endothelin-1 and Myocardial-Infarction

The fibroblast is a key mediator of wound healing in the heart and other organs, yet how it integrates multiple time-dependent paracrine signals to control extracellular matrix synthesis has been difficult to study in vivo. Here, we extended a computational model to simulate the dynamics of fibroblast signaling and fibrosis after myocardial infarction (MI) in response to time-dependent data for nine paracrine stimuli. This computational model was validated against dynamic collagen expression and collagen area fraction data from post-infarction rat hearts. The model predicted that while many features of the fibroblast phenotype at inflammatory or maturation phases of healing could be recapitulated by single static paracrine stimuli (interleukin-1 and angiotensin-II, respectively), mimicking the reparative phase required paired stimuli (e.g. TGFβ and endothelin-1). Virtual overexpression screens simulated with either static cytokine pairs or post-MI paracrine dynamic predicted phase-specific regulators of collagen expression. Several regulators increased (Smad3) or decreased (Smad7, protein kinase G) collagen expression specifically in the reparative phase. NADPH oxidase (NOX) overexpression sustained collagen expression from reparative to maturation phases, driven by TGFβ and endothelin positive feedback loops. Interleukin-1 overexpression had mixed effects, both enhancing collagen via the TGFβ positive feedback loop and suppressing collagen via NFκB and BAMBI (BMP and activin membrane-bound inhibitor) incoherent feed-forward loops. These model-based predictions reveal network mechanisms by which the dynamics of paracrine stimuli and interacting signaling pathways drive the progression of fibroblast phenotypes and fibrosis after myocardial infarction.

Topics: Angiotensin II; Animals; Cell Differentiation; Collagen; Computer Simulation; Endothelin-1; Extracellular Matrix; Fibroblasts; Gene Expression Regulation; Humans; Interleukin-1; Models, Biological; Myocardial Infarction; NF-kappa B; Paracrine Communication; Phenotype; Rats; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Wound Healing

Ventricular arrhythmogenesis during acute coronary syndromes is a common cause of sudden cardiac death, but the underlying mechanisms remain incompletely understood. Recent evidence indicates an emerging pathophysiologic role of endothelin-1 during myocardial ischaemia and evolving infarction. At the early stages post-coronary occlusion, endothelin-1 enhances sympathetic activation, an effect mediated via the ETA receptor, whereas the ETB receptor exerts protective actions. The importance of this interaction is clearly decreased during subsequent stages, during which endothelin-1 may participate in the genesis of ventricular tachycardia or fibrillation via other mechanisms; of these, the effects of endothelin-1 on repolarizing potassium currents and electrical conduction via gap junctions merit further research. The relative roles of ETA and ETB receptors during this phase are unclear. Evaluation of the arrhythmogenic effects of endothelin-1 during acute coronary syndromes may provide the tools towards lowering sudden cardiac death rates.

Topics: Animals; Endothelin-1; Humans; Myocardial Infarction; Receptors, Endothelin; Risk Factors; Sympathetic Nervous System; Tachycardia, Ventricular

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

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

Sudden cardiac death constitutes a major health-related problem. In the majority of cases, sudden cardiac death is due to ventricular tachyarrhythmias secondary to acute myocardial infarction. The pathophysiologic chain of events leading to ventricular tachyarrhythmias after acute coronary occlusion is complex and incompletely understood. Experimental and clinical studies have indicated that endothelin-1 production rises markedly very early in the course of myocardial infarction. Endothelin-1 exerts significant electrophysiologic actions on ventricular cardiomyocytes and participates in the genesis of ischemic ventricular tachyarrhythmias. Endothelin-1, acting via two G-protein-coupled receptors (ETA and ETB), prolongs the action potential duration and increases the occurrence of spontaneous calcium transients, resulting in early afterdepolarizations and ventricular tachyarrhythmias via triggered activity. Moreover, endothelin-1 enhances sympathetic stimulation, a well established contributor to ventricular arrhythmogenesis during acute myocardial infarction. Despite these considerations, the therapeutic potential of endothelin receptor antagonists as antiarrhythmic drugs during myocardial ischemia/infarction is still under investigation. To date, a number of endothelin-1 receptor antagonists are available, presenting different degrees of selectivity for ETA and ETB receptors. The arrhythmogenic effects of endothelin-1 are exerted mainly via stimulation of the ETA receptors, but the role of ETB receptors remains controversial, as previous studies have produced conflicting results. This review summarizes the current state-of-the-art on the role of endothelin-1 in the genesis of ventricular arrhythmias during acute myocardial infarction and raises some hypotheses that could be explored in future studies.

Topics: Animals; Coronary Occlusion; Endothelin-1; Humans; Myocardial Infarction; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Signal Transduction; Sympathetic Nervous System; Tachycardia, Ventricular

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

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

Myocardial remodeling invariably occurs in congestive heart failure (CHF) and is a response to a prolonged cardiovascular stress, which is characterized by a cascade of compensatory structural events. Remodeling of the myocardial interstitium occurs in CHF and likely contributes to the progression of the remodeling process. The myocardial matrix can be considered a biological highway in which a large amount of signaling proteins and structural proteins are being moved within the interstitium, entering and exiting the interstitial space, and docking to cellular components. The rates at which these events occur can accelerate and decelerate depending on the particular cardiac disease state and thereby can alter the course of myocardial remodeling. Once considered merely a scaffolding to align cells, the matrix plays a complex and divergent role in influencing cell behavior. For example, the matrix has a functional role in cell migration, proliferation, adhesion, and cell-to-cell signaling. In light of this, the myocardial matrix should not be regarded as merely a static structure, but rather, as a complex system of dynamic interactions between matrix molecules, signaling proteins, and transmembrane proteins. Specific strategies that are targeted at modifying activity along this matrix highway will likely alter the course of myocardial remodeling and heart failure.

