1 was reduced only after BQ-788 alone [-4.7 pg/min (SD 5.5), P < 0.01]. Because BQ-788 also reduced GFR, fractional excretion of ET-1 (FeET-1) was calculated. FeET-1 fell after BQ-788 alone [-41% (SD 26%), P < 0.01] or in combination with BQ-123 [-40% (SD 29%), P < 0.01]. FeET-1 was not altered by placebo or BQ-123 alone. In conclusion, urinary ET-1 excretion does not appear to relate to the pool of plasma ET-1. Because of the short duration of this study, it is unlikely that ET receptor blockade had significant effects on renal ET-1 production. Therefore, the reduction in FeET-1 after ETB blockade appears to indicate that renal excretion of ET-1 is at least partly facilitated by ETB receptor activation.

Topics: Adult; Aged; Chronic Disease; Double-Blind Method; Drug Combinations; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Oligopeptides; Osmolar Concentration; Peptides, Cyclic; Piperidines

Short-term infusion of carperitide (atrial natriuretic peptide) has beneficial effects on neurohumoral factors; however, it remains unclear whether the effects are sustained for long-term infusion. To evaluate the effects of long-term infusion of carperitide on neurohumoral factors in patients with chronic congestive heart failure (CHF), we measured neurohumoral factors before and 1 hour after stopping carperitide infusion in 42 CHF patients. Carperitide infusion was continued for more than 2 days until there was symptomatic improvement of CHF. Patients were divided into 2 groups by the median value of infusion duration: group 1 (less than 7 days, n=21) and group 2 (more than 7 days, n=21). In group 1, aldosterone (ALD) and endothelin-1 (ET-1) were significantly increased after stopping carperitide. In contrast, ALD and ET-1 did not change after stopping carperitide in group 2. The molar ratio of cyclic guanosine monophosphate/atrial natriuretic peptide before stopping carperitide was significantly lower in group 2 than in group 1. Suppression of ALD and ET-1 was maintained for 7 days of carperitide infusion, but the beneficial effect on neurohumoral factors was attenuated after more than 7 days, probably through down-regulation of biologic receptors coupled with guanylate cyclase in CHF patients.

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Dilated; Chronic Disease; Cyclic GMP; Endothelin-1; Female; Heart Failure; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Stroke Volume; Time Factors; Treatment Outcome

Angiotensin-converting enzyme (ACE) inhibitors exert their effects by modulating the neurohumoral milieu. Vasopeptidase inhibitors (VPI) are ACE and neutral endopeptidase inhibitors and may increase natriuretic peptides, bradykinin, and perhaps endothelin-1 in patients with congestive heart failure. Patients (n = 107) with ischemic or dilated cardiomyopathy, New York Heart Association functional class II to III, with left ventricular ejection fraction <40%, and on ACE inhibitor therapy were randomized to either the VPI omapatrilat 40 mg/day or the ACE inhibitor lisinopril 20 mg/day. Trough levels of neurohormones (24 hours after dosing) were assessed at baseline, and at 12 and 24 weeks of follow-up. C-terminal atrial natriuretic peptide (C-ANP) levels decreased with lisinopril (p = 0.035), but not with omapatrilat. In contrast, N-terminal ANP levels did not change, and brain natriuretic peptide (BNP) levels tended to decrease similarly in both groups. Endothelin-1 levels increased in both groups, the increase reaching statistical significance with omapatrilat (p = 0.008). Levels of the proinflammatory cytokine interleukin-6 tended to decrease, and the anti-inflammatory cytokine interleukin-10 increased in both groups, with statistical significance only for interleukin-10 with omapatrilat therapy. Neither agent changed catecholamines or angiotensin II. Thus, even at trough levels, omapatrilat potentiates C-ANP more than lisinopril. Potentially important effects of omapatrilat on endothelin-1 and anti-inflammatory cytokines were identified, providing potential explanations for differences in clinical outcome.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Cytokines; Double-Blind Method; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Humans; Lisinopril; Male; Middle Aged; Natriuretic Peptide, Brain; Neurotransmitter Agents; Predictive Value of Tests; Prospective Studies; Pyridines; Stroke Volume; Thiazepines; Treatment Outcome

Chronic heart failure (CHF) is associated with impaired endothelium-dependent vasodilation and increased basal vascular tone due, in part, to elevated endothelin-1 plasma levels. In the present study, we investigated whether a reduction of vascular tone using an endothelin A receptor blocker attenuates the impairment of endothelium-dependent, flow-mediated vasodilation (FMD).. Twenty-one patients with CHF randomly received either the endothelin A receptor blocker LU 135252 (30 mg/d, n=7; 300 mg/d, n=7) or a placebo (n=7). Using high-resolution ultrasound, FMD and endothelium-independent, nitroglycerin-induced dilation of the brachial artery were assessed at baseline in the 21 patients with CHF and in 11 controls and after 3 weeks treatment in the 21 patients with CHF. FMD at baseline was impaired in all 21 patients with CHF (3.2+/-2%) when compared with the 11 controls (9.7+/-4.9%; P=0.0005). In comparison with baseline, FMD significantly improved after 3 weeks of treatment with LU 135252 in all 14 patients receiving it (from 3.0+/-2.0% to 4.9+/-2.9%; P=0.04), but FMD remained unchanged with placebo. Subgroup analysis, according to different dosages, revealed a significant increase of FMD compared with baseline (from 2.4+/-1.5% to 5.5+/-2.4%; P=0.03) in the patients treated with the low-dose (30 mg/d), whereas a high dose of 300 mg/d failed to increase FMD significantly. Improvement in the high-dose group, however, may have been masked by reduced vasodilator capacity due to a significant increase in vessel size (from 4.8+/-0.4 to 5.1+/-0.7 mm; P=0.03).. These results suggest that endothelin A receptor blockade improves FMD in CHF patients.

Topics: Blood Flow Velocity; Brachial Artery; Chronic Disease; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Female; Heart Failure; Heart Function Tests; Humans; Linear Models; Male; Middle Aged; Nitroglycerin; Phenylpropionates; Protein Precursors; Pyrimidines; Receptor, Endothelin A; Treatment Outcome; Vasodilation

Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET(A) receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET(A) receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy.. This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index

Topics: Cardiac Output, Low; Chronic Disease; Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Female; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Pulmonary Circulation; Receptor, Endothelin A; Time Factors; Tumor Necrosis Factor-alpha; Vasodilation; Vasodilator Agents

Endothelial vascular tone modulators are thought to be involved in aetiopathogenesis of systemic sclerosis (SS) and of peripheral artery occlusive disease (PAOD). Iloprost, a prostacyclin (PGI2) analogue, induces clinical benefit in patients suffering from peripheral ischaemia. This study was performed to investigate the effect of this drug on endothelial function in vivo to elucidate the role of vascular tone modulators.. Fourteen PAOD and 15 SS patients were treated for 24 and 10 days respectively. On the first day, before and after therapy, nitric oxide metabolites (NO2-/NO3-) and endothelin-1 (ET-1) plasma concentrations were detected; moreover, the endothelium-dependent vasodilatation in response to artificial ischaemia was evaluated by means of an echo-Doppler device.. The echo-Doppler evaluation showed that the percentage of arterial reactive dilatation was not modified by placebo or by iloprost, and that the increase in blood velocity flow lasted for a significant longer time after drug infusion (226.79 +/- 17.49 vs. 310.71 +/- 36.32 s; P > 0.04). NO2-/NO3- and ET-1 plasma concentration were higher in patients than in control subjects (P < 0.004). After 6 h of iloprost infusion, no significant modifications were detected.. This study provides evidence that iloprost enhances the microvascular functional capacity and clinical benefit for patients. The effects of the drug seem to be independently or not directly correlated with its interactions with vascular tone modulators such as NO2-/NO3- or ET-1.

Topics: Adult; Aged; Arterial Occlusive Diseases; Chronic Disease; Endothelin-1; Endothelium, Vascular; Female; Humans; Iloprost; Infusions, Intravenous; Ischemia; Male; Microcirculation; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Scleroderma, Systemic; Ultrasonography; Vasodilator Agents

Topics: alpha-Cyclodextrins; Alprostadil; Arterial Occlusive Diseases; Chronic Disease; Cyclodextrins; Drug Administration Schedule; Endothelin-1; Humans; Infusions, Intra-Arterial; Leg; Peripheral Vascular Diseases

There is evidence that an activated renal endothelin (ET) system is involved in development of glomerulosclerosis. However it is still unknown if different ETs are involved in the pathogenesis of various types of glomerulonephritis (GN). This study characterized ET-1 and ET-3 levels in patients suffering from chronic GN. We performed a prospective study to evaluate the ET-1 and ET-3 levels in 19 patients with biopsy-proven GN, including four minimal-change nephropathies (MCN), six perimembraneous GN (PM-GN), and nine mesangioproliferative GN (MP-GN). Twelve healthy subjects matched for age and sex served as controls. ET-1 and ET-3 were measured in plasma (p) and in urine [spontaneous urine (sp.urine) and urine over 24 h (24-h urine)] using a specific radioimmunoassay. Patients and controls were compared using the Wilcoxon rank-sum test. In MCN, ET-1 levels were enhanced in sp. urine (p = 0.03) and 24-h urine (p = 0.01), whereas ET-3 levels did not differ from controls. In comparison, in PM-GN we found an increased ET-3 level in 24-h urine (p = 0.004). In MP-GN, ET-3 levels were also elevated in p (p = 0.0002) and urine specimens (sp. urine p = 0.05; 24-h urine p = 0.03). No positive correlation to C3 or C4 complement fractions was found. Age, blood pressure or renal function did not correlate with ET-1 or ET-3 levels. In MP-GN and PM-GN, ET-3 is elevated whereas ET-1 is not. In contrast ET-1 is increased in MC-GN. These data indicate an important role for the ET-1 and ET-3 systems in the pathophysiology of different forms of GN. This is significant with regard to an early preservation of renal function at the onset of GN by the use of selective ET antagonists.

Topics: Adult; Aged; Chronic Disease; Endothelin-1; Endothelin-3; Female; Glomerulonephritis; Humans; Male; Middle Aged; Radioimmunoassay

This study demonstrated an immediate and short-lasting endothelin-1 release in the circulation of patients with severe chronic congestive heart failure during isometric handgrip exercise, but not in normal subjects. Our data suggest that endothelin-1 levels may increase transiently during daily physical activity, thus contributing to progressive deterioration of left ventricular function.

Topics: Adult; Analysis of Variance; Chronic Disease; Endothelin-1; Exercise; Hand Strength; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Ventricular Function, Left

The importance of endothelin-1 in chronic heart failure (CHF) is unclear. We therefore investigated the effects of endothelin-converting enzyme (ECE) inhibition and endothelin ETA receptor blockade in CHF patients treated with ACE inhibitors. We also compared the function of ETA and ETB receptors in healthy subjects and patients with CHF.. Locally active doses of study drugs were infused into the nondominant brachial artery while forearm blood flow (FBF was measured by venous occlusion plethysmography. In CHF patients (n = 10), phosphoramidon (a combined ECE and neutral endopeptidase inhibitor) and BQ-123 (an ETA receptor antagonist) increased FBF by 52 +/- 10% (P = .0006) and 31 +/- 6% (P = .002), respectively, and thiorphan (a selective neutral endopeptidase inhibitor) reduced FBF by 15 +/- 5% (P = .0007). Forearm vasoconstriction to endothelin-1 (an ETA and ETB receptor agonist) was significantly blunted in CHF patients compared with control subjects (both n = 10; CHF versus control subjects, P < .001), whereas vasoconstriction to sarafotoxin S6c (an ETB receptor agonist) was significantly enhanced in CHF patients compared with control subjects (both n = 10; CHF versus control subjects. P < .05).. ECE inhibitors and ETA receptor antagonists may be useful as vasodilator agents in CHF patients already receiving treatment with an ACE inhibitor. Both ETA and ETB receptors can mediate agonist-induced vasoconstriction in healthy subjects and patients with CHF, but further studies are required to clarify the contribution of each receptor subtype in mediating the effects of endogenous endothelin-1.

Topics: Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Aspartic Acid Endopeptidases; Brachial Artery; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Female; Glycopeptides; Heart Failure; Humans; Male; Metalloendopeptidases; Middle Aged; Neprilysin; Peptides, Cyclic; Protease Inhibitors; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Regional Blood Flow; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Viper Venoms

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

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

Topics: Anti-Allergic Agents; C-Reactive Protein; Chronic Disease; Chronic Urticaria; Endothelin-1; Histamine Antagonists; Histamine H1 Antagonists; Humans; Inflammation; Interleukin-33; Omalizumab; Urticaria

To investigate the changes in serum levels of endothelin-1 (ET-1) and connective tissue growth factor (CTGF) in patients with atrial fibrillation (AF) and their value for predicting recurrence of AF after radiofrequency ablation (RFCA).. Sixty-six patients with paroxysmal AF (PaAF) and 72 with persistent AF (PaAF) admitted in our hospital were recruited as AF group and 80 patients with sinus rhythm as the control group, and in all the participants, serum levels of ET-1 and CTGF were measured using ELISA and Western blotting. From 6 patients with AF and 6 with sinus rhythm undergoing cardiac surgery in our hospital, tissue samples of the right atrial appendage were taken intraoperatively for observation of structural changes of the cardiomyocytes, myocardial fibrosis and expression of ET-1 and CTGF protein. In AF group, the patients receiving RFCA were followed up for 6 months following the procedure for assessment of the outcomes.. Compared with the control patients, the patients with AF showed obvious damages of the cardiomyocyte structure and myocardial fibrosis. Serum levels of ET-1 and CTGF levels were significantly higher in PaAF and PeAF groups than in the control group, and were higher in PeAF group than in PaAF group. In the patients with AF, serum ET-1 and CTGF levels were positively correlated with left atrial diameter (LAD) (. Serum levels of ET-1 and CTGF are significantly elevated in AF patients in positive correlation with AF duration. ET-1 and CTGF levels are higher in AF patients with postoperative recurrence, and they both have predictive value for recurrence of PeAF following RFCA.

Topics: Atrial Appendage; Atrial Fibrillation; Chronic Disease; Connective Tissue Growth Factor; Endothelin-1; Fibrosis; Humans

The roles of vascular dysfunction and chronic stress have been extensively discussed in the pathophysiology of glaucoma. Our aim was to test whether chronic stress causes retinal vascular dysfunction and therewith induces retinal ganglion cells (RGCs) loss.. Twelve mice underwent chronic social defeat (CSD) stress, while 12 mice received control treatment only. Intraocular pressure (IOP) was measured with a rebound tonometer. Blood plasma corticosterone concentration and adrenal gland weight were used to assess stress levels. Brn-3a staining in retinas and PPD staining in optic nerve cross sections were conducted to assess the survival of RGCs and axons respectively. The ET-1 and α-SMA levels were determined in retina. Retinal vascular autoregulation, functional response to various vasoactive agents and vascular mechanics were measured using video microscopy.. No significant difference in IOP levels was observed during and after CSD between CSD mice and controls. CSD stress caused hypercortisolemia 2 days post-CSD. However, increased corticosterone levels went back to normal 8 months after CSD. CSD-exposed mice developed adrenal hyperplasia 3 days post-CSD, which was normalized by 8 months. RGC and axon survival were similar between CSD mice and controls. However, CSD stress caused irreversible, impaired autoregulation and vascular dysfunction of retinal arterioles in CSD mice. In addition, impaired maximal dilator capacity of retinal arterioles was observed 8 months post-CSD rather than 3 days post-CSD. Remarkably, ET-1 levels were increased 3 days post-CSD while α-SMA levels were decreased 8 months post-CSD.. We found that CSD stress does not cause IOP elevation, nor loss of RGCs and their axons. However, it strikingly causes irreversible impaired autoregulation and endothelial function in murine retinal arterioles. In addition, CSD changed vascular mechanics on a long-term basis. Increased ET-1 levels and loss of pericytes in retina vessels may involve in this process.

Topics: Actins; Adrenal Hyperplasia, Congenital; Animals; Cell Survival; Chronic Disease; Corticosterone; Disease Models, Animal; Disorder of Sex Development, 46,XY; Endothelin-1; Intraocular Pressure; Male; Mice; Mice, Inbred C57BL; Ocular Hypertension; Optic Nerve; Retinal Artery; Retinal Diseases; Retinal Ganglion Cells; Social Defeat; Stress, Psychological; Tonometry, Ocular; Transcription Factor Brn-3A; Video Recording

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

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

To investigate the effects of ET-1 and TNF-α levels on cardiac function and prognosis in rats with chronic heart failure (CHF), to provide reference for clinical practice.. 120 SD rats were randomly divided into healthy group (n=60) and heart failure group (n=60). Rats from heart failure group were made into CHF models by an intraperitoneal injection of adriamycin. According to the average serum levels of ET-1 and TNF-α, 30 rats with higher level were enrolled in high expression subgroup, while 30 rats with lower level were enrolled in low expression subgroup. The sandwich enzyme-linked immunosorbent assay (ELISA) was employed to determine the ET-1 and TNF-α in rats from healthy group and heart failure group. Doppler echocardiography was used to measure the left ventricular ejection fraction, heart rate, and aortic diameter. After the death of heart failure rats, the total heart mass and left ventricle mass were measured and compared with those of the healthy rats. The serum levels of ET-1 and TNF-α were monitored to explore the influence of ET-1 and TNF-α levels on the prognosis of rats from study group.. The total heart mass and left ventricle mass of the heart failure group were higher than those of healthy group (p<0.05). The total heart mass and left ventricle mass of the low expression subgroup were lower than those of high expression subgroup (p<0.05).. The serum levels of ET-1 and TNF-α are higher than those in healthy rats. CHF rats with higher serum levels of ET-1 and TNF-α have a worse heart function and survival. Serum levels of ET-1 and TNF-α can be used as predictors of cardiac function and prognosis in CHF rats, providing references for clinical practice.

Topics: Animals; Chronic Disease; Endothelin-1; Female; Heart Failure; Male; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Topics: Animals; Cells, Cultured; Chronic Disease; Cytokines; Endothelin-1; Humans; Interleukin-6; Keratinocytes; Mice; Poly I-C; Pruritus; Skin; Thymic Stromal Lymphopoietin; Toll-Like Receptor 3; Up-Regulation

Chronic inflammation, as a consequence of the persistent infection with Trypanosoma cruzi, leads to continuous activation of the immune system in patients with chronic Chagas disease. We have previously shown that increased sera levels of soluble P-selectin are associated with the severity of the cardiomyopathy distinctive of chronic Chagas disease. In this study, we explored the expression of biomarkers of platelet and endothelial activation, tissue remodeling, and mediators of the coagulation cascade in patients at different clinical stages of chronic Chagas heart disease. The frequencies of activated platelets, measured by the expression of CD41a and CD62P were decreased in patients with chronic Chagas disease compared with those in uninfected subjects, with an inverse association with disease severity. Platelet activation in response to adenosine diphosphate was also decreased in T. cruzi-infected subjects. A major proportion of T. cruzi infected subjects showed increased serum levels of fibrinogen. Patients with severe cardiac dysfunction showed increased levels of endothelin-1 and normal values of procollagen I. In conclusion, chronic infection with T. cruzi induced hemostatic alterations, even in those patients who do not yet present cardiac symptoms.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Platelets; Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Endothelin-1; Female; Fibrinogen; Humans; Inflammation; Male; Middle Aged; P-Selectin; Procollagen; Trypanosoma cruzi; Young Adult

Secondary mitral regurgitation (sMR) drives adverse cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF). Progression in severity over time contributes to a transition towards more advanced HF stages. Early identification of patients at risk for sMR progression remains challenging. We therefore sought to assess a broad spectrum of neurohumoral biomarkers in patients with HFrEF to explore their ability to predict progression of sMR.. A total of 249 HFrEF patients were enrolled. Biomarkers encompassing key neurohumoral pathways in heart failure were sampled at baseline, and sMR progression was assessed over 3 years of follow-up.. Of 191 patients with nonsevere sMR at baseline, 18% showed progressive sMR within three years after study enrolment. Progression of sMR was associated with higher levels of MR-proADM (adj.OR 2.25, 95% CI 1.29-3.93; P = .004), MR-proANP (adj.OR 1.84, 95% CI 1.14-3.00; P = .012), copeptin (adj.OR 1.66, 95% CI 1.04-2.67; P = .035) and CT-pro-ET1 (adj.OR 1.68, 95% CI 1.06-2.68; P = .027) but not with NT-proBNP (P = .54).. Increased plasma levels of neurohumoral cardiac biomarkers are predictors of sMR progression in patients with HFrEF and add easily available incremental prognostic information for risk stratification. Importantly, NT-proBNP was not useful to predict progressive sMR in the present analysis. On the contrary, MR-proANP, primarily produced in the atria, copeptin partly triggered by intra-cardiac and intra-arterial pressures and MR-proADM, a marker of forward failure and peripheral released vasoactive CT-proET1, increase based on a progressive loading burden by sMR and may thus serve as better predictors of sMR progression.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Disease Progression; Echocardiography; Endothelin-1; Female; Glycopeptides; Heart Failure, Systolic; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Natriuretic Peptide, Brain; Peptide Fragments; Phenotype; Prognosis; Protein Precursors; Risk Assessment; Stroke Volume

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

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

Obstructive sleep apnea recently has been associated with a higher frequency of ischemic optic neuropathies. Intermittent hypoxia (IH) has been proposed as a major component of obstructive sleep apnea cardiovascular consequences. However, there currently are no pathophysiologic data regarding the effect of IH on the ocular vascular system. Thus, we assessed the impact of chronic IH exposure on the morphology and vascular reactivity of the rat ophthalmic artery (OA).. Rats were exposed to 14 days of IH or normoxia (NX). Ophthalmic artery reactivity was studied using wire myography in rats treated or not with tempol (1 mM/day). Expression of endothelin-1 (ET-1) and its receptors, and of the three nitric oxide synthase (NOS) isoform genes was quantified using quantitative polymerase chain reaction (qPCR) in the retina and optic nerve. Structural alterations (optical and electron microscopy) and superoxide anion production were studied in OA sections.. Superoxide ion expression in the OA wall was increased by 23% after IH exposure. Ophthalmic artery contractile response to 3.10-8 M ET-1 was increased by 18.6% and nitric oxide-mediated relaxation was significantly delayed in IH compared to NX rats. In the absence of nitric oxide, cytochrome P450 blockade increased relaxation to acetylcholine in IH rats and delayed it in NX rats. Tempol treatment abolished the IH-induced changes in OA reactivity.. These results strongly suggest that chronic IH induces oxidative stress in the rat OA, associated with endothelial dysfunction through alterations of nitric oxide and endothelium-derived hyperpolarising factors (EDHF) pathways.

Topics: Animals; Chronic Disease; Cyclic N-Oxides; Endothelin-1; Hypoxia; Male; Muscle, Smooth, Vascular; Myography; Nitric Oxide Synthase; Ophthalmic Artery; Oxidative Stress; Protein Synthesis Inhibitors; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptor, Endothelin A; RNA, Messenger; Spin Labels; Superoxides

Tanshinone IIA (Tan IIA) may exert significant protective effects against heart oxidative stress damage in obstructive sleep apnoea (OSA) syndrome. Chronic intermittent hypoxia (CIH)-triggered left ventricular dysfunction is used in a rat model to mimic CIH in OSA patients. 48 rats were randomly divided into three groups: normal control (NC) group, CIH group and CIH+Tan IIA group with 16 rats in each group. At the end of experiment (day 21), the blood pressure, Plasma ET-1 and NO content, hemodynamic indexes, heart histology, myocardial apoptosis as well as the expression of eNOS, ET-1, ET

Topics: Abietanes; Animals; Apoptosis; Blood Pressure; Cardiotonic Agents; Chronic Disease; Electrocardiography; Endothelin-1; Heart Function Tests; Hemodynamics; Hypoxia; Male; Myocardium; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase Type III; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Signal Transduction; Systole

Topics: Aged; Chronic Disease; Complementary Therapies; Endothelin-1; Forests; Heart Failure; Humans; Treatment Outcome

The activation of hepatic stellate cells (HSCs) is a key event in fibrotic pathogenesis. However, the mechanism involving activation of HSCs in chronic schistosomiasis is not entirely clear. Human HSC LX-2 and human umbilical vein endothelial cells (ECs) were cultured with Schistosoma japonicum antigens (SA) in vitro. Fibrosis-associated genes and cell proliferation were analyzed. HSCs were isolated from mice of chronic schistosomiasis with or without praziquantel (PZQ) treatment, followed by the microarray analysis for the liver fibrosis-associated pathways. Although SA inhibited the activation and proliferation of HSCs, it induced the EC proliferation and vascular endothelial growth factor-a (VEGF) production. VEGF significantly increased the proliferation of HSCs and upregulated the expression of collagen and α-smooth muscle actin. For in vivo study, we found that several fibrosis-associated pathways were involved in the HSCs during the reversal of liver fibrosis caused by schistosomiasis, including VEGF, platelet-derived growth factor, tumor necrosis factor and endothelin-1 pathways. The Ingenuity Pathway Analysis showed that VEGF directly regulated several pro-fibrotic and immune cytokine genes in HSCs, including integrin, fibronectin, interferon-γ, interleukin (IL)-6 and IL-10. Our data indicated the critical role of VEGF signaling in HSC activation in chronic schistosomiasis and highlighted several promising genes and pathways in HSCs as potential targets for therapeutic treatment of liver fibrosis.

Topics: Actins; Animals; Antigens, Helminth; Cell Proliferation; Chronic Disease; Collagen; Cytokines; Endothelin-1; Endothelium, Vascular; Female; Fibrosis; Hepatic Stellate Cells; Human Umbilical Vein Endothelial Cells; Humans; Liver; Mice; Mice, Inbred BALB C; Schistosoma japonicum; Schistosomiasis japonica; Transcriptome; Vascular Endothelial Growth Factor A

Recovery of hand function following lesions in the primary motor cortex (M1) is associated with a reorganization of premotor areas in the ipsilesional hemisphere, and this reorganization depends on the size of the lesion. It is not clear how lesion size affects motor representations in the contralesional hemisphere and how the effects in the 2 hemispheres compare. Our goal was to study how lesion size affects motor representations in the ipsilesional and contralesional hemispheres. In rats, we induced lesions of different sizes in the caudal forelimb area (CFA), the equivalent of M1. The effective lesion volume in each animal was quantified histologically. Behavioral recovery was evaluated with the Montoya Staircase task for 28 days after the lesion. Then, the organization of the CFA and the rostral forelimb area (RFA)--the putative premotor area in rats--in the 2 cerebral hemispheres was studied with intracortical microstimulation mapping techniques. The distal forelimb representation in the RFA of both the ipsilesional and contralesional hemispheres was positively correlated with the size of the lesion. In contrast, lesion size had no effect on the contralesional CFA, and there was no relationship between movement representations in the 2 hemispheres. Finally, only the contralesional RFA was negatively correlated with chronic motor deficits of the paretic forelimb. Our data show that lesion size has comparable effects on motor representations in premotor areas of both hemispheres and suggest that the contralesional premotor cortex may play a greater role in the recovery of the paretic forelimb following large lesions.

Topics: Animals; Brain Ischemia; Brain Mapping; Chronic Disease; Disease Models, Animal; Endothelin-1; Forelimb; Functional Laterality; Motor Activity; Motor Cortex; Movement Disorders; Neural Pathways; Neuronal Plasticity; Random Allocation; Rats; Rats, Sprague-Dawley; Recovery of Function

Chronic canine hypothyroidism is associated with blood-brain barrier (BBB) disruption. We hypothesized that this change is mediated by endothelin-1(ET-1) and matrix metalloproteinases (MMP) -2, -9, and -14, as evidenced by increased concentrations of these proteins in cerebrospinal fluid (CSF) compared to controls. CSF from 18 dogs, 9 controls and 9 with experimentally induced hypothyroidism was collected before and 6, 12, and 18 months after induction of hypothyroidism. Concentrations of ET-1 using an ELISA kit, and for MMP-2, -9, and -14 using gelatinase zymography were measured in CSF. ET-1 was undetectable in CSF of control and hypothyroid dogs at all time-points. Constitutively expressed MMP-2 was detectable in CSF samples in all dogs at all time-points. No other MMPs were detectable in CSF. No differences in CSF concentrations of ET-1 and MMP-2, 9, and 14 were found between hypothyroid and euthyroid dogs. Therefore, ET-1 and MMP-2, 9, and 14 are unlikely to be primary mediators of BBB damage in chronically hypothyroid dogs.

Topics: Animals; Blood-Brain Barrier; Chronic Disease; Dog Diseases; Dogs; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Hypothyroidism; Metalloendopeptidases

Topics: Acute Disease; Altitude Sickness; Chronic Disease; Endothelin-1; Humans; Mountaineering

Topics: Adult; Antiphospholipid Syndrome; Arginine; Chronic Disease; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Prognosis; Thrombosis; Young Adult

Stroke is the third leading cause of death and permanent disability in the United States, often producing long-term cognitive impairments, which are not easily recapitulated in animal models. The goals of this study were to assess whether: (1) the endothelin-1 (ET-1) model of chronic stroke produced discernable cognitive deficits; (2) a spatial operant reversal task (SORT) would accurately measure memory deficits in this model; and (3) bone-marrow-derived mesenchymal stem cells (BMMSCs) could reduce any observed deficits.. Rats were given unilateral intracerebral injections of vehicle or ET-1, a stroke-inducing agent, near the middle cerebral artery. Seven days later, they were given intrastriatal injections of BMMSCs or vehicle, near the ischemic penumbra. The cognitive abilities of the rats were assessed on a novel SORT, which was designed to efficiently distinguish cognitive deficits from potential motoric confounds.. Rats given ET-1 had significantly more cognitive errors at six weeks post-stroke on the SORT, and that these deficits were attenuated by BMMSC transplants.. These findings indicate that: (1) the ET-1 model produces chronic cognitive deficits; (2) the SORT efficiently measures cognitive deficits that are not confounded by motoric impairment; and (3) BMMSCs may be a viable treatment for stroke-induced cognitive dysfunction.

Topics: Animals; Body Weight; Brain; Chronic Disease; Cognition Disorders; Conditioning, Operant; Disease Models, Animal; Endothelin-1; Female; Male; Mesenchymal Stem Cell Transplantation; Psychological Tests; Rats, Sprague-Dawley; Stroke; Treatment Outcome

Endothelin-1 (ET-1) increases pulmonary vascular tone through direct effects on pulmonary artery smooth muscle cells (PASMC) via membrane-bound ET-1 receptors. Circulating ET-1 contributes to vascular remodeling by promoting SMC proliferation and migration and inhibiting SMC apoptosis. Although endothelial cells (EC) are the primary source of ET-1, whether ET-1 produced by SMC modulates pulmonary vascular tone is unknown. Using transgenic mice created by crossbreeding SM22α-Cre mice with ET-1(flox/flox) mice to selectively delete ET-1 in SMC, we tested the hypothesis that PASMC ET-1 gene expression modulates the pulmonary vascular response to hypoxia. ET-1 gene deletion and selective activity of SM22α promoter-driven Cre recombinase were confirmed. Functional assays were performed under normoxic (21% O2) or hypoxic (5% O2) conditions using murine PASMC obtained from ET-1(+/+) and ET-1(-/-) mic and in human PASMC (hPASMC) after silencing of ET-1 using siRNA. Under baseline conditions, there was no difference in right ventricular systolic pressure (RVSP) between SM22α-ET-1(-/-) and SM22α-ET-1(+/+) (control) littermates. After exposure to hypoxia (10% O2, 21-24 days), RVSP was and vascular remodeling were less in SM22α-ET-1(-/-) mice compared with control littermates (P < 0.01). Loss of ET-1 decreased PASMC proliferation and migration and increased apoptosis under normoxic and hypoxic conditions. Exposure to selective ET-1 receptor antagonists had no effect on either the hypoxia-induced hPASMC proliferative or migratory response. SMC-specific ET-1 deletion attenuates hypoxia-induced increases in pulmonary vascular tone and structural remodeling. The observation that loss of ET-1 inhibited SMC proliferation, survival, and migration represents evidence that ET-1 derived from SMC plays a previously undescribed role in modulating the response of the pulmonary circulation to hypoxia. Thus PASMC ET-1 may modulate vascular tone independently of ET-1 produced by EC.

Topics: Animals; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Chronic Disease; Endothelial Cells; Endothelin-1; Gene Expression Regulation; Gene Silencing; Humans; Hypoxia; Mice; Mice, Knockout; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulmonary Artery; Vascular Remodeling

Cognitive impairments are prevalent following clinical stroke; however, preclinical research has focused almost exclusively on motor deficits. In order to conduct systematic evaluations into the nature of post-stroke cognitive dysfunction and recovery, it is crucial to develop focal stroke models that predominantly affect cognition while leaving motor function intact. Herein, we evaluated a range of cognitive functions 1-4 months following focal medial prefrontal cortex (mPFC) stroke using a battery of tests. Male Sprague-Dawley rats underwent focal ischemia induced in the mPFC using bilateral intracerebral injections of endothelin-1, or sham surgery. Cognitive function was assessed using an open field, several object recognition tests, attentional set-shifting, light-dark box, spontaneous alternation, Barnes maze, and win-shift/win-stay tests. Prefrontal cortex damage resulted in significant changes in object recognition function, behavioural flexibility, and anxiety-like behaviour, while spontaneous alternation and locomotor function remained intact. These deficits are similar to the cognitive deficits following stroke in humans. Our results suggest that this model may be useful for identifying and developing potential therapies for improving post-stroke cognitive dysfunction.

Topics: Animals; Chronic Disease; Cognition; Cognition Disorders; Disease Models, Animal; Endothelin-1; Male; Motor Activity; Neuropsychological Tests; Prefrontal Cortex; Rats, Sprague-Dawley; Severity of Illness Index; Stroke

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

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

In the present study, we used chronic gavage administration of alcohol with gradual increases in alcohol concentration and volume to generate a rat model of chronic alcohol intoxication. We measured the changes in biological, behavioral, pathological and vascular injury-related molecular biological markers, and explored the effects of nimodipine intervention on alcohol intoxication. We found that chronic alcohol consumption induced a variety of behavioral abnormalities, accompanied by severe pathological changes in cerebral arterioles, prefrontal cortex and cerebellar tissue, as well as an upregulation of vascular endothelial growth factor (VEGF), leptin receptor (ob-R) and endothelin-1 (ET-1). Treatment with mimodipine for 15 days significantly improved behavioral abnormalities, alleviated the pathological changes in blood vessels and brain tissues, increased VEGF expression, decreased ob-R expression, reduced plasma ET-1 leakage and protected vascular and neuronal functions.

