endothelin-1 and Heart-Diseases

Exposure to particulate matter air pollution has been causally linked to cardiovascular disease in humans. Several broad and overlapping hypotheses describing the biological mechanisms by which particulate matter exposure leads to cardiovascular disease have been explored, although linkage with specific factors or genes remains limited. These hypotheses may or may not also lead to particulate matter-induced cardiac dysfunction. Evidence pointing to autocrine/paracrine signaling systems as modulators of cardiac dysfunction has increased interest in the emerging role of endothelins as mediators of cardiac function following particulate matter exposure. Endothelin-1, a well-described small peptide expressed in the pulmonary and cardiovascular systems, is best known for its ability to constrict blood vessels, although it can also induce extravascular effects. Research on the role of endothelins in the context of air pollution has largely focused on vascular effects, with limited investigation of responses resulting from the direct effects of endothelins on cardiac tissue. This represents a significant knowledge gap in air pollution health effects research, given the abundance of endothelin receptors found on cardiac tissue and the ability of endothelin-1 to modulate cardiac contractility, heart rate, and rhythm. The plausibility of endothelin-1 as a mediator of particulate matter-induced cardiac dysfunction is further supported by the therapeutic utility of certain endothelin receptor antagonists. The present review examines the possibility that endothelin-1 release caused by exposure to PM directly modulates extravascular effects on the heart, deleteriously altering cardiac function.

Topics: Animals; Cardiotoxicity; Endothelin Receptor Antagonists; Endothelin-1; Environmental Exposure; Heart Diseases; Humans; Myocardium; Particulate Matter; Signal Transduction

Radiation-induced heart disease (RIHD) is a serious side effect of radiotherapy for intrathoracic and chest wall tumors. The threshold dose for development of clinically significant RIHD is believed to be lower than previously assumed. Therefore, research into mechanisms of RIHD has gained substantial momentum. RIHD becomes clinically apparent ten to fifteen years after radiation exposure. Chronic manifestations of RIHD include accelerated atherosclerosis, cardiomyopathy, and valve abnormalities. Reducing exposure of the heart during radiotherapy is the only known method of preventing RIHD, and there are no approaches to reverse RIHD once it occurs. We use a combination of pharmacological and genetic animal models to determine biological mechanisms of RIHD. Major technological advances in small animal research have made this type of study more valuable. The long-term goal of this work is to identify targets for intervention in RIHD, thereby enhancing the efficacy and safety of thoracic radiotherapy.

Topics: Animals; Endothelin-1; Heart Diseases; Humans; Mast Cells; Radiation Injuries, Experimental; Radiotherapy; Thoracic Neoplasms

Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, "activated" fibroblasts migrate into the wound area, where they synthesize and remodel newly created extracellular matrix. The specialized type of fibroblast responsible for this action is the alpha-smooth muscle actin (alpha-SMA)-expressing myofibroblast. Abnormal persistence of the myofibroblast is a hallmark of fibrotic diseases. Proteins such as transforming growth factor (TGF)beta, endothelin-1, angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), and platelet-derived growth factor (PDGF) appear to act in a network that contributes to myofibroblast differentiation and persistence. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGFbeta, endothelin-1, Ang II, CCN2, and PDGF and to fibroblast activation in tissue repair and fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of cardiac fibrosis.

Topics: Angiotensin II; Animals; Cardiovascular Agents; Connective Tissue Growth Factor; Drug Design; Endothelin-1; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Heart Diseases; Humans; Myocardium; Platelet-Derived Growth Factor; Signal Transduction; Transforming Growth Factor beta

The cardiac Na+-Ca2+ exchanger (NCX) is an important regulator of intracellular ion homeostasis and cardiac function. Gaining insight into modulation of the NCX is therefore important in order to understand ion handling in the heart under physiological and pathological conditions. Typically, the functional contribution of the NCX is often regarded as "secondary" to the changes in luminal Na+ and Ca2+. Whilst it is well accepted that the NCX can be regulated by various factors, including the concentrations of transported ions, direct receptor-mediated modulation of the cardiac NCX is more controversial. Evidence from several different laboratories supports the notion that the cardiac NCX is a direct target of neurotransmitters and hormones and their downstream signalling pathways; however, the issue remains unresolved due to conflicting data showing a lack of direct modulation. The present review summarizes overall findings regarding the modulation of the cardiac NCX, in particular on molecular mechanisms of direct phosphorylation of NCX by beta-adrenergic/adenylate cyclase/protein kinase A and (for comparative purposes) on endothelin-1/protein kinase C signalling pathways. It also aims to consider whether it is currently possible to reconcile discrepancies between studies in the interpretation of the regulation of the cardiac NCX by agents stimulating the beta-adrenoceptor/PKA pathway.

Topics: Animals; Cyclic AMP-Dependent Protein Kinases; Endothelin-1; Feedback, Physiological; Gene Expression Regulation; Heart; Heart Diseases; Humans; Myocardial Contraction; Myocardium; Phosphorylation; Protein Kinase C; Receptors, Adrenergic, beta; Signal Transduction; Sodium-Calcium Exchanger

The heart is abundantly innervated, and the nervous system precisely controls the function of this organ. The density of cardiac innervation is altered in diseased hearts, which can lead to unbalanced neural activation and lethal arrhythmia. For example, diabetic sensory neuropathy causes silent myocardial ischemia, characterized by loss of pain perception during myocardial ischemia, and it is a major cause of sudden cardiac death in diabetes mellitus. Despite the clinical importance of cardiac innervation, the mechanisms underlying the control of this process remain poorly understood. We demonstrate that cardiac innervation is determined by the balance between neural chemoattractants and chemorepellents within the heart. Nerve growth factor (NGF), a potent chemoattractant, is synthesized abundantly by cardiomyocytes, and is induced by the upregulation of endothelin-1 during development. By comparison, the neural chemorepellent Sema3a is expressed at high levels in the subendocardium in the early stage of embryogenesis and is downregulated as development progresses, leading to epicardial-to-endocardial transmural sympathetic innervation patterning. We also show that the downregulation of cardiac NGF is a cause of diabetic neuropathy and that NGF supplementation prevents silent myocardial ischemia in diabetes mellitus. Both Sema3a-targeted and Sema3a-overexpressing mice display sudden cardiac death or lethal arrhythmias due to disruption of innervation patterning. The present review focuses on the regulatory mechanisms controlling cardiac innervation and the critical roles of these processes in cardiac performance.

Topics: Animals; Death, Sudden, Cardiac; Endothelin-1; Gene Expression Regulation; Heart; Heart Diseases; Humans; Myocytes, Cardiac; Nerve Growth Factor; Semaphorin-3A

Endothelin-1 (ET-1) is a powerful vasoconstrictor and mitogen that contributes to blood pressure elevation and related vascular remodeling and target organ damage. ET-1 also influences salt and water homeostasis through effects on the renin-angiotensin-aldosterone system and vasopressin, thus elevating blood pressure and increasing vascular tone. Circulating ET-1 levels are elevated in a variety of animal models of hypertension, particularly those that are salt-dependent, and in a subset of human hypertensives, i.e. African-Americans and those with renal dysfunction. ET type B receptors, which normally have vasodilator functions, mediate vasoconstriction in some hypertensives, and hypertensive African-American patients may have increased numbers of vasoconstrictor ET-B receptors in their vascular smooth muscle. Whether selective ET-A or combined ET-A/ET-B receptor antagonists are more efficacious in treating hypertension and related cardiovascular disease is controversial. ET antagonists have only modest BP lowering effects in the general population of essential hypertensives, but show promise in patients with severe, treatment resistant hypertension.