Topics: Angiotensin II; Disease Progression; Endothelin-1; Extracellular Matrix; Heart Failure; Humans; Hypertrophy, Left Ventricular; Integrins; Matrix Metalloproteinases; Myocardial Infarction; Myocardium; Transforming Growth Factor beta; Ventricular Remodeling

Soon after its identification as a powerful vasoconstrictor peptide, endothelin (ET-1) was implicated as a detrimental agent involved in determining the outcome of myocardial ischaemia and reperfusion. Early experimental studies demonstrated that ET(A) selective and mixed ET(A)/ET(B) receptor antagonists can reduce infarct size and prevent ischaemia-induced ventricular arrhythmias in models of ischaemia/reperfusion, implying that ET-1 acts through the ET(A) receptor to contribute to injury and arrhythmogenesis. However, as our understanding of the physiology of ET-1 has expanded, the role of ET-1 in the ischaemic heart appears ever more complex. Recent evidence suggests that ET-1 exerts actions on the heart that are not only detrimental (vasoconstriction, inhibition of NO production, activation of inflammatory cells), but which may also contribute to tissue repair, such as inhibition of cardiomyocyte apoptosis. In addition, ET-1-induced mast cell degranulation has been linked to a homeostatic mechanism that controls endogenous ET-1 levels, which may have important implications for the ischaemic heart. Furthermore the mechanism by which ET-1 promotes arrhythmogenesis remains controversial. Some studies imply a direct electrophysiological effect of ET-1, via ET(A) receptors, to increase monophasic action potential duration (MAPD) and induce early after-depolarisations (EADs), while other studies support the view that coronary constriction resulting in ischaemia is the basis for the generation of arrhythmias. Moreover, ET-1 can induce cardioprotection (precondition) against infarct size and ventricular arrhythmias, through as yet incompletely understood mechanisms. To enable us to identify the most appropriate means of targeting this system in a therapeutically meaningful way we need to continue to explore the physiology of ET-1, both in the normal and the ischaemic heart.

Topics: Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Endothelin Receptor Antagonists; Endothelin-1; Humans; Myocardial Infarction; Myocardial Ischemia; Myocardium

Endothelin (ET)-1 is a potent coronary vasoconstrictor. On the heart, ET-1 is a potent positive inotrope and may be pro-arrhythmic. Plasma ET-1 levels are raised after acute myocardial infarction (AMI) and recanalisation in humans. This probably contributes to the coronary vasoconstriction that underlies the myocardial ischaemia and ventricular dysfunction at this time. During occlusion of the rat coronary artery, ventricular arrhythmias are reduced by ET(A) receptor blockade. Short-term ET(A) receptor blockade also reduces infarct size in animal models of AMI (coronary occlusion followed by reperfusion). Blockade of the endothelin-converting enzyme with SM-19712 reduced the infarct size in the rabbit model of AMI. ET(A) receptor blockade is associated with coronary artery dilation in humans. As there are indications that ET(A) receptor antagonists are protective in animal models of AMI, short-term ET(A) receptor blockade should be considered for trial in human AMI.

Topics: Animals; Endothelin A Receptor Antagonists; Endothelin-1; Humans; Myocardial Infarction; Receptor, Endothelin A

Topics: Angiotensin II; Animals; Cell Division; Collagen; Endothelin-1; Extracellular Matrix; Fibroblast Growth Factor 2; Fibroblasts; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Liver Cirrhosis; Myoblasts, Cardiac; Myocardial Infarction; Pulmonary Fibrosis; Receptors, Endothelin; Transforming Growth Factor beta; Ventricular Remodeling

Pathophysiology of endothelin-1, a vasoconstrictor and a mitogenic peptide, has been extensively investigated in recent years. The authors have examined the main clinical and experimental evidence regarding the involvement of this peptide in some medical emergencies, namely myocardial infarction, stroke and hepato-renal syndrome. Literature data suggest an emerging pathophysiological role for endothelin in such clinical conditions.

Topics: Emergencies; Endothelin-1; Hepatorenal Syndrome; Humans; Myocardial Infarction; Stroke

Unlike the rare and severe genetic defects that cause monogenic diseases, the genetic factors that modulate the individual susceptibility to multifactorial diseases (cardiovascular diseases, cancers, diabetes, etc.) are common, functionally different, forms of genes (polymorphisms), which generally have a modest effect at an individual level but, because of their high frequency in the population, can be associated with a high attributable risk. Environmental factors can reveal or facilitate the phenotypic expression of such susceptibility genes. Indeed, in common diseases genetic effects can be considerably amplified in the presence of triggering factors. There is now accumulating evidence that most of the susceptibility genes for common diseases do not have a primary aetiological role in predisposition to disease, but rather act as response modifiers to exogenous factors such as stress, environment, disease, drug intake. A better characterisation of the interactions between environmental and genetic factors constitute a key issue in the understanding of the pathogenesis of multifactorial diseases. The present paper will review three examples of gene-environment interactions in the field of CHD.

Topics: Alcohol Drinking; Blood Pressure; Body Mass Index; Carrier Proteins; Cholesterol Ester Transfer Proteins; Coronary Disease; Endothelin-1; Environment; Genetic Predisposition to Disease; Glycoproteins; Humans; Life Style; Lipoprotein Lipase; Myocardial Infarction; Triglycerides

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

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

Congestive heart failure (CHF) is a disease process characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. Thus, mediators involved in the control of myocardial function and vascular tone may be involved in its pathophysiology. The family of endothelins (ET) consists of four closely related peptides, ET-1, ET-2, ET-3, and ET-4, which cause vasoconstriction, cell proliferation, and myocardial effects through activation of ET(A) receptors. In contrast, endothelial ET(B) receptors mediate vasodilation via release of nitric oxide and prostacyclin. In addition, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Thus, infusion of an ET(A) receptor antagonist into the brachial artery in healthy humans leads to vasodilation whereas infusion of an ET(B) receptor antagonist causes vasoconstriction. ET-1 plasma levels are elevated in CHF and correlate both with the hemodynamic severity and with symptoms. Plasma levels of ET-1 and its precursor, big ET-1, are strong independent predictors of death in patients after myocardial infarction and with CHF. ET-1 contributes to increased systemic and pulmonary vascular resistance, vascular dysfunction, myocardial ischemia, and renal impairment in CHF. Selective ET(A) as well as combined ET(A/B) receptor antagonists have been studied in patients with CHF showing impressive hemodynamic improvements (i.e. reduced peripheral vascular and pulmonary resistance as well as increased cardiac output). These results indicate that ET receptor antagonists indeed have a potential to improve hemodynamics, symptoms, and potentially prognosis of CHF which still carries a high mortality.