Topics: Alcohol Amnestic Disorder; Alcohol Drinking; Animals; Arterioles; Cerebellum; Cerebral Arteries; Chronic Disease; Down-Regulation; Endothelin-1; Male; Nimodipine; Prefrontal Cortex; Protective Agents; Rats; Rats, Wistar; Receptors, Leptin; Up-Regulation; Vascular Endothelial Growth Factor A

There is a growing body of evidence suggesting that epigallocatechin gallate (EGCG), a major catechin isolated from green tea, has several beneficial effects, such as anti-oxidant and anti-inflammatory activities. However, whether treatment with EGCG can suppress the endothelin-1 (ET-1)-induced contraction in carotid arteries from type 2 diabetic rats is unknown, especially at the chronic stage of the disease. We hypothesized that long-term treatment with EGCG would attenuate ET-1-induced contractions in type 2 diabetic arteries.. Otsuka Long-Evans Tokushima fatty (OLETF) rats (43 weeks old) were treated with EGCG (200 mg/kg/day for 2 months, p.o.), and the responsiveness to ET-1, phenylephrine (PE), acetylcholine (ACh) and sodium nitroprusside (SNP) was measured in common carotid artery (CA) from EGCG-treated and -untreated OLETF rats and control Long-Evans Tokushima Otsuka (LETO) rats.. In OLETF rats, EGCG attenuated responsiveness to ET-1 in CA compared to untreated groups. However, EGCG did not alter PE-induced contractions in CA from OLETF rats. In endothelium-denuded arteries, EGCG did not affect ET-1-induced contractions in either the OLETF or LETO group. Acetylcholine-induced relaxation was increased by EGCG treatment in CA from the OLETF group. The expressions of ET receptors, endothelial nitric oxide synthase, superoxide dismutases, and gp91(phox) [an NAD(P)H oxidase component] in CA were not altered by EGCG treatment in either group.. Our data suggest that, within the timescale investigated here, EGCG attenuates ET-1-induced contractions in CA from type 2 diabetic rats, and one of the mechanisms may involve normalizing endothelial function.

Topics: Acetylcholine; Animals; Carotid Arteries; Catechin; Chronic Disease; Diabetes Mellitus, Experimental; Endothelin-1; In Vitro Techniques; Male; NADPH Oxidases; Nitric Oxide Synthase Type III; Nitroprusside; Phenylephrine; Rats, Inbred OLETF; Receptors, Endothelin; Superoxide Dismutase; Vasoconstriction; Vasodilation

Chronic glomerulonephritis (CGN) is one of the most severe kidney diseases. Genes of vascular reactivity are thought to play an important role in development and progression of CGN. In this study, we analyzed association of genes of vascular homeostasis with hypertension and renal survival of CGN patients. The study sample included 238 patients with CGN and 304 healthy subjects of population control. Ten polymorphisms of ten genes of vascular homeostasis were genotyped through polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) analysis and TaqMan assays. Association of the genotypes with renal survival was analyzed by the Kaplan-Meier estimator. Genotypes 311SC and 311SS of the PON2 gene, (-1166)AC and (-1166)CC of the AGTR1 gene, (+46)AA of the ADRB2 gene, and 198KK and 198KN of the EDN1 gene were associated with decreased rate of renal survival of the patients. Polymorphisms S311C PON2, (-1166)A/C AGTR1, (+46)G/A ADRB2, and K198N EDN1 were associated with the accelerated decline in kidney function in the CGN patients.

Topics: Adult; Aryldialkylphosphatase; Case-Control Studies; Chronic Disease; Endothelin-1; Female; Glomerulonephritis; Homeostasis; Humans; Hypertension; Kidney; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Receptor, Angiotensin, Type 1; Receptors, Adrenergic, beta-2; Survival Rate

Rehabilitation is the only treatment option for chronic stroke deficits, but unfortunately, it often provides incomplete recovery. In this study, a novel combination of growth factor administration and rehabilitation therapy was used to facilitate functional recovery in a rat model of cortical stroke.. Ischemia was induced via injection of endothelin-1 into the sensorimotor cortex. This was followed by either a 2-week infusion of epidermal growth factor and erythropoietin or artificial cerebrospinal fluid into the ipsilateral lateral ventricle. Two weeks after ischemia, animals began an 8-week enriched rehabilitation program. Functional recovery was assessed after ischemia using the Montoya staircase-reaching task, beam-traversing, and cylinder test of forelimb asymmetry.. The combination of growth factor infusion and rehabilitation led to a significant acceleration in recovery in the staircase task. When compared with controls, animals receiving the combination treatment attained significant recovery of function at 4 weeks after stroke, whereas those receiving rehabilitation alone did not recover until 10 weeks. Significant recovery was also observed on the beam-traversing and cylinder tasks.. Combining behavioral rehabilitation with growth factor infusion accelerates motor recovery. These data suggest a promising new avenue of combination therapies that may have the potential to reduce the rehabilitation time necessary to recover from sensorimotor deficits arising from stroke.

Topics: Animals; Chronic Disease; Disease Models, Animal; Endothelin-1; Epidermal Growth Factor; Erythropoietin; Male; Motor Activity; Rats; Rats, Sprague-Dawley; Stroke; Stroke Rehabilitation

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

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

The paper presents data on the frequency of polymorphisms of candidate genes involved in the formation of endothelial dysfunction--endothelin-1 (EDN1 Lys198Asn) and endothelial nitric oxide synthase (NOS3 T786C) together with the concentrations of their active products (nitric oxide, endothelin-1) in individuals with chronic mercury intoxication. The concentration change of nitric oxide and endothelin-1 indicates the presence of endothelial dysfunction in the individuals examined. The studied polymorphisms appeared to play a minor role in the pathogenesis of endothelial dysfunction in patients with chronic mercury intoxication.

Topics: Biomarkers; Chronic Disease; Endothelin-1; Endothelium; Genotype; Humans; Male; Mercury Poisoning; Middle Aged; Nitric Oxide; Nitric Oxide Synthase Type III; Occupational Diseases; Occupational Exposure; Phenotype; Polymorphism, Genetic

Poor angiogenesis and impaired proliferation of cells responsible for the repair of chronic ischemic wounds result in impaired wound healing. The continuous and efficient expression of therapeutic factors by means of gene transfection is an ideal adjuvant treatment method to promote cell proliferation and angiogenesis.. A chimeric recombinant adenoviral vector, Ad5F35ET1-bFGF, was constructed that carried the basic fibroblast growth factor (bFGF) gene and used the endothelin-1 promoter to control the targeted expression of bFGF in endothelial cells and fibroblasts. Thus, the authors established a targeted gene therapy for chronic ischemic wounds.. The chimeric adenovirus Ad5F35ET1-bFGF efficiently infected the endothelin-1-positive endothelial cells and fibroblasts, specifically expressed bFGF, and promoted cell proliferation. In the rabbit wound healing model, the chimeric recombinant adenovirus expressed a high level of bFGF in wound tissues, which continuously promoted angiogenesis and cell proliferation and thus accelerated wound healing.. Targeted gene therapy that uses bFGF as a therapeutic gene provides an effective candidate strategy for the treatment of chronic ischemic wounds.

Topics: Adenoviridae; Animals; Cell Line; Cell Proliferation; Chronic Disease; Ear; Endothelin-1; Female; Fibroblast Growth Factor 2; Genetic Therapy; Genetic Vectors; Humans; Ischemia; Male; Neovascularization, Physiologic; Rabbits; Random Allocation; Recombinant Fusion Proteins; Transfection; Treatment Outcome; Wound Healing

To elucidate predictors of unfavorable cardiac events in patients with non-ischemic cardiomyopathy (CMP) complicated by congestive heart failure (CHF) with preserved myocardial coronary reserve (MCR).. We followed 114 patients with non-ischemic MCP and NYHA class III-IV CHF. MCR was estimated by dobutamine stress-echocardiography (SEchoCG). Prior to SEchoCG we measured blood von Willebrand factor (vWF) activity, content of endothelin-1 (ET), N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP), soluble vascular cell adhesion molecule-1 (sVCAM-1) and nitric oxide stable metabolites. At peak of dobutamine test blood was collected for measurement of ET, vWF, and NT-proBNP concentrations. Left ventricular ejection fraction (LVEF)sechoCG, ETsechoCG, vWFsechoCG and NT-proBNPsechoCG were calculated as percentage changes of these parameters from baseline at peak dobutamine load.. Groups with low and preserved MCR were not different by relative number of patients with unfavorable course of the disease (41.2 and 34.8%, p = 0.529, respectively). The following parameters were predictors of development of unfavorable cardiac events in patients with preserved MCR (LVEFsechoCG > 10%) during 24 months: initial hsCRP > 5.2 mg/ml, LVEFsechoCG < 19.7% and ETsechoCG > 11.8%. Logistic regression model combined with binary values of LVEFsechoCG and ETsechoCG demonstrated best prognostic efficacy (sensitivity--86.7%, specificity--83.3%, prognostic accuracy--84.6%).

Topics: Adult; C-Reactive Protein; Chronic Disease; Disease Progression; Echocardiography, Stress; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Sensitivity and Specificity; Severity of Illness Index; Vascular Cell Adhesion Molecule-1; Ventricular Function, Left; von Willebrand Factor

Hypertension is the most prevalent life-threatening disease worldwide and is frequently associated with chronic kidney disease (CKD). However, the molecular basis underlying hypertensive CKD is not fully understood.. We sought to identify specific factors and signaling pathways that contribute to hypertensive CKD and thereby exacerbate disease progression.. Using high-throughput quantitative reverse-transcription polymerase chain reaction profiling, we discovered that the expression level of 5'-ectonucleotidase (CD73), a key enzyme that produces extracellular adenosine, was significantly increased in the kidneys of angiotensin II-infused mice, an animal model of hypertensive nephropathy. Genetic and pharmacological studies in mice revealed that elevated CD73-mediated excess renal adenosine preferentially induced A2B adenosine receptor (ADORA2B) production and that enhanced kidney ADORA2B signaling contributes to angiotensin II-induced hypertension. Similarly, in humans, we found that CD73 and ADORA2B levels were significantly elevated in the kidneys of CKD patients compared with normal individuals and were further elevated in hypertensive CKD patients. These findings led us to further discover that elevated renal CD73 contributes to excess adenosine signaling via ADORA2B activation that directly stimulates endothelin-1 production in a hypoxia-inducible factor-α-dependent manner and underlies the pathogenesis of the disease. Finally, we revealed that hypoxia-inducible factor-α is an important factor responsible for angiotensin II-induced CD73 and ADORA2B expression at the transcriptional level.. Overall, our studies reveal that angiotensin II-induced renal CD73 promotes the production of renal adenosine that is a prominent driver of hypertensive CKD by enhanced ADORA2B signaling-mediated endothelin-1 induction in a hypoxia-inducible factor-α-dependent manner. The inhibition of excess adenosine-mediated ADORA2B signaling represents a novel therapeutic target for the disease.

Topics: 5'-Nucleotidase; Adenosine; Adult; Angiotensin II; Animals; Cells, Cultured; Chronic Disease; Endothelial Cells; Endothelin-1; Female; Gene Expression; GPI-Linked Proteins; Humans; Hypertension, Renal; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Receptor, Adenosine A2B; Signal Transduction; Vasoconstrictor Agents

The study included 60 patients with chronic Halicobacter gastritis (30 with chronic non-atrophic and 30 with atrophic Halicobacter gastritis (CNAHG and CAHG)). The control group was comprised of 15 practically healthy subjects. The aim of the work was to elucidate the role of Helicobacter infection, disturbances of regeneration, endothelin-1 and melatonin-secreting neuroendocrine cells of gastric antrum in progression of chronic Helicobacter gastritis (CHG). It was shown that CHG is due to H. pylori persistence and that patients with CNAHG undergo grade III microbial contamination while in CAHG patients atrophic changes are accompanied by metaplasia of gastric mucosa (GM) and inflammation of different severity. Patients with CNAHG has an increased number of melatonin-positive gastric cells and enhanced apoptotic activity of GM epitheliocytes. Patients with CAHG experience a reduction of melatonin-positive cells correlated with enhanced apoptotic activity of GM epitheliocytes. The number of endothelin-1 positive cells in patients with CNAHG and CAHG was similar to that in controls. Adequate eradication promoted normalization of the number of gastric endothelin-1 and melatonin-secreting neuroendocrine cells in patients with CHG. The apoptotic index reached the control value within 1 month after eradication in CNAHG patients but remained relatively high in CAHG patients.

Topics: Adult; Chronic Disease; Disease Progression; Endothelin-1; Gastritis; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Middle Aged; Pyloric Antrum; Severity of Illness Index

To study the expressions of differential proteins in the expressed prostatic secretion (EPS) of patients with III A chronic prostatitis and healthy men.. We collected EPS samples from 35 patients with III A chronic prostatitis and 18 age-matched healthy men, and detected the differentially expressed proteins in EPS by MALDI-TOF/MS. Based on the data obtained, we conducted a statistical analysis on the mass-to-charge (m/z) ratios of different proteins and a retrieval analysis on the relevant proteins using the protein database.. In the comparative studies of the III A chronic prostatitis patients and healthy men, 5 proteins were detected as at least 2-fold differentially expressed, which were probably brevinin-2Eg, big endothelin-1, alpha-defensin 15, beta-defensin 134 and prostatic steroid-binding protein C2. The m/z ratios were significantly up-regulated in 3 372, 3 487, 425 and 5 325 Da proteins (P < 0.01) and down-regulated in 10631Da (P < 0.01).. Proteins are differentially expressed in the EPS of III A chronic prostatitis patients and healthy men, and these proteins may be significantly correlated with the development and progression of III A chronic prostatitis.

Topics: Adult; Body Fluids; Case-Control Studies; Chronic Disease; Defensins; Endothelin-1; Humans; Male; Prostate; Prostatitis; Young Adult

Chronic liver diseases are commonly associated with tissue hypoxia that may cause inflammation, oxidative stress, liver cell injury and increased nuclear transcriptional regulation. The hepatic response to chronic hypoxia at the molecular level has not yet been clearly understood until now. The aim of this study is to investigate whether nuclear transcription factors [hypoxia-inducible factor-1 (HIF-1α), activator protein-1 (AP-1), nuclear factor-kappa B (NF-κB)] exhibit activity changes during hepatic response to chronic hypoxia. Blood and liver samples were collected from adult Sprague-Dawley rats living in atmospheric air or 10% oxygen for four weeks. Levels of serum alanine aminotransferase (ALT), 8-isoprostane and nitrotyrosine were measured. The activities of nuclear transcription factors and the expression of downstream genes (iNOS, eNOS, ET-1 and VEGF) were measured using RT-PCR, Western blotting and Gel shift analysis. Results showed that serum ALT level, 8-isoprostane level and formation of nitrotyrosine were within normal range at all time-points. In the hypoxic liver, DNA-binding activities of HIF-1α, NF-κB and AP-1 increased significantly. Expression levels of iNOS, VEGF and ET-1 progressively increased from day 7 to day 28. eNOS was also elevated in the hypoxic liver. In conclusion, our study suggests that increased activity of HIF-1α, AP-1 and NF-κB may partly play a significant role in the hepatic response to oxidative stress and liver injury under chronic hypoxia. The increased expression of VEGF, ET-1, iNOS and eNOS may be partly due to the compensatory mechanism in the vascular beds of the liver in response to chronic hypoxia.

Topics: Alanine Transaminase; Animals; Biomarkers; Blotting, Western; Chronic Disease; Dinoprost; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Endothelin-1; Gene Expression Regulation; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Male; NF-kappa B; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Transcription Factor AP-1; Tyrosine; Vascular Endothelial Growth Factor A

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

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

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

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

Obstructive sleep apnea, a condition resulting in chronic intermittent hypoxia (CIH), is an independent risk factor for stroke and dementia, but the mechanisms of the effect are unknown. We tested the hypothesis that CIH increases cerebrovascular risk by altering critical mechanisms regulating cerebral blood flow thereby lowering cerebrovascular reserves. Male C57Bl6/J mice were subjected to CIH (10% O(2) for 90 seconds/room air for 90 seconds; during sleep hours) or sham treatment for 35 days. Somatosensory cortex blood flow was assessed by laser Doppler flowmetry in anesthetized mice equipped with a cranial window. CIH increased mean arterial pressure (from 74±2 to 83±3 mm Hg; P<0.05) and attenuated the blood flow increase produced by neural activity (whisker stimulation; -39±2%; P<0.05) or neocortical application of endothelium-dependent vasodilators (acetylcholine response: -41±3%; P<0.05). The cerebrovascular dysfunction was associated with oxidative stress in cerebral resistance arterioles and was abrogated by free radical scavenging or NADPH oxidase inhibition. Furthermore, cerebrovascular dysfunction and free radical increase were not observed in mice lacking the NOX2 subunit of NADPH oxidase. CIH markedly increased endothelin 1 in cerebral blood vessels, whereas cerebrovascular dysfunction and oxidative stress were abrogated by neocortical application of the endothelin type A receptor antagonist BQ123. These data demonstrate for the first time that CIH alters key regulatory mechanisms of the cerebral circulation through endothelin 1 and NADPH oxidase-derived radicals. The ensuing cerebrovascular dysfunction may increase stroke risk in patients with sleep apnea by reducing cerebrovascular reserves and increasing the brain's susceptibility to cerebral ischemia.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Aspartic Acid Endopeptidases; Blood Pressure; Cerebrovascular Circulation; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Enzyme-Linked Immunosorbent Assay; Hypoxia; Laser-Doppler Flowmetry; Male; Membrane Glycoproteins; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidase 2; NADPH Oxidases; Peptides, Cyclic; Reactive Oxygen Species; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; Somatosensory Cortex; Vasodilator Agents

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

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

Chronic hypoxia (CH) induces an inflammatory response in rat carotid body that is characterized by immune cell invasion and the expression of pro-inflammatory cytokines. In the present study, we have investigated the role of type-A endothelin (ET-A) receptors in the development of CH-induced inflammation. After 7 days of CH (380 Torr), double-label immunofluorescence studies demonstrated elevated levels of ET-A receptor and tyrosine hydroxylase (TH) in O(2)-sensitive type I cells. Following CH, ET-A receptors were also expressed on resident and invasive CD45+ immune cells distributed in tissue surrounding chemosensory cell lobules. Immnofluorescence and quantitative PCR studies showed that concurrent treatment with the ET-A/B receptor antagonist, bosentan (200 mg/kg/day), blocked CH-induced ED-1+ macrophage invasion and the upregulation of cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and monocyte chemoattractant protein-1 (MCP-1). Moreover, bosentan treatment blocked the CH-induced increases in expression of acid-sensitive ion channels (ASICs) in chemoafferent neurons in the petrosal ganglion (PG). Our findings are consistent with the hypothesis that CH-induced inflammation involves the upregulation and release of ET-1 from type I cells. ET-1 may act in an autocrine/paracrine mechanism via ET-A receptors on chemosensory type I cells and immune cells to promote an inflammatory response.

Topics: Acid Sensing Ion Channels; Adaptation, Physiological; Animals; Antihypertensive Agents; Bosentan; Carotid Body; Cell Movement; Chemokine CCL2; Chemoreceptor Cells; Chronic Disease; Endothelin-1; Gene Expression; Hypoxia; Inflammation; Interleukin-1; Interleukin-1beta; Leukocyte Common Antigens; Macrophages; Rats; Receptor, Endothelin A; Sulfonamides; Tumor Necrosis Factor-alpha; Tyrosine 3-Monooxygenase

Stress is one of the most important variables to determine recovery following stroke. We have previously reported that post-stroke exposure to either stress or corticosterone (CORT) alleviates hippocampal ischemic outcome. The present experiment expands previous findings by investigating the influence of exposure to stress prior to ischemic event. Rats received either daily restraint stress (1h/day; 16 consecutive days) or CORT (0.5mg/kg; 16 consecutive days) prior to focal ischemic stroke in the hippocampus induced by bilateral injection of endothelin-1 (ET-1). All experimental groups were then tested in the ziggurat task, a new task for spatial cognition. The stress+stroke group showed significant deficits in both hippocampal structure and function. No deleterious effect of pre-stroke exposure to CORT was found in the CORT+stroke group. Our results indicate that a history of chronic stress sensitizes hippocampal cells to the damaging consequences of focal ischemia. The opposing effects of CORT-related experiences in this study not only reflect the diversity of glucocorticoid actions in the stress response, but also provide evidence that elevated CORT in the absence of emotional disturbance is not sufficient to produce hippocampal deficit.

Topics: Animals; Chronic Disease; Corticosterone; Disease Models, Animal; Endothelin-1; Glucocorticoids; Hippocampus; Male; Maze Learning; Problem Solving; Rats; Rats, Long-Evans; Spatial Behavior; Stress, Physiological; Stroke; Time Factors

We hypothesised that assessment of plasma C-terminal pro-endothelin-1 (CT-proET-1), a stable endothelin-1 precursor fragment, is of prognostic value in patients with chronic heart failure (CHF), beyond other prognosticators, including N-terminal pro-B-type natriuretic peptide (NT-proBNP).. We examined 491 patients with systolic CHF (age: 63±11 years, 91% men, New York Heart Association [NYHA] class [I/II/III/IV]: 9%/45%/38%/8%, 69% ischemic etiology). Plasma CT-proET-1 was detected using a chemiluminescence immunoassay.. Increasing CT-proET-1 was a predictor of increased cardiovascular mortality at 12-months of follow-up (standardized hazard ratio 1.42, 95% confidence interval [CI] 1.04-1.95, p = 0.03) after adjusting for NT-proBNP, left ventricular ejection fraction (LVEF), age, creatinine, NYHA class. In receiver operating characteristic curve analysis, areas under curve for 12-month follow-up were similar for CT-proET-1 and NT-proBNP (p = 0.40). Both NT-proBNP and CT-proET-1 added prognostic value to a base model that included LVEF, age, creatinine, and NYHA class. Adding CT-proET-1 to the base model had stronger prognostic power (p<0.01) than adding NT-proBNP (p<0.01). Adding CT-proET-1 to NT-proBNP in this model yielded further prognostic information (p = 0.02).. Plasma CT-proET-1 constitutes a novel predictor of increased 12-month cardiovascular mortality in patients with CHF. High CT-proET-1 together with high NT-proBNP enable to identify patients with CHF and particularly unfavourable outcomes.

Topics: Aged; Biomarkers; Chronic Disease; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Mortality; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Protein Precursors; Risk

To investigate the levels of endothelin-1 (ET-1) and nitric oxide (NO) in the aqueous humor and plasma of human eyes with different types of glaucoma: primary open-angle glaucoma (POAG) and chronic closed-angle glaucoma (CCAG).. Patients were classified into 3 groups: group I comprised 35 patients with POAG, group II comprised 25 patients with CCAG, and 30 patients with senile cataract (group III) were used as a control group. Aqueous humor and corresponding plasma were analyzed for ET-1 and NO concentrations by enzyme-linked immunosorbent assay. A Bonferroni correction for multiple comparisons was performed.. There was no significant difference in plasma levels of either ET-1 or NO metabolites between the groups studied. ET-1 and NO were significantly elevated in the aqueous humor of patients with CCAG and POAG compared to the corresponding value in patients with cataract (p < 0.001). ET-1 and NO concentrations in the aqueous humor were more marked in CCAG than in POAG. NO levels were correlated with ET-1 in the aqueous humor of patients with glaucoma (p < 0.001).. Increased concentrations of ET-1 and NO in aqueous humor may be useful with POAG and CCAG. In addition, ET-1 and NO may have useful metabolite levels in the aqueous humor of POAG and CCAG patients as a result of glaucoma damage and may not be a cause of it.

Topics: Aged; Aqueous Humor; Chronic Disease; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Glaucoma, Angle-Closure; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Nitric Oxide; Radioimmunoassay

Patients with chronic kidney disease (CKD) have increased risk of cardiovascular disease to which co-morbidity and associated conventional risk factors contribute. We hypothesised that arterial stiffness (AS) and endothelial dysfunction (ED), as surrogates of cardiovascular risk, would worsen as renal function declined even in patients without co-morbidity and that this would relate to emerging cardiovascular risk factors.. Carotid-femoral pulse wave velocity (PWV), as a measure of AS, and flow-mediated dilatation (FMD) of the brachial artery, as a measure of ED, were assessed in CKD patients without established cardiovascular disease or diabetes mellitus.. PWV increased linearly as renal function declined (r(2) = 0.08, p < 0.01) whereas FMD was reduced only in patients with advanced kidney disease. In multivariable analysis, blood pressure was the major determinant of PWV and FMD. High-sensitivity C-reactive protein and asymmetric dimethylarginine, and isoprostanes and endothelin-1, were independent predictors of PWV and FMD, respectively. However, renal function did not independently predict either AS or ED.. These findings suggest that declining renal function, in the absence of significant co-morbidity, is associated with progressive arterial stiffness, but only patients close to dialysis exhibit endothelial dysfunction. Whilst blood pressure remains the major determinant of PWV and FMD, inflammation, oxidative stress and endothelin-nitric oxide balance contribute to cardiovascular risk, in this non-comorbid cohort.

Topics: Adult; Analysis of Variance; Arginine; Biomarkers; Blood Pressure; Brachial Artery; C-Reactive Protein; Carotid Arteries; Case-Control Studies; Chronic Disease; Comorbidity; Compliance; Cross-Sectional Studies; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Femoral Artery; Glomerular Filtration Rate; Humans; Isoprostanes; Kidney; Kidney Diseases; Linear Models; Male; Middle Aged; Peripheral Arterial Disease; Prospective Studies; Pulsatile Flow; Risk Assessment; Risk Factors; Scotland; Uremia; Vasodilation

Chronic hypoxia (CH) activates the Ca(2+)-dependent transcription factor nuclear factor of activated T cells isoform c3 (NFATc3) in mouse pulmonary arteries. However, the mechanism of this response has not been explored. Since we have demonstrated that NFATc3 is required for CH-induced pulmonary arterial remodeling, establishing how CH activates NFATc3 is physiologically significant. The goal of this study was to test the hypothesis that endothelin-1 (ET-1) contributes to CH-induced NFATc3 activation. We propose that this mechanism requires increased pulmonary arterial smooth muscle cell (PASMC) intracellular Ca(2+) concentration ([Ca(2+)](i)) and stimulation of RhoA/Rho kinase (ROK), leading to calcineurin activation and actin cytoskeleton polymerization, respectively. We found that: 1) CH increases pulmonary arterial pre-pro-ET-1 mRNA expression and lung RhoA activity; 2) inhibition of ET receptors, calcineurin, L-type Ca(2+) channels, and ROK blunts CH-induced NFATc3 activation in isolated intrapulmonary arteries from NFAT-luciferase reporter mice; and 3) both ET-1-induced NFATc3 activation in isolated mouse pulmonary arteries ex vivo and ET-1-induced NFATc3-green fluorescence protein nuclear import in human PASMC depend on ROK and actin polymerization. This study suggests that CH increases ET-1 expression, thereby elevating PASMC [Ca(2+)](i) and RhoA/ROK activity. As previously demonstrated, elevated [Ca(2+)](i) is required to activate calcineurin, which dephosphorylates NFATc3, allowing its nuclear import. Here, we demonstrate that ROK increases actin polymerization, thus providing structural support for NFATc3 nuclear transport.

Topics: Actins; Active Transport, Cell Nucleus; Animals; Calcineurin; Calcineurin Inhibitors; Calcium Channels, L-Type; Calcium Signaling; Cells, Cultured; Chronic Disease; Cytoskeleton; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Genes, Reporter; Humans; Hypoxia; Male; Membrane Transport Modulators; Mice; Mice, Inbred BALB C; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NFATC Transcription Factors; Phosphorylation; Protein Kinase Inhibitors; Pulmonary Artery; Receptors, Endothelin; Recombinant Fusion Proteins; rho GTP-Binding Proteins; rho-Associated Kinases; rhoA GTP-Binding Protein; RNA, Messenger; Time Factors; Transcriptional Activation; Transfection; Up-Regulation

Endothelin-1, a vasoconstrictor peptide, influences cartilage metabolism mainly via endothelin receptor type A (ETA). Along with the inflammatory nonapeptide vasodilator bradykinin (BK), which acts via bradykinin receptor B1 (BKB1) in chronic inflammatory conditions, these vasoactive factors potentiate joint pain and inflammation. We describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists. We hypothesize that antagonism of both receptors will diminish osteoarthritis progress and articular nociception in a synergistic manner.. Osteoarthritis was surgically induced in male rats by transection of the right anterior cruciate ligament. Animals were subsequently treated with weekly intra-articular injections of specific peptide antagonists of ETA and/or BKB1. Hind limb nociception was measured by static weight bearing biweekly for two months post-operatively. Post-mortem, right knee joints were analyzed radiologically by X-ray and magnetic resonance, and histologically by the OARSI histopathology assessment system.. Single local BKB1 antagonist treatment diminished overall hind limb nociception, and accelerated post-operative recovery after disease induction. Both ETA and/or BKB1 antagonist treatments protected joint radiomorphology and histomorphology. Dual ETA/BKB1 antagonism was slightly more protective, as measured by radiology and histology.. BKB1 antagonism improves nociceptive tolerance, and both ETA and/or BKB1 antagonism prevents joint cartilage degradation in a surgical model of osteoarthritis. Therefore, they represent a novel therapeutic strategy: specific receptor antagonism may prove beneficial in disease management.

Topics: Animals; Anterior Cruciate Ligament; Arthralgia; Bradykinin; Bradykinin B1 Receptor Antagonists; Chronic Disease; Disease Models, Animal; Endothelin-1; Injections, Intra-Articular; Knee Joint; Male; Nociception; Osteoarthritis, Knee; Peptides, Cyclic; Rats; Rats, Inbred Lew; Weight-Bearing

Cocaine use has been related with the development of accelerated atherosclerosis and with an increased risk of cardiac and cerebrovascular events, such as myocardial infarction, sudden cardiac death, and ischemic stroke. The underlying mechanisms leading to these complications are not fully understood, although thrombus formation and altered vascular function are prominent findings.. Our aim was to evaluate markers of endothelial dysfunction in chronic cocaine consumers before and after drug withdrawal.. We determined circulating endothelial cells (CECs) and plasma levels of stromal cell-derived factor-1 (SDF-1), monocyte chemotactic protein-1(MCP-1), soluble intracellular adhesion molecule (sICAM), high-sensitivity C reactive protein (hsCRP) and endothelin-1(ET-1), in DSM-IV cocaine addicts at baseline and after one month of cocaine abstinence.. Cocaine users showed a strikingly higher numbers of CEC (62.35 ± 18.4 vs 8.25 ± 13.8 CEC/mL) and significantly elevated plasma levels for all the markers evaluated as compared to the control group. After cocaine withdrawal, patients improved SDF-1, ET-1, hsCRP and sICAM levels. However, CEC number and MCP-1 plasma levels remained significantly elevated. All the results were adjusted for blood levels of cholesterol and triglycerides and for smoking habit.. Our results demonstrated that chronic cocaine consumption alters several functions of the endothelium towards a pro-thrombotic condition and that some of those functions remain abnormal even after short-term drug withdrawal. These observations support the notion that endothelial dysfunction may play a key role in the pathogenesis of ischemic vascular disease observed in cocaine abusers.

Topics: Adult; Biomarkers; C-Reactive Protein; Case-Control Studies; Cell Count; Chemokine CXCL12; Chile; Chronic Disease; Cocaine-Related Disorders; Endothelial Cells; Endothelin-1; Female; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; Substance Withdrawal Syndrome; Time Factors; Up-Regulation; Young Adult

Hydrocele and elephantiasis are 2 clinically very diverse and often mutually exclusive chronic manifestations of human bancroftian filariasis. Plasma levels of endothelin-1 (ET-1), a major angiogenic factor, and tumor necrosis factor receptors (TNFRs) that regulate host inflammation have been associated with development of chronic filariasis, although their genetic basis are not known.. We studied polymorphisms of ET-1 (Ala288Ser) and TNFR-II (Met196Arg) genes by means of the polymerase chain reaction confronting 2 pairs primers method and restriction fragment length polymorphism, respectively. Plasma ET-1 level was measured by enzyme-linked immunosorbent assay.. Met196Arg genotype frequency of TNFR-II polymorphism was significantly greater in hydrocele patients, compared with elephantiasis patients (OR, 4.34 [95% CI, 2.04-9.20]). Conversely, a significantly high prevalence of the Ala288Ser mutation of ET-1 was observed in elephantiasis patients, compared with hydrocele cases (OR, 2.15 [95% CI, 1.13-4.10]). Decreased plasma ET-1 levels associated significantly with Ala288Ser mutation in the study population. A combined analysis indicated a 23-fold higher risk for developing elephantiasis in individuals with TNFR-II (Met196Met) and ET-1 mutants (Ala288Ser + Ser288Ser).. ET-1 (Ala288Ser) and TNFR-II (Met196Arg) polymorphisms are associated with development of one or the other form of chronic disease in bancroftian filariasis.