Topics: Animals; Endothelin-1; Heart Diseases; Humans; Hypertension; Kidney Tubules; Receptors, Endothelin

Heart disease is among the leading causes of death in all populations. Cardiac dysfunctions are major complications in patients with advanced viral or bacterial infection, severe trauma and burns accompanied with multiple organ failure - collectively known as systemic inflammatory response syndrome (SIRS). SIRS, which is often subsequent to sepsis, is clinically featured by hypotension, tachypnea, hypo- or hyperthermia, leukocytosis and myocardial dysfunction. The striking association between inflammation and cardiac dysfunction not only prognoses likelihood of survival in patients with SIRS but also prompts the necessity of understanding the pathophysiology of cardiac dysfunction in SIRS, so that effective therapeutic regimen may be identified. Compelling evidence has shown significant and independent link among inflammation, sepsis, insulin resistance and cardiac dysfunction. Several cytokine signaling molecules have been speculated to play important roles in the onset of cardiac dysfunction under SIRS including endothelin-1 and toll-like receptor. Involvement of these pathways in cardiac dysfunction has been convincingly validated with transgenic studies. Nevertheless, the precise mechanism of action underscoring inflammation-induced cardiac contractile dysfunction is far from being clear. Given the substantial impact of inflammation and SIRS on health care, ecosystems and national economy, it is imperative to understand the cellular mechanisms responsible for cardiac contractile dysfunction under inflammation and sepsis so that new and effective therapeutic strategy against such devastating heart problems may be developed.

Topics: Animals; Biopterins; Cytokines; Diabetes Mellitus; Endothelin-1; Heart Diseases; Humans; Inflammation; Insulin Resistance; Myocardium; Nitric Oxide; Sepsis; Shock, Septic; Systemic Inflammatory Response Syndrome; Toll-Like Receptors

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

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

Topics: Alcohol Drinking; Antioxidants; Dose-Response Relationship, Drug; Endothelin-1; Female; Flavonoids; Food, Organic; Heart Diseases; Humans; Lung Neoplasms; Male; Phenols; Polyphenols; Prostatic Neoplasms; Wine

The discovery of endothelin--a highly potent endogenous vasoconstrictor - in 1988 has led to considerable efforts to develop antagonists of endothelin receptors that could have therapeutic potential in disorders including hypertension, heart failure and renal diseases. However, in general, the results of trials in humans have not mirrored the highly promising effects in animal disease models. Here, we discuss preclinical and clinical results with endothelin antagonists, and consider possible approaches to fully realizing the potential of endothelin antagonism.

Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Heart Diseases; Humans; Hypertension

Topics: Animals; Coronary Circulation; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart; Heart Diseases; Humans; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Receptors, Endothelin; Second Messenger Systems; Sodium-Hydrogen Exchangers

Heparin-coated circuits attenuate the systemic inflammatory response to cardiopulmonary bypass. The present study compares two different heparin coatings in terms of the release of endothelin-1 and neutrophil glycoproteins.. Forty low-risk patients undergoing coronary artery bypass grafting were investigated, having cardiopulmonary bypass with a Duraflo II heparin-coated circuit (n = 10), an identical but uncoated circuit (n = 10), a Carmeda BioActive Surface heparin-coated circuit (n = 10), or an identical but uncoated circuit (n = 10). A standard systemic heparin dosage was used in all patients. Endothelin-1 and the neutrophil glycoproteins lactoferrin and myeloperoxidase were quantified throughout the operation and 3 hours postoperatively.. Enhanced plasma levels of endothelin-1, lactoferrin, and myeloperoxidase were observed during and after uncoated cardiopulmonary bypass, but this was not associated with clinical side effects. Compared with the respective uncoated controls, Duraflo II attenuated only the lactoferrin levels, whereas Carmeda BioActive Surface was associated with lower levels of both endothelin-1, lactoferrin, and myeloperoxidase. Of the two heparin coatings, Carmeda BioActive Surface proved more effective than Duraflo II in attenuating the levels of these substances.. The plasma levels of endothelin-1, lactoferrin, and myeloperoxidase increase during cardiopulmonary bypass in coronary artery bypass grafting, but this has no clinical side effects in low-risk patients. The increase is attenuated using heparin-coated extracorporeal circuits, and then more effectively by Carmeda BioActive Surface than by Duraflo II.

Topics: Cardiopulmonary Bypass; Coronary Artery Bypass; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fibrinolytic Agents; Heart Diseases; Heparin; Humans; Lactoferrin; Male; Neutrophil Activation; Peroxidase

Endothelin-1 (ET-1), a potent endogenous vasoconstrictor, stimulates production of reactive oxygen species. Endothelial monocyte-activating polypeptide-II (EMAP-II) is a multifunctional polypeptide.. To assess ET-1 gene polymorphism (G8002A) in pediatric patients with β-thalassemia major (β-TM) as a potential genetic marker for vascular dysfunction and its possible relation to EMAP II, oxidative stress and vascular complications.. β-TM patients (n = 95) without symptomatic cardiac or renal disease were compared with 95 healthy controls. Markers of hemolysis, serum ferritin, urinary albumin-to-creatinine ratio, serum EMAP II, malondialdehyde (MDA) and antioxidant enzymes; superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione reductase and catalase were measured. ET-1 gene polymorphism (G8002A) was determined using polymerase chain reaction‑restriction fragment length polymorphism.. β-TM patients had significantly higher EMAP II than healthy controls. EMAP II was significantly higher among patients with cardiac disease, pulmonary hypertension (PH) risk, nephropathy, poor compliance to therapy and ferritin ≥ 2500 μg/L. There were significant correlations between EMAP II and transfusion index, LDH, ferritin and oxidative stress markers. The AA genotype of ET-1 gene polymorphism (G8002A) was significantly higher among β-TM patients than controls. The number of patients with cardiac disease, PH risk or nephropathy was significantly higher among AA genotype compared with GG and GA genotypes. Lactate dehydrogenase (LDH), serum ferritin, EMAP II, MDA, SOD and GPx were significantly higher in AA genotype.. ET-1 gene polymorphism (G8002A) could be a possible genetic marker for prediction of increased susceptibility to cardiopulmonary and renal complications among pediatric patients with β-TM.

Topics: beta-Thalassemia; Child; Endothelin-1; Ferritins; Genetic Markers; Heart Diseases; Humans; Kidney Diseases; Polymorphism, Genetic; RNA-Binding Proteins; Superoxide Dismutase

High-salt diet has been suggested to increase the risk of heart disease. However, the mechanisms underlying coronary artery tension dysfunction caused by high-salt diet are unclear. Previous studies have shown that coronary artery spasm is often induced by endothelin-1 (ET-1) and thromboxane, leading to myocardial ischemia, while the store-operated Ca. Tension measurements of endothelium-denuded coronary artery ring segments showed that vasocontraction induced by U46619, ET-1, orSTIM1/Orai1-mediated SOCE was significantly lower in 4% high-salt diet rats than in control rats fed a regular diet. The results of western blotting and immunohistochemistry assays showed lower expression levels of endothelial receptors ET. Our findings indicated that coronary artery tension was significantly decreased in 4% high-salt diet rats and that this decrease may be due to the change of endothelin receptor and its downstream pathway SOCE related protein expression in coronary artery. Coronary fibrosis was observed in rats fed with high-salt diet. This study provides potential mechanistic insights into high-salt intake-induced heart disease.