Topics: Coronary Circulation; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Humans; Hypertension; Myocardial Infarction; Receptors, Endothelin; Treatment Outcome; Vascular Resistance

Topics: Animals; Bosentan; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; Humans; Mice; Myocardial Infarction; Myocardium; Peptides, Cyclic; Rats; Receptors, Endothelin; Stroke Volume; Sulfonamides; Time Factors

Objects The aim of this trial was to evaluate the effect of short-term high-dose atorvastatin therapy on levels of high-sensitivity C-reactive protein (hs-CRP), malonaldehyde (MDA), endothelin-1(ET-1), matrix metalloproteinases (MMPs), and left ventricular (LV) remodeling in patients with first time attack of acute anterior myocardial infarction (AAMI) .Methods A hundred and three patients with first time attack of AAMI who underwent successful primary percutaneous coronary intervention were randomized to receive atorvastatin 40 mg once daily for 1 week followed by 20 mg once daily (intensive treatment group, IT group, n=49), or atorvastatin 20 mg once daily (standard treatment group, ST group, n=54). Plasma levels of hs-CRP, MDA, ET-1, MMP-2 and MMP-9 were measured on admission, at 1 week, 2 weeks and 6 months follow up and compared between the IT group and ST group. Echocardiography was performed on admission, at 2 week, and 1 year follow up. The left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and left ventricular ejection fraction (LVEF) were measured at each echocardiographic examination and compared between the IT group and ST group.Results Plasma levels of hs-CRP (F=7.718, P=0.009), ET-1 (F=7.882, P=0.006), MMP-9 (F=4.834, P=0.028) and pro-BNP (F=4.603, P=0.032) were significantly lower at 1 week after initial onset of AAMI in the IT group compared with the ST group. The changes of LVEDV, LVESV, and LVEF at the 1 year follow-up from the admission did not differ between the IT group and the ST group (t=0.722, P=0.444; t=1.228, P=0.221; t=1.354, P=0.187, repectively).Conclusions Short-term high-dose atorvastatin treatment for AAMI was associated with lower hs-CRP, ET-1 and MMP-9 levels compared to the standard dose treatment. However, this beneficial effect is not likely to related to the left ventricular remodeling.

Topics: Adolescent; Adult; Aged; Atorvastatin; C-Reactive Protein; Drug Administration Schedule; Echocardiography; Endothelin-1; Female; Humans; Male; Malondialdehyde; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Middle Aged; Myocardial Infarction; Ventricular Function, Left; Ventricular Remodeling; Young Adult

Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI.. In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients.. When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint).. Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies.. In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies.

Topics: Aged; Biomarkers; Endothelin-1; Eplerenone; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Natriuretic Peptide, Brain; Predictive Value of Tests; Spironolactone; Survival Rate; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left

To evaluate the cardioprotection of remote ischemic postconditioning (RIPostC) in patients with acute ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI).. Forty-six STEMI patients undergoing primary PCI at Peking University Third Hospital from January to April 2014 were randomized to RIPostC group (n=23) and control group (n=23).The RIPostC protocol was started within 1 min after reflow by thrombus aspiration or balloon inflation and consisted of 3 cycles of 5 min/5 min ischemia/reperfusion by cuff inflation/deflation of the lower left limb. The enzymatic infarct size, rate of complete ST segment resolution, corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) in infarct-related artery (IRA) and plasma levels of malondialdehyde(MDA), endothelin-1(ET-1), tumor necrosis factor α (TNFα) of the two groups were compared.. There was no significant difference in enzymatic infarct size between the two groups (P>0.05). The rate of complete ST-segment resolution was significantly higher in RIPostC group than in control group (60.9%vs. 30.4%,P=0.04). There was a trend toward lower CTFC in RIPostC group than that in control group, but the difference was not statistically significant(28 ± 11 vs. 33 ± 11, P = 0.10). However, in the subgroup of anterior wall myocardial infarction CTFC in RIPostC group was significantly lower, compared with control group (25±9 vs. 39±10, P=0.01).There were lower plasma levels of MDA,ET-1,TNFα in RIPostC group than in control group at different time points after primary PCI (P<0.05).. In STEMI patients undergoing primary PCI, RIPostC may improve myocardial perfusion and attenuate ischemia reperfusion injury with the underlying mechanisms involving reduction of oxidative stress, protection of endothelial function and inhibition of inflammatory response.

Topics: Endothelin-1; Humans; Ischemic Postconditioning; Malondialdehyde; Myocardial Infarction; Myocardium; Percutaneous Coronary Intervention; Tumor Necrosis Factor-alpha

Endothelin (ET-1) is a potent vasoconstrictor. We compared patterns of ET-1 in percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) and correlated it with markers of inflammation. Patients with multivessel disease were enrolled in a prospective randomized study of PCI vs. on-pump CABG. Procedural myocardial injury was assessed biochemically (CK-MB) and with new late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI) one week postprocedure. ET-1 was measured at baseline, 1 h, 6 h, 12 h, 24 h and one week postprocedure. Log ET-1 values were compared between PCI and CABG and between patients without significant myocardial injury. Measurement of ET-1 values was performed in 36 PCI and 31 CABG patients. Baseline ET-1 values were similar between PCI and CABG patients (0.91 ± 0.36 vs. 1.0 ± 49 pg/ml, P = 0.38). Peak values were reached at 1 h in PCI and at 24 h in CABG patients and patients undergoing CABG had significantly higher log ET-1 values at 6 h, 12 h and 24 h. ET-1 did not correlate with biochemical or morphological markers of myocardial injury or change of left ventricular ejection fraction (LV-EF) but good linear correlation between max logET-1 and max logCRP was found (r = 0.44, P = 0.0002). ET-1 rise is more pronounced in on-pump CABG and ET-1 production could be driven by periprocedural inflammatory reaction.