Topics: Adolescent; Adult; Amino Acid Substitution; Chronic Disease; DNA Primers; Elephantiasis, Filarial; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Mutation, Missense; Polymerase Chain Reaction; Polymorphism, Genetic; Receptors, Tumor Necrosis Factor, Type II; Young Adult

Serial measurements of neurohormones have been shown to improve prognostication in the setting of acute heart failure (HF) or chronic HF without therapeutic intervention. We investigated the prognostic role of serial measurements of emerging neurohormones and BNP in a cohort of chronic HF patients undergoing increases in HF-specific therapy.. In this prospective study we included 181 patients with chronic systolic HF after an episode of hospitalization for worsening HF. Subsequently, HF therapy was gradually increased in the outpatient setting until optimized. We measured copeptin, midregional proadrenomedullin, C-terminal endothelin-1 precursor fragment, midregional proatrial natriuretic peptide, and B-type natriuretic peptide before and after optimization of HF therapy. The primary endpoint was all-cause mortality at 24 months.. Angiotensin-converting enzyme/angiotensin receptor blocker and beta-blockers were increased significantly during the 3-month titration period (P < 0.0001 for both). In a stepwise Cox regression analysis adjusted for age, sex, glomerular filtration rate, diabetes mellitus, and ischemic HF, baseline and follow-up neurohormone concentrations were predictors of the primary endpoint as follows (baseline hazard ratios): copeptin 1.92, 95% CI 1.233-3.007, P = 0.004; midregional proadrenomedullin 2.79, 95% CI 1.297-5.995, P = 0.009; midregional proatrial natriuretic peptide 2.05, 95% CI 1.136-3.686, P = 0.017; C-terminal endothelin-1 precursor fragment 2.24, 95% CI 1.133-4.425, P = 0.025; B-type natriuretic peptide 1.46, 95% CI 1.039-2.050, P = 0.029.. In pharmacologically unstable chronic HF patients, baseline values and follow-up measures of copeptin, midregional proadrenomedullin, C-terminal endothelin-1 precursor fragment, midregional proatrial natriuretic peptide, and B-type natriuretic peptide were equally predictive of all-cause mortality. Relative change of neurohormone values was noncontributory.

Topics: Adrenomedullin; Adult; Aged; Atrial Natriuretic Factor; Chronic Disease; Endothelin-1; Female; Glycopeptides; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neurotransmitter Agents; Prognosis; Protein Precursors

Chronic pulmonary hypertension in infancy and childhood is characterized by a fixed and progressive increase in pulmonary arterial pressure and resistance, pulmonary arterial remodeling, and right ventricular hypertrophy and systolic dysfunction. These abnormalities are replicated in neonatal rats chronically exposed to hypoxia from birth in which increased activity of Rho-kinase (ROCK) is critical to injury, as evidenced by preventive effects of ROCK inhibitors. Our objective in the present study was to examine the reversing effects of a late or rescue approach to treatment with a ROCK inhibitor on the pulmonary and cardiac manifestations of established chronic hypoxic pulmonary hypertension. Rat pups were exposed to air or hypoxia (13% O(2)) from postnatal day 1 and were treated with Y-27632 (15 mg/kg) or saline vehicle by twice daily subcutaneous injection commencing on day 14, for up to 7 days. Treatment with Y-27632 significantly attenuated right ventricular hypertrophy, reversed arterial wall remodeling, and completely normalized right ventricular systolic function in hypoxia-exposed animals. Reversal of arterial wall remodeling was accompanied by increased apoptosis and attenuated content of endothelin (ET)-1 and ET(A) receptors. Treatment of primary cultured juvenile rat pulmonary artery smooth muscle cells with Y-27632 attenuated serum-stimulated ROCK activity and proliferation and increased apoptosis. Smooth muscle apoptosis was also induced by short interfering RNA-mediated knockdown of ROCK-II, but not of ROCK-I. We conclude that sustained rescue treatment with a ROCK inhibitor reversed both the hemodynamic and structural abnormalities of chronic hypoxic pulmonary hypertension in juvenile rats and normalized right ventricular systolic function. Attenuated expression and activity of ET-1 and its A-type receptor on pulmonary arterial smooth muscle was a likely contributor to the stimulatory effects of ROCK inhibition on apoptosis. In addition, our data suggest that ROCK-II may be dominant in enhancing survival of pulmonary arterial smooth muscle.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Age Factors; Aging; Amides; Animals; Apoptosis; Cell Proliferation; Cells, Cultured; Chronic Disease; Disease Models, Animal; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Injections, Subcutaneous; Muscle, Smooth, Vascular; Myocardium; Protein Kinase Inhibitors; Pulmonary Artery; Pyridines; Rats; Receptor, Endothelin A; rho-Associated Kinases; RNA Interference; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Remodeling

There is increasing evidence that alkali therapy can retard progression of chronic kidney disease (CKD). We summarize recent studies and discuss a mechanism whereby alkali therapy may neutralize acid production associated with typical Western diets, which generate acid. We emphasize the rationale for using alkali therapy early in the course of CKD, even in the absence of overt metabolic acidosis, and we urge the pharmaceutical industry to develop palatable alkali-containing solutions.

Topics: Acid-Base Equilibrium; Acidosis; Administration, Oral; Aldosterone; Animals; Bicarbonates; Chronic Disease; Dietary Supplements; Disease Progression; Endothelin-1; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases

The level of endothelin-1 (ET-1) in blood serum and nasal secretion was simultaneously determine by the relevant immunoenzyme assay in 23 of patients presenting with chronic rhinitis and in12 healthy subjects. It was shown that both vasomotor and chronic hypertrophic rhinitides are characterized by a similar (two-fold) rise in the serum ET-1 concentration. The six-fold increase of the ET-1 level in nasal secretion in chronic hypertrophic rhinitis compared with the respective normal parameter exceeds that in the vasomotor form of this pathology.

Topics: Child; Child, Preschool; Chronic Disease; Endothelin-1; Humans; Mucus; Nasal Mucosa; Rhinitis; Serum

The purpose of this study was to determine whether endothelin B (ETB) receptor levels in the optic nerve are related to retinal ganglion cell (RGC) loss in a model of chronic endothelin-1 (ET-1) induced optic neuropathy. RGCs of adult Brown Norway rats were first retrogradely labeled with fluorochrome from the superior colliculi. An osmotic minipump was surgically implanted 7 days later to deliver 10(-11) M (n = 9), 10(-9) M (n = 12) or 10(-7) M (n = 9) ET-1 to the retrobulbar optic nerve for 28 days. RGC survival was expressed as the ratio of RGC counts in experimental versus control eyes in wholemounted retinas. Optic nerves were used for either ETB western blot analysis (n = 24) or immunohistochemistry (n = 6) for ETB and glial fibrillary acidic protein (GFAP) to localize astrocytes. ETB expression was higher in the experimental nerve compared to the fellow untreated control nerve in 19 (79%) of the 24 animals with a mean increase of 16.7 +/- 4.5% in densitometric analyses of the immunoblots. Experimental nerves showed stronger labeling for both ETB and GFAP compared to control nerves. ETB-positive cells almost completely co-localized with GFAP-positive cells in both experimental and untreated control nerves, however, ETB expression was stronger in the astrocyte soma and proximal processes, while GFAP was expressed more strongly in the distal processes. There was a weak relationship between RGC loss and increase in ETB expression (r = -0.417, p = 0.076). There is an upregulation of ETB expression in optic nerve astrocytes in ET-1 induced chronic optic neuropathy causing RGC loss.

Topics: Animals; Astrocytes; Cell Survival; Chronic Disease; Dose-Response Relationship, Drug; Endothelin-1; Glial Fibrillary Acidic Protein; Male; Microscopy, Confocal; Optic Nerve; Optic Nerve Diseases; Rats; Rats, Inbred BN; Receptor, Endothelin B; Retinal Ganglion Cells

Adrenomedullin (ADM) and endothelin-1 (ET-1) are novel promising peptide biomarkers in chronic heart failure (CHF). According to recent studies among their pleiotropic effect they play roles in the regulation of inflammation. The aim of the study was to measure the above mentioned two vasoactive peptides in parallel in a well characterized population of patients with CHF, and study their associations with inflammatory markers.. A total of 186 patients (138 male, 48 female) with <45% left ventricular ejection fraction (LVEF), and without acute inflammatory disease, were enrolled. Plasma midregional-proADM (MR-proADM) and C-terminal-proET-1 (CT-proET-1) were determined by a novel sandwich immunoluminometric assay.. Increased MR-proADM and CT-proET-1 plasma levels were measured in patients with severe CHF (NYHA III-IV) as compared to the group of NYHA I-II (p<0.0001). MR-proADM and CT-proET-1 levels showed significant negative correlation with serum albumin and prealbumin levels (p

Topics: Adrenomedullin; Aged; Biomarkers; Chronic Disease; Cross-Sectional Studies; Endothelin-1; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Ventricular Dysfunction, Left

Effects of chronic hypoxia (CH) on store- and receptor-operated Ca(2+) entry (SOCE, ROCE) in pulmonary vascular smooth muscle (VSM) are controversial, although whether genetic variation explains such discrepancies in commonly studied rat strains is unclear. Since protein kinase C (PKC) can inhibit Ca(2+) permeable nonselective cation channels, we hypothesized that CH differentially alters PKC-dependent inhibition of SOCE and ROCE in pulmonary VSM from Sprague-Dawley and Wistar rats. To test this hypothesis, we examined SOCE and endothelin-1 (ET-1)-induced ROCE in endothelium-disrupted, pressurized pulmonary arteries from control and CH Sprague-Dawley and Wistar rats. Basal VSM Ca(2+) was elevated in CH Wistar, but not Sprague-Dawley, rats. Further, CH attenuated SOCE in VSM from Sprague-Dawley rats, while augmenting this response in Wistar rats. CH reduced ROCE in arteries from both strains. PKC inhibition restored SOCE in CH Sprague-Dawley arteries to control levels, while having no effect on SOCE in Wistar arteries or on ROCE in either strain. We conclude that effects of CH on pulmonary VSM SOCE are strain dependent, whereas inhibitory effects of CH on ROCE are strain independent. Further, PKC inhibits SOCE following CH in Sprague-Dawley, but not Wistar, rats but does not contribute to ET-1-induced ROCE in either strain.

Topics: Animals; Biological Transport; Calcium; Chronic Disease; Endothelin-1; Hypoxia; Muscle, Smooth, Vascular; Protein Kinase C; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Rats, Wistar; Species Specificity

Hypoxia transiently increases transcription of the gene encoding heme oxygenase-1 (HO-1) and potently activates production of endothelin-1 (ET-1), the latter of which plays a central role in cellular adaptation to hypoxia. The ventilatory response to hypoxia attenuates with aging, and decreased responsiveness to hypoxia is seen in the aged vs. young rats, suggesting that the functionality of the oxygen-sensitive mechanism is age-dependent. In the present study, we examined the effects of aging on the expression of HO-1 and ET-1 in the carotid body, which is a small cluster of chemoreceptors and supporting cells that measure changes in the composition of arterial blood flowing through it. Our results revealed that HO-1 and ET-1 were expressed in carotid bodies of both young and old rats, although less so in the old ones. Exposure to chronic intermittent hypoxia significantly increased both HO-1 and ET-1 immunoreactivity in both young and old carotid body tissues, with the persisting age-dependent inequality to the disadvantage of old age. Considering that ET-1 is capable of enhancing intermittent hypoxia-induced chemosensory responses by the carotid body, our results suggest that decreased induction of ET-1 and HO-1 during aging could form the basis for age-related reductions in chemosensory discharge.

Topics: Aging; Animals; Carotid Body; Chronic Disease; Endothelin-1; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Hypoxia; Male; Rats; Rats, Wistar

To observe the effects of continuous subcutaneous adenosine infusion on pulmonary hypertension in chronically hypoxic rats.. Twenty-four SD rats were randomized into normoxic group, hypoxic group and adenosine-treated hypoxic group. Hypoxic environment was simulated in a chamber filled with 10% oxygen and 90% nitrogen. After 7 days of hypoxia, adenosine were administered subcutaneously in the rats in adenosine-treated group at the rate of 100 microg kg(-1) min(-1) via an Alzet micro-osmotic pump for 14 days, while the pumps in the other two groups contained normal saline. After 21 days of hypoxia, pulmonary artery pressure and tail-cuff blood pressure were measured, with the plasma rennin activity (RA), angiotensin II (AngII), endothelin (ET)-1, and nitric oxide (NO) determined. Inducible nitric oxide synthase (iNOS) expression in the pulmonary artery of the rats was detected using immunohistochemical method.. The mean pulmonary artery pressure (mPAP) was significantly higher in the hypoxic group than that in the normoxic group (P<0.01) and in the adenosine-treated group (P<0.01). Plasma ET-1 was significantly higher but plasma NO significantly lower in the hypoxic group than in the normoxic group (P<0.01) and the adenosine-treated group (P<0.01). iNOS expression in the pulmonary artery was higher in the hypoxic group than in normoxic group (P<0.01), and adenosine significantly increased iNOS expression in comparison with the normoxic and hypoxic groups (P<0.01). Plasma RA and AngII in the hypoxic group were significantly higher than those in the normoxic group (P<0.01) and the adenosine-treated (P<0.01).. Adenosine administered by continuous subcutaneous infusion alleviates chronically hypoxia-induced pulmonary hypertension in rats, in which rennin angiotensin system, ET-1, and iNOS/NO play a role.

Topics: Adenosine; Animals; Chronic Disease; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Infusions, Subcutaneous; Male; Nitric Oxide Synthase Type II; Random Allocation; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

Pulmonary hypertension is a kind of disease associated with a very high rate of mortality. There are not many effective drugs for the treatment of pulmonary hypertension. Treatment with ET-1 receptor antagonists was proved to be effective in the treatment of pulmonary hypertension. Aiming at developing new endothelin A receptor (ET(A)) antagonist for treatment of pulmonary hypertension, 242 peptide compounds were synthesized by structural optimization of a selective ET(A) receptor antagonist BQ-123. Among these, -azabicyclo[3,2,1]octane-1-yl-l-Leucyl-d-tryptophanyl-d-4-Cl-phenylalanine, named ETP-508, was selected for further harmacological characterization.. Radioligand binding assay was performed to study the binding affinity of ETP-508 for ET(A) and ET(B) receptors. The biological activity of ETP-508 was evaluated in isolated rat aortic ring experiment and in systemic arterial pressure experiment. In addition, hypotensive effect of ETP-508 was investigated on hypoxia-induced pulmonary hypertension.. ETP-508 binds to endothelin ET(A) receptor with >10,000-fold higher affinity than to endothelin B receptor in rat lung tissue preparation. ETP-508 inhibited endothelin-1 (ET-1)-induced contraction of isolated rat aortic ring and shifted the cumulative concentration-contraction response curve to ET-1 to right with no change in the maximal response. In vivo, ETP-508 inhibited the increased effect of ET-1 on mean systemic arterial pressure. Pre-treatment with ETP-508 by intravenous infusion significantly inhibited chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. ETP-508 also significantly inhibited the increase in lung ET-1 expression level, hemoglobin, red-cell count and red-cell hematocrit as induced by hypoxia. Furthermore, ETP-508 partially reversed pre-established pulmonary hypertension and right ventricle hypertrophy by chronic hypoxia.. These results indicated that ETP-508 is a novel highly selective ET(A) receptor antagonist and may have a great potential to be developed as a drug of anti-pulmonary hypertension.

Topics: Animals; Aorta, Thoracic; Azabicyclo Compounds; Azepines; Blood Pressure; Chronic Disease; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Lung; Male; Molecular Structure; Oligopeptides; Peptides, Cyclic; Rats; Rats, Wistar; Time Factors; Vasoconstriction

Recent evidence supports a prominent role for Rho kinase (ROK)-mediated pulmonary vasoconstriction in the development and maintenance of chronic hypoxia (CH)-induced pulmonary hypertension. Endothelin (ET)-1 contributes to the pulmonary hypertensive response to CH, and recent studies by our laboratory and others indicate that pulmonary vascular reactivity following CH is largely independent of changes in vascular smooth muscle (VSM) intracellular free calcium concentration ([Ca(2+)](i)). In addition, CH increases generation of reactive oxygen species (ROS) in pulmonary arteries, which may underlie the shift toward ROK-dependent Ca(2+) sensitization. Therefore, we hypothesized that ROS-dependent RhoA/ROK signaling mediates ET-1-induced Ca(2+) sensitization in pulmonary VSM following CH. To test this hypothesis, we determined the effect of pharmacological inhibitors of ROK, myosin light chain kinase (MLCK), tyrosine kinase (TK), and PKC on ET-1-induced vasoconstriction in endothelium-denuded, Ca(2+)-permeabilized small pulmonary arteries from control and CH (4 wk at 0.5 atm) rats. Further experiments examined ET-1-mediated, ROK-dependent phosphorylation of the regulatory subunit of myosin light chain phosphatase (MLCP), MYPT1. Finally, we measured ET-1-induced ROS generation in dihydroethidium-loaded small pulmonary arteries and investigated the role of ROS in mediating ET-1-induced, RhoA/ROK-dependent Ca(2+) sensitization using the superoxide anion scavenger, tiron. We found that CH increases ET-1-induced Ca(2+) sensitization that is sensitive to inhibition of ROK and MLCK, but not PKC or TK, and correlates with ROK-dependent MYPT1(Thr696) phosphorylation. Furthermore, tiron inhibited basal and ET-1-stimulated ROS generation, RhoA activation, and VSM Ca(2+) sensitization following CH. We conclude that CH augments ET-1-induced Ca(2+) sensitization through ROS-dependent activation of RhoA/ROK signaling in pulmonary VSM.

Topics: Animals; Calcium Signaling; Chronic Disease; Endothelin-1; Hypoxia; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Protein Phosphatase 1; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; rho-Associated Kinases; rhoA GTP-Binding Protein; Vasoconstriction

Exposure to allergens or air pollutants often leads to asthma exacerbations associated with aggravation of airway inflammation. Although, repeated allergen challenge often induces chronic allergic airway inflammation (CAAI) and airway remodelling, yet, the effects of brief exposure to air pollutants such as SO(2) on development of CAAI and airway remodelling remain to be clarified.. The aim of the experiment was to investigate the effects of acute neutrophilic airway inflammation induced by brief exposure to SO(2) on development of CAAI and subepithelial fibrosis (SEF) in a murine model of asthma.. Acute airway inflammation was induced by brief exposure to 50 p.p.m. SO(2) (1 h/d, 3 days). CAAI and SEF in BALB/c mice were induced by repeated challenge with ovalbumin (OVA) for 5 or 9 weeks with or without prior exposure to SO(2). Bronchoalveolar lavage fluid (BALF) eosinophilia as index of CAAI, BALF endothelin-1 (ET-1) and TGF-beta1 levels, morphometric evaluation of fibrotic area beneath subbasement membrane and lung hydroxyproline content (Hyp) as indexes of SEF were monitored.. Exposure to SO(2) led to acute neutrophilic inflammation and epithelial sloughing with profound elevation of BALF ET-1. Repeated OVA challenge resulted in CAAI and SEF along with elevation of Hyp, increase of fibrotic area beneath subbasement membrane and elevation of BALF TGF-beta1. Preceding SO(2) exposure exaggerated BALF eosinophilia, facilitated and enhanced SEF with more significant elevation of BALF ET-1 and TGF-beta1 levels compared with OVA-challenged mice without prior exposure to SO(2). The increase of Hyp was positively correlated with elevation of BALF TGF-beta1 during CAAI (r=0.842, P<0.01).. This data demonstrated that SEF developed in parallel with severity and time course of CAAI following repeated OVA challenge. SO(2)-induced acute epithelial injury and neutrophilic inflammation could enhance CAAI and promote SEF, probably through overexpression of ET-1 and TGF-beta1.

Topics: Air Pollutants; Allergens; Animals; Bronchitis; Bronchoalveolar Lavage Fluid; Chronic Disease; Endothelin-1; Female; Lung; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Pulmonary Fibrosis; Respiratory Mucosa; Sulfur Dioxide; Transforming Growth Factor beta

Impaired microcirculation during the chronic stage of complex regional pain syndrome (CRPS) is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Endothelial dysfunction is suggested to be the main cause of diminished blood flow. The aim of this study was to examine the distribution of endothelial nitric oxide synthase (eNOS) and endothelin-1(ET-1) relative to vascular density represented by the endothelial marker CD31-immunoreactivity in the skin tissue of patients with chronic CRPS.. We performed immunohistochemical staining on sections of skin specimens obtained from the amputated limbs (one arm and one leg) of two patients with CRPS.. In comparison to proximal specimens we found an increased number of migrated endothelial cells as well as an increase of eNOS activity in distal dermis specimens.. We found indications that endothelial dysfunction plays a role in chronic CRPS.

Topics: Adult; Amputation, Surgical; Chronic Disease; Complex Regional Pain Syndromes; Endothelin-1; Extremities; Female; Humans; Immunohistochemistry; Middle Aged; Nitric Oxide Synthase Type III; Platelet Endothelial Cell Adhesion Molecule-1; Skin

To establish the role of endothelin-1 and nitric oxide in the pathogenesis of hypertension in patients on chronic hemodialysis by correlating endothelin-1 and NO plasma concentrations to the level of arterial hypertension with respect to angiotensin-converting enzyme (ACE) inhibitor therapy.. We determined plasma concentrations of endothelin-1 and NO in patients on chronic hemodialysis (CHD) before and after hemodialysis treatment. The study included 30 CHD patients and 20 healthy participants as controls. Correlation to blood pressure was determined, as well as the effect of ACE inhibitors on the relationship between both endothelin-1 and NO in correlation with arterial hypertension.. Endothelin-1 plasma concentration was significantly higher in CHD patients before hemodialysis treatment than in healthy controls. Endothelin-1 plasma concentration was also significantly higher in CHD patients after hemodialysis than in healthy controls. There was a significant decrease in endothelin-1 plasma concentration after hemodialysis in comparison with its values before hemodialysis. In CHD patients, a positive correlation was found between endothelin-1 plasma concentration and systolic blood pressure after hemodialysis, irrespective of ACE inhibitors therapy. In CHD patients taking ACE inhibitors, systolic blood pressure increased with increasing endothelin-1 plasma concentration before as well as after hemodialysis. In patients taking ACE inhibitors, there was a tendency for diastolic blood pressure to increase with an increase in endothelin-1 plasma concentration after hemodialysis and to decrease with an increase in NO plasma concentration.. NO and endothelin-1 play a significant role in etiology of the hemodynamic changes of blood pressure during the dialysis.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Case-Control Studies; Chronic Disease; Cohort Studies; Endothelin-1; Female; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Nitric Oxide; Renal Dialysis

Chronic exposure to hypoxia, a common adverse consequence of most pulmonary disorders, can lead to a sustained increase in pulmonary arterial pressure (PAP), right ventricular hypertrophy, and is, therefore, closely associated with heart failure and increased mortality. Ghrelin, originally identified as an endogenous GH secretagogue, has recently been shown to possess potent vasodilator properties, likely involving modulation of the vascular endothelium and its associated vasoactive peptides. In this study we hypothesized that ghrelin would impede the pathogenesis of pulmonary arterial hypertension during chronic hypoxia (CH). PAP was continuously measured using radiotelemetry, in conscious male Sprague Dawley rats, in normoxia and during 2-wk CH (10% O(2)). During this hypoxic period, rats received a daily sc injection of either saline or ghrelin (150 microg/kg). Subsequently, heart and lung samples were collected for morphological, histological, and molecular analyses. CH significantly elevated PAP in saline-treated rats, increased wall thickness of peripheral pulmonary arteries, and, consequently, induced right ventricular hypertrophy. In these rats, CH also led to the overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA within the lung. Exogenous ghrelin administration attenuated the CH-induced overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA. Consequently, ghrelin significantly attenuated the development of pulmonary arterial hypertension, pulmonary vascular remodeling, and right ventricular hypertrophy. These results demonstrate the therapeutic benefits of ghrelin for impeding the pathogenesis of pulmonary hypertension and right ventricular hypertrophy, particularly in subjects prone to CH (e.g. pulmonary disorders).

Topics: Algorithms; Animals; Blood Glucose; Body Weight; Chronic Disease; Consciousness; Disease Progression; Drug Evaluation, Preclinical; Endothelin-1; Fatty Acids, Nonesterified; Ghrelin; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Male; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; RNA, Messenger

The present study was conducted to investigate whether hydroxysafflor yellow A (HSYA) has a protective effect on acute and chronic heart failure (AHF/CHF) induced by ligation of the left anterior descending coronary artery for 3 h and 8 weeks, respectively. The rats were divided into the following groups: sham operation, coronary artery ligation (CAL), CAL+HSYA (100 mg kg(-1) by gavage) and CAL+diltiazem (20 mg kg(-1) by gavage). In the AHF model, heart function, as determined by haemodynamic studies and echocardiography, was improved significantly by pretreatment with HSYA or diltiazem. Significant reductions in elevated serum creatine phosphokinase, lactate dehydrogenase, malondialdehyde (MDA), glutamic oxalacetic transaminase, glutamic pyruvic transaminase and blood viscosity were observed, and the activity of serum superoxide dismutase (SOD) was enhanced (all P<0.01). In the CHF model, HSYA and diltiazem restored abnormal heart function, and completely suppressed the elevated plasma atrial natriuretic polypeptide (ANP) and endothelin-1 (ET-1), serum and left-ventricular tissue inducible nitric oxide (NO) synthase (iNOS), NO and MDA, and improved the decrease in SOD. HSYA and diltiazem improved cardiac performance in AHF and reduced cardiac remodelling in CHF by reducing tissue weight indices: left ventricular weight/body weight (BW), right ventricular weight/BW, kidney weight/BW and lung weight/BW, and attenuating increases in infarct size, inner diameter of the left ventricle and collagen volume fraction in non-infarcted areas, and the decrease in mean wall thickness of infarcted myocardium. These results suggest that HSYA exerted beneficial actions in cardiac performance in models of both AHF and CHF, mainly by suppressing ET-1, iNOS and oxidative stress in infarcted tissue.

Topics: Acute Disease; Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Viscosity; Cardiotonic Agents; Chalcone; Chronic Disease; Coronary Vessels; Creatine Kinase; Diltiazem; Disease Models, Animal; Echocardiography; Endothelin-1; Heart Failure; Hemodynamics; L-Lactate Dehydrogenase; Ligation; Malondialdehyde; Nitric Oxide Synthase; Oxidative Stress; Quinones; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells (PASMCs) during hypoxia and may play a protective role in the response of the lung to hypoxia. Selective COX-2 inhibition may have detrimental pulmonary vascular consequences during hypoxia.. To investigate the role of COX-2 in the pulmonary vascular response to hypoxia, we subjected wild-type and COX-2-deficient mice to a model of chronic normobaric hypoxia. COX-2-null mice developed severe pulmonary hypertension with exaggerated elevation of right ventricular systolic pressure, significant right ventricular hypertrophy, and striking vascular remodeling after hypoxia. Pulmonary vascular remodeling in COX-2-deficient mice was characterized by PASMC hypertrophy but not increased proliferation. Furthermore, COX-2-deficient mice had significant upregulation of the endothelin-1 receptor (ET(A)) in the lung after hypoxia. Similarly, selective pharmacological inhibition of COX-2 in wild-type mice exacerbated hypoxia-induced pulmonary hypertension and resulted in PASMC hypertrophy and increased ET(A) receptor expression in pulmonary arterioles. The absence of COX-2 in vascular smooth muscle cells during hypoxia in vitro augmented traction forces and enhanced contractility of an extracellular matrix. Treatment of COX-2-deficient PASMCs with iloprost, a prostaglandin I(2) analog, and prostaglandin E(2) abrogated the potent contractile response to hypoxia and restored the wild-type phenotype.. Our findings reveal that hypoxia-induced pulmonary hypertension and vascular remodeling are exacerbated in the absence of COX-2 with enhanced ET(A) receptor expression and increased PASMC hypertrophy. COX-2-deficient PASMCs have a maladaptive response to hypoxia manifested by exaggerated contractility, which may be rescued by either COX-2-derived prostaglandin I(2) or prostaglandin E(2).

Topics: Animals; Blood Pressure; Cells, Cultured; Chronic Disease; Collagen; Cyclooxygenase 2; Dinoprostone; Endothelin-1; Gels; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Iloprost; Mice; Mice, Mutant Strains; Muscle Contraction; Muscle, Smooth, Vascular; Pulmonary Artery; Receptor, Endothelin A; Traction; Vasoconstriction; Vasodilator Agents

The study objective is to prove an association among plasma concentration of big endothelin and endothelin-1, other clinical parameters and two frequent polymorphisms - G8002A and -3A/-4A - in the endothelin-1 (EDN-1) coding gene (6p21-23), and among plasma concentration of TNF alpha and gene polymorphisms TNF alpha -308 A/G, -238 A/G, TNF beta Ncol and 3'TACE (tumour necrosis factor alpha converting enzyme) in patients with chronic heart failure (CHF). The second objective is to find an association between polymorphisms G8002A and -3A/4A EDN-1 with diabetes mellitus (DM), peripheral artery disease (PAD) and myocardial infarction (MI) in patients with chronic heart failure (CHF). The study population included 266 patients with symptomatic CHF and proven dysfunction of the left ventricle (LV). Genotyping and plasma concentrations of humoral substances were examined in 224 patients with ejection fraction (EF) below 40%. No associations between plasma concentrations of endothelin-1 and big endothelin and polymorphisms G8002A (p=0.87, p=0.81) and -3A/-4A (p=0.871, p=0.749) in the gene coding endothelin-1 were found. No associations were observed between plasma concentration of TNF alpha and genotypes in four polymorphisms in TNF alpha, beta and TACE genes. A significant correlation was seen between plasma concentration of big endothelin and pulmonary congestion. Patients with ischemic heart disease (IHD) and previous MI showed a difference in the distribution of genotype G8002A for endothelin-1: allele G 0.718 and A 0.282 vs those without MI: allele G 0.882 and A 0.118, (p<0.05). Patients with IHD and DM had allele G in 0.67 and A 0.33, while those without DM had allele G in 0.790 and A in 0.209 (p<0.03). Patients with IHD and concomitant PAD had allele G in 0.718 and A in 0.282 vs those without PAD allele G in 0.882 and A in 0.118 (p<0.0004). Patients with dilative cardiomyopathy (DCMP) showed no differences in genotype G8002A and presence of DM or PAD. It might be speculated that in the case of endothelin-1 and TNF alpha in CHF the genetic determination is not important, and plasma concentrations are influenced more by the disease severity. Ischemics with previous MI, concomitant DM or PAD showed more frequently allele A and less often allele G than those without these diseases. A genotype with allele A is associated with higher risk of concomitant diseases.

Topics: Biomarkers; Chronic Disease; Cytokines; Diabetes Mellitus; Endothelin-1; Female; Genetic Predisposition to Disease; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Peripheral Vascular Diseases; Polymorphism, Genetic; Risk Assessment

Endothelin-1 is a 21-amino-acid peptide with multifunctional regulation. Initial research indicated that endothelin-1 levels in the gingival crevicular fluid from patients with chronic periodontitis were higher than those in the gingival crevicular fluid from healthy subjects. The aim of the present study was to assess the relationship between the clinical parameters and the concentrations of endothelin-1 within the gingival crevicular fluid from inflamed gingiva and periodontitis sites and, subsequently, after the treatment of periodontitis sites.. A total of 60 subjects were divided into three groups - healthy (group I), gingivitis (group II) and chronic periodontitis (group III) - based on gingival index, pocket probing depth and clinical attachment loss. A fourth group consisted of 20 subjects from group III, 6-8 wk after treatment (i.e. scaling and root planing). Gingival crevicular fluid samples collected from each patient were quantified for endothelin-1 using an enzymatic immunometric assay.. Endothelin-1 was not detected in any sample from any of the study groups.. The results showed that all the gingival crevicular fluid samples were negative for the endothelin-1 molecule. Therefore, endothelin-1 cannot be considered as a potential biomarker of periodontal disease progression.

Topics: Adult; Biomarkers; Case-Control Studies; Chronic Disease; Endothelin-1; Female; Gingival Crevicular Fluid; Gingivitis; Humans; Male; Periodontitis

Increased levels of endothelin-1 (ET-1) in the carotid body (CB) contribute to the enhancement of chemosensory responses to acute hypoxia in cats exposed to chronic intermittent hypoxia (CIH). However, it is not known if the ET receptor types A (ETA-R) and B (ETB-R) are upregulated. Thus, we studied the expression and localization of ETA-R and ETB-R using Western blot and immunohistochemistry (IHC) in CBs from cats exposed to cyclic hypoxic episodes, repeated during 8 hr for 4 days. In addition, we determined if ET-1 is expressed in the chemoreceptor cells using double immunofluorescence for ET-1 and tyrosine hydroxylase (TH). We found that ET-1 expression was ubiquitous in the blood vessels and CB parenchyma, although double ET-1 and TH-positive chemoreceptor cells were mostly found in the parenchyma. ETAR was expressed in most chemoreceptor cells and blood vessels of the CB vascular pole. ETB-R was expressed in chemoreceptor cells, parenchymal capillaries, and blood vessels of the vascular pole. CIH upregulated ETB-R expression by approximately 2.1 (Western blot) and 1.6-fold (IHC) but did not change ETA-R expression. Present results suggest that ET-1,ETA-R, and ETB-R are involved in the enhanced CB chemosensory responses to acute hypoxia induced by CIH.

Topics: Animals; Blotting, Western; Carotid Body; Cats; Chronic Disease; Endothelin-1; Endothelins; Hypoxia; Immunohistochemistry; Male; Receptor, Endothelin A; Receptor, Endothelin B; Tyrosine 3-Monooxygenase

Acute hypoxia causes pulmonary vasoconstriction and coronary vasodilation. The divergent effects of hypoxia on pulmonary and coronary vascular smooth muscle cells suggest that the mechanisms involved in oxygen sensing and downstream effectors are different in these two types of cells. Since production of reactive oxygen species (ROS) is regulated by oxygen tension, ROS have been hypothesized to be a signaling mechanism in hypoxia-induced pulmonary vasoconstriction and vascular remodeling. Furthermore, an increased ROS production is also implicated in arteriosclerosis. In this study, we determined and compared the effects of hypoxia on ROS levels in human pulmonary arterial smooth muscle cells (PASMC) and coronary arterial smooth muscle cells (CASMC). Our results indicated that acute exposure to hypoxia (Po(2) = 25-30 mmHg for 5-10 min) significantly and rapidly decreased ROS levels in both PASMC and CASMC. However, chronic exposure to hypoxia (Po(2) = 30 mmHg for 48 h) markedly increased ROS levels in PASMC, but decreased ROS production in CASMC. Furthermore, chronic treatment with endothelin-1, a potent vasoconstrictor and mitogen, caused a significant increase in ROS production in both PASMC and CASMC. The inhibitory effect of acute hypoxia on ROS production in PASMC was also accelerated in cells chronically treated with endothelin-1. While the decreased ROS in PASMC and CASMC after acute exposure to hypoxia may reflect the lower level of oxygen substrate available for ROS production, the increased ROS production in PASMC during chronic hypoxia may reflect a pathophysiological response unique to the pulmonary vasculature that contributes to the development of pulmonary vascular remodeling in patients with hypoxia-associated pulmonary hypertension.