Topics: Animals; Calcium; Coronary Vessels; Diet; Endothelin-1; Heart Diseases; Muscle, Smooth, Vascular; Rats; Receptors, Endothelin; Sodium Chloride, Dietary

Topics: Animals; Brain; Brain Ischemia; Endothelin-1; Heart Diseases; Infarction, Middle Cerebral Artery; Inflammation; Mice; Molecular Imaging; Positron-Emission Tomography; Stroke; Vasoconstrictor Agents

Cardiac biomarkers are important tools for monitoring disease progress and can monitor progression of therapy. Endothelin-1 (ET-1) has been studied for its use as a cardiac biomarker in human and small animal medicine while in horses with cardiac disease it has not been evaluated yet. The objective of the present study was to determine the concentration of plasma ET-1 in healthy horses and compare it with ET-1 concentration in horses with cardiac disease during rest and after exercise. Fifty four horses admitted to the Equine Clinic of Free University of Berlin were used in the present study, of which 15 horses were clinically healthy with no evidence of cardiac disease (Group 1), 22 horses suffered from cardiac disease with normal heart dimensions (Group 2) and 17 horses with cardiac disease and enlarged heart diameters (Group 3). Clinical examination, electrocardiography and echocardiography were performed. Endothelin-1 concentration was determined using ET-1 ELISA kit. The concentration of plasma ET-1 was significantly increased in horses with cardiac disease and normal cardiac dimensions (Group 2) and in horses with cardiac disease and enlargement of the left atrium (Group 3) compared to its concentration in clinically healthy horses (Group 1). In addition, the concentration of plasma ET-1 after exercise was significantly increased in diseased horses compared to its concentration at rest. Detection of ET-1 plasma concentration in horses at rest may be useful for detecting horses with changes in left atrial cardiac dimensions.

Topics: Animals; Biomarkers; Echocardiography; Electrocardiography; Endothelin-1; Female; Heart Diseases; Horse Diseases; Horses; Male; Physical Conditioning, Animal; Rest

Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.

Topics: Adult; Biomarkers; Blotting, Western; Case-Control Studies; Clinical Trials as Topic; Coronary Artery Disease; Endothelin-1; Female; Gene Expression Profiling; Graft Rejection; Heart Diseases; Heart Transplantation; Humans; Male; Middle Aged; Prospective Studies; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A

To estimate the prognostic value of the hypoxic test, intragastric pH-metry, and endothelial dysfunction in cardiosurgical patients at risk of gastrointestinal hemorrhage.. This prospective study approved by the ethical committee was performed based at the Department of Anesthesiology and Resuscitation, Research Institute of Cardiology, Tomsk, in 2012-2013. It included 30 patients who had previously undergone myocardial revascularization with artificial circulation. Gastroduodenal complications were predicted based on the results of the general hypoxic test, monitoring intragastric pH, and determination of endothelial function markers (endothelin-1, nitric oxide metabolites) intra- and postoperatively.. 17 (56.7%) patients with negative results of hypoxic test were referred to the group at low-risk of gastrointestinal complications and given no antisecretory therapy. Plasma ET-1 level in the patients with gastric hemorrhage was almost 10 times that in the absence of complications. Multiple organ insufficiency was associated with a rise in RT-1 levels by the end of the first postoperative day. High ET-1 levels suggested the predominance of vasoconstrictive effect that eventually resulted in a break of the vascular wall and hypoperfusion of gastric mucosa.. High ET-1 levels and disbalance of nitric oxide metabolites in blood are the main predictors of postoperative complications that characterize the functional state of vascular endothelium and may cause vascular rupture in case of the atherosclerotic process. The use of hypoxic test and gastric pH-metry in the preoperative period make it possible to distinguish patients that do not need preventive antisecretory therapy.

Topics: Cardiovascular Surgical Procedures; Endothelin-1; Endothelium, Vascular; Female; Gastrointestinal Hemorrhage; Heart Diseases; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Nitric Oxide; Predictive Value of Tests; Prospective Studies

We aimed to investigate whether atrial natriuretic peptide (ANP) attenuates angiotensin II (Ang II)-induced myocardial remodeling and to clarify the possible molecular mechanisms involved. Thirty-five 8-week-old male Wistar-Kyoto rats were divided into control, Ang II, Ang II + ANP, and ANP groups. The Ang II and Ang II + ANP rats received 1 μg/kg/min Ang II for 14 days. The Ang II + ANP and ANP rats also received 0.1 μg/kg/min ANP intravenously. The Ang II and Ang II + ANP rats showed comparable blood pressure. Left ventricular fractional shortening and ejection fraction were lower in the Ang II rats than in controls; these indices were higher (P < 0.001) in the Ang II + ANP rats than in the Ang II rats. In the Ang II rats, the peak velocity of mitral early inflow and its ratio to atrial contraction-related peak flow velocity were lower, and the deceleration time of mitral early inflow was significantly prolonged; these changes were decreased by ANP. Percent fibrosis was higher (P < 0.001) and average myocyte diameters greater (P < 0.01) in the Ang II rats than in controls. ANP decreased both myocardial fibrosis (P < 0.01) and myocyte hypertrophy (P < 0.01). Macrophage infiltration, expression of mRNA levels of collagen types I and III, monocyte chemotactic protein-1, and a profibrotic/proinflammatory molecule, tenascin-C (TN-C) were increased in the Ang II rats; ANP significantly decreased these changes. In vitro, Ang II increased expression of TN-C and endothelin-1 (ET-1) in cardiac fibroblasts, which were reduced by ANP. ET-1 upregulated TN-C expression via endothelin type A receptor. These results suggest that ANP may protect the heart from Ang II-induced remodeling by attenuating inflammation, at least partly through endothelin 1/endothelin receptor A cascade.

Topics: Angiotensin II; Animals; Anti-Inflammatory Agents; Atrial Natriuretic Factor; Cardiomegaly; Cells, Cultured; Disease Models, Animal; Endothelin-1; Fibrillar Collagens; Fibroblasts; Fibrosis; Heart Diseases; Inflammation; Inflammation Mediators; Infusions, Intravenous; Macrophages; Male; Mitral Valve; Myocardial Contraction; Myocardium; Rats; Rats, Inbred WKY; Receptor, Endothelin A; Signal Transduction; Stroke Volume; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Previous studies showed that angiotensin-(1-7) [Ang-(1-7)] attenuates cardiac remodeling by reducing both interstitial and perivascular fibrosis. Although a high affinity binding site for Ang-(1-7) was identified on cardiac fibroblasts, the molecular mechanisms activated by the heptapeptide hormone were not identified. We isolated cardiac fibroblasts from neonatal rat hearts to investigate signaling pathways activated by Ang-(1-7) that participate in fibroblast proliferation. Ang-(1-7) reduced (3)H-thymidine, -leucine and -proline incorporation into cardiac fibroblasts stimulated with serum or the mitogen endothelin-1 (ET-1), demonstrating that the heptapeptide hormone decreases DNA, protein and collagen synthesis. The reduction in DNA synthesis by Ang-(1-7) was blocked by the AT((1-7)) receptor antagonist [d-Ala(7)]-Ang-(1-7), showing specificity of the response. Treatment of cardiac fibroblasts with Ang-(1-7) reduced the Ang II- or ET-1-stimulated increase in phospho-ERK1 and -ERK2. In contrast, Ang-(1-7) increased dual-specificity phosphatase DUSP1 immunoreactivity and mRNA, suggesting that the heptapeptide hormone increases DUSP1 to reduce MAP kinase phosphorylation and activity. Incubation of cardiac fibroblasts with ET-1 increased cyclooxygenase 2 (COX-2) and prostaglandin synthase (PGES) mRNAs, while Ang-(1-7) blocked the increase in both enzymes, suggesting that the heptapeptide hormone alters the concentration and the balance between the proliferative and anti-proliferative prostaglandins. Collectively, these results indicate that Ang-(1-7) participates in maintaining cardiac homeostasis by reducing proliferation and collagen production by cardiac fibroblasts in association with up-regulation of DUSP1 to reduce MAP kinase activities and attenuation of the synthesis of mitogenic prostaglandins. Increased Ang-(1-7) or agents that enhance production of the heptapeptide hormone may prevent abnormal fibrosis that occurs during cardiac pathologies.