Topics: Aged; Analysis of Variance; Angioplasty, Balloon, Coronary; Biomarkers; Cardiopulmonary Bypass; Chi-Square Distribution; Contrast Media; Coronary Artery Bypass; Coronary Artery Disease; Creatine Kinase, MB Form; Endothelin-1; England; Female; Humans; Inflammation; Inflammation Mediators; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Myocardium; Predictive Value of Tests; Prospective Studies; Stroke Volume; Time Factors; Treatment Outcome; Troponin I; Up-Regulation; Ventricular Function, Left

Reperfusion after myocardial ischaemia is associated with a distinct ischaemia/reperfusion injury. Since ACE-inhibition, beyond its influence on cardiac angiotensin II formation and kinin metabolism, has been shown to be cardioprotective by decreasing leucocyte adhesion and endothelin-1 (ET-1) release, we investigated the effects of intracoronary (i.c.) enalaprilat during primary angioplasty in acute myocardial infarction.. Twenty-two patients were randomized to receive i.c. enalaprilat (50 micro g) or placebo immediately after reopening of the infarct-related artery (IRA). Plasma concentrations of soluble L-selectin, P-selectin, intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), ET-1 and nitric oxide metabolite concentrations (NOx) were measured in pulmonary arterial blood. Coronary blood flow was assessed using corrected thrombolysis in myocardial infarction (TIMI) frame counts (CTFC). During reperfusion, there was a significant increase in sL-selectin, sP-selectin and ET-1 in the placebo group, which was greatly diminished by enalaprilat. Levels of sVCAM-1 and sICAM-1 were not affected in either group. CTFC in the placebo group remained higher than normal in both the IRA and nonculprit vessels, whereas myocardial blood flow improved with enalaprilat.. Enalaprilat as adjunct to primary angioplasty might be a protective approach to prevent leucocyte adhesion and the release of ET-1, thereby improving coronary blood flow.

Topics: Aged; Analysis of Variance; Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Combined Modality Therapy; Coronary Vessels; Enalaprilat; Endothelin-1; Female; Humans; Injections; L-Selectin; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Nitric Oxide; Norepinephrine; P-Selectin; Pulmonary Artery; Recurrence; Vascular Cell Adhesion Molecule-1

To assess the effect of trimetazidine as an adjunctive treatment to reperfusion therapy in acute myocardial infarction.. Sixty patients with acute myocardial infarction were randomized to receive trimetazidine (a loading dose of 60 mg followed by 20 mg 3 times daily) for 2 weeks (n = 32) or to be controls (n = 28). The loading dose was started early before the reperfusion therapy. Patients received intermittent ST-segment monitoring to assess the resolution of ST-segment deviation one hour after reperfusion therapy. Venous blood samples for measurement of malondialdehyde (MDA) and endothelin (ET-1) were taken immediately on admission and 1, 4, 8, 24 and 48 hours as well as 7 days after reperfusion. In-hospital and 3-months major adverse cardiac events were recorded.. Blinded ST-segment analysis showed that there was a more marked return towards baseline one hour after reperfusion therapy in the trimetazidine group, than in the control group [change (7.14 +/- 3.50) mm vs (3.79 +/- 1.32) mm, P = 0.041]. The measurement of plasma MDA showed that, there was a significantly lower level in the trimetazidine group 4, 8, 24, 48 hours and 7 days after reperfusion (P < 0.05). The level of plasma ET-1 was significantly lower in the trimetazidine group 8 hours and 7 days after reperfusion (P < 0.05). There was no side effect due to trimetazidine. Clinical outcomes were similar between the two groups.. Trimetazidine is effective for the resolution of ST-segment elevation. The effect of trimetazidine against malondialdehyde and ET-1 formation suggested that it might be the mechanism of the myocardial protection.

Topics: Aged; Endothelin-1; Follow-Up Studies; Humans; Male; Malondialdehyde; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Trimetazidine; Vasodilator Agents

The true existence of a class effect in angiotensin-converting enzyme (ACE) inhibitors remains controversial. The present trial explored the effects of 2 ACE inhibitors after acute myocardial infarction and found no difference in endothelin-1 production but a greater increase in the production of total nitric oxide with quinapril than with enalapril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Vessels; Enalapril; Endothelin-1; Humans; Middle Aged; Myocardial Infarction; Nitric Oxide; Quinapril; Tetrahydroisoquinolines

The aim of this prospective cross-over study was to investigate the effect of two low-dosed oral contraceptives on markers of endothelial function and plasma lipids. Twelve healthy, nonsmoking women (mean age: 21.7 years) were recruited from the family planning clinic of the university hospital Zurich. For 6 months the participants received a treatment with two contraceptive pills containing 30 microg ethinyl estradiol/150 microg levonorgestrel (three cycles) and 30 microg ethinyl estradiol/75 microg gestodene (three cycles). Plasma levels of endothelin-1, nitric oxide, cholesterol, and HDL were measurement before and during treatment with both oral contraceptive treatments. No significant changes in the plasma levels of nitric oxide and endothelin-1, both important regulators of the vascular tone, were observed during oral contraceptive use. A significant negative correlation was found between nitric oxide and endothelin-1 and nitric oxide and cholesterol. There was a positive correlation between endothelin-1 and cholesterol. In conclusion, the investigated contraceptive pills did not cause major changes in circulating nitric oxide and endothelin-1 plasma levels.