Topics: Acute Disease; Cells, Cultured; Chronic Disease; Coronary Vessels; Drug Administration Schedule; Endothelin-1; Humans; Hypoxia; Mitogens; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulmonary Artery; Reactive Oxygen Species; Superoxides; Vasoconstrictor Agents

We studied the effect of chronic endothelin A receptor blockade by atrasentan on the pulmonary endothelin-1 system and vascular endothelial growth factor (VEGF) expression in piglets with high pulmonary blood flow. Twenty-five 4-week-old piglets with high pulmonary blood flow were randomized to three groups: sham operated (n = 8), placebo (water) (n = 7), or treatment with atrasentan (2 mg/kg per day) (n = 10). After 3 months, mean pulmonary arterial pressure (PAP) was higher in the placebo group than in the sham group [18 +/- 2 mm Hg versus 14 +/- 1 mm Hg; P < 0.05 (ANOVA)]. Atrasentan treatment was associated with lower cardiac output, PAP (14 +/- 1 mm Hg), and medial wall thickness of pulmonary arteries (diameter: 50-150 microM) compared with placebo [13.6 +/- 3.0% versus 18.1 +/- 4.2%; P < 0.05 (ANOVA)]. Quantitative real-time polymerase chain reaction for endothelin-1, endothelin B receptor, and endothelin-converting enzyme-1 mRNA in lung tissue did not differ. However, immunostaining as well as mRNA for VEGF were lower in atrasentan-treated animals (relative gene expression: atrasentan versus placebo: 0.8 +/- 0.3 versus 1.5 +/- 0.3; P = 0.009). Atrasentan treatment effectively reduces medial hypertrophy in piglets with chronic pulmonary hyperperfusion. Chronic endothelin A receptor blockade by atrasentan may interfere with the expression of VEGF.

Topics: Animals; Atrasentan; Blood Pressure; Cardiac Output; Chronic Disease; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Hypertension, Pulmonary; Hypertrophy; Immunohistochemistry; Lung; Pulmonary Artery; Pulmonary Circulation; Pyrrolidines; Random Allocation; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Swine; Vascular Endothelial Growth Factor A

The severity and dynamics of renal tissue damage in chronic kidney disease (CKD) may be reflected by the urinary excretion of vasoactive and growth factors released by the damaged kidney. Urinary excretion of ET-1, TGF-beta1 and VEGF(165) was evaluated in 303 children with CKD stage II-IV (GFR 48 +/- 22 ml/min/1.73 m(2)) and 81 age-matched healthy controls. Major renal disease groups were hypo-/dysplastic kidney disease (N = 183), obstructive uropathies (N = 47), glomerulopathies (N = 34), nephronophthisis (N = 19) and polycystic kidney disease (N = 20).. The mean urinary excretion rates of each of the three putative biomarkers were significantly elevated in CKD patients compared to controls: 965 +/- 2042 vs 216 +/- 335 fmol/g creatinine for ET-1; 252 +/- 338 vs 155 +/- 158 ng/g for VEGF; 31.6 +/- 37.0 vs 10.9 +/- 9.8 ng/g for TGF-beta1 (each P < 0.0001). The excretion of ET-1 and TGF-beta1 was highest in patients with obstructive uropathies. In the patients, ET-1, TGF-beta1 and VEGF excretion rates were inversely correlated with age (r = -0.22, -0.32 and -0.17, all P < 0.005) and renal function (r = -0.21, -0.13 and -0.15; P < 0.001; < 0.05; < 0.01; respectively) VEGF and TGF-beta1 excretion rates were positively correlated both in patients and controls.. Children with CKD exhibit significantly elevated urinary excretion of ET-1, TGF-beta1 and VEGF(165) in comparison to healthy children. Urinary excretion of these biomarkers was most enhanced in patients with obstructive uropathies. A positive correlation between urinary TGF-beta1 and VEGF(165) excretion, shown both in patients and healthy controls, indicates an interdependent nature of their generation.

Topics: Child; Chronic Disease; Clinical Trials as Topic; Endothelin-1; Humans; Kidney Diseases; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

We recently developed a model of chronic intermittent hypoxia (CIH) (FiO2 5%, 8 h/day, 35 days) in the rat that was associated with an increased infarction in isolated heart. The aim of the present study was to characterize its functional consequences on vasoreactivity. Aorta and carotid artery were studied using organ bath technique while mesenteric vascular bed was perfused. In the three vascular beds, relaxation to acetylcholine was similar in CIH and control normoxic (NX) rats. Contractions to noradrenaline and angiotensin II were similar between CIH and NX rats. In contrast, contraction to endothelin-1 was increased by 17% (P < 0.05) in carotid artery from CIH rats. Indomethacin pre-treatment reduced by 24% (P < 0.001) contraction to endothelin-1 in carotid artery from CIH rats only. These data suggested that 35-day CIH-exposure induced no change in endothelial function of aorta, carotid artery and mesenteric bed. In contrast, CIH-exposure induced an increased contractile response to endothelin-1 in carotid artery, presumably owing to the release of constrictor cyclooxygenase-derived products.

Topics: Analysis of Variance; Animals; Aorta; Carotid Arteries; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Endothelin-1; Hypoxia, Brain; In Vitro Techniques; Male; Mesenteric Arteries; Potassium Chloride; Rats; Rats, Wistar; Vasoconstriction; Vasoconstrictor Agents

To describe and evaluate a semiquantitative optic nerve grading scheme for assessing axonal loss in endothelin (ET)-1-induced chronic optic neuropathy.. Optic nerve cross-sections from both eyes of 39 Brown Norway rats unilaterally treated with various concentrations of ET-1 or physiological saline solution via a surgically implanted osmotic minipump were processed for light and transmission electron microscopy (TEM). The optic nerve damage grade, between 0 (no damage) and 10 (total damage), was based on the number of zones of approximately equal damage and the mean percentage of damage within each zone. Grading was performed under light microscopy by three observers and compared with axonal survival determined with TEM using two quantification methods: the sampling method, in which approximately 10% of the section was counted, and the full-count method, in which the whole section was counted (n = 12). Axonal survival was expressed as a ratio of axon counts in the experimental to control eye. Before these comparisons, the inter- and intraobserver agreement rates were determined in another group of 85 and 12 ET-1-treated animals, respectively.. The interobserver kappa was 0.66 (95% confidence interval [CI]: 0.58-0.74) for all eyes and 0.55 (95% CI: 0.43-0.67) for the experimental eyes only. The intraobserver kappa was 0.80, 0.81, and 0.80 for all 24 eyes and 0.60, 0.64, and 0.71 for experimental eyes only. The correlation between damage grade in the experimental eye and axonal survival using the TEM sampling method (Spearman's rho = -0.677 for all animals and -0.827 for the subset of animals with full counts only) was lower than that with the full-count method (Spearman's rho = -0.926). When axonal survival was less than 0.7, the sampling method always underestimated the extent of damage.. The grading scheme had good inter- and intraobserver agreement, and high correlation with the TEM methods. It is a practical and time-saving method, requiring less than 1 minute per nerve and is an alternative to sampling methods that can yield significant errors.

Topics: Animals; Axons; Cell Count; Cell Survival; Chronic Disease; Disease Models, Animal; Endothelin-1; Male; Observer Variation; Optic Nerve; Optic Nerve Diseases; Rats; Rats, Inbred BN; Retinal Ganglion Cells

Topics: Animals; Carotid Body; Chronic Disease; Endothelin-1; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Rats; Rats, Sprague-Dawley; Time Factors

Topics: Animals; Bosentan; Carotid Body; Cats; Chronic Disease; Electrophysiology; Endothelin Receptor Antagonists; Endothelin-1; Hypoxia; Immunohistochemistry; In Vitro Techniques; Male; Sulfonamides

Elevated plasma and tissue endothelin (ET)-1 levels in patients with critical limb ischemia (CLI) has been described. Here the effect of a period of acute ischemia and subsequent reperfusion on plasma ET-1 and tissue ET-1/ET receptors in skeletal muscle biopsies from CLI patients undergoing femoro-distal bypass surgery was studied. Peripheral and "local" blood and muscle biopsies were obtained from patients undergoing femoro-distal bypass surgery, at the start of the procedure (control), after a period of vascular clamping (ischemia), and after clamp release (reperfusion). Plasma ET-1 was determined by enzyme-linked immunosorbent assay. Tissue ET-1 was assessed by counting ET-1 immunostaining cells per unit area, and ET(A)/ET(B) receptors were identified on sections by in vitro autoradiography in which binding was quantitatively assessed by densitometry. There was no significant effect of ischemia or reperfusion on plasma ET-1 levels or on ET(A)/ET(B) receptor binding. However, tissue ET-1 increased during both acute ischemia and reperfusion (P < 0.05). A high proportion of positive ET-1 immunostaining was associated with microvessels and also exhibited a similar distribution to macrophages. Previously, it has been shown that both plasma ET-1 and tissue ET-1/ET receptors are increased in CLI patients compared with atherosclerotic controls. Also, increased muscle ET-1 levels have been described in acute ischemia caused by tourniquet application in nonischemic patients undergoing total knee replacement. In CLI patients, in whom ET-1 is already upregulated, this further increase may exacerbate existing pathologic processes and contribute to ischemia-reperfusion injury. ET-1 antagonists may therefore be useful adjuncts in CLI and other surgical procedures in which ischemia-reperfusion damage occurs.

Topics: Acute Disease; Chronic Disease; Endothelin-1; Humans; Immunohistochemistry; Ischemia; Leg; Receptor, Endothelin A; Receptor, Endothelin B; Reperfusion

Endothelin regulates cytokine expression in vitro and in vivo. This study investigated the effects of chronic allograft rejection on hepatic endothelin-converting enzyme-1 (ECE-1) gene expression and endothelin-1 (ET-1) plasma clearance. Using the Lewis-F344 minor histocompatibility mismatch model of heterotopic cardiac transplantation, hepatic ECE-1 gene expression was measured by real-time polymerase chain reaction and host plasma clearance of ET-1 was measured 8 weeks after transplantation in the absence of immunosuppression. In animals undergoing allograft rejection, hepatic ECE-1 gene expression increased 2-fold (P < 0.05), whereas no effect of rejection on ET-1 clearance from plasma was observed. In summary, upregulation of ECE-1 gene expression occurs in the liver of the host during chronic allograft rejection. Because the liver represents both a key organ for cytokine production and for endothelin metabolism, increased hepatic ECE-1-mediated ET-1 synthesis may contribute to host responses and cytokine production during allograft rejection.

Topics: Animals; Aspartic Acid Endopeptidases; Chronic Disease; Endothelin-1; Endothelin-Converting Enzymes; Gene Expression Regulation, Enzymologic; Graft Rejection; Heart Transplantation; Liver; Metalloendopeptidases; Rats; Rats, Inbred F344; Rats, Inbred Lew; Time Factors; Transplantation, Homologous; Up-Regulation

Pressure overload in the left ventricle of the heart follows a chronic and progressive course, resulting in eventual left heart failure and pulmonary hypertension (PH). The purpose of this research was to determine whether a differential pulmonary gene change of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS) occurred in adult rats with left ventricular overload. Eight groups of eight rats each were used (four rats with banding and four rats with sham operations). The rats underwent ascending aortic banding for 1 day, 2 weeks, 4 weeks, and 12 weeks before sacrifice. Significant medial hypertrophy of the pulmonary arterioles developed in two groups (4 and 12 weeks). Increased pulmonary arterial pressures were noted in three groups (1 day, 4 weeks, and 12 weeks). The aortic banding led to significant increases in pulmonary preproET-1 messenger RNA (mRNA) at 1 day and 12 weeks, and in pulmonary eNOS mRNA at 1 day and 12 weeks. In addition, there was increased pulmonary eNOS content at 1 day and 12 weeks in the banded rats, and increased lung cGMP levels were observed at 1 day. Increased lung ET-1 levels were also noted at 1 day (banded, 310 +/- 12 ng/g protein; sham, 201 +/- 12 ng/g protein; P < 0.01), 4 weeks (banded, 232 +/- 12 ng/g protein; sham, 201 +/- 12 ng/g protein; P < 0.01) and 12 weeks (banded, 242 +/- 12 ng/g protein; sham, 202 +/- 12 ng/g protein; P < 0.01). This indicates that the upregulated expression of ET-1 developed at least 4 weeks before eNOS expression in the course of PH, and, thus, medication against ET-1 could play a crucial role in treating PH with cardiac dysfunction secondary to aortic banding.

Topics: Animals; Chronic Disease; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Lung; Male; Nitric Oxide Synthase Type III; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Ventricular Dysfunction, Left

Endothelin is elevated in heart failure and contributes to neurohormonal activation, hemodynamic deterioration, and cardiovascular remodeling. Here, we examined its prognostic value in a large population of patients with chronic heart failure.. Big endothelin-1 (Big ET-1) and 4 other neurohormones were measured at study entry in 2359 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) and their concentrations related to outcome over a median follow-up of 23 months. Baseline concentration of Big ET-1 (median 0.80 pmol/L) was proportional to severity of disease (New York Heart Association class, left ventricular structure and function). High circulating concentrations of brain natriuretic peptide (BNP), creatinine and bilirubin, advanced New York Heart Association class, elevated body mass index, and the presence of atrial fibrillation were independently associated to higher concentrations of Big ET-1. Big ET-1 (ranking second just behind BNP among neurohormonal factors) was an independent predictor of outcome defined as all-cause mortality (hazard ratio 1.49, 95% CI 1.20-1.84, P = .0003) or the combined endpoint of mortality and morbidity (hazard ratio 1.43, 95% CI 1.20-1.69, P < .0001) and provided incremental prognostic value compared with BNP.. In a large population of patients with symptomatic heart failure, the circulating concentration of Big ET-1, a precursor of the paracrine and bioactive peptide ET-1, was an independent marker of mortality and morbidity. In this setting, BNP remained the strongest neurohormonal prognostic factor.

Topics: Aged; Cardiac Output, Low; Chronic Disease; Endothelin-1; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Natriuretic Peptide, Brain; Osmolar Concentration; Prognosis; Proportional Hazards Models; Randomized Controlled Trials as Topic; Severity of Illness Index

Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO(2)) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO(2) would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO(2) was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O(2)) or moderate hypoxia (13% O(2)). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO(2) (but not to 5.5% CO(2)) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals (P < 0.05), whereas both concentrations of CO(2) normalized right ventricular performance. Exposure to 10% CO(2) attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO(2) on the lung and consequent modulating effects on the endothelin pathway.

Topics: Animals; Animals, Newborn; Body Weight; Carbon Dioxide; Carboxylic Acids; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Female; Hematocrit; Hypercapnia; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Indans; Oxidative Stress; Oxygen; Pregnancy; Pulmonary Artery; Pulmonary Circulation; Rats; Up-Regulation

Chronic allograft nephropathy is a sclerotic process characterized by an increased extracellular matrix (ECM) protein deposition. Fibronectin (FN) is a major component of ECM. FN has been reported to undergo alternative splicing and produce several isoforms including the extra domain-B (ED-B) containing embryonic isoform. In the present study, we investigated ED-B FN expression in chronic allograft nephropathy and its relationship with endothelins (ET).. To establish chronic allograft nephropathy, allografts were performed between Fisher 344 --> Lewis rats. Allograft recipients were then randomly divided into two groups, allografts and allografts treated with ET receptor antagonist bosentan. Lewis --> Lewis recipients were used as isograft controls. Grafts were harvested at 30, 90 and 140 days for histological and gene expression analyses with respect to ED-B FN, ET-1 and transforming growth factor-beta1 (TGF-beta1) mRNA. ED-B FN protein levels were assessed by immunohistochemical analysis. Additionally, we analyzed human renal allograft biopsies.. Our data demonstrates that rat chronic allograft nephropathy is associated with progressive upregulation of ED-B FN mRNA and protein. ET-1 and TGF-beta1 mRNA were also upregulated. Treatment of allograft recipient rats with bosentan prevented upregulation of ED-B FN and TGF-beta1. We further show that total FN, ED-B FN, ET-1 and TGF-beta1 mRNA expression were upregulated in human chronic allograft nephropathy specimens.. Results obtained from both human and rat renal allograft tissues suggest that expression of ED-B FN is upregulated in chronic allograft nephropathy and such upregulation is mediated via ET-1 and its interaction with TGF-beta1.

Topics: Adolescent; Adult; Aged; Animals; Biopsy; Child; Chronic Disease; Endothelin-1; Female; Fibronectins; Gene Expression Regulation; Graft Rejection; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Nephritis; Protein Isoforms; Rats; RNA, Messenger; Transforming Growth Factor beta; Transplantation, Homologous

On the basis of previous observations, endothelin 1 (ET-1) has been suggested as contributing to the pathogenesis of Chagasic cardiomyopathy. Therefore, ET-1flox/flox;alpha-MHC-Cre(+) mice in which the ET-1 gene was deleted from cardiac myocytes and ET-1flox/flox;Tie 2 Cre(+) mice in which the ET-1 gene was deleted from endothelial cells were infected with Trypanosoma cruzi. Genetic controls for these cell-specific ET-1 knockout mice were used. Ninety percentage of all mice survived acute infection with the Brazil strain and were evaluated 130 days postinfection. Inflammation and fibrosis were observed in all infected mice; however, fibrosis was reduced in ET-1flox/flox;alpha-MHC-Cre(+) mice. Cardiac magnetic resonance imaging revealed that infection resulted in a significant increase in right ventricular internal diameter (RVID) in all mice except ET-1flox/flox;alpha-MHC-Cre(+) mice; i.e., RVID was not changed in infected ET-1flox/flox;alpha-MHC-Cre(+) mice. Echocardiography of the left ventricle demonstrated increased left ventricular end-diastolic diameter, reduced fractional shortening, and decreased relative wall thickness in infected mice. However, the magnitude of the changes was significantly less in ET-1flox/flox;alpha-MHC-Cre(+) mice compared to other groups. These data provide further evidence of a role for ET-1, particularly cardiac myocyte-derived ET-1, in the pathogenesis of chronic Chagasic cardiomyopathy.

Topics: Animals; Chagas Cardiomyopathy; Chronic Disease; Echocardiography; Endothelin-1; Magnetic Resonance Imaging; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Parasitemia

Effacement of podocyte foot processes occurs in many proteinuric nephropathies and is accompanied by rearrangement of the actin cytoskeleton. Here, we studied whether protein overload affects intracellular pathways, leading to cytoskeletal architecture changes and ultimately to podocyte dysfunction. Mouse podocytes bound and endocytosed both albumin and IgG via receptor-specific mechanisms. Protein overload caused redistribution of F-actin fibers instrumental to up-regulation of the prepro-endothelin (ET)-1 gene and production of the corresponding peptide. Increased DNA-binding activity for nuclear factor (NF)-kappaB and Ap-1 nuclear proteins was measured in nuclear extracts of podocytes exposed to excess proteins. Both Y27632, which inhibits Rho kinase-dependent stress fiber formation, and jasplakinolide, an F-actin stabilizer, decreased NF-kappaB and Ap-1 activity and reduced ET-1 expression. This suggested a role for the cytoskeleton, through activated Rho, in the regulation of the ET-1 peptide. Focal adhesion kinase (FAK), an integrin-associated nonreceptor tyrosine kinase, was phosphorylated by albumin treatment via Rho kinase-triggered actin reorganization. FAK activation led to NF-kappaB- and Ap-1-dependent ET-1 expression. These data suggest that reorganization of the actin cytoskeletal network in response to protein load is implicated in modulation of the ET-1 gene via Rho kinase-dependent FAK activation of NF-kappaB and Ap-1 in differentiated podocytes. Increased ET-1 generation might alter glomerular permselectivity and amplify the noxious effect of protein overload on dysfunctional podocytes.

Topics: Actins; Animals; Cell Differentiation; Cell Line, Transformed; Chronic Disease; Cytoskeleton; Endothelin-1; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Gene Expression; Humans; Immunoglobulin G; Intracellular Membranes; Kidney; Kidney Diseases; Mice; Microfilament Proteins; NF-kappa B; Permeability; Protein-Tyrosine Kinases; Serum Albumin; Signal Transduction; Tissue Distribution; Transcription Factor AP-1

We evaluated whether there was any relation between myocardial injury and endothelin-1 (ET-1) levels, which has been suggested as a contributor to the progression of ischemic heart failure. One hundred and twenty-one patients with chronic ischemic heart failure and 37 healthy individuals were included in the study. Cardiac troponin-I (cTn-I) and ET-1 levels of all subjects were measured on admission. Echocardiographic evaluations were also performed. The positivity of cTn-I increased significantly as the severity changed from New York Heart Association (NHYA) Class I to IV (P < 0.01). This was also true for quantitative cTn-I levels (P < 0.05). The ET-1 levels of patients were higher than controls on admission (P < 0.001). The ET-1 levels increased significantly upon the progression from NHYA Class I to IV (P < 0.001). Moreover, patients with cTn-I positivity had higher ET-1 levels (P < 0.05) and a lower ejection fraction (P < 0.001). A negative correlation was found between ejection fraction and the ET-1 levels (r = -0.312, P = 0.019). In patients with cTn-I positivity, the cTn-I levels showed a positive correlation with the ET-1 levels (r = 0.328, P = 0.014) and a negative correlation with ejection fraction (r = -0.671, P < 0.001). In chronic ischemic heart failure, an increase in ET-1 may exert an influence on the progression of cardiac failure by leading to myocardial injury which may be demonstrated by higher cTn-I levels.

Topics: Analysis of Variance; Case-Control Studies; Chi-Square Distribution; Chronic Disease; Echocardiography; Endothelin-1; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Severity of Illness Index; Troponin I

Chronic hypoxia (CH) is a common cause of pulmonary hypertension (PH). Accumulating evidence suggests that changes in the activity of endothelin (ET)-1 receptors may play an important role in CH-induced PH. After 3 weeks of CH (10% O2) exposure, we found that the isolated intra-pulmonary artery (PA) constrictor response to ET-1 was significantly increased in wild-type (wt) mice. The administration of Cu/Zn superoxide dismutase (SOD) markedly reduced the CH-enhanced maximal PA constrictor response to ET-1, demonstrating the contribution of superoxide to CH-enhanced PA constrictor responses. Using mice that are completely deficient in gp91phox (a subunit protein of the superoxide producing nicotinamide adenine dinucleotide phosphate [NADPH] oxidase), we found that CH-enhanced PA constriction to ET-1 was completely blocked (decreases in mean [+/- SE] maximal isometric tension from 5.43 +/- 0.35 to 3.33 +/- 0.19 mN; n = 7; p < 0.01). Using a lucigenin-enhanced chemiluminescence technique to measure superoxide, we found that the 3 weeks of CH significantly increased superoxide levels in PA isolated from wt mice. The addition of ET-1 further increased superoxide production. To demonstrate that the increased chemiluminescence is due to superoxide generation, we added Cu/Zn SOD, which markedly decreased chemiluminescence, demonstrating the specificity of this assay. When gp91phox knockout mice were exposed to CH, they had significantly reduced levels of superoxide compared to CH-treated wt mice. Our results demonstrate that the CH-enhanced PA constrictor response to ET-1 is mediated by NADPH oxidase (gp91phox)-derived superoxide overproduction that may contribute to the pathogenesis of CH-induced PH.

Topics: Animals; Chronic Disease; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Luminescence; Luminescent Measurements; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; NADPH Oxidase 2; NADPH Oxidases; Pulmonary Artery; Superoxides; Vasoconstriction

1. The purpose of this study was to investigate whether a membrane-permeable superoxide dismutase mimetic, tempol, added either alone or in combination with the nitric oxide (NO) donor molsidomine, prevents the development of pulmonary hypertension (PH) in chronic hypoxic rats. 2. Chronic hypobaric hypoxia (10% oxygen) for 2 weeks increased the right ventricular systolic pressure (RVSP), right ventricle and lung wet weight. Relaxations evoked by acetylcholine (ACh) and the molsidomine metabolite SIN-1 were impaired in isolated proximal, but not distal pulmonary arteries, from chronic hypoxic rats. 3. Treatment with tempol (86 mg x kg(-1) day(-1) in drinking water) normalized RVSP and reduced right ventricular hypertrophy, while systemic blood pressure, lung and liver weights, and blunted ACh relaxation of pulmonary arteries were unchanged. 4. Treatment with molsidomine (15 mg x kg(-1) day(-1) in drinking water) had the same effects as tempol, except that liver weight was reduced, and potassium and U46619-evoked vasoconstrictions in pulmonary arteries were increased. Combining tempol and molsidomine did not have additional effects compared to tempol alone. ACh relaxation in pulmonary arteries was not normalized by these treatments. 5. The media to lumen diameter ratio of the pulmonary arteries was greater for the hypoxic rats compared to the normoxic rats, and was not reversed by treatment with tempol, molsidomine, or the combination of tempol and molsidomine. 6. We conclude that tempol, like molsidomine, is able to correct RVSP and reduce right ventricular weight in the rat hypoxic model. Functional and structural properties of pulmonary small arteries were little affected. The results support the possibility that superoxide dismutase mimetics may be a useful means for the treatment of PH.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Administration, Oral; Animals; Body Weight; Chronic Disease; Cyclic N-Oxides; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Endothelin-1; Free Radical Scavengers; Heart Rate; Hypertrophy, Right Ventricular; Hypoxia; Male; Molsidomine; Muscle, Smooth, Vascular; Organ Size; Pulmonary Artery; Rats; Rats, Wistar; Spin Labels; Superoxide Dismutase; Vasoconstriction; Vasodilation; Ventricular Pressure

1. Peroxisome proliferator activated receptor gamma (PPARgamma) has been implicated in several cellular pathways assumed to beneficially affect heart failure progression. In contrast, population-based studies demonstrate an increased incidence of heart failure in patients treated with PPARgamma agonists. Therefore, we examined the effect of pioglitazone, a PPARgamma agonist, on chronic left ventricular remodeling after experimental myocardial infarction (MI) in mice. 2. Mice were treated with placebo or pioglitazone (20 mg x kg(-1) by gavage) from week 1 to week 6 after ligation of the left anterior descending artery. Serial transthoracic echocardiography was performed at weeks 1, 3, and 6. 3. Over 6 weeks, there was no difference in mortality (placebo 12%, pioglitazone 10%). Echocardiography showed significant left ventricular dilatation in animals with MI (week 6, end-systolic area, placebo sham 9.6+/-1.3 vs placebo MI 14.4+/-2.5 mm(2)). However, there was no difference between the placebo and pioglitazone groups (week 6, end-systolic area, pioglitazone MI 14.8+/-2.9 mm(2), P=NS vs placebo). 4. Moreover, there were no changes in metabolic parameters, inflammation, and collagen deposition. Endothelial function in the aorta was not changed by PPARgamma activation. 5. In conclusion, PPARgamma activation did not adversely affect left ventricular remodeling and survival in mice with chronic MI. However, we were also not able to identify a protective effect of pioglitazone.

Topics: Animals; Aorta; Blood Glucose; Body Weight; Chronic Disease; Collagen; Coronary Vessels; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Echocardiography; Endothelin-1; Endothelium, Vascular; Inflammation Mediators; Intubation, Gastrointestinal; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Organ Size; Phenylephrine; Pioglitazone; Thiazolidinediones; Triglycerides; Vasoconstriction; Ventricular Dysfunction, Left; Ventricular Remodeling

To describe a model of chronic endothelin (ET)-1 administration to the optic nerve and evaluate its effect on retinal ganglion cell (RGC) and axon survival in rat.. Osmotic minipumps were surgically implanted in one eye of 113 Brown Norway rats to deliver 0.05, 0.10, 0.20, or 0.40 microg ET-1 per day (3.3, 6.7, 13.4, and 26.8 microM, respectively), or balanced salt solution (BSS) to the immediate retrobulbar optic nerve; the fellow untreated eye served as the control. Before pump implantation, RGCs were retrogradely labeled with fluorochrome. Animals were killed at 21, 42, or 84 days. RGC survival was expressed as the ratio of RGC counts in experimental versus control eyes in wholemounted retinas, whereas axon survival was expressed similarly from electron micrographs of the optic nerves. Serial optic disc changes were evaluated using scanning laser tomography. The effect of ET-1 (3 microL topical application of 10(-5) M) on blood flow in the surgically exposed optic nerve was measured using laser Doppler flowmetry in a separate group of five animals.. ET-1 led to a mean reduction in optic nerve blood flow of 68%. There were no significant differences in RGC survival among the four ET-1 doses used in this study. Pooled across all ET-1 doses, RGC survival decreased incrementally at 21, 42, and 84 days (P < 0.001; mean +/- SD, 0.77 +/- 0.25, 0.60 +/- 0.27, and 0.50 +/- 0.26, respectively) and was statistically significantly lower at each time point than in the BSS-treated animals. The axon survival data also showed a similar time-dependent loss. Only one of 21 animals showed significantly increased disc cupping, and there was no relationship between RGC survival and change in cupping. CONCLUSIONS. Chronic administration of ET-1 to the rat optic nerve results in a time-dependent loss of RGCs and their axons without apparent change in optic disc topography.

Topics: Animals; Axons; Cell Survival; Chronic Disease; Disease Models, Animal; Endothelin-1; Infusion Pumps, Implantable; Laser-Doppler Flowmetry; Male; Optic Disk; Optic Nerve Diseases; Rats; Rats, Inbred BN; Regional Blood Flow; Retinal Ganglion Cells

The first objective of the study was to compare the levels of big endothelin and endothelin-1 and other noninvasive parameters used for evaluation of disease severity in patients with stable chronic heart failure (CHF). Endothelin-1 and big endothelin plasma concentrations were measured in 124 chronic heart failure patients. The second objective of the study was to prove an association between endothelin-1 and big endothelin plasma levels and two frequent polymorphisms in the endothelin-1 coding gene (6p21-23) -3A/-4A and G (8002) A in patients with chronic heart failure. Thirdly, we tried to associate other noninvasive parameters of CHF, especially cardiothoracic index (CTI), NYHA classification, signs of pulmonary congestion (PC) and ejection fraction (EF) with determined genotypes of the two ET-1 polymorphic variants. There were significant differences between big endothelin levels in NYHA II versus IV (P<0.001) and NYHA III versus IV (P<0.001) and endothelin-1 in NYHA II versus IV (P<0.001) and NYHA III versus IV (P<0.001). No associations between plasma levels of endothelin-1 and big endothelin and polymorphisms G (8002) A and -3A/-4A in gene coding endothelin-1 were found. In patients with CHF with CTI above 60% the number of carriers of genotypes with ET-1 8002A (AA and AG genotypes) increases. Concerning on the -3A/-4A ET-1 polymorphism, we observed a significant difference in genotype distribution as well as in allelic frequency in the group of patients with CTI above 60% between patients without and with pulmonary congestion. The allelic frequency of 3A allele is twice elevated in the patients with pulmonary congestion (37.8 vs. 78.1%, respectively).

Topics: Analysis of Variance; Cardiac Output, Low; Chi-Square Distribution; Chronic Disease; Endothelin-1; Endothelins; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Protein Precursors; Risk Factors

Endothelin-1 (ET-1) concentrations are elevated in patients with congestive heart failure (CHF), although the cause of this increase remains uncertain. We hypothesized that abnormalities in ET-1 production, clearance, or a combination of these may be the cause of elevated ET-1 concentrations in chronic CHF. The kinetics of clearance of ET-1 were measured with (125)I-labeled ET-1 in eight patients with CHF and five age-matched normal individuals. In both normal subjects and the CHF group, the kinetics of ET-1 clearance were best described by a three-compartment model. The steady-state volume of distribution of ET-1 was significantly greater in the CHF group compared with normal subjects (25.2 +/- 3.9 vs. 13.8 +/- 2.1 l/kg; P < 0.05). The total clearance rate from plasma was greater in the CHF group (0.119 +/- 0.018 vs. 0.047 +/- 0.013 l.kg(-1).min(-1); P = 0.05). The total body production rate of ET-1 was also significantly higher in patients with CHF (0.21 +/- 0.03. vs. 0.06 +/- 0.02 ng.kg(-1).min(-1); P < 0.05). It appears that increased ET-1 production rather than decreased clearance is the cause of elevated ET-1 concentrations in patients with chronic CHF.