Topics: Angiotensin I; Angiotensin II; Animals; Animals, Newborn; Cell Proliferation; Cells, Cultured; Collagen; Cyclooxygenase 2; DNA; Dual Specificity Phosphatase 1; Endothelin-1; Fibroblasts; Fibrosis; Gene Expression Regulation; Heart Diseases; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocardium; Peptide Fragments; Phosphorylation; Prostaglandin-Endoperoxide Synthases; Rats; Signal Transduction

The association between hyperuricemia and cardiovascular diseases has long been recognized. Elevated levels of uric acid may have a causal role in hypertension and cardiovascular diseases. However, the direct effect of uric acid on cardiac cells remains unclear. Therefore, this study was aimed to examine the effect of uric acid in rat cardiac fibroblasts and to identify the putative underlying signaling pathways.. Cultured rat cardiac fibroblasts were stimulated with uric acid; cell proliferation and endothelin-1 (ET-1) gene expression were examined. The effect of uric acid on NADPH oxidase activity, reactive oxygen species (ROS) formation, and extracellular signal-regulated kinases (ERK) phosphorylation were tested to elucidate the intracellular mechanism of uric acid in ET-1 gene expression.. Uric acid-increased cell proliferation and ET-1 gene expression. Uric acid also increased NADPH oxidase activity, ROS formation, ERK phosphorylation, and activator protein-1 (AP-1)-mediated reporter activity. Antioxidants suppressed uric acid-induced ET-1 gene expression, and ERK phosphorylation, and AP-1 reporter activities. Mutational analysis of the ET-1 gene promoter showed that AP-1 binding site was an important cis-element in uric acid-induced ET-1 gene expression.. These results suggest that uric acid-induced ET-1 gene expression, partially by the activation of ERK pathway via ROS generation in cardiac fibroblasts.

Topics: Animals; Antioxidants; Cell Division; Cells, Cultured; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Gene Expression; Heart Diseases; Hyperuricemia; MAP Kinase Signaling System; Myocardium; NADPH Oxidases; Phosphorylation; Promoter Regions, Genetic; Rats; Reactive Oxygen Species; Transcription Factor AP-1; Uric Acid

Atrial fibrillation (AF) promotes atrial remodeling and can develop secondary to heart failure or mitral valve disease. Cardiac endothelin-1 (ET-1) expression responds to wall stress and can promote myocyte hypertrophy and interstitial fibrosis. We tested the hypothesis that atrial ET-1 is elevated in AF and is associated with AF persistence.. Left atrial appendage tissue was studied from coronary artery bypass graft, valve repair, and/or Maze procedure in patients in sinus rhythm with no history of AF (SR, n=21), with history of AF but in SR at surgery (AF/SR, n=23), and in AF at surgery (AF/AF, n=32). The correlation of LA size with atrial protein and mRNA expression of ET-1 and ET-1 receptors (ETAR and ETBR) was evaluated. LA appendage ET-1 content was higher in AF/AF than in SR, but receptor levels were similar. Immunostaining revealed that ET-1 and its receptors were present both in atrial myocytes and in fibroblasts. ET-1 content was positively correlated with LA size, heart failure, AF persistence, and severity of mitral regurgitation. Multivariate analysis confirmed associations of ET-1 with AF, hypertension, and LA size. LA size was associated with ET-1 and MR severity. ET-1 mRNA levels were correlated with genes involved in cardiac dilatation, hypertrophy, and fibrosis.. Elevated atrial ET-1 content is associated with increased LA size, AF rhythm, hypertension, and heart failure. ET-1 is associated with atrial dilatation, fibrosis, and hypertrophy and probably contributes to AF persistence. Interventions that reduce atrial ET-1 expression and/or block its receptors may slow AF progression.

Topics: Aged; Atrial Appendage; Atrial Fibrillation; Atrial Function, Left; Cardiomegaly; Echocardiography; Endothelin-1; Female; Fibrosis; Heart Diseases; Heart Failure; Humans; Hypertension; Linear Models; Male; Middle Aged; Mitral Valve Insufficiency; Receptor, Endothelin A; Receptor, Endothelin B; Risk Assessment; Risk Factors; RNA, Messenger; Up-Regulation

The treatment of end-stage heart failure can include heart transplantation. During this procedure, cardiac lymphatics are disrupted, which has been demonstrated in animal models to alter left ventricular function, and this compromise itself can cause an increase in endothelin-1 and angiotensin II. We undertook a study in rabbits to assess the effect of cardiac lymphatic obstruction on left ventricular function and plasma levels of endothelin-1 and angiotensin II. Sixty-three New Zealand white rabbits were divided into study (n = 41) and control (n = 22) groups. Plasma levels of endothelin and angiotensin II were measured before, and at 3, 7, 14, 30, 90 and 180 days following the obstruction of cardiac lymphatic vessels. Left ventricular function was assessed by echocardiography. Six months following the surgery, 18 study and 6 control animals survived. In the study group, a significant decrease was seen in left ventricular ejection fraction within the first three months following the lymphatic obstruction (0.76 +/- 0.04 vs 0.72 +/- 0.01, p < 0.01). Levels of plasma endothelin-1 and angiotensin II were elevated following ligation of cardiac lymphatic vessels with a peak between 3-7 days following lymphatic obstruction (all p < 0.05). Plasma endothelin-1 and angiotensin II began to decline 14 days after lymphatic obstruction and returned to almost baseline levels in 6 months. The left ventricular ejection fraction, plasma endothelin-1 and angiotensin in the control group remained unchanged (all p > 0.05). We conclude that cardiac lymphatic obstruction reduces left ventricular function in the first three months following obstruction. Cardiac lymphatic obstruction also increases plasma levels of endothelin-1 and angiotensin II. The clinical significance of these transitory changes requires further investigation.

Topics: Angiotensin II; Animals; Endothelin-1; Female; Heart Diseases; Lymphatic Diseases; Male; Rabbits; Stroke Volume; Ventricular Dysfunction, Left

Tandem autologous hematopoetic stem cell transplantation (HSCT) is an effective treatment in patients with multiple myeloma (MM). Patients receive high-dose cyclophosphamide (CY) followed by two myeloablative dosages of melphalan (MEL). Cardiotoxicity treatment related data are scanty. In 30 patients with MM chemotherapy was followed by high-dose CY (cycle CY), and two autologous tandem HSCT treatments with MEL (cycles MEL I and MEL II). During each 15-day treatment troponin I (TnI), brain natriuretic peptide (BNP) and endothelin-1 (ET-1) were controlled at six time points. All patients underwent conventional and tissue Doppler echocardiography prior to CY therapy (Eho 0), before cycle MEL I (Eho 1), before cycle MEL II (Eho 2), and 3 months after the completion of therapy (Eho 3). None of the patients developed clinical signs of heart failure. The peak TnI concentrations were noted at days 8, 11, and 15 during all three chemotherapy cycles. During all three cycles there was a significant increase in baseline BNP concentrations and BNP levels measured at day 1 after treatment with CY and MEL (CY: P = 0.0001, MEL I: P = 0.001, MEL II: P = 0.001). The highest BNP concentration occurred during CY treatment (0.517 +/- 0.391 microg/L). During cycles MEL I and MEL II we noted the peak BNP concentrations at day 4 following chemotherapy (MEL I 0.376 +/- 0.418 microg/L; MEL II 0.363 +/- 0.379 microg/L). During all three cycles the highest ET-1 levels occurred at day 1 after chemotherapy (CY 1.146 +/- 1.313 ng/L; MEL I 1.054 +/- 2.242 ng/L; MEL II 0.618 +/- 0.539 ng/L). A significant increase in ET-1 concentrations relative to the basal values occurred only in cycle MEL II (P = 0.003). The duration of wave a in the Doppler pulmonary vein flow increased significantly (Eho 0/Eho 1: P = 0.008, Eho 0/Eho 3: P = 0.026). There was a significant decrease in the A/a ratio in flow velocities during chemotherapy (Eho 0/Eho 1: P = 0.002, Eho 0/Eho 3: P < 0.0001). Early diastolic tissue Doppler velocities (Em) decreased significantly during individual cycles of chemotherapy (P = 0.006). A significant post-treatment increase in the incidence of mitral regurgitation was observed (Eho 0/Eho 3: P = 0.003). Treatment of MM patients with tandem autologous HSCT is cardiotoxic. Our patients did not develop clinically overt heart failure or myocardial necrosis. Increased plasma levels of BNP and ET-1 were compatible with transient neurohormonal activation of heart failure. Doppler echo