Topics: Adult; Cholesterol, HDL; Contraceptives, Oral, Combined; Contraceptives, Oral, Synthetic; Cross-Over Studies; Endothelin-1; Ethinyl Estradiol; Female; Humans; Levonorgestrel; Myocardial Infarction; Nitric Oxide; Norpregnenes; Premenopause; Prospective Studies; Statistics, Nonparametric; Time Factors

Morphine has multiple cardiovascular effects, but its action on hydrolysis of endothelin 1 (ET-1) has not been investigated.. We measured plasma levels of ET-1, C-terminal degradation products of ET-1, and neutral endopeptidase 24.11 (NEP) in 68 patients with acute Q-wave myocardial infarction and 29 control subjects. All the patients underwent blood sampling at initial presentation and 10 minutes later. Thirty-six of those with Q-wave myocardial infarction intravenously received 3 mg of morphine immediately after the first sampling (group 1), and the other 32 received the same after the second sampling (group 2). Twenty-four of the control subjects (group 3) were randomized to the protocol of group 1, and the remaining 5 subjects (group 4) were randomized to the protocol of group 2.. The plasma ET-1 levels were significantly higher in groups 1 and 2 than in groups 3 and 4 (control groups). In group 1, the ET-1 level decreased significantly at second blood samplings (2.5+/-0.4 pmol/L versus 1.7+/-0.6 pmol/L, P <.001), whereas there were no definite changes of ET-1 levels in group 2 (2.5+/-0.5 pmol/L versus 2.6+/-0.6 pmol/L, P =not significant). However, the C-terminal degradation products increased significantly at second blood samplings in group 1 (0.8+/-0.2 pmol/L versus 1.3+/-0.4 pmol/L, P <.001), whereas there were no definite changes in group 2 (0.9+/-0.3 pmol/L versus 0.9+/-0.4 pmol/L, P =not significant). There was no significant difference in baseline NEP activities between groups 1 and 2 (5.02+/-1.30 nmol/mg protein versus 5.06+/-1.48 nmol/mg protein, P =not significant). However, the NEP activities at second blood samplings declined significantly in group 1 (9.76+/-1.76 nmol/mg protein, P <.001 versus baseline), whereas no definite changes were observed in group 2 (5.09+/-1.62 nmol/mg protein, P =not significant versus baseline).. Intravenous morphine may increase NEP activities to accentuate hydrolysis of ET-1.

Topics: Aged; Analgesics, Opioid; Creatine Kinase; Drug Monitoring; Emergency Treatment; Endothelin-1; Enzyme Activation; Female; Humans; Hydrolysis; Infusions, Intravenous; Male; Middle Aged; Morphine; Myocardial Infarction; Neprilysin

Tamoxifen protects against myocardial infarction through mechanisms that are poorly understood. We studied the effects of tamoxifen and another antiestrogen, toremifene, on the production of vasoconstrictive endothelin-1 and of vasodilatory nitric oxide in 44 postmenopausal patients with breast cancer. These started treatment, in randomized order, with either tamoxifen (20 mg/day; n = 25) or toremifene (40 mg/day; n = 19). Plasma samples collected before treatment and after 6 and 12 months of both regimens were assayed for endothelin-1 with a specific radioimmunoassay and for nitrite/nitrate with a method based on the Griess reaction. The antiestrogen group as a whole showed a fall in endothelin-1 at 6 months (5.9 +/- 3.3%; p = 0.06) (mean +/- SE) and at 12 months (7.1 +/- 5.5%; p = 0.03). This fall was solely due to toremifene, the use of which was associated with falls in endothelin-1 at 6 months (12.9 +/- 4.7%; p = 0.01) and 12 months (9.2 +/- 6.2%; p = 0.06). The antiestrogen regimen failed to affect plasma nitric oxide significantly but nevertheless the ratio between nitric oxide and endothelin-1 rose by 31.6 +/- 13.3% at 6 months and by 35.6 +/- 15.3% at 12 months in the antiestrogen users, an effect similar in the tamoxifen and toremifene groups. We conclude that antiestrogens may protect against myocardial infarction by preventing the release of endothelin-1 and by shifting the balance between nitric oxide and endothelin-1 to the dominance of the former. Our data predict that toremifene and tamoxifen at the doses studied here will provide similar cardiovascular protection.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Endothelin-1; Estrogen Antagonists; Female; Humans; Middle Aged; Myocardial Infarction; Nitrates; Postmenopause; Tamoxifen; Toremifene

The aim of this study was to investigate the behavior of plasma endothelin-1 (ET-1) in 23 patients with acute myocardial infarction, complicated and uncomplicated by left ventricular failure, and treated with and without thrombolytic agents. ET-1 was measured on admission; on days 2, 3, and 5; and again on discharge. In addition, on discharge, ET-1 was correlated with left ventricular systolic function. Left ventricular failure was present, on admission, in 14 patients, whereas the other nine did not have any hemodynamic impairment. On discharge, no patients had left ventricular failure, but 11 had moderate to severe left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) < 40%. Fourteen subjects, matched for age and sex, served as a control group. Compared with the control range, ET-1 was highly elevated on the first day, in both uncomplicated (p < 0.01) and complicated patients (p < 0.001). Then it decreased rapidly in the uncomplicated group, reaching the control range within day 5, whereas in the complicated group it remained significantly elevated in comparison with both the control subjects and the uncomplicated patients, until discharge. ET-1 was not correlated with the peak of creatine-kinase MB isoenzyme in any group. In seven patients submitted to thrombolytic treatment ET-1 was always significantly lower than in the nonthrombolyzed patients (p < 0.05), but the pattern of variation across time was no different. On discharge, the difference in plasma ET-1 between patients with LVEF < 40% and the control group was significant (p < 0.001), as was the difference between patients with and without moderate to severe systolic dysfunction (p < 0.01). ET-1 was closely and inversely correlated with LVEF when patients were considered as a whole (p < 0.001). These results suggest that the ET-1 increase in the early phase of myocardial infarction could be due to an ischemic process, to stress reaction, and to cardiac hemodynamic impairment, and therefore, ET-1 may be a good marker of disease. In the following phase the ET-1, being correlated with LVEF, could be a reliable index of systolic function.