Topics: Blood Pressure; Chronic Disease; Endothelin-1; Female; Heart Failure; Heart Rate; Humans; Iodine Radioisotopes; Kinetics; Male; Middle Aged; Models, Biological

To evaluate the effect of tumor necrosis factor (TNF), endothelin (ET) and nitric oxide (NO) on hyperdynamic circulation (HC) of rats with acute and chronic portal hypertension (PHT).. Chronic portal hypertension was induced in Wistar rats by injection of carbon tetrachloride. After two weeks of cirrhosis formation, L-NMMA (25 mg/kg) was injected into one group of cirrhotic rats via femoral vein and the experiment was begun immediately. Another group of cirrhotic rats was injected with anti-rat TNFalpha (300 mg/kg) via abdominal cavity twice within 48 h and the experiment was performed 24 h after the second injection. The blood concentrations of TNFalpha, ET-1 and NO in portal vein and the nitric oxide synthase (NOS) activity in hepatic tissue were determined pre-and post-injection of anti-rat TNFalpha or L-NMMA. Stroke volume (SV), cardiac output (CO), portal pressure (PP), superior mesenteric artery blood flow (SMA flow) and iliac artery blood flow (IAflow) were measured simultaneously. Acute portal hypertension was established in Wistar rats by partial portal-vein ligation (PVL). The parameters mentioned above were determined at 0.5 h, 24 h, 48 h, 72 h and 120 h after PVL. After the formation of stable PHT, the PVL rats were injected with anti-rat TNFalpha or L-NMMA according to different groups, the parameters mentioned above were also determined.. In cirrhotic rats, the blood levels of TNFalpha, NO in portal vein and the liver NOS activity were significantly increased (P<0.05) while the blood level of ET-1 was not statistically different (P>0.05) from the control animals (477.67+/-83.81 pg/mL vs 48.87+/-32.79 pg/mL, 278.41+/-20.11 micromol/L vs 113.28+/-14.51 micromol/L, 1.81+/-0.06 u/mg.prot vs 0.87+/-0.03 u/mg.prot and 14.33+/-4.42 pg/mL vs 8.72+/-0.79 pg/mL, respectively). After injection of anti-rat TNFalpha, the blood level of TNFalpha was lower than that in controls (15.17+/-18.79 pg/mL vs 48.87+/-32.79 pg/mL). The blood level of NO and the liver NOS activity were significantly decreased, but still higher than those of the controls. The blood level of ET-1 was not significantly changed. PP, SV, CO, SMAflow and IAflow were ameliorated. After injection of L-NMMA, the blood level of NO and the liver NOS activity were recovered to those of the controls. PP and CO were also recovered to those of the controls. SV, SMAflow and IAflow were ameliorated. In PVL rats, the blood levels of TNFalpha, NO in portal vein and the liver NOS activity were gradually increased and reached the highest levels at 48 h after PVL. The blood level of ET-1 among different staged animals was not significantly different from the control animals. PP among different staged animals (2.4+/-0.18 kPa at 0.5 h, 1.56+/-0.08 kPa at 24 h, 1.74+/-0.1 kPa at 48 h, 2.38+/-0.05 kPa at 72 h, 2.39+/-0.16 kPa at 120 h) was significantly higher than that in controls (0.9+/-0.16 kPa). After injection of anti-rat TNFalpha in 72 h PVL rats, the blood level of TNFalpha was lower than that in controls (14+/-14 pg/mL vs 48.87+/-32.79 pg/mL). The blood level of NO and the liver NOS activity were significantly decreased, but still higher than those of the controls. The blood level of ET-1 was not significantly changed. PP was decreased from 2.38+/-0.05 kPa to 1.68+/-0.12 kPa, but significantly higher than that in controls. SV, CO, SMAflow and IAflow were ameliorated. After injection of L-NMMA in 72 h PVL rats, the blood level of NO and the liver NOS activity were recovered to those of the controls. PP, SV, CO, SMAflow and IAflow were also recovered to those of the controls.. NO plays a critical role in the development and maintenance of HC in acute PHT and is a key factor for maintenance of HC in chronic PHT. TNFalpha may not participate in the hemodynamic changes of HC directly, while play an indirect role by inducing the production of NO through activating NOS. No evidence that circulating ET-1 plays a role in both models of portal hypertension has been found.

Topics: Acute Disease; Animals; Antineoplastic Agents; Chronic Disease; Endothelin-1; Enzyme Inhibitors; Hypertension, Portal; Liver; Liver Circulation; Male; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Portal Vein; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Chronic metabolic acidosis leads to an increase in NHE3 activity that is mediated by endothelin-1 (ET-1) expression and activation of the proximal tubule endothelin B receptor. Chronic metabolic acidosis increases preproET-1 mRNA abundance in kidney cortex, but the cell responsible has not been identified.. PreproET-1 mRNA abundance was quantified by competitive reverse transcription-polymerase chain reaction (RT-PCR) on tissue harvested from control rats or rats in which chronic metabolic acidosis was induced by addition of NH(4)Cl to the drinking water.. Chronic metabolic acidosis leads to an increase in preproET-1 mRNA expression in kidney cortex, proximal tubules, and glomeruli. The increase in preproET-1 expression correlates with the decrease in blood [HCO3(-)]. ET-1 expression is also increased by acidosis in abdominal aorta, but not in cardiac muscle.. In the renal proximal tubule, chronic metabolic acidosis induces an increase in preproET-1 expression, providing a mechanism for autocrine regulation of proximal tubule NHE3 activity. This response is not unique to the proximal tubule cell, but is also not ubiquitous.

Topics: Acidosis; Animals; Aorta; Autocrine Communication; Chronic Disease; Endothelin-1; In Vitro Techniques; Kidney Cortex; Kidney Glomerulus; Kidney Tubules, Proximal; Male; Myocardium; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers

Glaucoma is a progressive optic neuropathy with characteristic optic disc changes, retinal ganglion cell loss and progressive visual field defects. Elevated intraocular pressure is considered to be a major risk factor in glaucomatous neuropathy. This study aimed to characterize and document a new chronic glaucoma model in the rat with respect to the effect of elevated intraocular pressure on overall retinal dysfunction and retinal ganglion cell loss, and to elucidate the possible mechanisms underlying this cell loss. Intraocular pressure (IOP) was measured in rats using a Tonopen. RGCs were retrogradely labeled with the fluorescent dye, 4-[didecylaminostyryl]-N-methyl-pyridinium-iodide (4-Di-10 ASP) and quantified on retinal flat mounts using fluorescence microscopy. The optic nerve head was examined fundoscopically. Changes in the histological appearance of the whole eyes was studied in paraffin sections, and immunohistochemistry was carried out on cryostat sections. The levels of mRNA for several genes were compared between control and glaucomatous retinae using semi-quantitative RT-PCR. Mutant animals are affected with either a unilateral or bilateral enlargement of the globes having an IOP that ranged from 25 to 45 mmHg, as compared to control values of 12-16 mmHg. The IOP of glaucomatous eyes increased significantly with age to attain a value of 35+/-7.3 at 1.5 years. Concomitant with the rise in IOP, the number of labeled RGCs continued to decrease in number with age. A total of 1887+/-117RGC mm(-2) could be labeled in wild-type control and juvenile mutant pre-glaucomatous retinas, whereas this number dropped to 92+/-26RGC mm(-2) at 1.5 years. Ophthalmoscopy revealed atrophied optic nerve heads in the affected eyes. The pars plicata and the pars plana of the ciliary body of glaucomatous eyes were hypertrophied and elongated, respectively. The anterior chamber was narrow and the irido-corneal angle open in glaucoma eyes. The mRNA of glial-fibrillary-acidic protein, endothelin-1, STAT-3 and STAT-6 increased in the retinas correlating with the severity and duration of the disease. Changes in the expression of GFAP and endothelin-1 could be confirmed using immunohistochemistry. This model may help to address several fundamental issues in the pathogenesis of glaucoma and aid in the development of neuroprotective strategies.

Topics: Animals; Cell Count; Chronic Disease; Ciliary Body; DNA-Binding Proteins; Endothelin-1; Female; Glaucoma; Glial Fibrillary Acidic Protein; Immunohistochemistry; Male; Models, Animal; Optic Nerve; Phenotype; Rats; Rats, Mutant Strains; Retina; Retinal Ganglion Cells; RNA, Messenger; STAT3 Transcription Factor; STAT6 Transcription Factor; Trans-Activators

To study the role of calcineurin in the progression of right ventricle myocardial hypertrophy in rats exposed to chronic hypoxia by examining the effect of Ca(2+) channel blockers on the activation of calcineurin and plasma levels of nitric oxide (NO), NO synthase, and endothelin-1 (ET-1).. Rat models of right ventricle myocardial hypertrophy were established by exposing the rats to chronic hypoxia in 10.0%+/-0.5% O(2) for 7 d. The 24 rat models were assigned into normoxic group, hypoxic group and cyclosporin A (CsA)-treated hypoxic group. The rats in normoxic group were kept under normoxic environment, while those in the other 2 groups were subjected to further hypoxic treatment for 14 d, with the rats in CsA group receiving intraperitoneal CsA injection at 20 mg/kg on a daily basis. On day 21 of the experiment, all the rats were killed to collect the hearts for measuring the weight ratio of the right ventricle to the left ventricle and interventricular septum [RV/ LV+S ], as well as the right ventricle to body weight ratio (RV/BW); blood samples were also drawn from the ventricles for measuring plasma NO, iNOS, and ET-1 levels, with the ventricular myocardial [Ca(2+)](i) and the activity of calcineurin also determined.. The RV/(LV+S) and RV/BW were significantly higher in hypoxic group than those of the normoxic and CsA groups (P<0.01); the right ventricular myocardial [Ca(2+)](i) in CsA group was significantly higher than that in the other two groups (P<0.01). In comparison with the normoxic group, the right ventricular myocardial calcineurin activity was significantly increased in the hypoxic group. CsA treatment significantly suppressed calcineurin activity (P<0.01).. Calcineurin possibly plays a role in the progression of right ventricle myocardial hypertrophy in rats with chronic hypoxia. Blocking L-type Ca(2+) channels with CsA effectively prevents the development of myocardial hypertrophy possibly by inhibiting calcium influx and suppressing calcineurin activity.

Topics: Animals; Calcineurin; Chronic Disease; Cyclosporine; Endothelin-1; Female; Hypoxia; Immunosuppressive Agents; Male; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Rats

A comprehensive evaluation of the effects of neuroprotection, neurogenesis, and compensatory mechanisms on the outcome of ischemic insults requires assessment of morphological and functional parameters. Behavioural tests are essential when recording performance throughout the time course of an experiment and the results bear predictive value in preclinical animal models. The goal of this study was to establish a behavioural test procedure for a model of transient focal ischemia induced by injection of endothelin-1 (eMCAO) that results in relatively mild behavioural deficits. The test protocol used in the present study allows evaluation of quantitative and qualitative impairments in skilled motor performance and is sensitive to detect chronic deficits at chronic post-ischemic time intervals. The ladder rung walking task [J. Neurosci. Methods 115 (2002) 169] is a motor test that assesses skilled walking and measures both forelimb and hindlimb placing, stepping and inter-limb co-ordination. In this study we tested the effect of two different technical variants of endothelin-1 application on infarct volume and motor skills (1) application via pre-implanted guiding cannula in awake animals and (2) via direct injection under halothane anaesthesia. We showed that the ladder rung walking task is sensitive in the assessment of loss of fine motor function after induction of relatively small lesions. In animals with implanted cannulas we found a smaller infarct area and an increase in placement errors prior to ischemia animals with eMCAO under anaesthesia showed a long lasting impairment of the contralateral forelimb up to 4 weeks post-eMCAO.

Topics: Anesthetics, Inhalation; Animals; Behavior, Animal; Brain Infarction; Brain Ischemia; Chronic Disease; Disease Models, Animal; Endothelin-1; Halothane; Hindlimb; Male; Physical Conditioning, Animal; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Somatosensory Cortex; Statistics, Nonparametric; Time Factors; Wakefulness; Walking

To evaluate the effects of chronic optic nerve ischemia in a nonhuman primate model and to evaluate the regional variability of axonal loss.. Unilateral ischemic optic neuropathy was induced by administration of endothelin-1 to the retrobulbar space via osmotic pumps in 12 primates for 6 to 12 months. The transversely cut sections were stained and divided into 16 regions. Average axonal density in each region was quantified and compared with the untreated contralateral control eyes.. Mean axonal density was 208 310/mm(2) and 220 661/mm(2) in treated and control eyes, respectively (P = .03, 1-tailed paired t test), for the entire group. Two-way analysis of variance showed a significant effect of endothelin-1 on overall axonal density for the experimental group (P<.001). Among the nerves with significant axonal loss, the mean axonal loss was 11.6% (4%-21%). Regional mapping of the damage showed the axonal loss varied in the damaged nerves; the damaged regions often clustered within specific quadrants.. Chronic ischemia induced by local administration of endothelin-1 causes significant loss of optic nerve axons with varying regional susceptibility. Clinical Relevance Localized damage occurs in other types of optic neuropathy, such as glaucoma, and may result from regional differences in anatomy, metabolism, or vasculature of the primate optic nerve.

Topics: Animals; Axons; Cell Count; Chronic Disease; Disease Models, Animal; Endothelin-1; Female; Intraocular Pressure; Macaca mulatta; Optic Nerve; Optic Neuropathy, Ischemic

To investigate the hemodynamic effects of tezosentan in the intact lamb both at rest and during acute and chronic pulmonary hypertension.. Prospective, randomized experimental study.. University-based research laboratory.. Lambs with and without pulmonary hypertension.. Six newborn lambs were instrumented to measure vascular pressures and left pulmonary blood flow. The hemodynamic effects of tezosentan (0.5, 1.0, 5.0 mg/kg, intravenously) were studied at rest and during U46619-induced pulmonary hypertension. Following in utero placement of an aortopulmonary vascular graft, nine additional lambs with increased pulmonary blood flow and chronic pulmonary hypertension (shunt) were also studied at 1 wk (n = 5) and 8 wks (n = 4) of age.. At rest, tezosentan had no significant effect on any of the variables. During acute U46619-induced pulmonary hypertension, tezosentan caused a dose-dependent decrease in pulmonary arterial pressure (from 5.9% +/- 4.7 to 16.0% +/- 10.7; p < .05) and pulmonary vascular resistance (from 6.2% +/- 8.0 to 21% +/- 8.8; p < .05). Mean systemic arterial pressure was unchanged. In 1- and 8-wk-old shunt lambs with increased pulmonary blood flow, tezosentan (1 mg/kg) produced potent nonselective pulmonary vasodilation.. Tezosentan, a combined endothelin receptor antagonist optimized for parenteral use, induces potent selective pulmonary vasodilation during acute U46619-induced pulmonary hypertension and potent nonselective vasodilation in chronic pulmonary hypertension secondary to increased pulmonary blood flow. In general, the hemodynamic effects of bolus doses of tezosentan occurred within 60 secs of administration and lasted approximately 5-10 mins. The hemodynamic profile of intravenous tezosentan may make it a useful adjunct therapy for acute pulmonary hypertensive disorders and warrants further study.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Disease; Animals; Animals, Newborn; Chronic Disease; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hypertension, Pulmonary; Injections, Intra-Arterial; Pulmonary Circulation; Pyridines; Random Allocation; Sheep; Tetrazoles; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Endothelin-1[1-31] is a recently discovered member of the endothelin family with vasoactive properties in several animal models and in man in vivo. It is generated from big endothelin-1 by human mast cell chymase and may be a novel intermediary peptide in the production of endothelin-1[1-21]. Given that both big endothelin-1[1-38] and chymase activity are increased in chronic heart failure, the aim of this study was to determine whether plasma endothelin-1[1-31] concentrations are elevated in patients with chronic heart failure. Plasma endothelin-1[1-31] concentrations were measured by enzyme-linked immunosorbent assay in nine patients with chronic heart failure, and nine age- and sex-matched control subjects. Consistent with previous studies, plasma concentrations of big endothelin-1[1-38] were elevated in patients compared with controls (17.1 +/- 4.4 pg/mL vs 8.9 +/- 3.4 pg/mL, P = 0.002), although there were no differences in plasma endothelin-1[1-21] (3.3 +/- 0.4 pg/mL vs 3.4 +/- 0.7 pg/mL, P = 0.7) or endothelin-1[1-31] (both 1.1 +/- 0.1 pg/mL, P = 0.2) concentrations. We have demonstrated that patients with chronic heart failure have normal plasma endothelin-1[1-31] concentrations. This suggests that, in contrast to big endothelin-1[1-38], plasma endothelin-1[1-31] is unlikely to be a useful prognostic marker in patients with chronic heart failure.

Topics: Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Chronic Disease; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Heart Failure; Humans; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests; Reproducibility of Results

We tested the hypothesis that pulmonary endothelial nitric oxide synthase (eNOS) gene expression is primarily regulated by hemodynamic factors and is thus increased in rats with chronic hypoxic pulmonary hypertension. Furthermore, we examined the role of endothelin (ET)-1 in this regulatory process, since ET-1 is able to induce eNOS via activation of the ET-B receptor. Therefore, chronic hypoxic rats (10% O(2)) were treated with the selective ET-A receptor antagonist LU-135252 (50 mg x kg(-1) x day(-1)). Right ventricular systolic pressure and cross-sectional medial vascular wall area of pulmonary arteries rose significantly, and eNOS mRNA levels increased 1.8- and 2.6-fold after 2 and 4 wk of hypoxia, respectively (each P < 0.05). Pulmonary ET-1 mRNA and ET-1 plasma levels increased significantly after 4 wk of hypoxia (each P < 0.05). LU-135252 reduced right ventricular systolic pressure, vascular remodeling, and eNOS gene expression in chronic hypoxic rats (each P < 0.05), whereas ET-1 production was not altered. We conclude that eNOS expression in chronic hypoxic rat lungs is modified predominantly by hemodynamic factors, whereas the ET-B receptor-mediated pathway and hypoxia seem to be less important.

Topics: Animals; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression; Glyceraldehyde-3-Phosphate Dehydrogenases; Hematocrit; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Phenylpropionates; Pressure; Pulmonary Artery; Pulmonary Circulation; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; RNA, Messenger; Systole; Ventricular Function, Right

endogenous vasoconstrictor peptides may play a role in the pathophysiology of critical limb ischaemia (CLI). This study investigated endothelin-1 (ET-1) and urotensin-II (U-II) mRNA expression, peptide distribution and ET receptor subtype binding in chronically ischaemic muscle.. open muscle biopsies were taken from patients undergoing amputations for CLI and from patients undergoing coronary artery bypass surgery (controls). ET-1 and U-II mRNA expression in muscle biopsies was studied using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). ET-1 and U-II immunohistochemistry was performed on muscle sections and ET receptor binding studied using in vitro autoradiography.. ET-1 mRNA expression was significantly increased in CLI compared to controls (p<0.05) whilst no significant change in U-II expression occurred. ET-1 immunoreactivity was also increased in CLI with no difference in U-II immunostaining observed. ET(B) receptor binding was significantly increased in CLI (median 4, range 1-8 vs 2, range 1-3, dpm x 10(3)/mm(2), p=0.01, Mann-Whitney test) whilst ET(A) receptor binding was not significantly raised. Binding was associated with microvessels and macrophages.. in CLI, the ET-1 pathway is upregulated but U-II is unaffected. ET-1 may vasoconstrict microvessels and mediate inflammation in chronically ischaemic muscle. ET-1 binding to ET(B) receptors in particular may play an important role in the pathophysiology of CLI underscoring the therapeutic potential of ET(B) receptor antagonists in the management of CLI.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Autoradiography; Case-Control Studies; Chronic Disease; Endothelin-1; Female; Humans; Immunoenzyme Techniques; Ischemia; Leg; Male; Middle Aged; Muscle, Skeletal; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric; Up-Regulation; Urotensins

Recent reports have indicated that endothelin-induced vasoconstriction in isolated aortic vascular rings may be mediated by the production of superoxide anion. The purpose of this study was to determine the role of superoxide anion in mediating the chronic renal and hypertensive actions of endothelin. Endothelin-1 (5 pmol/kg per minute) was chronically infused into the jugular vein by use of mini-osmotic pump for 9 days in male Sprague-Dawley rats and in rats treated with the superoxide anion scavenger tempol (30 mg/kg per day). Mean arterial pressure in the endothelin-1-treated rats was 141+/-3 mm Hg, compared with 125+/-2 mm Hg in control rats. Endothelin-1 increased renal vascular resistance (15.3+/-2.5 versus 10+/-1.3 mm Hg/mL per minute) and decreased renal plasma flow (6.5+/-0.9 versus 8.7+/-0.7 mL/min) in control rats. Endothelin-1 also significantly increased TBARS in the kidney and urinary 8-isoprostaglandin F2alpha excretion. The increase in arterial pressure in response to endothelin-1 was completely abolished by tempol (127+/-4 versus 127+/-4 mm Hg). Tempol also markedly attenuated the renal plasma flow and renal vascular resistance response to endothelin-1. Tempol also significantly decreased the level of 8-isoprostaglandin F2alpha in the endothelin-1-treated rats. Tempol had no effect on arterial pressure or renal hemodynamics in control rats. These data indicate that formation of reactive oxygen species may play an important role in mediating hypertension induced by chronic elevations in endothelin.

Topics: Animals; Cells, Cultured; Chronic Disease; Cyclic N-Oxides; Dinoprost; Endothelin-1; F2-Isoprostanes; Free Radical Scavengers; Hemodynamics; Hypertension; Kidney; Male; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Spin Labels; Superoxides; Thiobarbituric Acid Reactive Substances; Vasoconstrictor Agents

The pathogenesis of arterial hypertension in autosomal dominant polycystic kidney disease (ADPKD) is complex and likely dependent on interaction of hemodynamic, endocrine and neurogenic factors. We decided to evaluate the role of endothelin (ET1) and nitric oxide (NO) in the regulation of arterial blood pressure (BP) and to determine plasma levels of ET1 and NO in the group of patients with ADPKD. The ADPKD group (18 patients, 6 men + 12 women, mean age 44.6+/-11.7 years, with creatinine clearancecorrig > 1.1 ml/s) was compared with a control group of 27 healthy volunteers of comparable age. Plasma levels of ET1 assessed by direct RIA determination in the group of ADPKD patients (11.03+/-1.8 fmol/ml) were significantly increased (p<0.001) in comparison with the control group (2.66+/-0.58 fmol/ml), while no significant differences were observed between normotensive and hypertensive patients in the ADPKD group. Serum levels of NO were evaluated according to the determination of serum levels of their metabolites - nitrites/nitrates. Serum levels of NO in the group of ADPKD patients (39.85+/-.38 micro mol/l) were significantly higher (p<0.05) in comparison with the control group (22.7+/-1.20 micro mol/l), whereas in the ADPKD group no significant differences were observed between normotensive and hypertensive patients. Thus, our study supports the concept of complex alteration of both vasoconstrictor and vasodilator systems in the pathogenesis of arterial hypertension in ADPKD.

Topics: Adult; Aged; Antioxidants; Chronic Disease; Creatine; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension; Lipid Peroxidation; Male; Middle Aged; Nitric Oxide; Polycystic Kidney, Autosomal Dominant

Endothelin (ET) and natriuretic peptides have prognostic significance in chronic heart failure (CHF). Because stimuli for forming these neurohormones differ, this study investigates whether their prognostic power depends on clinical stage and on length of the observation period.. Plasma big ET, B-type natriuretic peptide (BNP), N-terminal BNP (N-BNP), and N-terminal atrial natriuretic peptide (N-ANP), in addition to 11 clinical and hemodynamic variables, were obtained from 452 patients with left ventricular ejection fraction (LVEF)

Topics: Biomarkers; Cardiac Output, Low; Chronic Disease; Endothelin-1; Female; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptides; Prognosis; Risk Factors; Ventricular Dysfunction, Left

There is evidence that dampened responses to endogenous vasoconstrictors contribute to the hyperdynamic circulation that is characteristic of advanced cirrhosis. The aim of this study was to determine whether there is an altered vascular responsiveness to the endothelium derived constricting factor endothelin-1 (ET-1) in patients with decompensated chronic liver disease which might contribute to this abnormal circulatory state, and whether normal endothelin responses are restored following liver transplantation.. Using forearm plethysmography, we studied the vascular response to an intra-arterial ET-1 infusion in six patients with end stage cirrhosis, before and after liver transplantation, compared with six normal control subjects. Responses to the selective endothelin A (ET(A)) receptor subtype antagonist, BQ123, were also examined.. The forearm vessels of patients with cirrhosis vasodilated in response to ET-1 infusion while in healthy controls a marked vasoconstriction response was observed (p<0.0001, area under the curve time-blood flow was normal compared with the cirrhosis groups, ANOVA). Prior to commencement of liver transplant surgery, cirrhotic patients were confirmed to have a hyperdynamic circulation with a high cardiac index (4.07 (0.23) l/min/m(2) (normal range 2.8-3.6 l/min/m(2))) and low systemic vascular resistance index (1284 (115) dynxs/cm(5)/m(2) (normal range 1760-2600 dynxs/cm(5)/m(2))). Following transplantation, normal vasoconstrictor responses to ET-1 were restored. Responses to BQ123 were not different in patients with advanced cirrhosis compared with controls.. In patients with end stage cirrhosis, ET-1 produces vasodilatation at a dose that causes marked vasoconstriction in normal control subjects. This effect is not attributable to impairment of ET(A) receptor responses. Our findings suggest that altered endothelin responses may contribute to the generalised dilatation of the circulation that occurs in patients with advanced liver disease.

Topics: Analysis of Variance; Case-Control Studies; Chronic Disease; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Forearm; Humans; Infusions, Intravenous; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Peptides, Cyclic; Plethysmography; Postoperative Period; Vasodilation; Vasodilator Agents

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, and patients with chronic heart failure (CHF) are reported to have high plasma ET-1 levels. The aim of this study was to investigate the relation between plasma ET-1 levels and clinical correlates in patients with CHF. The effects of maximal exercise on plasma ET-1 levels were also investigated.. Plasma concentrations of ET-1, norepinephrine, and atrial and brain natriuretic peptide (ANP and BNP) both at rest and after maximal cardiopulmonary exercise test were determined in 100 patients with CHF (60 +/- 12 years, New York Heart Association [NYHA] class I-III, left ventricular ejection fraction [LVEF]=36 +/- 8%, peak oxygen uptake [VO2] = 18.2 +/- 5.0 mL/min/kg) and 27 controls.. Patients with NYHA class II and III CHF had higher ET-1 levels (controls, NYHA class I, II, III: 2.1 +/- 0.6, 2.1 +/- 1.0, 2.6 +/- 0.9, 3.4 +/- 0.8 pg/mL, analysis of variance P <.0001). Maximal exercise did not alter ET-1 levels in controls or in each CHF subgroup. When all CHF patients were analyzed together, cardiothoracic ratio (P<.01), peak VO2 (P<.001), plasma norepinephrine (P<.01), plasma ANP (P<.01), and plasma BNP (P<.001) were significantly related with resting ET-1 levels on univariate analysis. Multivariate analysis revealed peak VO2 and plasma BNP levels showed an independent and significant relationship with the resting plasma ET-1 levels.. Resting ET-1 levels were increased in symptomatic patients with CHF, and maximal exercise did not increase ET-1 levels. Peak VO2 and plasma BNP levels were independently associated with resting plasma ET-1 levels in patients with CHF.

Topics: Aged; Anaerobic Threshold; Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Endothelin-1; Exercise; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Norepinephrine; Severity of Illness Index; Statistics as Topic; Systole; Ventricular Dysfunction, Left

The work shows that patients with chronic colitis have an expressed endothelial dysfunction, which becomes apparent as an increase of the level of vasoconstrictor endothelin-1 and decrease of the level of vasodilator nitric oxide. The obtained data indicate the role of the endothelial dysfunction in the pathogenesis of chronic colitis. The efficiency of the complex therapy with the use of folic acid and zinkteral for the restoration of the endothelium function is marked in comparison with the group of the patients treated with the help of the basic therapy.

Topics: Adult; Chronic Disease; Colitis; Endothelin-1; Endothelium, Vascular; Female; Folic Acid; Humans; Male; Middle Aged; Nitric Oxide; Zinc Sulfate

Salivary endothelin (ET) concentrations have been shown to correlate with disease severity in patients with chronic heart failure (CHF). We undertook the present study to evaluate the stability of salivary ET under different handling conditions to assess its suitability as a biochemical marker in screening, diagnosis, and management of CHF.. Saliva samples were collected from healthy individuals and/or CHF patients, subjected to different handling conditions, and then stored at -80 degrees C until assayed by an ELISA for ET.. Salivary ET concentrations showed a time-dependent increase during storage at room temperature. After 72 h of incubation at room temperature, ET increased approximately 2.8-fold (P = 0.03). Simultaneously, salivary big ET showed a time-dependent 11.2-fold decrease (P <0.0001). This activity was blocked by an ET-converting enzyme (ECE) inhibitor, suggesting that these changes were attributable to ECE-dependent cleavage of endogenous big ET in saliva. Ex vivo conversion was also observed when samples were stored at 4 degrees C, but the magnitude of these changes was markedly smaller (P <0.0001). Posture also affected salivary ET concentrations in CHF patients. With a change from supine to seated rest, salivary ET concentrations increased 1.5- and 1.8-fold after 20 and 40 min, respectively (P = 0.01). With a return to supine rest, salivary ET concentrations returned to baseline concentrations (P = 0.008).. These data suggest that saliva sampling and handling conditions could markedly affect measurement of salivary ET. In particular, care should be taken to minimize ECE-dependent enzymatic conversion of endogenous big ET in saliva.

Topics: Adult; Aspartic Acid Endopeptidases; Biomarkers; Chronic Disease; Circadian Rhythm; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Enzyme-Linked Immunosorbent Assay; Heart Failure; Humans; Luminescent Measurements; Metalloendopeptidases; Middle Aged; Posture; Saliva; Specimen Handling; Temperature

Topics: Adaptation, Physiological; Animals; Carotid Body; Chronic Disease; Endothelin-1; Gene Expression Regulation; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Models, Neurological; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Transcription Factors; Vascular Endothelial Growth Factor A

We have previously shown that correction of hypomagnesemia by magnesium (Mg) supplementation ameliorates chronic cyclosporine A (CsA) nephropathy via inhibiting gene expression of fibrogenic molecules. Experiments were conducted to further elucidate upstream mechanism of the beneficial effects upon CsA nephrotoxicity.. CsA (15 mg/kg/day, subcutaneous [SC]) was administered daily to rats maintained on low sodium diet for 7, 14, and 28 days. Because blockade of renin-angiotensin system improves chronic CsA nephropathy, the effects of Mg supplementation and those of angiotensin-converting enzyme inhibitor (ACEI) were compared on renal function, renal histology, mononuclear cell infiltration, and gene expression profile.. CsA induced a decline in glomerular filtration and developed characteristic striped fibrosis that were mostly evident at day 28. Mg attenuated CsA-induced impaired renal function, whereas ACEI did not. Interstitial inflammation as evidenced by monocyte/macrophage infiltration preceded the renal fibrosis and increased progressively with the CsA treatment period. Concomitantly, CsA markedly up-regulated expression of chemoattractant proteins, osteopontin, and monocyte chemoattractant protein-1. These changes were abolished by Mg but were only partially affected with ACEI. CsA promoted renal mRNA expression of fibrogenic molecules and extracellular matrices that were almost completely abolished by Mg but partially suppressed by ACEI. Similarly, CsA-induced chronic fibrotic lesion was markedly attenuated by Mg supplementation but was partially attenuated by ACEI.. Mg supplementation abolished CsA-induced precedent interstitial inflammation possibly via inhibition of chemoattractants expression and consequently attenuated tubulointerstitial fibrosis. In this protective mechanism, factors independent of the renin-angiotensin system appears to be mainly involved.

Topics: Animals; Blotting, Northern; Chemokine CCL2; Chronic Disease; Collagen; Cyclosporine; Endothelin-1; Immunohistochemistry; Immunosuppressive Agents; Kidney; Magnesium; Male; Osteopontin; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Messenger; Sialoglycoproteins; Tissue Inhibitor of Metalloproteinase-1

To investigate the clinical effect and therapeutic mechanism of Nanmiqing capsule made of rheum palmatum, leech, astragalus memberanaceus on patients with chronic prostatitis(CP).. Seventy-six CP cases were treated with Nanmiqing, while 32 CP cases were treated with Qianliekang as a control. The changes of EPS were observed pre- and post-treatment. The rat model of CP got by Xiaozhiling inducing were treated with Nanmiqing and Qianliekang respectively. The concentration of endothelin, TXB2, 6-keto-PGF1 alpha and SOD, IgG, IgA in plasma were measured pre- and post-treatment, meanwhile, pathological changes of prostate tissues were observed.. The total effective rate was 89.47% in treatment group, which was significantly higher than 71.88% in the control group (P < 0.01). Experimental study for CP rats showed that the Nanmiqing was more effective medicine than Qianliekang (P < 0.01).. Nanmiqing was an effective medicine for CP. The mechanism of clearing heat and resolving toxin, activating blood and removing stasis and reinforcing Qi in chinese medicine could be the explanation of the useful treatment including three therapentic ways.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Capsules; Chronic Disease; Drugs, Chinese Herbal; Endothelin-1; Humans; Immunoglobulin A; Immunoglobulin G; Male; Middle Aged; Prostatitis; Superoxide Dismutase; Thromboxane B2; Treatment Outcome

Endothelin-1 (ET-1) excites carotid body (CB) chemoreceptors and induces mitosis of the chemoreceptors in chronic hypoxia. The aim of the present study was to examine the hypothesis that up-regulation of both ETA receptor and endogenous ET-1 expression in CB chemoreceptors enhances the response of intracellular Ca2+ to ET-1 following adaptation to chronic hypoxia (10% inspired O2 for 3-4 weeks). Cytosolic free [Ca2+] ([Ca2+]i) in type-I (glomus) cells freshly dissociated from rat CBs was measured by spectrofluorometry. Application of exogenous ET-1 (1-100 nM) concentration-dependently elevated [Ca2+]i in the glomus cells. This response to ET-1 (100 nM) was 49% greater in the chronically hypoxic (CH) group. The ET-1 response was abolished completely by the ETA receptor antagonist BQ610 (1 microM), but not by the ETB antagonist BQ788 (1 microM). The transient [Ca2+]i elevation induced by caffeine (30 mM) in the normoxic group was similar to that in the CH group, suggesting no differences in the intracellular Ca2+ stores. In situ hybridization with a digoxigenin-labelled antisense ETA receptor mRNA oligonucleotide probe revealed very intense and ubiquitous specific expression of ETA receptors in the lobules of glomus cells in the CH group, whereas staining in normoxic controls was light. Immunohistochemical studies revealed intense cytoplasmic staining for ET-1-immunoreactivity in most of the cell clusters in glomera in the CBs of CH rats but was faint in normoxic CBs. These findings indicate increased expression of both the ETA receptor and ET-1 in CB chemoreceptors during chronic hypoxia. Taken together, our results suggest that the [Ca2+]i response to ET-1 in rat CB chemoreceptors is augmented by up-regulation of ETA receptors and ET-1 expression. The enhancement of the paracrine/autocrine effect of ET-1 on the chemoreceptors is consistent with an excitatory and mitogenic role of the ET-1 and ETA receptor in the CB during chronic hypoxia.