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Combined Modality Therapy; Cyclophosphamide; Echocardiography; Endothelin-1; Female; Heart Diseases; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Natriuretic Peptide, Brain; Troponin I

Endothelin-1 (ET-1) has potent vasoconstrictor and hypertrophic actions. Pharmacological antagonists of endothelin receptors attenuate cardiac hypertrophy, have been approved for treatment of pulmonary hypertension, and are under investigation for treatment of heart failure. To investigate the role of ET-1 in the heart, we created mice with cardiomyocyte deletion of ET-1.. Mice with cardiomyocyte-specific deletion of ET-1 are phenotypically normal when young. Remarkably, as the mice age or when young animals are subjected to aortic banding, they develop an unexpected phenotype of progressive systolic dysfunction and cardiac dilation. Echocardiography, necropsy, histology, and molecular phenotype confirm a dilated cardiomyopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis reveals greater abundance of apoptotic nuclei in the ET-1-deficient hearts. Transcriptional and Western analyses suggest enhanced tumor necrosis factor (TNF)-mediated apoptosis with increases in caspase-8 activity. These ET-1-deficient hearts also have diminished nuclear factor (NF)-kappaB activity, resulting in diminution of downstream inhibitors of TNF signaling.. Local ET-1 gene expression is necessary to maintain normal cardiac function and cardiomyocyte survival in mice with both age and hemodynamic stress. This cardiac-protective effect is mediated by paracrine ET-1 modulation of TNF-related apoptosis, in part through upregulation of NF-kappaB signaling.

Topics: Aging; Animals; Apoptosis; Base Sequence; Consensus Sequence; DNA Nucleotidylexotransferase; Endothelin-1; Gene Deletion; Heart Diseases; Hemodynamics; Mice; Mice, Knockout; Muscle Cells; Myocardium; NF-kappa B

We examined the role of endothelial dysfunction in the development and progression of cardiorenal syndrome in 93 patients with type 1 diabetes mellitus.. According to the stage of renal insufficiency all patients were divided into equal groups: those with normal albumin excretion rate, with microalbuminuria, with proteinuria, and with chronic renal failure. We analyzed endothelial flow-mediated dilation of the brachial artery, levels of endothelin-1, von Willerbrand factor, C-reactive protein, renal:albumin and protein excretion rates, glomerular filtration rate (GFR), and cardiovascular (ECG, echocardiography, blood pressure monitoring) functions.. There were negative correlations between the GFR, BP level and endothelial dysfunction markers. At the same time GFR correlated positively with the coefficient of sensitivity of endothelium to shear stress. There were also positive correlations between BP, permeability of glomerular filter and endothelial dysfunction markers and negative correlation with the coefficient of sensitivity of endothelium to shear stress and GFR. Left ventricle mass correlated with markers of endothelial dysfunction and stage of renal disease. Patients with chronic renal failure had negative correlations between LVM and GFR, ILVM and GFR and a positive correlation between ejection fraction and GFR.. There is a close relationship between endothelial dysfunction and development and progression of renal and cardiovascular pathology in patients with type 1 diabetes mellitus.

Topics: Adolescent; Adult; Blood Pressure; C-Reactive Protein; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Echocardiography; Endothelin-1; Endothelium, Vascular; Female; Glomerular Filtration Rate; Heart Diseases; Humans; Male; Middle Aged; Ventricular Dysfunction, Left; Ventricular Function, Left

To elucidate the role of endothelial dysfunction in formation of cardiorenal syndrome in patients with type 1 diabetes and diabetic nephropathy.. Sixty patients with type 1 diabetes were divided according to severity of nephropathy into the following groups: with normal albuminuria (n=15), microalbuminuria (n=15), proteinuria (n=15), and chronic renal failure (n=15). Control group consisted of 15 healthy subjects of similar age and sex. Methods of investigation included assessment of brachial artery endothelium dependent dilation by duplex scanning during test with reactive hyperemia, measurement of levels of serum markers of endothelial dysfunction (endothelin-1, von-Willebrand factor), and inflammation (C-reactive protein), analysis of parameters of 24-hour blood pressure monitoring and echocardiography data.. More severe diabetic nephropathy was associated with higher prevalence of cardiac pathology. Frequency of ischemic heart disease was 13 (2/15), 33 (5/15) and 53% (8/15), frequency of left ventricular concentric hypertrophy and remodeling - 33 (5/15), 40 (6/15) and 60% (9/15) among patients with microalbuminuria, proteinuria and chronic renal failure, respectively. Abnormalities of 24-hour blood pressure rhythm as well as signs of endothelial dysfunction were more pronounced in patients with more severe nephropathy. Correlation analysis revealed significant relationships between markers of endothelial dysfunction, parameters of renal function, blood pressure level and mass of left ventricular myocardium.. In patients with type 1 diabetes: endothelial dysfunction represents a link integrating processes of progression of nephropathy and development of cardiovascular pathology; close relationship between these processes constitutes a basis of cardiorenal syndrome; active search for cardiac pathology should be initiated on the stage of microalbuminuria.

Topics: Adolescent; Adult; Biomarkers; Brachial Artery; C-Reactive Protein; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Heart Diseases; Humans; Male; Middle Aged; Prognosis; Syndrome; Ultrasonography, Doppler, Duplex; Vasodilation; von Willebrand Factor

We explored the involvement of endothelin-1 (ET-1) in the pathophysiology of dog dirofilariasis (heartworm disease caused by Dirofilaria immitis) by analyzing mRNA levels of preproendothelin-1 (PPET-1), the precursor form of ET-1, in cardiopulmonary organs as well as ET-1 peptide levels in plasma. To determine the cDNA sequence and primary protein structure of dog PPET-1, we performed molecular cloning of the full-length cDNA. Based on the determined sequence information, comparative expression analysis of PPET-1 mRNA was carried out by real-time polymerase chain reaction on cardiopulmonary organs from healthy (n=5) and filarial (n=5) dogs. Filarial dogs showed a significantly (p<0.05) higher mRNA expression level in the heart (about one hundred times) and lung (about ten times) than healthy dogs. Analysis of plasma ET-1 levels in healthy (n=10) and filarial (n=10) dogs showed that filarial dogs (6.9+/-2.7 pg/ml) have significantly (p<0.01) increased plasma ET-1 levels compared with healthy dogs (1.4+/-0.3 pg/ml). To assess the pathophysiological significance of ET-1 in dirofilariasis relative to other cardiopulmonary disorders, plasma ET-1 levels determined in dogs diagnosed with mitral regurgitation (n=10), tricuspid regurgitation (n=5), ventricular septal defect (n=5), and patent ductus arteriosus (n=5) were compared to plasma ET-1 levels in filarial dogs. Filarial dogs, which commonly develop serious pulmonary hypertension, exhibited by far the highest ET-1 levels of the disease states examined. Based on the fact that ET-1 is a potent bioactive mediator that induces vasoconstriction and promotes vascular remodeling, these findings suggest that ET-1 plays an important role in the pathophysiology of dog dirofilariasis as an aggravating factor by inducing pulmonary hypertension.