Topics: Aged; Aged, 80 and over; Biomarkers; Creatine Kinase; Electrocardiography; Endothelin-1; Female; Fibrinolytic Agents; Follow-Up Studies; Heart Failure; Heart Ventricles; Humans; Isoenzymes; Male; Middle Aged; Myocardial Contraction; Myocardial Infarction; Prognosis; Radioimmunoassay; Stroke Volume; Thrombolytic Therapy; Ventricular Dysfunction, Left

Studies showed that endothelin-1 (ET-1) was increased in the acute myocardial infarction (AMI). Experimental studies reported that captopril was able to reduce ET-1 secretion. In addition increased levels of ET-1 were reported as a negative prognostic index. The study was aimed to verify whether captopril was able to reduce plasma ET-1 levels in the acute and subacute phases of AMI.. Forty five patients, hospitalized for suspected anterior AMI within 4 h since the onset of symptoms, suitable for thrombolysis (first episode), in Killip class 1-2, were randomized (double blind) into two groups: Group A (23 patients, pts), 7 females and 16 males, received captopril 6.25 mg orally (as first dose) 2-4 h after starting thrombolysis, and the doses of captopril were successively increased up to 25 mg every 8 h. Group B: (22 pts), 5 females and 17 males, received placebo after thrombolysis. All the patients met the reperfusion criteria.. The two groups were similar for age, sex, CK peak, ejection fraction, end systolic volume and risk factors. Plasma ET levels were checked on admission, and 2, 12, 24, 48, 72 hours, after starting thrombolysis. Mean concentrations of ET +/- SD: Group A: basal 1.50 +/- 0.67, at 2 h 2.31 +/- 1.24, 12 h 1.84 +/- 1.45, 24 h 1.30 +/- 0.72, 48 h 0.95 +/- 0.50, 72 h 0.60 +/- 0.15 fmol/ml (p < 0.001). Group B: basal 1.58 +/- 0.83, at 2 h 2.38 +/- 1.35, 12 h 2.33 +/- 1.71, 24 h 1.80 +/- 1.41, 48 h 1.46 +/- 0.88, 72 h 0.93 +/- 0.44 fmol/ml (p < 0.001). Difference between the two groups was significant at 48 h (p < 0.05), and 72 h (p < 0.001).. Our data suggest that captopril affects plasma endothelin levels in the acute and subacute phases of AMI. In addition, our results seem to be an additional support to the beneficial effects of early captopril treatment in patients with AMI.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Captopril; Creatine Kinase; Double-Blind Method; Endothelin-1; Female; Humans; Isoenzymes; Male; Middle Aged; Myocardial Infarction; Thrombolytic Therapy; Time Factors

Topics: Adult; Angina, Unstable; Coronary Artery Disease; Endothelial Cells; Endothelin-1; Humans; Myocardial Infarction; Peptides; Plasma; Tissue Plasminogen Activator; von Willebrand Factor

Topics: Electrocardiography; Endothelin-1; Hospitalization; Humans; Myocardial Infarction; Non-ST Elevated Myocardial Infarction; ST Elevation Myocardial Infarction

Cardiac fibrosis is an important pathological change after myocardial infarction (MI). High concentration of tumor necrosis factor-α (TNF-α) contributes to cardiac fibrosis, and TNF-α has been demonstrated to be involved in transforming growth factor-β1-induced endothelial-to-mesenchymal transition (EndMT). However, the role and molecular mechanisms of TNF-α during cardiac fibrosis remain largely unexplored. In this study, we demonstrated that TNF-α and endothelin-1 (ET-1) were upregulated in cardiac fibrosis after MI, and genes associated with EndMT were also upregulated. An in vitro model of EndMT demonstrated that TNF-α promoted EndMT by upregulation of vimentin and α-smooth muscle actin, and which strongly increased ET-1 expression. ET-1 promoted TNF-α-induced expression of gene program through phosphorylation levels of SMAD family member 2, while subsequent inhibition of ET-1 almost abolished the effect of TNF-α during the process of EndMT. In summary, these findings demonstrated that ET-1 is involved in the EndMT induced by TNF-α during cardiac fibrosis.

Topics: Endothelin-1; Endothelium; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Myocardial Infarction; Signal Transduction; Tumor Necrosis Factor-alpha

An association has been suggested between acute myocardial infarction (AMI) and obstructive sleep apnea (OSA). Considering the role of adipose-tissue-derived inflammatory mediators (adipokines) and the shared risk factor of obesity in OSA and AMI, this study aimed to investigate the involvement of adipokines in AMI patients with and without OSA. Serum levels of adipokines and inflammatory mediators were quantified, and home respiratory polygraphy was conducted. A total of 30 AMI patients and 25 controls were included. Patients with AMI exhibited elevated levels of resistin (7.4 vs. 3.7 ng/mL), interleukin-6 (8.8 vs. 1.3 pg/mL), and endothelin-1 (3.31 vs. 1.8 pg/mL). Remarkably, AMI patients with concomitant OSA exhibited higher levels of resistin (7.1 vs. 3.7 ng/mL), interleukin-6 (8.9 vs. 1.3 pg/mL), endothelin-1 (3.2 vs. 1.8 pg/mL), creatin kinase (1430 vs. 377 U/L), creatine kinase-MB (64.6 vs. 9.7 ng/mL), and troponin T (2298 vs. 356 pg/mL) than their non-OSA counterparts. Leptin showed a correlation with OSA severity markers. OSA was associated with greater cardiac damage in AMI patients. Our findings underscore that adipokines alone are not sufficient to discriminate the risk of AMI in the presence of OSA. Further research is necessary to determine the potential mechanisms contributing to exacerbated cardiac damage in patients with both conditions.