Topics: Adaptation, Physiological; Animals; Calcium; Carotid Body; Chemoreceptor Cells; Chronic Disease; Endothelin-1; Female; Hypoxia; In Situ Hybridization; Male; Mitosis; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; RNA, Messenger; Up-Regulation

Chronic exposure in a low-PO(2) environment (i.e., chronic hypoxia, CH) elicits an elevated hypoxic ventilatory response and increased hypoxic chemosensitivity in arterial chemoreceptors in the carotid body. In the present study, we examine the hypothesis that changes in chemosensitivity are mediated by endothelin (ET), a 21-amino-acid peptide, and ET(A) receptors, both of which are normally expressed by O(2)-sensitive type I cells. Immunocytochemical staining showed incremental increases in ET and ET(A) expression in type I cells after 3, 7, and 14 days of CH (380 Torr). Peptide and receptor upregulation was confirmed in quantitative RT-PCR assays conducted after 14 days of CH. In vitro recordings of carotid sinus nerve activity after in vivo exposure to CH for 1-16 days demonstrated a time-dependent increase in chemoreceptor activity evoked by acute hypoxia. In normal carotid body, the specific ET(A) antagonist BQ-123 (5 microM) inhibited 11% of the nerve discharge elicited by hypoxia, and after 3 days of CH the drug diminished the hypoxia-evoked discharge by 20% (P < 0.01). This inhibitory effect progressed to 45% at day 9 of CH and to nearly 50% after 12, 14, and 16 days of CH. Furthermore, in the presence of BQ-123, the magnitude of the activity evoked by hypoxia did not differ in normal vs. CH preparations, indicating that the increased activity was the result of endogenous ET acting on an increasing number of ET(A). Collectively, our data suggest that ET and ET(A) autoreceptors on O(2)-sensitive type I cells play a critical role in CH-induced increased chemosensitivity in the rat carotid body.

Topics: Adaptation, Physiological; Animals; Antihypertensive Agents; Carotid Body; Chemoreceptor Cells; Chronic Disease; Electrophysiology; Endothelin Receptor Antagonists; Endothelin-1; Hypoxia; In Vitro Techniques; Male; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; RNA, Messenger; Time Factors

Given the high incidence of sudden death in patients with chronic heart failure (CHF) and the efficacy of implantable cardioverter-defibrillators, an appropriate tool for the prediction of sudden death is desirable. B-type natriuretic peptide (BNP) has prognostic significance in CHF, and the stimuli for its production cause electrophysiological abnormalities. This study tests BNP levels as a predictor of sudden death.. BNP levels, in addition to other neurohormonal, clinical, and hemodynamic variables, were obtained from 452 patients with a left ventricular ejection fraction (LVEF) < or =35%. For prediction of sudden death, only survivors without heart transplantation (HTx) or a mechanical assist device and patients who died suddenly were analyzed. Up to 3 years, 293 patients survived without HTx or a mechanical assist device, 89 patients died, and 65 patients underwent HTx. Mode of death was sudden in 44 patients (49%), whereas 31 patients (35%) had pump failure and 14 patients (16%) died from other causes. Univariate risk factors of sudden death were log BNP (P=0.0006), log N-terminal atrial natriuretic peptide (P=0.003), LVEF (P=0.005), log N-terminal BNP (P=0.006), systolic blood pressure (P=0.01), big endothelin (P=0.03), and NYHA class (P=0.04). In the multivariate model, log BNP level was the only independent predictor of sudden death (P=0.0006). Using a cutoff point of log BNP <2.11 (130 pg/mL), Kaplan-Meier sudden death-free survival rates were significantly higher in patients below (99%) compared with patients above (81%) this cutoff point (P=0.0001).. BNP levels are a strong, independent predictor of sudden death in patients with CHF.

Topics: Adrenergic beta-Antagonists; Alprostadil; Angiotensin-Converting Enzyme Inhibitors; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Cardiotonic Agents; Chronic Disease; Comorbidity; Death, Sudden, Cardiac; Endothelin-1; Endothelins; Enzyme-Linked Immunosorbent Assay; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Predictive Value of Tests; Prognosis; Protein Precursors; Risk Factors; Stroke Volume; Survival Analysis; Treatment Outcome

The regulation of pulmonary prostacyclin synthesis is not completely understood. We tested the hypothesis that prostacyclin production is predominantly stimulated by hemodynamic factors, such as increased shear-stress, and is thus increased in rats with chronic hypoxic pulmonary hypertension.. To this end, we determined pulmonary prostacyclin synthase (PGIS) gene expression, circulating levels of the stable prostacyclin metabolite 6-keto prostaglandin F(1alpha) (6-keto-PGF(1alpha)), pulmonary endothelin (ET)-1 gene expression, and ET-1 plasma levels in rats exposed to 4 weeks of hypoxia (10% O(2)) in the presence or absence of either the nitric oxide (NO) donor molsidomine (MD, 15 mg/kg/day) or the ET-A receptor antagonist LU135252 (LU, 50 mg/kg/day).. Right ventricular systolic pressure (RVSP), the cross-sectional medial vascular wall area of pulmonary arteries, and ET-1 production increased significantly during hypoxia. PGIS mRNA levels increased 1.7-fold, and 6-keto-PGF(1alpha) plasma levels rose from 8.2+/-0.8 to 12.2+/-2.2 ng/ml during hypoxia (each P<0.05 vs. normoxic controls). MD and LU reduced RVSP and pulmonary vascular remodeling similarly (each P<0.05 vs. hypoxia), but only MD inhibited pulmonary ET-1 formation (P<0.05 vs. hypoxia). Nevertheless, both drugs attenuated the increase in PGIS gene expression and plasma 6-keto-PGF(1alpha) levels (each P<0.05 vs. hypoxia).. Our data suggest that prostacyclin production in hypertensive rat lungs is predominantly increased by hemodynamic factors while hypoxia, NO and ET-1 per are less important stimuli, and that this increase may serve as a compensatory mechanism to partially negate the hypoxia-induced elevation in pulmonary vascular tone.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Chronic Disease; Cytochrome P-450 Enzyme System; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Intramolecular Oxidoreductases; Male; Models, Animal; Molsidomine; Nitric Oxide Donors; Phenylpropionates; Pulmonary Artery; Pyrimidines; Random Allocation; Rats; Rats, Wistar; Receptor, Endothelin A; RNA, Messenger; Systole; Ventricular Pressure

Altered regulation of blood pressure (BP) in hemodialysis patients is associated with increased morbidity and mortality. Regulation of BP is dependent in part on such vasoactive agents as nitric oxide (NO) and endothelin-1 (ET-1). Cytokine-mediated NO synthase activation during dialysis previously has been reported. The purpose of this study is to investigate the relationship between cytokine-mediated activation of the NO and ET-1 systems and BP regulation in hemodialysis patients.. Nine patients with chronic hypotension (predialysis systolic BP < 110 mm Hg, duration > 1 month), nine patients with hypertension (predialysis systolic BP > or = 180 mm Hg), and nine age- and sex-matched normotensive controls were enrolled.. Predialysis NO end product levels in the hypotensive group were greater than in controls (17.63 +/- 5.9 versus 11.06 +/- 2.12 microm/mL; P = 0.01), whereas the hypertensive group showed lower levels (4.76 +/- 2.33 microm/mL; P < 0.01). The hypotensive group had low postdialysis levels (3.45 +/- 1.11 microm/mL; P = 0.01). Predialysis ET-1 levels in the hypotensive and hypertensive groups were greater in comparison to the normotensive group (7.54 +/- 4.52 and 8.95 +/- 3.52 versus 4.41 +/- 0.6 pg/mL; P < 0.01). Postdialysis endothelin levels increased in both the control and hypertensive groups (P < 0.01). Interleukin-1 and tumor necrosis factor-alpha levels increased postdialysis in all groups, but not significantly.. High levels of NO end products in hypotensive patients and low levels in hypertensive patients suggest a critical influence of NO in BP control. In addition, elevated ET-1 levels in hypertensive patients may contribute to systemic vasoconstriction and may suggest vascular dysfunction in this patient population.

Topics: Adolescent; Adult; Blood Pressure; Chronic Disease; Endothelin-1; Female; Humans; Hypertension; Hypotension; Interleukin-1; Male; Middle Aged; Nitric Oxide; Renal Dialysis; Tumor Necrosis Factor-alpha

Filariasis, a mosquito-borne parasitic disease, is a worldwide health problem. There is still, some controversial concerning the diagnosis of acute and chronic infections. The serum levels of endothelin-1 (ET-1), interleukin-2 (IL-2) and amino-terminal propeptide Type III (PIII NP) was measured in patients with acute and chronic filariasis as compared with controls. The ET-1, IL-2 and PIII NP levels were significantly high in chronic cases than in acute. On the other hand, the serum levels of IL-2 and PIII NP were significantly high in acute cases than in the controls. These three immuno-mediators play role in the pathogenesis of filariasis particularly. The chronic cases. So, these mediators can be used as markers for diagnosis of human cases infected with chronic and acute filariasis.

Topics: Acute Disease; Adult; Animals; Chronic Disease; Endothelin-1; Female; Filariasis; Humans; Interleukin-2; Male; Peptide Fragments; Procollagen; Wuchereria bancrofti

We investigated the effects of the nitric oxide (NO) donor molsidomine and the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) on pulmonary endothelin (ET)-1 gene expression and ET-1 plasma levels in chronic hypoxic rats. Two and four weeks of hypoxia (10% O2) significantly increased right ventricular systolic pressure, the medial cross-sectional vascular wall area of the pulmonary arteries, and pulmonary ET-1 mRNA expression (2-fold and 3.2-fold, respectively). ET-1 plasma levels were elevated after 4 wk of hypoxia. In rats exposed to 4 wk of hypoxia, molsidomine (15 mg x kg(-1) x day(-1)) given either from the beginning or after 2 wk of hypoxia significantly reduced pulmonary hypertension, pulmonary vascular remodeling, pulmonary ET-1 gene expression, and ET-1 plasma levels. L-NAME administration (45 mg x kg(-1) x day(-1)) in rats subjected to 2 wk of hypoxia did not modify these parameters. Our findings suggest that in chronic hypoxic rats, exogenously administered NO acts in part by suppressing the formation of ET-1. In contrast, inhibition of endogenous NO production exerts only minor effects on the pulmonary circulation and pulmonary ET-1 synthesis in these animals.

Topics: Animals; Chronic Disease; Disease Models, Animal; Endothelin-1; Enzyme Inhibitors; Gene Expression Regulation; Glyceraldehyde-3-Phosphate Dehydrogenases; Hematocrit; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Molsidomine; NG-Nitroarginine Methyl Ester; Nitric Oxide Donors; Nitric Oxide Synthase; Pulmonary Artery; Rats; Rats, Wistar; RNA, Messenger; Vasodilator Agents

Recurrent episodic hypoxia (EH) is a feature of sleep apnea that may be responsible for some chronic cardiovascular sequelae such as systemic hypertension. Chronic EH (8 h/day for 35 days) causes elevation of diurnal resting (unstimulated) mean arterial blood pressure (MAP) in the rat. We used in vivo video microscopy to examine arteriolar reactivity in the cremaster muscle of male Sprague-Dawley rats subjected to 35 days of EH. Cremaster muscles of EH (n = 6) and control (n = 6) rats were exposed to varying doses of norepinephrine (NE) (10(-10) to 10(-5) M), ACh (10(-9) to 10(-5) M), and endothelin-1 (10(-12) to 10(-8) M). In a separate experiment, EH (n = 5) and control (n = 6) rats were given one dose of a nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 10(-5) M). We also examined endothelial NOS mRNA from the kidneys of EH-stimulated and control (unstimulated) rats. Telemetry-monitored EH rats showed a 16-mmHg increase in MAP over 35 days, whereas control rats showed no change. The response to NE and endothelin-1 were similar for EH and control rats. ACh vasodilatation of arterioles in EH rats was significantly attenuated compared with that of controls. The degree of vasoconstriction in response to blockade of the nitric oxide system by L-NAME was significantly less (83% of baseline diameter with L-NAME) for arterioles of EH rats compared with that for controls (61% of baseline diameter), implying lower basal resting nitric oxide release in the EH rats. Whole kidney mRNA endothelial NOS levels were not different between groups. These data support the hypothesis that chronic elevation of blood pressure associated with EH involves increased peripheral resistance from decreased basal release or production of nitric oxide after 35 days of EH.

Topics: Acetylcholine; Animals; Arterioles; Blood Pressure; Chronic Disease; Circadian Rhythm; Disease Models, Animal; Endothelin-1; Gene Expression Regulation, Enzymologic; Hypoxia; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Norepinephrine; Rats; Rats, Sprague-Dawley; Sleep Apnea Syndromes; Telemetry; Transcription, Genetic; Vasodilation

Endothelin-1 (ET-1) is elevated in chronic heart failure (CHF). In this study, we determined the effects of chronic ET-1 blockade on renal sympathetic nerve activity (RSNA) in conscious rabbits with pacing-induced CHF. Rabbits were chronically paced at 320--340 beats/min for 3--4 wk until clinical and hemodynamic signs of CHF were present. Resting RSNA and arterial baroreflex control of RSNA were determined. Responses were determined before and after the ET-1 antagonist L-754,142 (a combined ET(A) and ET(B) receptor antagonist, n = 5) was administered by osmotic minipump infusion (0.5 mg. kg(-1) x h(-1) for 48 h). In addition, five rabbits with CHF were treated with the specific ET(A) receptor antagonist BQ-123. Baseline RSNA (expressed as a percentage of the maximum nerve activity during sodium nitroprusside infusion) was significantly higher (58.3 +/- 4.9 vs. 27.0 +/- 1.0, P < 0.001), whereas baroreflex sensitivity was significantly lower in rabbits with CHF compared with control (3.09 +/- 0.19 vs. 6.04 +/- 0.73, P < 0.001). L-754,142 caused a time-dependent reduction in arterial pressure and RSNA in rabbits with CHF. In addition, BQ-123 caused a reduction in resting RSNA. For both compounds, RSNA returned to near control levels 24 h after removal of the minipump. These data suggest that ET-1 contributes to sympathoexcitation in the CHF state. Enhancement of arterial baroreflex sensitivity may further contribute to sympathoinhibition after ET-1 blockade in heart failure.

Topics: Acetamides; Animals; Antihypertensive Agents; Arteries; Baroreflex; Blood Pressure; Cardiac Output, Low; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Kidney; Peptides, Cyclic; Rabbits; Receptor, Endothelin A; Sympathetic Nervous System; Time Factors

Topics: Adult; Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Endothelin-1; Female; Humans; Male; Middle Aged; Radioimmunoassay

Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its products, we hypothesized that HO would be important for the regulation of blood pressure and ischemic injury. We studied chronic renovascular hypertension in mice deficient in the inducible isoform of HO (HO-1) using a one kidney-one clip (1K1C) model of disease. Systolic blood pressure was not different between wild-type (HO-1(+/+)), heterozygous (HO-1(+/-)), and homozygous null (HO-1(-/-)) mice at baseline. After 1K1C surgery, HO-1(+/+) mice developed hypertension (140+/-2 mm Hg) and cardiac hypertrophy (cardiac weight index of 5.0+/-0.2 mg/g) compared with sham-operated HO-1(+/+) mice (108+/-5 mm Hg and 4.1+/-0.1 mg/g, respectively). However, 1K1C produced more severe hypertension (164+/-2 mm Hg) and cardiac hypertrophy (6.9+/-0.6 mg/g) in HO-1(-/-) mice. HO-1(-/-) mice also experienced a high rate of death (56%) within 72 hours after 1K1C surgery compared with HO-1(+/+) (25%) and HO-1(+/-) (28%) mice. Assessment of renal function showed a significantly higher plasma creatinine in HO-1(-/-) mice compared with HO-1(+/-) mice. Histological analysis of kidneys from 1K1C HO-1(-/-) mice revealed extensive ischemic injury at the corticomedullary junction, whereas kidneys from sham HO-1(-/-) and 1K1C HO-1(+/-) mice appeared normal. Taken together, these data suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to an acute increase in ischemic damage and death in the absence of HO-1.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Cardiomegaly; Chronic Disease; Creatinine; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Heterozygote; Homozygote; Hypertension, Renovascular; Immunohistochemistry; Kidney; Membrane Proteins; Mice; Mice, Knockout; Nephrectomy; Organ Size; Receptor, Endothelin A; Renal Artery Obstruction; RNA, Messenger; Severity of Illness Index; Survival Rate

The effect of chronic hypoxia (CH) for 14 days on Ca2+ signaling and contraction induced by agonists in the rat main pulmonary artery (MPA) was investigated. In MPA myocytes obtained from control (normoxic) rats, endothelin (ET)-1, angiotensin II (ANG II), and ATP induced oscillations in intracellular Ca2+ concentration ([Ca2+]i) in 85-90% of cells, whereas they disappeared in myocytes from chronically hypoxic rats together with a decrease in the percentage of responding cells. However, both the amount of mobilized Ca2+ and the sources of Ca2+ implicated in the agonist-induced response were not changed. Analysis of the transient caffeine-induced [Ca2+]i response revealed that recovery of the resting [Ca2+]i value was delayed in myocytes from chronically hypoxic rats. The maximal contraction induced by ET-1 or ANG II in MPA rings from chronically hypoxic rats was decreased by 30% compared with control values. Moreover, the D-600- and thapsigargin-resistant component of contraction was decreased by 40% in chronically hypoxic rats. These data indicate that CH alters pulmonary arterial reactivity as a consequence of an effect on both Ca2+ signaling and Ca2+ sensitivity of the contractile apparatus. A Ca2+ reuptake mechanism appears as a CH-sensitive phenomenon that may account for the main effect of CH on Ca2+ signaling.

Topics: Adenosine Triphosphate; Angiotensin II; Animals; Caffeine; Calcium; Calcium Signaling; Chronic Disease; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Indoles; Intracellular Membranes; Male; Muscle, Smooth, Vascular; Pulmonary Artery; Rats; Rats, Wistar; Reference Values; Vasoconstriction; Vasodilator Agents; Vasomotor System

Decreases in blood pH activate NHE3, the proximal tubular apical membrane Na/H antiporter. In cultured renal epithelial cells, activation of the endothelin-B (ET(B)) receptor increases NHE3 activity. To examine the role of the ET(B) receptor in the response to acidosis in vivo, the present studies examined ET(B) receptor-deficient mice, rescued from neonatal lethality by expression of a dopamine beta-hydroxylase promoter/ET(B) receptor transgene (Tg/Tg:ET(B)(-/-) mice). In proximal tubule suspensions from Tg/Tg:ET(B)(+/-) mice, 10(-8) M endothelin-1 (ET-1) increased NHE3 activity, but this treatment had no effect on tubules from Tg/Tg:ET(B)(-/-) mice. Acid ingestion for 7 days caused a greater decrease in blood HCO(3)(-) concentration in Tg/Tg:ET(B)(-/-) mice compared with Tg/Tg:ET(B)(+/+) and Tg/Tg:ET(B)(+/-) mice. Whereas acid ingestion increased apical membrane NHE3 by 42-46% in Tg/Tg:ET(B)(+/+) and Tg/Tg:ET(B)(+/-) mice, it had no effect on NHE3 in Tg/Tg:ET(B)(-/-) mice. In C57BL/6 mice, excess acid ingestion increased renal cortical preproET-1 mRNA expression 2.4-fold and decreased preproET-3 mRNA expression by 37%. On a control diet, Tg/Tg:ET(B)(-/-) mice had low rates of ammonium excretion, which could not be attributed to an inability to acidify the urine, as well as hypercitraturia, with increased titratable acid excretion. Acid ingestion increased ammonium excretion, citrate absorption, and titratable acid excretion to the same levels in Tg/Tg:ET(B)(-/-) and Tg/Tg:ET(B)(+/+) mice. In conclusion, metabolic acidosis increases ET-1 expression, which increases NHE3 activity via the ET(B) receptor.

Topics: Acidosis; Ammonia; Animals; Bicarbonates; Chronic Disease; Citric Acid; Culture Techniques; Endothelin-1; Endothelins; Kidney Tubules, Proximal; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Protein Precursors; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Sodium; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers

This study was designed to analyze the pathophysiological role of the endogenous endothelin (ET) system and the therapeutic approach to congestive heart failure (CHF) with ET(A)/ET(B) receptor antagonists in a canine CHF model. After 3 weeks of rapid right ventricular pacing (240 beats/min), concentrations of immunoreactive ET-1 in dogs increased approximately 2-fold in plasma and in the left and right ventricles but not in the lung. There were no meaningful changes in the density and affinity of total ET receptors, or in the ratio of ET(A) to ET(B) receptors. To clarify the functional role of endogenous ET, we examined the effects of acute injection of J-104132 (1 and 3 mg/kg i.v.), an ET(A)/ET(B) receptor antagonist, on cardiovascular and renal function in dogs with CHF. Compared with vehicle, J-104132 at both doses significantly decreased pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and mean arterial pressure (MAP), and increased cardiac output (CO) and renal blood flow. J-104132 had no effects on heart rate and cardiac contractility. In addition, we examined whether J-104132 has an additive effect in the presence of enalaprilat. J-104132 (1 mg/kg i.v.) administered after enalaprilat (0.05 mg/kg i.v.) induced further decreases in MAP, PCWP and PAP, and further increases in CO, resulting in further decreases in total peripheral resistance. These results indicate that the endogenous ET system is exaggerated in CHF and has a detrimental effect on cardiac function. Therefore, J-104132 given alone or as combination therapy may play a beneficial role in the treatment of CHF in humans.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Pacing, Artificial; Chronic Disease; Dogs; Echocardiography; Enalaprilat; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Pyridines; Receptors, Endothelin; Tissue Distribution; Ventricular Function

Endothelin-converting enzyme (ECE)-1 activates endothelin-1 (ET-1) and may thus contribute to the regulation of vascular tone and cell growth during atherosclerosis.. To evaluate ECE-1 immunoreactivity concerning big ET-1/ET-1, we performed qualitative and quantitative immunohistochemistry in normal internal mammary arteries (n=10), in coronary arteries with adaptive intimal fibrosis (n=10), in aortic fatty streaks (n=10), and in distinct regions of advanced carotid plaques (n=15). Furthermore, we determined ECE-1 activity in the control specimens and in the inflammatory intimal regions of carotid plaques. Double immunolabeling showed that ECE-1 was present in endothelial cells, vascular smooth muscle cells, and macrophages. All ET-1(+) cells were simultaneously ECE-1(+). Most importantly, there were significantly more ET-1(+) cells in the intima and media when atherosclerosis was in an inflammatory stage than when it was in a noninflammatory stage. Moreover, ECE-1 activity was upregulated in the intima of carotid plaques, although immunohistochemically, there were no significant differences between the number of ECE(+) cells in the different compartments of the arterial wall.. Together with ET-1, ECE-1 is abundantly present in human arteries and at different stages of atherosclerotic plaque evolution. The upregulation of the ECE-1/ET-1 system is closely linked to the presence of chronic inflammation and is present in very early stages of plaque evolution. Therefore, enhanced production of active ET-1 may substantially contribute to cell growth and the regulation of vascular tone in advanced atherosclerotic lesions and in the very early stages of plaque evolution, when a plaque is still imperceptible clinically.

Topics: Aorta; Aortic Diseases; Arteriosclerosis; Aspartic Acid Endopeptidases; Carotid Arteries; Carotid Stenosis; Chronic Disease; Coronary Disease; Coronary Vessels; Disease Progression; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Activation; Humans; Immunohistochemistry; Inflammation; Mammary Arteries; Metalloendopeptidases; Tunica Intima; Tunica Media

Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (n=8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding -log concentrations of agonist required to effect a 50% response (pD(2)) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.

Topics: Adrenomedullin; Antihypertensive Agents; Arteries; Chronic Disease; Dose-Response Relationship, Drug; Endothelin-1; Female; Heart Failure; Humans; In Vitro Techniques; Male; Peptides; Protease Inhibitors; Thiorphan; Vascular Resistance; Vasoconstriction

Topics: Acute Disease; Antihypertensive Agents; Bosentan; Chronic Disease; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Exercise Tolerance; Heart Failure; Hemodynamics; Humans; Phenylpropionates; Pyridines; Pyrimidines; Sulfonamides; Tetrazoles; Treatment Outcome; Vasodilator Agents

The mechanisms controlling the coronary vascular responses of vessels perfusing the left ventricular (LV) myocardium that is hypertrophied from chronic volume overload are unclear. We hypothesised that endothelial function is compromised, and receptor-mediated contraction is exacerbated, in coronary resistance vessels from rabbits with LV hypertrophy compared to controls. The mitral valve of 10 rabbits was damaged surgically to cause mitral regurgitation and chronic volume overload, resulting in LV hypertrophy (LV hypertrophy rabbits). Echocardiographic assessment at 12 weeks verified that mitral regurgitation was present in LV hypertrophy but not sham-operated, weight- and age-matched animals (control rabbits; n = 17). Percentage increases from weeks 0 to 12 in LV cross-sectional area (47 +/- 7 % vs. 2 +/- 8 %), LV volume (47 +/- 14 % vs. 7 +/- 10 %) and LV mass (27 +/- 4 % vs. 3 +/- 6 %), were greater (all P < 0.05) in LV hypertrophy vs. control rabbits, respectively. At 12 weeks, coronary resistance vessel (approximately 130 microm, internal diameter) reactivity was evaluated using wire myography. Endothelium-dependent (i.e. acetylcholine, 10(-8)-10(-5) M) and -independent (i.e. sodium nitroprusside, 10(-9)-10(-4) M) relaxation, and receptor-mediated vasocontraction (i.e. endothelin-1, 10(-11)-10(-7) M) were similar between groups. However, tension development in response to nitric oxide synthase inhibition (10(-6) M N (G)-monomethyl-L-arginine) was greater (P < 0.05) in LV hypertrophy compared to control rabbits. These results indicate that while coronary resistance vessel function is similar between groups, our estimate of basal nitric oxide production is greater in vessels from LV hypertrophy than control rabbits.

Topics: Acetylcholine; Animals; Blood Vessels; Chronic Disease; Coronary Circulation; Endothelin-1; Hyperemia; Hypertrophy, Left Ventricular; Male; Microcirculation; Mitral Valve Insufficiency; Myocardial Contraction; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Rabbits; Reference Values; Vasodilation; Vasodilator Agents; Ventricular Function, Left

The Hilltop (H) strain compared to the Madison (M) strain of Sprague-Dawley rats develops severe pulmonary hypertension in response to chronic hypoxia. We tested the hypothesis that endothelin-1 (ET-1) contributes to these strain-related differences. Plasma ET-1 content was not modified by chronic hypoxia in either strain. The lung ET-1 peptide and preproET-1 mRNA content were significantly increased to the same magnitude in both strains at 2 and 3 weeks of hypoxia. The ET(A) receptor mRNA increased more at 3 weeks of hypoxia in the lungs of H rats than in M rats, but not at other time points. The ET(B) receptor mRNA was not modified by hypoxia in either strain. After 3 days of normoxic recovery following 2 weeks of hypoxia, ET-1 protein and mRNA levels decreased to baseline levels in both rat strains. We conclude that ET-1 does not contribute to the development of cardiopulmonary differences between the H and M strains in response to hypoxia.

Topics: Animals; Chronic Disease; Endothelin-1; Endothelins; Genetic Predisposition to Disease; Hematocrit; Hypertension, Pulmonary; Hypoxia; Immunoblotting; Lung; Male; Organ Size; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reference Standards; Reverse Transcriptase Polymerase Chain Reaction; RNA Probes; RNA, Messenger; Species Specificity; Ventricular Function

The effects of hypoxia on renin secretion and renin gene expression have been controversial. In recent studies, we have demonstrated that acute hypoxia of 6 h duration caused a marked stimulation of renin secretion and renal renin gene expression. This hypoxia-induced stimulation of the renin-angiotensin system might contribute, for example, to the progression of chronic renal failure and to the development of hypertension in the sleep-apnoea syndrome. For this reason, we were interested in the more chronic effects of hypoxia on renal renin gene expression and its possible regulation.. Male rats were exposed to chronic normobaric hypoxia (10% O(2)) for 2 and 4 weeks. Additional groups of rats were treated with an endothelin ET(A) receptor antagonist, LU135252, or a NO donor, molsidomine, respectively. Systolic blood pressure and right ventricular pressures were measured. Renal renin, endothelin-1 and endothelin-3 gene expression were quantitated using RNAase protection assays.. During chronic hypoxia, haematocrit increased to 72+/-2%, and right ventricular pressure increased by a mean of 26 mmHg. Renal renin gene expression was halved during 4 weeks of chronic hypoxia. This decrease was reversed by endothelin receptor blockade (105 or 140% of baseline values after treatment for weeks 3-4 or 1-4). Furthermore, there was a trend of increasing renal endothelin-1 gene expression (to 173% of baseline values) after 4 weeks of hypoxia. Systolic blood pressure increased moderately during 4 weeks of chronic hypoxia from 129+/-2 to 150+/-4 mmHg. This blood pressure increase was higher in rats treated for 4 weeks with an endothelin receptor antagonist (196+/-11 mmHg).. Chronic hypoxia (in contrast to acute hypoxia) suppresses renal renin gene expression. This inhibition presumably is mediated by endothelins.

Topics: Animals; Blood Pressure; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Gene Expression; Hypoxia; Kidney; Male; Molsidomine; Nitric Oxide Donors; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Renin; RNA, Messenger

Plasma endothelin-1 (ET-1) levels are increased in patients with cirrhosis and ET-1 production is increased in the liver itself during experimental injury. These data suggest a possible role for this vasoactive peptide in intrahepatic microcirculatory changes that contribute to the pathogenesis of portal hypertension in cirrhosis. Therefore the aims of this study were to determine whether ET-1 levels were abnormal in the livers of patients with cirrhosis and to investigate possible clinical correlates of altered hepatic ET-1 in cirrhosis.. Liver specimens were obtained from explants at the time of liver transplantation in 62 cirrhotic patients; 49 without pretransplantation transjugular intrahepatic portosystemic shunt (TIPS) and 13 with pretransplantation TIPS. The presence of ascites was evaluated by physical examination and ultrasonography. Control specimens consisted of livers with normal morphology obtained from patients who died from nonliver-related causes. Hepatic ET-1 was measured by enzyme immunoassay.. Hepatic ET-1 levels in cirrhotics without (0.17 pg/mg liver tissue) or with TIPS (0.12 pg/mg) were higher than in control patients [0.04 pg/mg (p = 0.02 for ET-1 levels in cirrhotics with or without TIPS vs. control)]. In cirrhotics without ascites who had not had TIPS, ET-1 levels (0.07 pg/mg [0.04-1.00]) were similar to those of the controls. In contrast, ET-1 content was increased in cirrhotics with small (0.11 pg/mg; p = 0.0002) and moderate-to-large (0.69 pg/mg; p = 0.0002) amounts of ascites compared to patients without ascites. There was a modest correlation between ET-1 levels and Child-Pugh score (correlation coefficient 0.32; p = 0.03) and ET-1 levels were significantly higher in patients with Child-Pugh score of 13 or greater (0.88 pg/mg; p = 0.02) than in those with Child-Pugh score of 12 or less (0.16 pg/mg).. Hepatic tissue ET-1 levels are increased in the liver of patients with cirrhosis. This increase appears to be proportional to the severity of both liver disease and ascites. These data raise a possible role for ET-1 in modulation of intrahepatic resistance in cirrhotic portal hypertension.

Topics: Adult; Aged; Ascites; Biomarkers; Chronic Disease; Endothelin-1; Female; Humans; Hypertension, Portal; Liver; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Portasystemic Shunt, Transjugular Intrahepatic

The objective was to determine the independent association between atrial fibrillation (A-Fib) and activation of natriuretic peptides.. The association of A-Fib with activation of N-terminal atrial and brain natriuretic peptides (N-ANPs and BNPs, respectively) is uncertain but of great importance for the diagnostic utilization of natriuretic peptides. This uncertainty is related to the lack of appropriate controls, with left ventricular (LV) and atrial overload similar to A-Fib.. We prospectively measured N-terminal atrial and BNPs and endothelin-1 levels in 100 patients and 14 age- and gender-matched control subjects. The 32 patients with A-Fib were compared with 68 patients in sinus rhythm and similar LV and atrial overload (due to mitral regurgitation or LV dysfunction) measured simultaneously with hormonal levels with comprehensive Doppler echocardiography.. Patients with A-Fib compared with those in sinus rhythm had similar symptoms, comorbid conditions, cardioactive medications, pulmonary pressure, left atrial volume, and LV ejection fraction and filling characteristics but demonstrated higher N-ANP levels (2,613 +/- 1,681 vs. 1,654 +/- 1,323 pg/ml, p = 0.007) even after adjustment for the underlying cardiac disease (p < 0.0001). Conversely, BNP levels were similar in both groups (165 +/- 163 vs. 160 +/- 269 pg/ml, p = 0.9). In multivariate analysis, a higher N-ANP level was associated with A-Fib (p = 0.0003), symptom class (p < 0.0001) and endothelin-1 level (p = 0.032) independently of left atrial volume and LV ejection fraction. Conversely, BNP showed no independent association with and was most strongly associated with LV ejection fraction (p < 0.0001).. Atrial fibrillation is an independent determinant of higher N-ANP levels and blurs its association with LV dysfunction. Conversely, the BNP is not independently associated with A-Fib and is strongly determined by LV dysfunction, for which it is an independent marker.