Topics: Amino Acid Sequence; Animals; Base Sequence; Cloning, Molecular; Dirofilariasis; DNA Primers; DNA, Complementary; Dog Diseases; Dogs; Endothelin-1; Heart Diseases; Lung; Molecular Sequence Data; Myocardium; RNA, Messenger; Sequence Analysis, DNA

Anthracyclines are widely used chemotherapeutic agents in the treatment of lymphomas known to induce cardiomyopathy in more than 20% of patients. There is increasing experimental evidence that cardiac endothelial cells regulate cardiac performance and that endothelin-1 (ET-1) is a central substance in this regulatory mechanism. Twenty (seven male, aged 20-68 years) patients with Hodgkin's or non-Hodgkin's lymphoma treated with anthracycline were followed-up for 1 year. At baseline, after cessation of anthracycline treatment and at 1 year, the plasma ET-1 level was measured by enzyme-linked immunosorbent assay and cardiac function was estimated by echocardiographic measurement of the ejection fraction, the E/A ratio and the deceleration time. The ET-1 level decreased significantly after therapy (5.47 +/- 3.34 pg/mL versus 3.44 +/- 0.69 pg/mL, P < 0.02), and remained significant at 1 year (3.43 +/- 0.57 pg/mL, P < 0.008). The ejection fraction (57.80 +/- 4.73% versus 48.05 +/- 5.65%, P < 0.0001) and the E/A ratio (1.35 +/- 0.40 versus 1.15 +/- 0.40, P < 0.01) decreased, and the deceleration time (177.00 +/- 44.96 ms versus 209.50 +/- 66.25 ms, P < 0.04) increased significantly after therapy, showing that both systolic and diastolic left ventricular performance were deteriorated. Compared with the baseline, the same significant changes were found at 1 year (ejection fraction, 50.65 +/- 8.87%, P < 0.0007; E/A ratio, 1.10 +/- 0.34, P < 0.003; deceleration time, 223.25 +/- 46.85 ms, P < 0.002). The decrease of the ET-1 concentration might be a result of anthracyclines' direct cytotoxic effect and the decreasing level of ET-1 may play a role in the ejection fraction reduction. The results of 1-year follow-up suggest that, although anthracycline toxicity occurs shortly after treatment, the undesirable effect remains.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Dacarbazine; Down-Regulation; Doxorubicin; Echocardiography, Doppler; Endothelin-1; Female; Follow-Up Studies; Heart Diseases; Hodgkin Disease; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Prednisone; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Function, Left; Vinblastine; Vincristine

Endothelin-1 (ET-1, "mature ET-1") is a potent vasoconstrictor peptide that is made along with "big ET-1" from its precursor, preproET-1. Increased plasma concentrations of ET-1 and big ET-1 occur with various forms of cardiovascular disease in humans. Our laboratory is investigating plasma endothelins as diagnostic tests of cardiovascular disease in dogs and cats; however, commercial immunoassays designed specifically for use in dogs and cats are limited.. Amino acid sequences of feline and canine big ET-1 were obtained and used to predict antibody cross-reactivity with immunoassay test kits from other species.. Genomic DNA was extracted from peripheral blood and total RNA was extracted from canine and feline left ventricles for reverse transcription polymerase chain reaction (PCR) and PCR amplification of segments of the canine and feline preprohormone containing the big ET-1 sequences. The derived amino acid sequences were compared with known big ET-1 and ET-1 sequences of several other species, including human, mouse, and rat.. Feline and canine big ET-1 had 87-97% and 89-100% homology, respectively, with that of other mammalian species. Canine ET-1 was identical to human, mouse, and rat ET-1. In contrast, the amino acid sequence of feline ET-1 was unique owing to a leucine for methionine substitution at position 7.. It is highly likely that anti-human and anti-rodent ET-1 antibodies will cross-react with mature canine ET-1. In contrast, antibodies to mature ET-1 intended for use with feline tissues and antibodies to big ET-1 in either dogs or cats may have partial or no cross-reactivity depending on the peptide sequences used to produce the antibodies.

Topics: Amino Acid Sequence; Animals; Antibodies; Base Sequence; Cat Diseases; Cats; Cross Reactions; Dog Diseases; Dogs; Endothelin-1; Female; Gene Amplification; Heart Diseases; Immunoassay; Male; Molecular Sequence Data; Peptide Fragments; Reverse Transcriptase Polymerase Chain Reaction; Sequence Homology, Nucleic Acid; Species Specificity

The incidence of ventricular tachyarrhythmias in the early post-operative period following implantable cardioverter-defibrillator (ICD) implantation is relatively high compared with that in control periods. Since endothelin-1 (ET-1) has been proven to be an endogenous arrhythmogenic substance, we investigated the changes in serum ET-1 and big-ET levels in patients undergoing ICD implantation. Serum concentrations of ET-1 and big-ET were measured in 14 patients with various heart diseases before the operation, as well as 1 min and 1 h after the last shock therapy. Big-ET levels and the sum of ET-1 and big-ET levels were unchanged immediately after the operation, but had increased significantly by 1 h after implantation (before, 1.57+/-0.61 pmol/l; 1 min, 1.86+/-0.87 pmol/l; 1 h, 4.29+/-1.65 pmol/l for big-ET; before, 3.44+/-1.07 pmol/l; 1 min, 3.79+/-1.29 pmol/l; 1 h, 6.36+/-2.03 pmol/l for big-ET+ET-1). There was a significant correlation between left ventricular ejection fraction and big-ET level measured 1 h after the last shock delivery (r=-0.542, P<0.05). We conclude that the increased big-ET level observed 1 h after the last induction and shock therapy of ventricular fibrillation might have a pathophysiological role in the increased incidence of post-operative spontaneous ventricular arrhythmias.

Topics: Aged; Defibrillators, Implantable; Endothelin-1; Endothelins; Female; Heart Diseases; Humans; Male; Middle Aged; Protein Precursors; Tachycardia, Ventricular; Time Factors

We tested the hypothesis that endothelin-converting enzyme (ECE) inhibition ameliorates end-organ damage in rats harboring both human renin and human angiotensinogen genes (dTGR). Hypertension develops in the animals, and they die by age 7 weeks of heart and kidney failure. Three groups were studied: dTGR (n=12) receiving vehicle, dTGR receiving ECE inhibitor (RO0687629; 30 mg/kg by gavage; n=10), and Sprague-Dawley control rats (SD; n=10) receiving vehicle, all after week 4, with euthanasia at week 7. Systolic blood pressure was not reduced by ECE inhibitor compared with dTGR (205+/-6 versus 206+/-6 mm Hg at week 7, respectively). In contrast, ECE inhibitor treatment significantly reduced mortality rate to 20% (2 of 10), whereas untreated dTGR had a 52% mortality rate (7 of 12). ECE inhibitor treatment ameliorated cardiac damage and reduced left ventricular ECE activity below SD levels. Echocardiography at week 7 showed reduced cardiac hypertrophy (4.8+/-0.2 versus 5.7+/-0.2 mg/g, P<0.01) and increased left ventricular cavity diameter (5.5+/-0.3 versus 3.1+/-0.1 mm, P<0.001) and filling volume (0.42+/-0.04 versus 0.16+/-0.06 mL, P<0.05) after ECE inhibitor compared with untreated dTGR. ECE inhibitor treatment also reduced cardiac fibrosis, tissue factor expression, left ventricular basic fibroblast growth factor mRNA levels, and immunostaining in the vessel wall, independent of high blood pressure. In contrast, the ECE inhibitor treatment showed no renoprotective effect. These data are the first to show that ECE inhibition reduces angiotensin II-induced cardiac damage.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Aorta; Aspartic Acid Endopeptidases; Disease Models, Animal; Echocardiography; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Extracellular Matrix; Fibroblast Growth Factor 2; Fibronectins; Heart Diseases; Heart Ventricles; Humans; Immunohistochemistry; Kidney; Male; Metalloendopeptidases; Prodrugs; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

Topics: Endothelin-1; Flavonoids; Heart Diseases; Humans; Phenols; Polyphenols; Vasoconstriction; Vitis; Wine