Topics: Adipokines; Endothelin-1; Humans; Inflammation Mediators; Interleukin-6; Myocardial Infarction; Resistin; Sleep Apnea, Obstructive

Cardiovascular diseases are the most common causes of death, in both Poland and the world. Their development and progression are largely influenced by the lifestyle with the presence/occurrence of classic, modifiable risk factors. Among them, low physical activity plays a significant role. The aim of the study was to evaluate the expression of the endothelin-1 gene and its type A receptor, taking into account physical activity (International Physical Activity Questionnaire-IPAQ) among patients with acute myocardial infarction. A total of 234 patients with acute myocardial infarction were examined, including 167 patients undergoing early post-hospital cardiac rehabilitation and 67 not participating in it. All of them were assessed with the IPAQ questionnaire and the quantitative real-time polymerase reaction method (QRT-PCR). Physical activity in the group of patients after early post-hospital cardiac rehabilitation increased after rehabilitation. Transcriptional activity of the endothelin-1 (ET-1) gene in both studied group of patients increased significantly, but in a group of patients not participating in early post-hospital cardiac rehabilitation more than in a group of patients participating in it. In our study, the expression of ET-1 was also significantly higher in the group of patients with acute myocardial infarction with ST-segment elevation, without diabetes, with lipid disorders, smoking, with normal body weight. Expression of the ENDRA (Endothelin receptor A) gene increased with age. These results prove the beneficial effect of rehabilitation and may indicate another pathomechanism of pro-atherogenic activity of above-mentioned factors.

Topics: Cardiac Rehabilitation; Endothelin-1; Exercise; Humans; Myocardial Infarction; Time Factors

Auraptene derived from the peel of Citrus hassaku possesses anti-tumor, anti-inflammatory, and neuroprotective activities. Thus, it could be a valuable pharmacological alternative to treat some diseases. However, the therapeutic value of auraptene for heart failure (HF) is unknown.. In cultured cardiomyocytes from neonatal rats, the effect of auraptene on phenylephrine-induced hypertrophic responses and peroxisome proliferator-activated receptor-alpha (PPARα)-dependent gene transcriptions. To investigate whether auraptene prevents the development of heart failure after myocardial infarction (MI) in vivo, Sprague-Dawley rats with moderate MI (fractional shortening < 40%) were randomly assigned for treatment with low- or high-dose auraptene (5 or 50 mg/kg/day, respectively) or vehicle for 6 weeks. The effects of auraptene were evaluated by echocardiography, histological analysis, and the measurement of mRNA levels of hypertrophy, fibrosis, and PPARα-associated genes.. In cultured cardiomyocytes, auraptene repressed phenylephrine-induced hypertrophic responses, such as increases in cell size and activities of atrial natriuretic factor and endothelin-1 promoters. Auraptene induced PPARα-dependent gene activation by enhancing cardiomyocyte peroxisome proliferator-responsive element reporter activity. The inhibition of PPARα abrogated the protective effect of auraptene on phenylephrine-induced hypertrophic responses. In rats with MI, auraptene significantly improved MI-induced systolic dysfunction and increased posterior wall thickness compared to the vehicle. Auraptene treatment also suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, and expression of hypertrophy and fibrosis response markers at the mRNA level compared with vehicle treatment. MI-induced decreases in the expression of PPARα-dependent genes were improved by auraptene treatment.. Auraptene has beneficial effects on MI-induced cardiac hypertrophy and left ventricular systolic dysfunction in rats, at least partly due to PPARα activation. Further clinical studies are required to evaluate the efficacy of auraptene in patients with HF.

Topics: Animals; Atrial Natriuretic Factor; Biological Products; Cardiomegaly; Citrus; Coumarins; Endothelin-1; Fibrosis; Heart Failure; Myocardial Infarction; Peroxisome Proliferators; Phenylephrine; PPAR alpha; Rats; Rats, Sprague-Dawley; RNA, Messenger

Myocardial infarction (MI) and underlining atherosclerosis are the main causes of death worldwide. Phosphatase and actin regulator 1 (PHACTR1) variants have been associated with early onset MI, coronary artery disease and carotid dissection. PHACTR1 mRNA expression has been detected in tissues and cells related to atherosclerosis. Nonetheless, the true effect of PHACTR1 on vascular diseases is still unknown. Our aim was to examine the association of PHACTR1 intronic variants, rs9349379, rs2026458 and rs2876300, with MI and multi-vessel disease (MVD) and to assess their effect on PHACTR1 and EDN1 mRNA expression in PBMCs of patients six months after MI.. The study enrolled 537 patients with the first MI and 310 controls. Gene expression was assessed in 74 patients six months after MI and 37 healthy controls. Rs9349379, rs2026458, rs2876300 and relative mRNA expressions were detected by TaqMan® technology.. The significant association between PHACTR1 variants and MI was not found, either individually or in haplotype. A higher frequency of rs2876300G-allele in MVD was rendered not significant after Bonferroni correction. PHACTR1 mRNA was significantly increased in PBMCs of patients six months after MI compared to controls (p = 0.02). Patients that carry ACG haplotype have increased PHACTR1 mRNA expression in PBMCs (p = 0.04). There was no effect of PHACTR1 variants on EDN1 mRNA expression.. Our findings suggest that PHACTR1 intronic variants may have a role in severity and progression of coronary atherosclerosis. Future research is needed to clarify the mechanism underlying the role of PHACTR1 in coronary atherosclerosis and MI.

Topics: Adult; Age of Onset; Aged; Case-Control Studies; Endothelin-1; Female; Genetic Association Studies; Humans; Introns; Male; Microfilament Proteins; Middle Aged; Myocardial Infarction; Polymorphism, Single Nucleotide; Severity of Illness Index; Up-Regulation

Hypercholesterolemia is a hazard for increasing susceptibility of the heart to myocardial infarction (MI) by inducing platelet hyperaggregability. Clopidogrel and prasugrel have documented cardioprotective effects in clinical studies. Herein, we investigated whether clopidogrel and prasugrel could protect against isoproterenol-induced acute MI (A-MI) under hypercholesterolemic conditions in rats.. Dietary hypercholesterolemic rats were subjected to acute doses of isoproterenol. Serum lipids, inflammatory markers, aortic endothelin1 and endothelial nitric oxide synthase (eNOS) mRNAs expression and immunexpression of BCL2 were determined.. Hypercholesterolemic rats showed infiltration of inflammatory cells and reduction in aortic wall thickness, deposition of fibrous tissue between cardiac muscle fibers. Protective doses of prasugrel or clopidogrel for 28 days before A-MI increased survival, amended the ECG parameters -including ST segment elevation- and improved the histopathological picture in hypercholesterolemic rats. This was coupled with reductions in platelet aggregation, creatine kinase-MB activity, endothelin 1, systemic inflammation and cardiac lipid peroxidation and increment in aortic eNOS expression. Clopidogrel and prasugrel groups showed enhanced BCL2 expression in cardiac fibers and aortic wall.. Prasugrel and clopidogrel protected against A-MI via anti-aggregatory and anti-inflammatory effects. These results add to the value of these drugs in correcting cardiovascular dysfunction in patients vulnerable to A-MI after confirmation by appropriate human studies.