Topics: Aged; Atrial Fibrillation; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Chronic Disease; Echocardiography, Doppler; Endothelin-1; Female; Humans; Male; Multivariate Analysis; Natriuretic Peptide, Brain; Prospective Studies; Protein Precursors; Reproducibility of Results; Severity of Illness Index; Stroke Volume; Ventricular Dysfunction, Left

Alterations of vasoreactivity are a well-known phenomenon in chronic heart failure (CHF), and activation of the endogenous endothelin (ET) system is suspected to contribute significantly. Regional differences in alterations of vasoreactivity exist; however, nothing is known about cerebrovascular reactivity in CHF. This is of interest in view of increased stroke risk in CHF. Therefore, 12 weeks after coronary artery ligation to induce CHF in rats, studies of vasoreactivity of the isolated basilar artery (BA) were performed and compared with third-order branches (MA-A3) and the main trunk (MA) of the superior mesenteric artery. Some of the animals received long-term ET-receptor antagonism by 11 weeks of treatment with the selective ET(A)-receptor antagonist LU 135252 or the mixed ET(A)/ET(B)-receptor antagonist bosentan. In rats with CHF, endothelium-dependent relaxation by acetylcholine and A23187 as well as endothelium-independent relaxation by sodium nitroprusside (SNP) was largely unaffected in BA or MA. However, in MA-A3, potency of SNP was diminished without change of maximal effect. ET-1-induced contraction did not differ in arteries from CHF and control rats, either in placeboor ET-receptor antagonist-treated animals. In summary, there was essentially no change of vascular reactivity in similar sized arteries obtained from brain and mesentery. This is in contrast to results on arteries from a variety of vascular regions published previously, thus supporting the concept of organ- and probably time-related changes of vascular function in the development of CHF. The absence of significant alteration of cerebral vasoreactivity may be taken to indicate that changes in cerebral blood flow and increased incidence of ischemic stroke in patients with CHF are caused not by local alterations of vascular function.

Topics: Acetylcholine; Animals; Basilar Artery; Calcimycin; Cardiac Output, Low; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Male; Mesenteric Arteries; Nitroprusside; Rats; Rats, Wistar; Vasoconstriction; Vasodilation; Vasodilator Agents

Endothelin-converting enzyme-1 (ECE-1) processes big endothelin-1 (ET-1) to ET-1, a peptide implicated in atheroma formation. ECE-1 exists in 2 isoforms (ECE-1alpha and ECE-1beta), the result of alternative splicing of a common gene. Neutral endopeptidase (NEP) is a genetically distinct metallopeptidase that degrades the natriuretic peptides. These peptides mediate antiproliferative and vasodilating actions. We sought to demonstrate the distribution of the 2 ECE-1 isoforms in experimental atherosclerosis, to determine the effects of chronic NEP-I on plasma cGMP concentrations, vascular wall ECE-1 activity, and ET-1 concentration, and to correlate these actions with atheroma formation. Our hypothesis was that chronic NEP-I, in association with augmented cGMP, would inhibit ECE-1 conversion of big ET-1 to active ET-1, thus reducing tissue ET-1 concentrations and associated atheroma formation.. Cholesterol-fed New Zealand White rabbits (n=8, 1% cholesterol diet) and NEP-I-treated cholesterol-fed New Zealand White rabbits (n=8; candoxatril, 30 mg/kg per day, Pfizer) were euthanized after 8 weeks of feeding. ECE-1alpha and ECE-1beta immunoreactivity was present in the aortas of both groups. Compared with control values, plasma cGMP concentrations were increased (2.8+/-0.6 versus 8.4+/-1.2 pmol/mL, P<0.05), ECE-1 activity was attenuated (68+/-3% versus 32+/-8%, P<0. 05), aortic tissue ET-1 concentrations were reduced (4.6+/-0.5 versus 3.2+/-0.3 pg/mg protein, P<0.05), and atheroma formation was attenuated (62+/-6% versus 34+/-5%, P<0.01) by NEP-I.. These studies suggest that ECE-1 is present and functionally active in the vascular wall in atherosclerosis. Inhibition of ECE-1 by NEP-I represents a novel approach to interruption of the endothelin system in this cardiovascular disease state.

Topics: Animals; Aorta; Arteriosclerosis; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Diet, Atherogenic; Disease Models, Animal; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; In Vitro Techniques; Isoenzymes; Male; Metalloendopeptidases; Neprilysin; Protein Precursors; Rabbits; Time Factors; Vasoconstriction

It is well known that endothelin (ET)-1 mediates vascular remodelling in various kinds of clinical and experimental pulmonary hypertension. The aim of this study was to investigate whether ET-1 is associated with the development of pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Pulmonary hypertension was induced in 10 mongrel dogs by repeated embolization with ceramic beads. In five of the dogs, bosentan, a nonselective ET receptor antagonist, was administered throughout the study. Haemodynamic measurements and plasma ET-1 assays were performed every 2 months. Eight months after initial embolization, computer-assisted morphometry and immunohistochemistry were performed on the lung tissue including that from three control dogs. Pulmonary arterial pressure and pulmonary vascular resistance were increased in all embolized dogs, compared to baseline. In nontreated embolized dogs, plasma ET-1 concentration and pulmonary arterial wall thickness were increased compared to control animals, and ET-1 immunoreactivity was detected in thickened pulmonary arteries. In bosentan treated dogs, pulmonary arterial walls were not significantly thickened. Pulmonary vascular remodelling, associated with elevated plasma endothelin-1 levels and positive endothelin-1 immunoreactivity in lung tissue is attenuated by the endothelin receptor antagonist, bosentan. These findings suggest that endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Bosentan; Chronic Disease; Culture Techniques; Disease Models, Animal; Dogs; Endothelin-1; Female; Hemodynamics; Hypertension, Pulmonary; Immunohistochemistry; Lung; Male; Probability; Pulmonary Artery; Pulmonary Circulation; Pulmonary Embolism; Reference Values; Sulfonamides; Tomography, Emission-Computed; Vascular Resistance

Chronic hypoxia leads to a greater degree of pulmonary hypertension in the Wistar-Kyoto (WKY) rat than in the Fischer 344 (F-344) rat. We questioned whether this difference is associated with baseline differences in pulmonary artery anatomy, a greater degree of hypoxia-induced pulmonary vascular remodeling in the WKY rat, and/or differences in expression of endothelin (ET)-1. Male F-344 and WKY rats were maintained in normoxia or normobaric hypoxia for 21 days. Morphometry revealed that baseline pulmonary artery anatomy was similar in the two strains. However, during chronic hypoxia, the WKY rats developed a greater degree of muscularization of small pulmonary arteries. Baseline plasma and lung immunoreactive ET-1 levels were similar in the WKY and F-344 rats and increased significantly during hypoxia in the WKY rats. Northern analysis demonstrated increased lung preproET-1 mRNA during hypoxia in both strains, with a greater increase in WKY rats. Immunostaining demonstrated increased ET-1 in bronchial epithelium and peripheral pulmonary arteries during hypoxia, although to a greater degree in the WKY rats. We conclude that the WKY strain demonstrates increased susceptibility to hypoxia-induced pulmonary vascular remodeling compared with the F-344 strain and that increased lung and circulating ET-1 levels during hypoxia may partly explain this difference.

Topics: Animals; Blotting, Northern; Chronic Disease; Endothelin-1; Endothelins; Epithelial Cells; Gene Expression; Hypoxia; Immunohistochemistry; Male; Protein Precursors; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Inbred F344; Rats, Inbred WKY; RNA, Messenger; Species Specificity

The pulmonary endothelin (ET) system has been implicated in the pathogenesis of chronic lung diseases such as pulmonary hypertension, asthma, chronic obstructive lung disease, idiopathic pulmonary fibrosis, and bronchiolitis obliterans. However, the etiologic role of ET-1 in these diseases has not yet been established. We recently demonstrated that ET-1 transgenic mice, generated using the human prepro-ET-1 expression cassette including the cis-acting transcriptional regulatory elements, had predominant transgene expression in lung, brain, and kidney. We used these mice in the present study to analyze the pathophysiologic consequences of long-term pulmonary overexpression of ET-1. We found that ET-1 overexpression in the lungs did not result in significant pulmonary hypertension, but did result in development of a progressive pulmonary fibrosis and recruitment of inflammatory cells (predominantly CD4-positive cells). Our study provides evidence that a long-term activated pulmonary ET system, without any other stimuli, produces chronic lymphocytic inflammation and lung fibrosis. This suggests that overexpression of ET-1 may be a central event in the pathogenesis of lung diseases associated with fibrosis and chronic inflammation, such as pulmonary fibrosis and bronchiolitis.

Topics: Animals; Apoptosis; Blood Gas Analysis; Bronchi; CD4-Positive T-Lymphocytes; Cell Division; Chronic Disease; Endothelin-1; Humans; Hypertension, Pulmonary; Immunohistochemistry; Inflammation; Lung; Male; Mice; Mice, Transgenic; Neovascularization, Physiologic; Organ Size; Organ Specificity; Pulmonary Artery; Pulmonary Fibrosis; Receptors, Endothelin; Transgenes; Ventricular Pressure

Previous studies have established short-term variability in the circulating plasma levels of cardiac peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Our aim was to investigate whether such variable patterns could be observed in other vasoactive peptides.. We measured the immunoreactivity of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in peripheral venous plasma collected at 2-min intervals over a 20-min period from patients with chronic cardiac failure (CCF) and from control subjects. In a second study, blood samples were obtained at 2-min intervals from the pulmonary artery, femoral artery and antecubital vein from patients with normal cardiac function while right atrial pressure and heart rate were constant.. Peripheral blood VIP, NPY and ET-1 had peaks and troughs (levels > 2SD from the mean) in both patients and controls, with approximate intervals of 10 min. Levels of CGRP showed little variation. The overall levels [median (range); pmol L-1] of VIP [patients 27 (2.1-85.5); controls 9.8 (0-34)] and NPY [patients 20 (0-110); controls 12 (5-19)] were higher in patients (P < 0.05). Circulating plasma levels of ET-1 and CGRP were about the same in both groups [ET-1: patients 18 (2-84); controls 18 (0-48); CGRP: patients 4 (1-18.5), controls 5.5 (1-15); P = NS]. Levels of CGRP, VIP and ET-1 were similar in the pulmonary and femoral arteries, whereas systemic arterial levels of NPY were higher than in the pulmonary artery.. The data demonstrate marked variability in circulating levels of the neuropeptides studied. In addition, peaks and troughs were observed every 10-15 min from all three vascular beds. If these peptides are secreted in a pulsatile pattern, then interpretations of single measurements should be guarded. Furthermore, this study raises interesting questions about the physiology of hormone secretion in man.

Topics: Aged; Calcitonin Gene-Related Peptide; Chronic Disease; Endothelin-1; Femoral Artery; Heart Failure; Humans; Middle Aged; Neuropeptide Y; Neuropeptides; Pulmonary Artery; Radioimmunoassay; Vasoactive Intestinal Peptide; Veins

Endothelins (ET) are a family of vasoactive peptides that play an important role in several disorders affecting kidneys. In this study we investigated the expressions of ET-1, ET-3, and their receptors, ET(A) and ET(B), in a rat chronic renal transplant rejection model. Renal allografts were performed (F344 --> Lewis) with bilateral nephrectomy in recipients. For isograft control, lewis --> lewis transplantations were performed. All recipients were sacrificed 140 days after transplantation and the grafts were analyzed histologically. ET-1 and ET-3 protein expression in grafts was measured by immunohistochemistry and ELISA. Semiquantitative RT-PCR methods were used for mRNA levels of ET-1, ET-3, ET(A) and ET(B). No evidence of chronical rejection was manifested in isografts. The allografted rats showed proteinuria and increased serum creatinine levels. Histologically, renal allografts showed atrophy and sclerosis of the glomeruli, cortical scarring and vascular intimal thickening. Immunohistochemically, ET-1 and ET-3 were localized in the convoluted tubules, collecting ducts, endothelium and smooth muscle cells of the large blood vessels. Significantly increased staining for ET-1 and ET-3 were found in allografts compared to isografts. Simultaneously, ELISA for ET-1 and ET-3 showed elevated protein concentrations in allografts compared to isografts. Allografts showed significantly increased ET-1- and ET-3 mRNA compared to isografts. On the other hand, a significant down regulation of the ET(A) mRNA was noted, and the ET(B) mRNA remained unchanged. The data from the present study suggest that alteration of ET system may be of importance in the pathogenesis of chronic renal transplant rejection.

Topics: Animals; Chronic Disease; Endothelin-1; Endothelin-3; Enzyme-Linked Immunosorbent Assay; Graft Rejection; Immunohistochemistry; Kidney Transplantation; Male; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Transplantation, Homologous

We compared the value of plasma neurohormones and cardiopulmonary exercise testing for predicting long-term prognosis in patients with moderate congestive heart failure (CHF). We studied 264 consecutive patients with CHF due to left ventricular systolic dysfunction. Plasma atrial natriuretic peptide (ANP), norepinephrine, and endothelin-1 were measured at rest in all patients, who also underwent a symptom-limited maximal exercise with oxygen consumption (VO(2)) determination. After a median follow-up of 789 days, 52 deaths and 31 heart transplantations occurred, of which 4 were urgent. In an univariate analysis, New York Heart Association functional class, systolic blood pressure at rest, left ventricular end-diastolic diameter, left ventricular ejection fraction, peak VO(2), percent of predicted peak VO(2), plasma ANP, plasma norepinephrine, and plasma endothelin-1 were associated with survival without urgent heart transplantation. In a multivariate stepwise regression analysis, only plasma ANP (p = 0.0001), left ventricular ejection fraction (p = 0.007), and plasma norepinephrine (p = 0.035), but neither peak VO(2) nor percentage of predicted peak VO(2), were independent predictors of death or urgent heart transplantation. Determination of plasma ANP and norepinephrine provides additional independent information for long-term prognostic determination compared with exercise testing alone. Measurement of plasma neurohormones should therefore be considered routinely as a complementary or alternative tool for identifying high-risk patients with moderate CHF.

Topics: Atrial Natriuretic Factor; Chronic Disease; Disease-Free Survival; Endothelin-1; Exercise Test; Female; Heart Failure; Heart Transplantation; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Oxygen Consumption; Prognosis; Stroke Volume

Liver failure represents a major therapeutic challenge, and yet basic pathophysiological questions about hepatic perfusion and oxygenation in this condition have been poorly investigated. In this study, hepatic blood flow (HBF) and splanchnic oxygen delivery (DO2, sp) and oxygen consumption (VO2,sp) were assessed in patients with liver failure defined as hepatic encephalopathy grade II or more. Measurements were repeated after high-volume plasmapheresis (HVP) with exchange of 8 to 10 L of plasma. HBF was estimated by use of constant infusion of D-sorbitol and calculated according to Fick's principle from peripheral artery and hepatic vein concentrations. In 14 patients with acute liver failure (ALF), HBF (1.78 +/- 0.78 L/min) and VO2,sp (3.9 +/- 0.9 mmol/min) were higher than in 11 patients without liver disease (1.07 +/- 0.19 L/min, P <.01) and (2.3 +/- 0.7 mmol/min, P <.001). In 9 patients with acute on chronic liver disease (AOCLD), HBF (1.96 +/- 1.19 L/min) and VO2,sp (3.9 +/- 2.3 mmol/min) were higher than in 18 patients with stable cirrhosis (1.00 +/- 0.36 L/min, P <.005; and 2.0 +/- 0.6 mmol/min, P <.005). During HVP, HBF increased from 1.67 +/- 0.72 to 2.07 +/- 1.11 L/min (n=11) in ALF, and from 1.89 +/- 1.32 to 2.34 +/- 1.54 L/min (n=7) in AOCLD, P <.05 in both cases. In patients with ALF, cardiac output (thermodilution) was unchanged (6.7 +/- 2.5 vs. 6.6 +/- 2.2 L/min, NS) during HVP. Blood flow was redirected to the liver as the systemic vascular resistance index increased (1,587 +/- 650 vs. 2, 020 +/- 806 Dyne. s. cm-5. m2, P <.01) whereas splanchnic vascular resistance was unchanged. In AOCLD, neither systemic nor splanchnic vascular resistance was affected by HVP, but as cardiac output increased from 9.1 +/- 2.8 to 10.1 +/- 2.9 L/min (P <.01) more blood was directed to the splanchnic region. In all liver failure patients treated with HVP (n=18), DO2,sp increased by 15% (P <.05) whereas VO2,sp was unchanged. Endothelin-1 (ET-1) and ET-3 were determined before and after HVP. Changes of ET-1 were positively correlated with changes in HBF (P <.005) and VO2,sp (P <.05), indicating a role for ET-1 in splanchnic circulation and oxygenation. ET-3 was negatively correlated with systemic vascular resistance index before HVP (P <.05) but changes during HVP did not correlate. Our data suggest that liver failure is associated with increased HBF and VO2, sp. HVP further increased HBF and DO2,sp but VO2,sp was unchanged, indicating that splanchnic hypoxia

Topics: Acute Disease; Adult; Blood Flow Velocity; Chronic Disease; Endothelin-1; Endothelin-3; Female; Hepatic Encephalopathy; Humans; Liver Circulation; Liver Diseases; Liver Failure; Liver Failure, Acute; Male; Middle Aged; Oxygen Consumption; Plasmapheresis; Splanchnic Circulation

This study was designed to assess the functional importance of endothelin (ET)B receptors in patients with left ventricular systolic dysfunction (LVSD) by comparing the hemodynamic effects of ET-1, a nonselective ET(A) and ET(B) agonist, with ET-3, a selective ET(B) receptor agonist.. Knowledge of the functional importance of ET(B) receptors in mediating vasoconstriction in chronic heart failure will help determine whether antagonists at both ET(A) and ET(B) receptors are required to fully prevent vasoconstriction to endogenously produced ET-1.. We infused ET-1 (5 and 15 pmol/min) and ET-3 (5 and 15 pmol/min) into two separate groups of eight patients with LVSD with similar baseline hemodynamic indices. Hemodynamics were measured using a pulmonary thermodilution catheter and an arterial line.. Endothelin-1 infusion led to systemic vasoconstriction, with a rise in mean arterial pressure (mean +/- SEM 100 +/- 3 to 105 +/- 3 mm Hg, p < 0.02) and systemic vascular resistance (1,727 +/- 142 to 2,055 +/- 164 dyn/s/cm(-5), p < 0.001) and a fall in cardiac index (2.44 +/- 0.21 to 2.22 +/- 0.20 liters/min/m , p < 0.01). Endothelin-3 infusion also led to systemic vasoconstriction, with a rise in mean arterial pressure (99 +/- 6 to 105 +/- 6 mm Hg, p < 0.01) and systemic vascular resistance (1,639 +/- 210 to 1,918 +/- 245 dyn/s/cm(-5), p < 0.01) and a fall in cardiac index (2.66 +/- 0.28 to 2.42 +/- 0.24 liters/min/m2, p < 0.05). Pulmonary hemodynamic measurements did not change significantly in either group.. Both ET-1 and ET-3 infusions led to systemic vasoconstriction; the hemodynamic changes observed were of a similar magnitude at the same molar concentration. This suggests that ET(B) receptors are functionally important in mediating vasoconstriction, at least in the systemic circulation, in patients with LVSD.

Topics: Aged; Chronic Disease; Endothelin-1; Endothelin-3; Female; Hemodynamics; Humans; Male; Middle Aged; Receptor, Endothelin B; Receptors, Endothelin; Systole; Vasoconstriction; Ventricular Dysfunction, Left; Ventricular Function, Left

We investigated the effect of chronic alcohol ingestion on buccal mucosal ulcer healing by analyzing the interplay between mucosal expression of tumor necrosis factor-alpha (TNF-alpha), endothelin-1 (ET-1), and interleukin-4 (IL-4). Chronic ulceration was induced in rats maintained for 5 weeks on alcohol-containing or control liquid diet. In both groups, the ulcer onset was characterized by a massive increase (6.5-8.9-fold) in TNF-alpha and ET-1 (1.6-4.0-fold), and a decrease (1.4-1.5-fold) in IL-4. However, the group on the alcohol diet exhibited a 38.3% higher mucosal expression of TNF-alpha, a 26. 2% higher ET-1 level, and a 6.5% lower content of IL-4. While in both groups the ulcer healing was accompanied by an increase in buccal mucosal expression of IL-4, and a decline in ET-1 and TNF-alpha, the changes were significantly slower in the alcohol diet group and manifested by a 4 day delay in ulcer healing. The results suggest that chronic alcohol ingestion exerts detrimental effects on the buccal mucosal IL-4 expression, causing dysregulation of ET-1 production, induction of TNF-alpha, and triggering apoptotic events that delay the mucosal repair.

Topics: Acetic Acid; Animals; Apoptosis; Chronic Disease; Endothelin-1; Ethanol; Gene Expression; Interleukin-4; Mouth Mucosa; Rats; Rats, Sprague-Dawley; Time Factors; Tumor Necrosis Factor-alpha; Ulcer

This study aimed to investigate whether nitric oxide (NO) could inhibit the elevated endothelin-1 (ET-1) gene expression by pulmonary artery endothelial cells or smooth muscle cells in chronically hypoxic rats by use of in situ hybridization. Male Wistar rats (n = 40) were randomly divided into 1-week hypoxia group, 1-week hypoxia with L-arginine (L-arg) group, 1-week hypoxia with N(omega)-nitro-L-arginine methyl ester (L-NAME) group, 2-week hypoxia group, 2-week hypoxia with L-arg group, and 2-week hypoxia with L-NAME group. All rats were put into a normobaric hypoxic chamber with an oxygen concentration of 10 +/- 0.5% for hypoxic challenge. The results showed that most pulmonary arteries had 1-50% of the endothelial cells showing positive signals for ET-1 expression in hypoxic rats, which was significantly suppressed by L-arg. L-NAME, however, significantly augmented ET-1 gene expression in pulmonary artery endothelial cells and smooth muscle cells. The results suggest that endogenous NO markedly inhibits ET-1 mRNA expression in both pulmonary artery endothelial cells and smooth muscle cells in chronically hypoxic rats, which may be one of the mechanisms by which NO modulates hypoxic pulmonary circulation.

Topics: Animals; Arginine; Chronic Disease; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Gene Expression Regulation; Hypoxia; In Situ Hybridization; Male; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pulmonary Artery; Pulmonary Circulation; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Vasodilator Agents

Biosynthesis of endothelin-1 (ET-1), the most potent endogenous vasoconstrictor yet identified, is increased following myocardial infarction (MI) in man. Pathological events which occur in the connective tissues of the equine hoof during laminitis are similar in some respects, to changes occurring in the myocardial connective tissues following MI in man. The objective of this study was to determine whether ET-1 expression in connective tissues obtained from the hoof of laminitic horses is increased compared with tissues obtained from healthy horses. Expression of ET-1 in connective tissues of the equine hoof was measured following tissue extraction from 3 groups of horses: horses in which acute laminitis had been induced by the administration of starch; chronically foundered horses; nonlaminitic horses. The concentration of ET-1 in laminar connective tissues obtained from all laminitic horses (1573.0 +/- 392.8 pg/g of tissue; n = 10) was increased when compared with tissues obtained from nonlaminitic horses (392.5 +/- 117.4 pg/g of tissue; n = 5) (P<0.05). The concentration of ET-1 in laminar connective tissues obtained from the experimentally induced, acute laminitic horses (1043.6 +/- 254.4 pg/g of tissue; n = 7) and from the spontaneously affected, chronic laminitic horses (2808.3 +/- 878.6 pg/g of tissue; n = 3) was increased compared with the control group (P<0.05, P<0.01, respectively). The concentration of ET-1 in laminar connective tissues obtained from the chronic laminitic horses was greater than that of the experimentally induced, acute laminitic group (P<0.05). It is suggested that the data provide a strong argument that increased ET-1 expression in the connective tissues of the equine hoof represent a potentially important and hitherto unrecognised component of the pathophysiology of equine laminitis. Further studies are needed to determine whether inhibitors of ET-1 converting enzyme or antagonists of ET-1 receptors might be useful in the treatment and prevention of laminitis in horses.

Topics: Acute Disease; Animals; Chronic Disease; Connective Tissue; Endothelin-1; Female; Foot Diseases; Hoof and Claw; Horse Diseases; Horses; Inflammation; Male

Endothelin (ET)-1 has been implicated as a critical mediator in the pathogenesis of hypoxic pulmonary hypertension. We questioned whether, during exposure to chronic hypobaric hypoxia, rat pulmonary artery smooth muscle cells (PASMC) became sensitized to ET-1. Two effects of ET-1, inhibition of voltage-gated K(+) (K(v)) channels and release of intracellular Ca(2+), were studied using whole cell patch clamp and single cell indo 1 fluorescence, respectively. In both normotensive and chronically hypoxic-hypertensive PASMC, ET-1 caused concentration-dependent inhibition of voltage-gated K(+) current [I(K(v))], with maximum inhibition of 12-18% seen at a concentration of 0.1-1 nM. Although the chronically hypoxic-hypertensive PASMC was no more susceptible to ET-1-mediated I(K(v)) inhibition, a switch in coupling between ET-1 and I(K(v)) from ET(B) to ET(A) receptors occurred. This switch in receptor coupling, combined with reduced I(K(v)) density and increased ET-1 production in the hypoxic rat lung, may help explain the ability of ET(A)-receptor blockers to attenuate the development of hypoxic pulmonary hypertension in vivo.

Topics: Animals; Antihypertensive Agents; Calcium; Chronic Disease; Electrophysiology; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Hypoxia; Male; Muscle, Smooth, Vascular; Oligopeptides; Peptides, Cyclic; Piperidines; Potassium Channel Blockers; Potassium Channels; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin

Glaucoma is an optic nerve head neuropathy in which retinal ganglion cells are lost. A clear association exists between glaucoma and different risk factors, such as high intraocular pressure (IOP) or blood-flow dysregulation. Nitric oxide (NO) and endothelin, two recently identified cellular mediators, appear to be involved in the regulation of IOP as well as in the modulation of ocular blood flow. To some extent, NO is also involved in apoptosis, a mechanism of cell death that can lead to retinal ganglion cell loss in glaucoma. This article provides a short and simplified overview of the biochemistry of NO and endothelin and highlights the potential role of these two mediators in certain important aspects related to the pathogenesis of glaucoma.

Topics: Apoptosis; Arteries; Blood Flow Velocity; Chronic Disease; Endothelin-1; Eye; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Nitric Oxide; Retinal Ganglion Cells; Vasoconstriction

We tested the hypothesis that chronic hypoxia alters the regulation of K+ channels in intrapulmonary arterial smooth muscle cells (PASMCs). Charybdotoxin-insensitive, 4-aminopyridine-sensitive voltage-gated K+ (K(V,CI)) and Ca2+-activated K+ (KCa) currents were measured in freshly isolated PASMCs from rats exposed to 21 or 10% O2 for 17-21 days. In chronically hypoxic PASMCs, K(V, CI) current was reduced and KCa current was enhanced. 4-Aminopyridine (10 mM) depolarized both normoxic and chronically hypoxic PASMCs, whereas charybdotoxin (100 nM) had no effect in either group. The inhibitory effect of endothelin (ET)-1 (10(-7) M) on K(V,CI) current was significantly reduced in PASMCs from chronically hypoxic rats, whereas inhibition by angiotensin (ANG) II (10(-7) M) was enhanced. Neither ET-1 nor ANG II altered K(Ca) current in normoxic PASMCs; however, both stimulated K(Ca) current at positive potentials in chronically hypoxic PASMCs. These results suggest that although modulation of K(V,CI) and KCa channels by ET-1 and ANG II is altered by chronic hypoxia, the role of these channels in the regulation of resting membrane potential was not changed.

Topics: Angiotensin II; Animals; Chronic Disease; Electric Conductivity; Endothelin-1; Heart Ventricles; Hypoxia; Male; Muscle, Smooth, Vascular; Myocardium; Organ Size; Potassium Channels; Pulmonary Artery; Rats; Rats, Wistar

We investigated the course of events associated with gastric ulcer healing by analyzing mucosal expression of interleukin-4 (IL-4), endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-alpha), and the activity of constitutive (cNOS) and inducible nitric oxide synthase (NOS-2). Ulcer onset was characterized by a massive epithelial apoptosis associated with a 5.7-fold increase in TNF-alpha, a 17.5-fold increase in NOS-2, and a 3.9-fold increase in ET-1, while mucosal expression of cNOS showed a 7.6-fold drop and IL-4 fell by 37.2%. Healing was accompanied by a rapid raise in IL-4; decrease in apoptosis, TNF-alpha, ET-1, and NOS-2; and a slow recovery in cNOS. The expression of IL-4 returned to control levels by the 7th day of healing and that of ET-1 and TNF-alpha by the 14th day, while apoptotic DNA fragmentation and the activity of NOS-2 remained significantly elevated beyond the 14-day period. The results suggest that a decrease in the mucosal level of IL-4 at ulcer onset may well be a key factor causing dysregulation of ET-1 production, induction of TNF-alpha, and triggering the apoptotic events that affect the efficiency of mucosal repair.

Topics: Animals; Chronic Disease; Down-Regulation; Endothelin-1; Gastric Mucosa; Interleukin-4; Laparotomy; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Stomach; Stomach Ulcer; Tumor Necrosis Factor-alpha; Wound Healing

We evaluate the acute hemodynamic and neurohormonal effects of losartan in 15 patients with symptomatic chronic heart failure (CHF), mean age 72+/-8 years, which were classified in two subgroups: (A) Patients with left ventricular ejection fraction (LVEF)< or =0.35 (n = 7); (B) subjects with LVEF>0.35 (n = 8). Sympathetic reactivity (blood pressure, heart rate and plasma norepinephrine) and plasma endothelin-1 (ET-1) were evaluated by a cold pressor test (CPT). Single doses of losartan (50 mg p.o.) lowered delta DBP in both subgroups (A, 8+/-9 to 0+/-5 mm Hg, P<0.05; B, 10+/-6 to 3+/-4 mm Hg, P<0.05) and attenuated the rise of HR in patients with mild (4+/-6 to -1+/-2 bpm, P<0.05) but not with severe (4+/-5 to 2+/-5 bpm, n.s.) impairment of left ventricular function. Losartan blunted the response (delta) of PNE during CPT (A, 142+/-131 to 10+/-74 pg/ml, P<0.05; B, 129+/-72 to 1+/-144 pg/ml, P<0.01). A significant rise in plasma ET-1 was observed during CPT in patients from subgroup B (0.64+/-0.40 to 0.81+/-0.40 fmol/ml, P<0.05) but not in patients with LVEF< or =0.35 (1.79+/-0.44 to 1.51+/-0.66 fmol/ml, n.s.). Losartan attenuated the rise in ET-1 during CPT in patients with LVEF>0.35 (delta ET-1 0.17+/-0.86 to 0.03+/-0.11 fmol/ml, P<0.05), with no significant changes in subgroup A. Acute effects of losartan were characterized by a more favorable hemodynamic and neurohumoral response in patients with chronic heart failure and preserved systolic ventricular function related to subjects with lower ejection fractions.

Topics: Aged; Aged, 80 and over; Angiotensin II; Antihypertensive Agents; Blood Pressure; Chronic Disease; Cold Temperature; Endothelin-1; Exercise Test; Female; Heart Failure; Heart Rate; Humans; Losartan; Male; Middle Aged; Norepinephrine; Sympathetic Nervous System; Vasoconstriction

Vascular insufficiency of the optic nerve head may contribute to glaucomatous optic neuropathy, especially in normal-tension glaucoma. We investigated the effect of chronic optic nerve head ischemia, created by repeated intravitreal injection of endothelin-1 (ET-1), on the morphology and function of the optic nerve.. In pigmented rabbits, we injected ET-1 (10(-6) M, 10 microL) into the posterior vitreous of one eye twice a week for 4 weeks (N = 7). The vehicle for ET-1 was injected into the contralateral eye as a control (N = 7). The subsequent observation period was set at 8 weeks. The microcirculation of the optic nerve head was noninvasively monitored with a laser speckle circulation analyzer. To evaluate the changes of visual function, visual-evoked potentials were recorded. Morphologic changes of the optic nerve head were analyzed with stereography, and the ratio of cup area (CA) to disk area (DA) was measured by calculating the number of pixels in each area with a microcomputer.. Capillary blood flow in the optic nerve head was continuously below 80% of the baseline throughout the study. The visual-evoked potential latency was significantly delayed in ET-1-treated eyes. The CA/DA ratio was significantly increased relative to baseline in the ET-1 treated eyes. Histologic examination showed axonal loss and demyelination affecting the prelaminar portion of the optic nerve. The intraocular pressure was not significantly different from the control value.. Optic nerve head ischemia could contribute to the enlargement and excavation of the disk cup independent of the intraocular pressure level.

Topics: Animals; Capillaries; Chronic Disease; Endothelin-1; Evoked Potentials, Visual; Humans; Injections; Intraocular Pressure; Ischemia; Myelin Sheath; Optic Disk; Rabbits; Reaction Time; Regional Blood Flow; Vitreous Body

Increased pressure in pulmonary artery is connected among other things with increased endothelin plasma concentration. The aim of the study was to assess plasma endothelin concentration in patients with pulmonary hypertension. The analysis comprised 22 patients with increased pressure in pulmonary artery in the course of pulmonary thromboembolism or chronic exacerbated left ventricular failure and 10 patients with chronic exacerbated left ventricular failure without pulmonary hypertension. Plasma endothelin concentration was measured in pulmonary artery and capillary wedge pressure were evaluated with Swan-Ganz catheter and also peripheral and pulmonary vascular resistance were calculated. Endothelin plasma concentration in peripheral vein was compared between patients and healthy volunteers. Plasma endothelin concentration in pulmonary artery, peripheral artery and vein was higher in patients with pulmonary hypertension than in patients with chronic exacerbated left ventricular failure without pulmonary hypertension. Plasma endothelin concentration in patients with chronic exacerbated left ventricular failure without pulmonary hypertension was higher in pulmonary artery than in peripheral artery and vein. At these patients plasma endothelin concentration in the peripheral vein didn't differ significantly from the healthy volunteers.

Topics: Adult; Aged; Chronic Disease; Endothelin-1; Endothelin-2; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Ventricular Dysfunction, Left

The mammalian carotid body (CB) contains O2-chemoreceptors, i.e. glomus cells, which display increased mitoses and endothelin-1 (ET-1) expression during chronic hypoxia. To investigate whether endogenous ET-1 might mediate these mitogenic effects, we quantified bromodeoxyuridine (BrdU) uptake by tyrosine hydroxylase (TH)-positive glomus cells in rat CB cultures using double-label immunofluorescence. In normoxia (20% O2), 2-day exposure to ET-1 (10-1000 nM) caused a dose-dependent increase in BrdU uptake which peaked (approximately 55% of TH+ cells) at around 500 nM ET-1. In chronic hypoxia (5% O2) alone, BrdU uptake was stimulated (approximately 46% of TH+ cells) relative to normoxia (approximately 30%), but the effect was abolished in the presence of specific (BQ 123) or non-specific (PD 142893) ETA receptor antagonists (10(-5) M). Thus paracrine/autocrine release of ET-1 in the hypoxic carotid body may promote glomus cell mitosis via ET(A) receptors.