The alteration of endothelin (ET) levels in diabetic patients with cardiac autonomic neuropathy (CAN) has not been studied extensively and its correlation with cardiac function parameters has not been discussed.. The aim of the present study was to discuss the correlation between the degree of cardiac autonomic neuropathy, plasma big-ET levels, and cardiac functions in diabetic patients who were clinically free of cardiovascular disease.. Twenty subjects (32.1 +/- 7.8 years, 11 men, 9 women) with insulin-dependent diabetes mellitus (IDDM) were studied to evaluate the relationship between circulating big-endothelin (big-ET1) levels, CAN, and cardiac functions. The severity of CAN was scored according to Ewing's criteria. Cardiac functions were assessed using Doppler echocardiography.. Left ventricular systolic function in the patient group was within normal limits and comparable with the values of the control group (n = 10). The mean E/A values of diabetics with CAN (1.15 +/- 0.33, p = 0.004) and without CAN (1.34 +/- 0.17) were significantly lower than those of controls (1.57 +/- 0.27). Diabetics with CAN had significantly higher big-ET1 values (81.1 +/- 94 pg/ml) compared with others (12.4 +/- 5.9 and 21.1 +/- 17.7 pg/ml, p = 0.04). Circulating big-ET1 levels showed a significant correlation with E/A values in the control group (p = 0.01, r = -0.7) and with peak A values (p = 0.003, r = 0.64) in diabetics. The CAN score correlated negatively with E/A values (p = 0.01, r = 0.54).. High big-ET levels might have an important role in the pathogenesis or consequences of diastolic dysfunction in diabetics with CAN. Their role in cardiac autonomic neuropathy and diastolic dysfunction should be investigated further.

Topics: Adult; Autonomic Nervous System Diseases; Biomarkers; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Endothelin-1; Endothelins; Female; Heart; Heart Diseases; Humans; Male; Myocardial Contraction; Prognosis; Protein Precursors; Radioimmunoassay; Ventricular Function, Left

Aging is an independent risk factor for cardiovascular and renal disease. The study reported here investigated whether aging affects endothelin-1 (ET-1) and tissue levels of the nitric oxide metabolites nitrite/nitrate in the kidney of rodents. Blood pressure was measured by the tail-cuff method, ET-1 protein was determined by radioimmunoassay/high-performance liquid chromatography (RIA/HPLC) and nitrite/nitrate was measured by ion-pairing chromatography. Compared to young male Wistar Kyoto rats (3 months of age), renal ET-1 protein levels in whole kidneys increased 3.6-fold at 24 months of age (from 70 +/- 9 to 253 +/- 43 pg/g tissue, p < 0.05, n = 6 each group). Similarly, renal ET-1 protein increased 1.7-fold in 18-month-old C57BL/6J mice as compared to 8-month-old adult animals (from 188 +/- 18 to 319 +/- 14 pg/g tissue, p < 0.05, n = 5-7). In female RoRo-Wistar rats (6, 18 and 33 months of age), tissue nitrite/nitrate levels in whole kidneys decreased with increasing age (from 232 +/- 25 to 130 +/- 6 micromol/l/g tissue, p < 0.05). Thus, aging in healthy rodents is associated with a marked upregulation of renal ET-1 protein content and a decrease in tissue nitrite/nitrate levels in whole kidneys, independent of blood pressure. Activation of the ET pathway with aging may promote the development of age-dependent diseases such as glomerulosclerosis, hypertension and atherosclerosis.

Topics: Aging; Animals; Endothelin-1; Female; Heart Diseases; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Nitrates; Nitric Oxide; Nitrites; Rats; Rats, Inbred WKY

1. We have investigated the expression and pharmacology of endothelin (ET) receptors in human aortocoronary saphenous vein grafts. 2. Subtype-selective ligands were used to autoradiographically identify ET(A) ([125I]-PD151242) and ET(B)([125I]-BQ3020) receptors. In graft saphenous vein ETA receptors predominated in the media, with few ET(B) receptors identified. Neither subtype was detected in the thickened neointima. 3. The ratio of medial ET(A):ET(B) receptors was 75%: 25% in both graft and control saphenous vein. 4. ET-1 contracted control (EC50 2.9 nM) and graft (EC50 4.5 nM) saphenous vein more potently than diseased coronary artery (EC50 25.5 nM). 5. In all three blood vessels ET-1 was 100 times more potent than ET-3 and three times more potent than sarafotoxin 6b (S6b). Little or no response was obtained in any vessel with the ET(B) agonist sarafotoxin 6c (S6c). 6. The ET(A) antagonist PD156707 (100 nM) blocked ET-1 responses in all three vessels with pKb values of approximately 8.0. 7. For individual graft veins the EC50 value for ET-1 and 'age' of graft in years showed a significant negative correlation. 8. In conclusion there is no alteration in ET receptor expression in the media of saphenous veins grafted into the coronary circulation compared to control veins. ETA receptors predominantly mediate the vasoconstrictor response to ET-1 in graft vein, with no apparent up-regulation of ET(B) receptors. The sensitivity of the graft vein to ET-1 increased with graft 'age', suggesting that these vessels may be particularly vulnerable to the increased plasma ET levels that are detected in patients with cardiovascular disease.

Topics: Adult; Aged; Autoradiography; Azepines; Coronary Vessels; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Female; Heart Diseases; Humans; In Vitro Techniques; Iodine Radioisotopes; Male; Middle Aged; Oligopeptides; Potassium; Radioligand Assay; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Saphenous Vein; Serotonin; Time Factors; Vasoconstriction; Vasoconstrictor Agents; Viper Venoms

The importance of early cardiac myocyte damage during postburn trauma has been emphasized in recent years. However, its pathogenesis, prevention, and treatment have not been fully clarified. The aim of this study is to define its pathogenesis.. Rats with 30% third-degree burns were used. Cardiac biochemical markers reflecting cardiac myocyte damage including troponin T, cardiac myosin light chain 1, creatinine kinase and its cardiac-specific isoenzyme compound, as well as inflammatory mediators such as tumor necrosis factor, endothelin/nitric oxide ratio, malondialdehyde, and superoxide dismutase, were determined.. Cardiac biochemical markers reflecting cardiac myocyte damage, including troponin T, cardiac myosin light chain 1, cardiac-specific isoenzyme compound, were all significantly elevated between 3 hours and 24 hours after burn. Changes in tumor necrosis factor, endothelin/nitric oxide ratio, and malondialdehyde were similar to those of cardiac biochemical markers. In contrast, levels of superoxide dismutase declined markedly after burn.. The findings of this study showed that considerable amounts of myocardial constructive protein degradation and release due to destruction of cardiac myocytes occurred early after severe burns. The inflammatory mediators released after burn injury may be involved in the pathogenesis of myocardial destruction.

Topics: Animals; Biomarkers; Burns; Creatine Kinase; Disease Models, Animal; Endothelin-1; Heart Diseases; Inflammation; Male; Malondialdehyde; Myocardium; Myosin-Light-Chain Kinase; Nitric Oxide; Rats; Rats, Wistar; Superoxide Dismutase; Time Factors; Troponin T; Tumor Necrosis Factor-alpha

Cardiac troponin T (cTnT) is a highly sensitive marker for the detection of myocardial damage. However, patients maintained on chronic dialysis often have increased serum cTnT concentrations without evidence of acute myocardial injury. The reason for this is unclear. In chronic haemodialysis patients, elevated plasma concentrations of big endothelin-1 (big ET-1) and endothelin-1 (ET-1) have been reported which may be associated with ischaemic heart disease. The aim of the present study was to investigate possible associations between cTnT, big ET-1, ET-1, other cardiac markers and cardiac disease in dialysis patients.. Thirty-six haemodialysis (HD) patients and 26 peritoneal dialysis (PD) patients without symptoms of acute myocardial ischaemia were investigated. In all patients, serum concentrations of cTnT (2nd generation ELISA), cardiac troponin I (TnI) (Opus, Behring), creatine kinase MB (CKMB) mass and creatine kinase (CK) were determined, in HD patients before and after dialysis. Additionally, in HD patients, plasma ET-1 and big ET-1 were measured. In 27 HD patients, left ventricular mass index (LVMI) was determined. Patients with ischaemic heart disease (IHD) were compared with non-IHD patients.. Serum cTnT was elevated (> or =0.10 microg/l) in 20 of 36 HD patients and in eight of 26 PD patients. cTnI was elevated (> or =0.5 microg/l) in four of 62 dialysis patients. HD+PD patients with IHD showed higher cTnT than HD+PD patients without IHD, and ET-1 concentrations were higher in HD patients with than without IHD. In HD patients, there was a positive correlation between cTnT and big ET-1. In HD patients with left ventricular hypertrophy (LVH), serum cTnT, CKMB mass and post-dialysis plasma big ET-1 were higher than in patients with normal LVMI. Furthermore there was a positive correlation between cTnT levels and LVMI.. These findings suggest that circulating cTnT may reflect left ventricular hypertrophy and/or myocardial ischaemia in dialysis patients, and indicate that ET-1 and big ET-1 might be associated with these conditions.

Topics: Adult; Aged; Aged, 80 and over; Creatine Kinase; Endothelin-1; Endothelins; Female; Heart Diseases; Humans; Hypertrophy, Left Ventricular; Isoenzymes; Male; Middle Aged; Myocardial Ischemia; Osmolar Concentration; Peritoneal Dialysis; Protein Precursors; Renal Dialysis; Troponin T; Ultrasonography

We investigated the effects of endothelin-1 (ET-1) on growth of cultured human coronary artery smooth muscle cells (cSMC). ET-1 alone stimulated DNA synthesis in growth-arrested cSMC as measured by [3H]thymidine incorporation, with a maximum 63 +/- 23% increase above control by 10(-7) M (P < 0.05). ET-1 (10(-7) M) also stimulated increases in cyclin D1 protein levels after 24 h, and in absolute cell number after 4 days. Furthermore, ET-1 stimulated protein synthesis (maximum 73 +/- 32% increase in [3H]leucine incorporation by 10(-7) M (P < 0.05)), as well as triggering intracellular calcium transients in human cSMC, as visualised under fura-2 fluorescence microscopy. The selective ET(A) receptor antagonist BQ123 inhibited the increases in DNA synthesis, cell number, protein synthesis and intracellular calcium concentration in response to ET-1, whereas the ET(B) receptor antagonist BQ788 had no such effects. Furthermore, the ET(B) agonist sarafotoxin 6c had no effect on cSMC DNA synthesis. In addition, co-incubation of ET-1 with threshold concentrations of the growth factors, platelet-derived growth factor-BB (PDGF-BB), basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF), resulted in pronounced synergistic increases in DNA synthesis over that observed with the factors alone. In conclusion, we have shown that ET-1 stimulates proliferation of human cSMC via the ET(A) receptor and is also a co-mitogen with the growth factors tested. These findings indicate a role for ET-1 in the development of coronary intimal hyperplasia in man.

Topics: Becaplermin; Blotting, Western; Calcium; Cell Count; Coronary Vessels; DNA; Endothelin Receptor Antagonists; Endothelin-1; Epidermal Growth Factor; Fibroblast Growth Factor 2; Growth Substances; Heart Diseases; Humans; Intracellular Fluid; Microscopy, Fluorescence; Mitosis; Muscle Development; Muscle, Smooth, Vascular; Peptides, Cyclic; Platelet-Derived Growth Factor; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-sis; Receptor, Endothelin A; Receptors, Endothelin; Recombinant Proteins; Thymidine

Recent studies have suggested that the plasma concentrations of endothelin-1, a potent vasoconstrictive peptide, are increased in patients with congestive heart failure. This study aimed to evaluate a new direct ELISA for big endothelin-1 (the precursor of endothelin-1), in comparison with a big endothelin-1 ELISA using plasma sample extraction, and to investigate whether plasma big endothelin-1 concentrations correlate with indicators of left ventricular function. The direct ELISA yielded significantly (P < 0.001) lower results than the assay with extracted samples (0.9 +/- 0.5 pmol/L vs 2.7 +/- 1.9 pmol/L; n = 90); however, the results of the two assays were closely correlated (r = 0.86, P < 0.001). Plasma big endothelin-1 concentrations exhibited a significant (P < 0.001) negative correlation (r = -0.46, r = -0.40) with the left ventricular ejection fraction and a significant positive correlation (r = 0.40, P < 0.001; r = 0.36, P < 0.01) with the left ventricular end-diastolic pressure and the left ventricular end-diastolic (r = 0.42, r = 0.38, P < 0.001) and end-systolic (r = 0.52, r = 0.47, P < 0.001) volume indices. Plasma big endothelin-1 concentrations were notably greater in patients with New York Heart Association (NYHA) class II-IV symptoms than in patients without cardiac disease or in patients categorized to NYHA class I. These data suggest that plasma big endothelin-1 concentrations, measured by a direct ELISA, correlate with hemodynamic indicators and symptoms of left ventricular dysfunction.

Topics: Adult; Aged; Endothelin-1; Endothelins; Enzyme-Linked Immunosorbent Assay; Female; Heart Diseases; Hemodynamics; Humans; Male; Middle Aged; Protein Precursors; Statistics as Topic; Ventricular Function, Left

Cardiotoxicity is an uncommon side-effect of 5-FU-based chemotherapy. Coronary artery vasospasms have been postulated to be involved in the pathogenesis of this rare but serious problem. We found high plasma levels of ET-1, a potent natural vasoconstrictor, in two patients who experienced two of the commonest clinical manifestations of 5-FU-induced cardiac toxicity--i.e., angina pectoris and chronic heart failure. We, therefore, propose ET-1 as the ultimate mediator of this toxicity, even though the mechanism of ET-1 increase in peripheral venous blood is still unknown. Finally, another important question still remains unresolved: is the release of ET-1 from normal coronary endothelial cells the prime cause or simply the consequence of 5-FU-related cardiotoxicity?

Topics: Aged; Antimetabolites, Antineoplastic; Coronary Vasospasm; Endothelin-1; Female; Fluorouracil; Heart Diseases; Humans; Male; Middle Aged

The effects of KRN4884 (5-amino-N-[2-(2-chrolophenyl)ethyl]-N'-cyano-3-pyridinecarboxa midine), a novel K+ channel opener, on the electrocardiogram changes caused by the intracoronary administration of endothelin-1 (ET-1) were studied in anesthetized rats and compared with the effects of levcromakalim, a K+ channel opener; nilvadipine, a Ca2+ antagonist; and propranolol, a beta-adrenoceptor antagonist. KRN4884 (50 microg/kg, i.v.) and levcromakalim (300 microg/kg, i.v.) inhibited the ST segment elevation and the development of arrhythmias induced by ET-1 (5 microg, i.c.) and decreased the incidence of death. Nilvadipine (300 microg/kg, i.v.) and propranolol (1000 and 3000 microg/kg, i.v.) each prevented the ST segment elevation, but the suppressions of the occurrence of arrhythmias produced by nilvadipine and propranolol were less than that shown by KRN4884. KRN4884 (30 and 50 microg/kg, i.v.), levcromakalim (100 and 300 microg/kg, i.v.) and nilvadipine (100 and 300 microg/kg, i.v.) significantly decreased the mean blood pressure in a dose-dependent manner, but propranolol did not. The heart rate was decreased by nilvadipine (100 and 300 microg/kg, i.v.) and propranolol (1000 and 3000 microg/kg, i.v.), but was not affected by KRN4884 (30 and 50 microg/kg, i.v.) or levcromakalim (100 and 300 microg/kg, i.v.). These results suggest that pretreatments with KRN4884 and levcromakalim are more effective on ET-1-induced electrocardiogram changes than those with nilvadipine and propranolol.

Topics: Anesthesia; Animals; Antihypertensive Agents; Blood Pressure; Bronchoconstrictor Agents; Cromakalim; Electrocardiography; Endothelin-1; Heart Diseases; Heart Rate; Injections, Intra-Arterial; Male; Methacholine Chloride; Nifedipine; Potassium Channels; Propranolol; Pyridines; Rats; Rats, Wistar