Topics: Animals; Bromodeoxyuridine; Carotid Body; Cell Survival; Cells, Cultured; Chemoreceptor Cells; Chronic Disease; Endothelin-1; Hypoxia; Mitosis; Rats; Receptor, Endothelin A; Receptors, Endothelin; Reference Values

To investigate the relationship between plasma endothelin(ET), nitric oxide(NO) levels and, renal hypertension and renal function.. The plasma concentration of ET-1 was detected by immunofluorescence assay. The plasma concentration of NO was detected by biochemistry assay.. 1. In renal disease patients, plasma concentration ET-1 was markedly elevated, and plasma concentration of NO was decreased, compared with the healthy subjects(P < 0.01). 2. Plasma concentration of ET-1 was markedly increased and plasma concentration of NO was decreased in the patients with renal hypertension. 3. Plasma level of ET-1 was higher, and plasma level of NO was lower in the patients with renal function damage than that of those without renal function damage. 4. BP, BUN and Scr were positively correlated with plasma ET-1, but they were negatively correlated with plasma concentration of NO.. Plasma ET-1 and NO may play an important role in pathogenesis of renal hypertension; the change of their levels may be related to the progress of these renal diseases.

Topics: Adult; Chronic Disease; Endothelin-1; Female; Glomerulonephritis; Humans; Hypertension, Renal; Kidney Function Tests; Lupus Nephritis; Male; Middle Aged; Nitric Oxide

Endothelins (ETs) belong to a family of vasoactive peptides implicated in several disorders of the microvasculature. In the present study, we investigated ET-1 and ET-3 peptide mRNAs and ETA, ETB receptor mRNAs in the retina of diabetic BB/W rats and age-matched, non-diabetic control animals, following six months of diabetes.. Total mRNA was extracted from each retina and was subjected to reverse transcriptase polymerase chain reaction for ET-1, ET-3, ETA and ETB. Simultaneously, beta-globin was amplified and used as a housekeeping gene. The products were analyzed on agarose gels and the specificity of the amplification was established by hybridization with amplification-specific biotinylated oligoprobes. For quantification, the products from the linear phase of amplification were subjected to serial dilution slot-blot hybridization and densitometry.. ETs and their receptor mRNA expressions were present in the retina. Retinas from the diabetic animals showed significant increases in ET-1, ET-3 ET(A), ET(B) mRNA expressions compared to those from control rats.. These findings indicate that retinal ET-1, ET-3, ET(A) and ET(B) mRNA expression in increased in the chronically diabetic BB/W rat. Augmented gene expression of ETs and their receptors potentially may be of importance in the pathogenesis of retinal microangiopathy in diabetes.

Topics: Animals; Blotting, Southern; Chronic Disease; Diabetes Mellitus, Type 1; Diabetic Retinopathy; DNA Primers; DNA, Antisense; Endothelin-1; Endothelin-3; Endothelins; Gene Expression; Male; Polymerase Chain Reaction; Rats; Rats, Inbred BB; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Retina; RNA; RNA, Messenger

The cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are increased in the circulation of patients with chronic heart failure. However, their correlation with left ventricular dysfunction has not yet been thoroughly evaluated, and their interrelation with other neurohumoral systems, such as the adrenergic system and endothelin, is unclear. Therefore TNF-alpha, its soluble receptor II, IL-6, big endothelin, and noradrenaline levels were simultaneously measured in venous blood from 65 patients with heart failure in New York Heart Association (NYHA) class II to IV during therapy with digitalis, furosemide, and enalapril. TNF-alpha plasma levels were 3.2+/-0.2 SEM pg/ml in 38 patients in NYHA function class II, 4.0+/-0.3 SEM pg/ml in 16 patients in NYHA function class III, and 5.3+/-0.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.001 vs NYHA function class II). IL-6 plasma levels were 3.1+/-0.6 SEM pg/ml in 38 patients in NYHA function class II, 5.2+/-0.8 SEM pg/ml in 16 patients in NYHA function class III, and 13.3+/-3.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.0001 vs NYHA function class II andp < 0.0001 vs NYHA class III). Thus both cytokines increased with increasing severity of heart failure, but only IL-6 plasma levels were different in patients in the more severe function classes. TNF-alpha correlated closely with TNF soluble receptor II (r = 0.8, p < 0.0001) and modestly with serum creatinine (r = 0.6, p < 0.0001), whereas IL-6 plasma levels were not statistically related to kidney function. Significant modest correlations were also found among TNF-alpha and IL-6 (r = 0.3, p < 0.01), big endothelin (r = 0.3, p < 0.01), and noradrenaline levels (r = 0.4, <0.001). This study supports the hypothesis that in heart failure both cytokines, TNF-alpha, and IL-6, as well as neurohumoral factors, play a role in the clinical progression of the disease. Thereby levels of TNF-alpha but not IL-6 seem to be related to concomitant kidney dysfunction.

Topics: Adrenergic Agonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiotonic Agents; Chronic Disease; Creatinine; Digitalis Glycosides; Disease Progression; Diuretics; Enalapril; Endothelin-1; Endothelins; Female; Furosemide; Heart Failure; Humans; Interleukin-6; Kidney; Linear Models; Male; Middle Aged; Multivariate Analysis; Neurotransmitter Agents; Norepinephrine; Protein Precursors; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left

The effect of hypoxic shock on the ability of endothelin (ET) receptors to interact with the cAMP second messenger system was assessed in rat pulmonary arteries. Whole pieces of tissue were dissected from the pulmonary arterial system of control and hypoxic (10% O2, 14 days) rats, incubated, where appropriate, with ET-1 (0.1 microM), and the levels of intracellular cAMP measured. Maintenance of rats under hypoxic conditions significantly reduced the basal cAMP levels in all of the arterial branches with the exception of the pulmonary resistance vessels, in which no change was observed. Incubation of the main and first branch extralobar pulmonary arteries from control rats with ET-1 resulted in a consistent decrease in the levels of intracellular cAMP. The ETA receptor antagonist FR139317 partially blocked this ET-1-mediated inhibition of cAMP accumulation in the main extralobar artery. In contrast, ET-1 caused a threefold increase in the levels of this cyclic nucleotide in the pulmonary resistance vessels from the normoxic rat. No ET-1-mediated reduction in intracellular cAMP levels was observed in any of the vessels isolated from hypoxic animals. All vessels showed ligand-activated increases in cAMP production. These results suggest differential modulation of cAMP in the different pulmonary arteries, either by direct activation through Gi and Gs or indirectly via a uncharacterized cross-talk mechanism.

Topics: Animals; Azepines; Chronic Disease; Cyclic AMP; Endothelin Receptor Antagonists; Endothelin-1; Hypoxia; Indoles; Male; Pulmonary Artery; Rats; Rats, Wistar; Signal Transduction

Endothelin (ET)-1 increases in plasma during congestive heart failure (CHF). Some ET antagonists improve hemodynamics, suggesting its potential benefits in the treatment of CHF. We examined the acute and chronic effects of a new ET receptor antagonist, T-0201 (Tanabe Seiyaku Co. Ltd., Japan), in CHF. To confirm the in vivo effects of T-0201, we observed the inhibitory effects of T-0201 (1-100 micrograms/kg) on the response of blood pressure to exogenously administered ET-1 (0.75 nmol/kg) in conscious normal dogs. Pretreatment with T-0201 significantly inhibited the ET-1-induced initial hypotension that is mediated by ETB receptors, and attenuated the subsequent hypertension, which is primarily mediated by ETA receptors. Thus, T-0201 at a dose of 100 micrograms/kg not only works as a potent ETA antagonist but also shows antagonist activity for ETB receptors in dogs. To evaluate the chronic therapeutic effects of T-0201, we administered T-0201 (0.3 mg/kg/day; n = 5) orally to dogs with CHF induced by rapid right ventricular pacing (22 days, 270 beats/min) for 15 days, beginning 8 days after pacing. T-0201 significantly prevented the deterioration of cardiorenal function during the development of CHF, expressed as a decrease in cardiac pressure and an increase in cardiac and urine output. These results suggest that chronic antagonism of both ET receptors prevents the progressive exacerbation of CHF.

Topics: Animals; Blood Pressure; Cardiac Output; Cardiac Pacing, Artificial; Chronic Disease; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Pulmonary Wedge Pressure; Urodynamics

We previously showed that CI-1020, an endothelin (ET)-A-selective receptor antagonist, dose-dependently blocked acute hypoxic pulmonary hypertension (PH) in rats. In this study we show that CI-1020 can reverse existing PH and prevent progression of right ventricular hypertrophy (RVH) in rats exposed to chronic hypoxia. Male Sprague-Dawley rats were exposed to 20 days of hypoxia (10% O2) with CI-1020 treatment (20 or 40 mg/kg/day) starting on day 10. On day 20 of hypoxia, the rats were instrumented under anesthesia with a pulmonary artery cannula and allowed to recover to consciousness before measurement of mean pulmonary arterial pressure (MPAP). Blood samples were then collected for plasma ET-1 measurements, the rats killed, and their hearts dissected, dried, and weighed. RV/LV + septum ratio (g/g) was used as an index of RVH (RVHi). Normoxic rats and rats exposed to hypoxia for only 10 days were also evaluated as controls. Normoxic rats had MPAPs of 13 +/- 1 mm Hg, plasma ET-1 levels of 2.1 +/- 0.1 pg/ml, and an average RVHi of 0.29 +/- 0.03. Rats exposed to 10 or 20 days of hypoxia had MPAPs of 33 +/- 2 and 44 +/- 0 mm Hg, plasma ET-1 levels of 4.2 +/- 0.8 and 4.6 +/- 0.8 pg/ml, and average RVHis of 0.47 +/- 0.05 and 0.52 +/- 0.03, respectively. In comparison, rats treated with CI-1020 had MPAPs that were 37% (20 mg/kg/day) and 44% (40 mg/kg/day) lower than untreated 20-day hypoxic rats. Furthermore, rats dosed with 40 mg/kg/day of CI-1020 had MPAPs that were significantly lower (24%) than control 10-day hypoxic rats, indicating a significant reversal of PH. Along with this reversal in PH, their average RVHi was 23% lower (p < 0.05) relative to untreated 20-day hypoxic rats.

Topics: Animals; Blood Pressure; Cardiomegaly; Chronic Disease; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

1. We examined the endothelin (ET) receptors mediating contractions to ET-1, ET-3 and sarafotoxin S6c (SX6c) in rat pulmonary resistance arteries by use of peptide and non-peptide ET receptor antagonists. Changes induced by pulmonary hypertension were examined in the chronically hypoxic rat. The effect of the mixed ET(A)/ET(B) receptor antagonist SB 209670 on endothelin-mediated contraction was also examined in human pulmonary resistance arteries. 2. In rat vessels, the order of potency for the endothelin agonists was SX6c = ET-3 > ET-1 (pEC50 values in control rats: 9.12+/-0.10, 8.76+/-0.14 and 8.12+/-0.04, respectively). Maximum contractions induced by ET-3 and ET-1 were increased in vessels from chronically hypoxic rats. 3. The ET(A) receptor antagonist FR 139317 (1 microM) had no effect on the potency of ET-1 in any vessel studied but abolished the increased response to ET-1 in the chronically hypoxic vessels. The ET(A) receptor antagonist BMS 182874 (1 microM) increased the potency of ET-1 in control rat vessels without effecting potency in the pulmonary hypertensive rat vessels. 4. Bosentan (non-peptide mixed ET(A)/ET(B) receptor antagonist) increased the potency of ET-1 in control rat vessels but was without effect in the pulmonary hypertensive rat vessels. Bosentan (1 microM) inhibited responses to SX6c in control and chronically hypoxic rat vessels with pKb values of 5.84 and 6.11, respectively. The ET(B) receptor antagonist BQ-788 (1 microM) did not inhibit responses to ET-1 in any vessel tested but did inhibit responses to both SX6c and ET-3 (pKb values in control and chronically hypoxic rat vessels respectively: SX6c 7.15 and 7.22; ET-3: 6.68 and 6.89). BQ-788 (1 microM) added with BMS 182874 (10 microM) did not inhibit responses to ET-1 in control vessels but caused a significant inhibition of responses to ET-1 in chronically hypoxic preparations. 5. SB 209670 inhibited responses to ET-1 in both control and chronically hypoxic vessels with pKb values of 7.36 and 7.39, respectively. SB 209670 (0.1 and 1 microM) virtually abolished responses to ET-1 in the human pulmonary resistance artery. 6. In conclusion, in rat pulmonary resistance arteries, vasoconstrictions induced by ET-1, SX6c and ET-3 are mediated predominantly by activation of an ET(B)-like receptor. However, lack of effect of some antagonists on ET-1 induced vasoconstriction suggests that ET-1 stimulates an atypical ET(B) receptor. The increase in potency of ET-1 in the presence of s

Topics: Animals; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Humans; Hypoxia; In Vitro Techniques; Indans; Male; Muscle Contraction; Pulmonary Artery; Rats; Rats, Wistar; Receptors, Endothelin; Vascular Resistance; Vasoconstriction

Topics: Animals; Chronic Disease; Endothelin-1; Endothelins; Endothelium, Vascular; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Protein Precursors; Rats

Topics: Animals; Chronic Disease; Disease Models, Animal; Endothelin-1; Endothelins; Fetal Diseases; Hypertension, Pulmonary; Lung; Protein Precursors; Receptors, Endothelin; RNA, Messenger; Sheep; Vasoconstriction

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Chronic Disease; Endothelin-1; Glomerulonephritis; Rats

The effect of acute oxygen administration on endothelin-1 (ET-1) and nitrates (NO.2/NO.3), the latter as stable end products of nitric oxide (NO), were evaluated in arterial and venous blood of chronic respiratory failure (CRF) patients underwent to a continuous long-term oxygen therapy (LTOT). After one hour of oxygen supplementation, ET-1 showed a marked and significant decrease more pronounced in venous blood whereas no statistical change in NO.2/NO.3 concentrations were observed in both arterial and venous blood. There are evidences for increased expression of ET-1 in several pulmonary diseases and for ET-1 plasma reduction in Adult Respiratory Distress Syndrome (ARDS) in patients which recovered. ET-1 is a potent human pulmonary vessel constrictor and may have other effects including plasma exudation, increased mucus secretion and a increased fibrinogenesis. Our data suggest that the improvement in air function, evaluated in part by the decreased release of inflammatory mediators and mainly by reduction in the pulmonary arterial resistance, may be a consequence of the decrease in ET-1 content in the lungs of CRF patients treated with LTOT.

Topics: Aged; Chronic Disease; Endothelin-1; Female; Humans; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Oxygen; Respiratory Insufficiency

Smooth muscle reactivity is one of the factors involved in the pathogenesis of varicose veins. We investigated the myotropic effects of the 3 main vasoconstrictor agents norepinephrine (NE), angiotensin II (Ang II), and endothelin-1 (ET-1) in isolated human saphenous veins.. Human saphenous veins were collected from 23 patients with primary chronic venous insufficiency who underwent elective varicose vein resections and who were stratified into the following 3 groups: group 1, 7 patients in clinical class 2; group 2, 9 patients in clinical classes 3 and 4; and group 3, 7 patients in clinical classes 5 and 6. Moreover, 6 patients who underwent arterial bypass grafting procedures represented the control group. The tissues were suspended in organ baths that contained Krebs solution, and their mechanical responses were measured isometrically. The cumulative concentration-response curves to Ang II, NE, and ET-1 were performed at 90-minute intervals in each tissue.. In the control tissues, NE, Ang II, and ET-1 induced concentration-dependent contractions with apparent affinities (pEC50, the negative logarithm to base 10 of the molar concentration of the agonist, which produces the 50% of the maximal effect) and maximal effects (maximum effect, g of contraction) that were equal to 7.06 +/- 0.23, 8.53 +/- 0.34, 7.63 +/- 0.10, and 2.21 +/- 0.33, 1.65 +/- 0.31, 2.60 +/- 0.77, respectively. Two main findings were evident in comparison of varicose veins with control tissues. First, the maximum effect that was evoked by all of the stimulants was reduced progressively with the increasing severity of the disease, which raised the third group to statistical significance for both NE and Ang II (P <.05). Second, a marked reduction of Ang II apparent affinity was already evident in tissues that were taken from patients in an early stage of the disease (P <.05).. The demonstration of a significant reduction in Ang II and NE contractile activities and the important reduction of that of ET-1 in the diseased veins as compared with the control tissues extends the previous observations regarding the impairment of smooth muscle contractility in primary chronic venous insufficiency. Moreover, the dramatic reduction of Ang II affinity, which appears in an early stage of the disease, supports the hypothesis that such abnormality within the venous wall could play a role in the pathogenesis of primary varicose vein disease.

Topics: Angiotensin II; Chronic Disease; Endothelin-1; Female; Humans; In Vitro Techniques; Male; Middle Aged; Muscle, Smooth, Vascular; Norepinephrine; Saphenous Vein; Vasoconstrictor Agents; Venous Insufficiency

Endothelin-1 is a potent vasoconstrictive and multifunctional peptide. Elevated concentrations have been reported in congestive heart failure. We hypothesized that the level of endothelin-1 in plasma is a prognostic marker in congestive heart failure.. Plasma levels of endothelin-1 were measured by radioimmunoassay in 120 congestive heart failure patients with ischaemic or non-ischaemic cardiomyopathy (mean ejection fraction 28 +/- 11%, in New York Heart Association (NYHA) functional class I:21, class II 35, class III: 61, class IV: 3). During a median follow-up of 361 +/- 338 days, 14 cardiac deaths occurred. In the univariate Cox model, endothelin-1 was the most powerful prognostic marker among the variables tested (P = 0.0001). A multivariate model, including plasma atrial natriuretic peptide and noradrenaline, NYHA class, age, and echocardiographic left ventricular end-diastolic diameter index was highly predictive of mortality (P = 0.00008), but only endothelin-1 remained significantly associated with outcome (P = 0.02). Patients with plasma endothelin-1 > or = 5 pg. ml-1 had a higher mortality rate than those with endothelin-1 < 5 pg. ml-1 (21% vs 4%, P = 0.001).. Our results suggest that elevated endothelin-1 plasma levels are associated with a poor prognosis and routine plasma endothelin-1 determination provides important prognostic information in mild to moderate heart failure.

Topics: Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Death; Echocardiography; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Norepinephrine; Prognosis; Radioimmunoassay; Survival Rate

Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF.. Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)). Bosentan 100 mg x kg(-1) markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg x kg(-1)), which had no major hemodynamic or structural effects, also had no effect on survival.. Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Cardiac Volume; Chronic Disease; Collagen; Consciousness; Coronary Vessels; Cyclic GMP; Echocardiography; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Heart Ventricles; Male; Myocardial Infarction; Myocardium; Norepinephrine; Pressure; Protein Precursors; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Survival Analysis; Ventricular Function, Left

Although phorbol esters, synthetic activators of protein kinase C (PKC), can stimulate large increases in the binding of cytosolic PKC to form membrane-bound PKC (PKCm, an indicator of PKC activation), the authors report that even small increases in PKCm induced by phorbol esters (8-12% of total PKC content) can be associated with significant PKC-mediated contractions in vitro (50-85% of maximum) in normal canine cerebral arteries. Increases in PKCm of similarly small magnitude were found in vitro when control artery segments were exposed to hemolysate, but only if the arterial smooth-muscle cells were first slightly depolarized by increased extracellular potassium to values of membrane potential similar to those observed in canine cerebral arteries during chronic cerebral vasospasm. These increases in PKCm (6-8% of total PKC content) coincided with a greatly augmented contractile response to hemolysate. These results show that the previous observation of only a small increase in PKCm (approximately 7% of total PKC content) after experimental subarachnoid hemorrhage in the canine model does not preclude a potentially important role for PKC-mediated contraction in the pathogenesis of cerebral vasospasm.

Topics: Animals; Cell Membrane; Cerebral Arteries; Chronic Disease; Cytosol; Dogs; Endothelin-1; Enzyme Activation; Enzyme Inhibitors; Hemolysis; Ischemic Attack, Transient; Membrane Potentials; Muscle, Smooth, Vascular; Naphthalenes; Phorbol 12,13-Dibutyrate; Phorbol Esters; Potassium; Protein Binding; Protein Kinase C; Stress, Mechanical; Subarachnoid Hemorrhage; Vasoconstriction; Vasoconstrictor Agents

To investigate the impact of nitric oxide on endothelin-1 (ET-1) mRNA expression in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of chronic hypoxic rats.. In situ hybridization was performed on lung sections from 40 chronic hypoxic rats treated either with L-Arginine (L-Arg) or N omega-nitro-L-arginine methyl ester (L-NAME) by using cRNA probe for ET-1.. Most intrapulmonary arteries had 1%-50% of the endothelial cells expressing ET-1 mRNA in both one-week and two-week hypoxic rats (75% +/- 3% and 71% +/- 6%, respectively), which was significantly inhibited by L-Arg but augmented by L-NAME administration. Most pulmonary artery smooth muscle cells showed no ET-1 mRNA signals in both one-week and two-week hypoxic rats (85% +/- 6% and 98% +/- 2%, respectively). However, L-NAME increased ET-1 mRNA expression in pulmonary artery smooth muscle cells of hypoxic rats.. Nitric oxide inhibited ET gene expression in both pulmonary artery endothelial cells and smooth muscle cells of rats exposed to chronic hypoxia.

Topics: Animals; Chronic Disease; Endothelin-1; Gene Expression; Hypoxia; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pulmonary Artery; Rats; Rats, Wistar; RNA, Messenger

The authers investigated the levels of plasma EDRF-nitric oxide (NO) and ET-1 in 10 cases of cor pulmonale at exercise.. Using the technologies of cardiac catheter, radioimmunization and biochemical analysis.. The level of plasma NO was lower in group A (mean pulmonary artery pressure (mPAP) < 2.67 kPa) than in group B (mPAP > or = 2.67 kPa) at rest; the content of plasma NO increased more markedly in group A than in group B during exercise; there was no change in the content of ET-1 in both groups; mPAP strongly correlated with plasma NO or ET-1 in both groups.. The patients with cor pulmonale at early stage may be in a state of compensated release of NO, but its release reserve has been reduced.

Topics: Aged; Chronic Disease; Endothelin-1; Exercise Test; Female; Humans; Male; Middle Aged; Nitric Oxide; Pulmonary Heart Disease

To evaluate the secretion of vasoactive factors in vascular endothelium of patients with non-insulin-dependent diabetes mellitus (NIDDM) the authors examined 31 NIDDM patients. Of them, 18 had no signs of renal involvement, 13 patients showed apparent diabetic nephropathy (DN). In the former patients the blood contained much greater content of vasodilating factor prostacyclin than of vasoconstricting factor endothelin-1 (ET-1) and thromboxan A2 (TxA2). In diabetic nephropathy the balance of vasoactive factors shifted to predominance of vasoconstrictors ET-1 and TxA2. Such rearrangement of vasoactive factors to higher quantities of vasoconstrictors in diabetes mellitus may initiate or promote progression of diabetic nephropathy with resultant spasm of afferent glomerular vessels, reduced glomerular filtration and renal blood flow rates, arterial hypertension, increased thrombogenesis. Thus, elevated levels of ET-1 and TxA2 in diabetics and their rise with progression of diabetic nephropathy are likely to act as pathogenetic factors underlying onset and progression of nephroangiopathy.

Topics: Albuminuria; Chronic Disease; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; Humans; Male; Middle Aged; Thromboxane A2

Chronic pancreatitis (CP) is characterized by the presence of an inflammatory infiltrate with progressive destruction of acinar cells and fibrosis. The finding that endothelin-1 (ET-1), an endothelium-derived peptide having vasoconstrictive and mitogenic properties, reduces pancreatic blood flow (PBF) in normal rats suggested that the peptide may be associated with the reduced PBF seen in animal models of CP and with the morphological abnormalities of the disease. This study investigates changes in blood flow to the pancreas and other abdominal organs in a rat model of CP and compares ET-1 production in the pancreata of these rats and normal controls. CP was induced in male Wistar rats by the injection of oleic acid into the common bile/pancreatic duct. The radiolabeled microsphere technique was employed to measure blood flow to the pancreas, duodenum, liver, spleen, and kidneys. Immunohistochemistry was used to investigate the cellular production of ET-1. After 3 weeks, significant decreases were noted in body weight, pancreatic weight, and pancreatic DNA, amylase, and protein content in the animals with CP. PBF was reduced by 64% and duodenal blood flow by 80% relative to those in control animals. Hepatic and splenic blood flows were increased by 91 and 88%, respectively, compared to those in controls. A 50% decrease in renal blood flows were increased by 91 and 88%, respectively, compared to those in controls. A 50% decrease in renal blood flow was also seen in the experimental group after 3 weeks. Pancreata from animals with CP stained diffusely for ET-1 in the cytoplasm of vascular endothelial, acinar, and ductal cells. In the control pancreata, focal staining for ET-1 was observed only in acinar cells. This difference was significant in endothelial and ductal cells. There was weak staining of islet cells in both groups. The results suggest that elevation in local production of ET-1 may be associated with the morphological and hemodynamic changes of CP.

Topics: Animals; Blood Flow Velocity; Chronic Disease; Disease Models, Animal; Endothelin-1; Immunohistochemistry; Male; Microcirculation; Microspheres; Pancreas; Pancreatitis; Rats; Rats, Wistar; Regional Blood Flow

The purpose of this study was to evaluate flow reduction to the optic nerve after chronic administration of endothelin-1 in primates.. Endothelin-1 (three rhesus monkeys), in a dosage of 0.1 microgram/day, or balanced salt solution (three rhesus monkeys) was delivered to the perineural region of the anterior optic nerve via osmotically driven minipumps. Optic nerve blood flow was determined by means of a colored microspheres technique after 7 days of local endothelin-1 or balanced salt solution administration. The effect of endothelin-1 on optic nerve blood flow was analyzed by analysis of convariance (ANCOVA) in a 2 (between groups: endothelin-1, balanced salt solution) x 2 (within subject: blood flow minipump optic nerve, blood flow controls) design, with intraocular pressure as a changing covariate.. The decrease of optic nerve blood flow in the endothelin-1 eyes was significant compared to the balanced salt solution eyes (ANCOVA p = 0.015). Among the monkeys implanted with endothelin-1 minipumps, the decrease in optic nerve blood flow in the experimental eye compared to the contralateral eye (mean +/- SD 35.7 +/- 9.1%) was significant (p = 0.01), while that among the monkeys implanted with balanced salt solution minipumps (mean +/- SD 0.7 +/- 5.5%) was not (p = 0.73).. This new primate model of chronic optic nerve ischemia may represent a method to evaluate experimentally the implication of a local hemodynamic perturbation in various optic neuropathies.

Topics: Animals; Chronic Disease; Endothelin-1; Intraocular Pressure; Ischemia; Macaca mulatta; Microspheres; Optic Nerve; Regional Blood Flow

To ascertain the pathophysiological roles of the renin-angiotensin system and endothelin in heart failure and cardiac hypertrophy, we assessed changes in cardiac angiotensin converting enzyme (ACE) and endothelin-1 (ET-1) receptor using rats in which myocardial infarction was induced by left coronary ligation. The animals were decapitated 1 or 8 months after the operation. Cardiac ACE and ET-1 receptor were quantified by computerized in vitro autoradiography using 125I-MK351A (a lisinopril derivative) and 125I-ET-1. One month after myocardial infarction, cardiac weight and plasma atrial natriuretic peptide had increased in rats with infarction, compared to sham-operated controls, indicating the presence of chronic left ventricular dysfunction, although exchangeable body sodium and plasma renin activity were unchanged. Cardiac ACE increased markedly in the infarcted area and moderately in hypertrophied myocardium without any change in affinity compared to sham-operated rats. On the other hand, there was no change in cardiac ET-1 receptors in infarcted rats. The same results were found even at 8 months after myocardial infarction. The present study indicates that cardiac ACE may participate in tissue repair at the site of myocardial infarction and may also play a role in the pathophysiology of cardiac hypertrophy in rats with chronic heart failure. However, the present results do not reveal whether ET-1 receptor participates in the pathophysiology of cardiac hypertrophy in this model.

Topics: Angiotensin II; Animals; Autoradiography; Cardiomegaly; Chronic Disease; Endothelin-1; Female; Heart Failure; Image Processing, Computer-Assisted; Iodine Radioisotopes; Ligation; Myocardial Infarction; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Receptors, Endothelin; Renin; Ventricular Function, Left

The role of endothelin (ET)-1 in pulmonary arterial pressure (Ppa) homeostasis and hypoxia-induced pulmonary hypertension was examined. ET-1 was chronically infused (2 and 4 pmol.kg-1.min-1) into the pulmonary circulation of male Sprague-Dawley rats for 3, 7, and 14 days while they were exposed to normoxia or hypobaric hypoxia (inspired O2 fraction 10%). The role of endogenous ET was examined by infusion of ET antiserum (ET-AS; 0.25 and 0.5 microliter.rat-1.h-1; cross-reacting with ET-1, -2, and -3) or the ETA-receptor blocker BQ-123 (10 pmol.kg-1.min-1). ET-1 (4 pmol) increased Ppa at 3 and 7 days in normoxia and hypoxia and was ineffective at 14 days, probably from ETA-receptor downregulation. BQ-123 blunted the hypoxic Ppa rise at all times, confirming a role for ETA receptors. ET-AS (0.5 microliter) was mostly ineffective but exacerbated hypoxic Ppa at 14 days, in contrast to BQ-123, suggesting that a different ET receptor could be involved. ET-1 infusion (2 pmol) caused right ventricular hypertrophy (RVH) in normoxia and exacerbated RVH in hypoxia, whereas BQ-123 and ET-AS (0.25 microliter) reduced hypoxic RVH. In conclusion, endogenous ET-1 plays a role in hypoxia-induced pulmonary hypertension and RVH by augmenting the level of hypoxic response. ET-1 also affects hematocrit and may reduce blood levels of the vasodilator calcitonin gene-related peptide.

Topics: Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Hematocrit; Hypoxia; Immune Sera; Longitudinal Studies; Lung; Male; Myocardium; Organ Size; Peptides, Cyclic; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Reference Values

The purpose of this study was to evaluate the effects induced by chronic microapplication of endothelin-1 on the anterior optic nerve microvasculature and to determine the dose-response characteristics of endothelin-1 on this vascular bed. Daily dosages between 4.69 x 10(-4) and 9.0 x 10(-1) micrograms/day of endothelin-1 were delivered continually over 3 days, and at a constant flow rate, to the perineural region of the anterior optic nerve of 15 albino rabbits via osmotically-driven minipumps. The vasomotor effect of local endothelin-1 on the microvasculature of the optic nerve was examined using intraluminal microvascular corrosion casting technique. The vasomotor effects were quantified by measuring the relative amount of vasoconstriction of the arterioles supplying the anterior optic nerve (primary and secondary branches of the short posterior ciliary arteries). The average constriction was calculated for the endothelin-treated eyes and the untreated, contralateral eyes. The mean vasoconstriction in the endothelin treated eyes ranged from 14.7% to 30.0% and was highly correlated with the logarithmic value of the daily dose of endothelin-1 (R2 = 0.59, p = 0.00083). The interocular difference (between treated and untreated eyes) of the optic nerve vasoconstriction ranged from 0-19% (mean +/- SD: 7.23 +/- 5.7%). This interocular difference also correlated highly with the log of the daily endothelin-1 dosage (R2 = 0.80; p < 0.0001). By additionally accounting for the weight and sex in a multiple linear regression function, the correlation was markedly improved (R2 = 0.92; p < 0.0001). In conclusion, the microvasculature supplying the anterior optic nerve of the rabbit demonstrates a dose-dependent vasoconstriction with chronic local application of endothelin-1. This in vivo, experimental model offers a titratable method with which the effects of chronic vasoconstriction and vascular insufficiency on the optic nerve can be examined.

Topics: Animals; Chronic Disease; Dose-Response Relationship, Drug; Endothelin-1; Female; Infusion Pumps; Intraocular Pressure; Ischemia; Male; Microcirculation; Microscopy, Electron, Scanning; Optic Nerve; Rabbits; Vasoconstriction

The role of endogenous circulating or locally produced endothelin-1 (ET-1) in pulmonary hypertensive states is unknown. To investigate this we measured ET-1 levels and preproendothelin-1 (prepro-ET-1) mRNA expression at various ages in control Sprague-Dawley (SDR) rats and in fawn-hooded rats (FHR), a strain which develops idiopathic pulmonary hypertension. Although serum ET-1 levels were similar in SDR and FHR, we found twofold increases in FHR whole lung homogenate ET-1 levels by radioimmunoassay. Coexisting threefold increases in preproET-1 mRNA expression were found in FHR lungs by densitometric analysis of Northern blots and by filter hybridization, suggesting the increase in lung ET-1 was due to enhanced intrapulmonary production of the peptide. To test whether the increase in lung preproET-1 mRNA was primary or secondary to established pulmonary hypertension, we compared preproET-1 mRNA expression prior to development of pulmonary hypertension in fetal (19 day gestation) and neonatal (5 day old) FHR and SDR. Despite similar right ventricular size in SDR and FHR, preproET-1 mRNA was already elevated in neonatal FHR lungs. Furthermore, we found no increase in lung preproET-1 mRNA or ET-1 levels in adult SDR with an equivalent degree of pulmonary hypertension due to chronic hypoxia, implying that the increases in ET-1 production in FHR were not a common consequence of all pulmonary hypertensive states. The functional significance of these observations remains unclear but raises the possibility of a role for ET-1 in the pathophysiology of pulmonary hypertension in the FHR.

Topics: Animals; Cardiomegaly; Cell Nucleus; Chronic Disease; Endothelin-1; Endothelins; Hemodynamics; Hypertension, Pulmonary; Lung; Peptide Chain Elongation, Translational; Protein Precursors; Radioimmunoassay; Rats; Rats, Inbred Strains; RNA, Messenger; Transcription, Genetic