Topics: Animals; Cardiovascular System; Clopidogrel; Creatine Kinase, MB Form; Endothelin-1; Gene Expression Regulation; Hypercholesterolemia; Male; Models, Animal; Mortality; Myocardial Infarction; Nitric Oxide Synthase Type III; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Signal Transduction; Treatment Outcome

Exercise training is beneficial for cardiac rehabilitation. Nevertheless, few study focused on the role of high-intensity interval training (HIIT) in cardiac repair. The current study aimed to elucidate the effect of HIIT on cardiac rehabilitation and the involved mechanisms after acute myocardial infarction (MI).. A total of 65 male rats underwent coronary ligation or sham operation and were randomly assigned to 4 groups: sham (n = 10), sedentary (MI-Sed, n = 12), moderate-intensity continuous training (MI-MCT, n = 12) and HIIT (MI-HIIT, n = 12). One week after MI induction, adaptive training starts follow by formal training. After the experiment, cardiac functions were determined by echocardiography and hemodynamic measurements. Changes in infarct size, collagen accumulation, myofibroblasts, angiogenesis, inflammation level, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system (RAAS) activities were measured. Data were analyzed by one-way ANOVA.. After MI, cardiac structure and function were significantly deteriorated. However, post-MI HIIT for 8 weeks had significantly ameliorated left ventricular end-diastolic pressure (LVEDP), LV systolic pressure (LVSP), and maximum peak velocities of relaxation (-dP/dtmax). Moreover, it preserved cardiac functions, reduced infarct size, protected the myocardium structure, increased angiogenesis and decreased the myofibroblasts and collagen accumulation. HIIT for 4 weeks had no effect on LVEDP, -dP/dtmax, infarct size and angiogenesis. Additionally, it induced inflammation response and repressed ET-1 and RAAS activities were found in myocardium and peripheral circulation after HIIT.. Our results suggested that post-MI HIIT had a positive role in cardiac repair, which might be linked with the induction of inflammation and inhibition of ET-1 and RAAS activities.

Topics: Animals; Endothelin-1; Male; Myocardial Infarction; Myocardium; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Ventricular Remodeling

Ventricular tachyarrhythmia is the leading cause of death in post-infarction patients. Big endothelin-1 (ET-1) is a potent vasoconstrictor peptide and plays a role in ventricular tachyarrhythmia development. The aim of this study was to investigate the association between the serum concentration of big ET-1 and ventricular tachyarrhythmia in post-infarction left ventricular aneurysm (PI-LVA) patients.. A total of 222 consecutive PI-LVA patients who had received medical therapy were enrolled in the study. There were 43 (19%) patients who had ventricular tachycardia/ventricular fibrillation (VT/VF) at the time of admission. The clinical characteristics were observed and the plasma big ET-1 level was measured. Associations between big ET-1 and the presence of VT/VF were assessed. Patients were followed up to check for outcomes related to cardiovascular mortality, VT/VF attack, and all-cause mortality.. The median concentration of big ET-1 was 0.635 pg/mL. Patients with big ET-1 concentrations above the median were more likely to have higher risk clinical features. There was a positive correlation between the level of big ET-1 with VT/VF attack (r=0.354, p<0.001). In the multiple logistic regression analysis, big ET-1 (OR=4.06, 95% CI: 1.77-9.28, p<0.001) appeared as an independent predictive factor for the presence of VT/VF. Multiple Cox regression analysis suggested that big ET-1 concentration was independently predictive of VT/VF attack (OR=2.5, 95% CI 1.4-4.5, p<0.001). NT-proBNP and left ventricular ejection fraction of ≤35% were demonstrated to be independently predictive of cardiovascular mortality and all-cause mortality.. Increased big ET-1 concentration in PI-LVA patients is a valuable independent predictor for the prevalence of ventricular tachyarrhythmias and VT/VF attacks during follow-up after PI-LVA treatment.

Topics: Biomarkers; Endothelin-1; Female; Heart Aneurysm; Humans; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; Proportional Hazards Models; Survival Analysis; Tachycardia, Ventricular; Turkey

Endothelin has been implicated in various processes in the brain, including the modulation of sympathetic responses. The present study examined the pathophysiologic role of brain endothelin-receptors in the setting of acute myocardial infarction, characterized by high incidence of ventricular tachyarrhythmias.. We investigated the effects of intracerebroventricular administration of antagonists of endothelin-receptors ET. Sympathetic-activity was decreased and vagal-activity was enhanced after intracerebroventricular ET. ET

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Autonomic Nervous System; Brain; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Rate; Male; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sympathetic Nervous System; Tachycardia, Ventricular

The Raf/MAPK/ERK kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is activated in cardiac hypertrophy after a myocardial infarction. Although heat-shock protein 90 (Hsp90) may regulate the Raf/Mek/Erk signal pathway, the role of Hsp90 in pathophysiological cardiac hypertrophy remains unclear. In this study, we examined the role of Hsp90 in this pathway in cardiac hypertrophy under in vivo and in vitro experimental conditions. Cultured rat cardiomyocytes were treated with the Hsp90 inhibitor 17-(allylamino)-17-dimethoxy-geldanamycin (17-AAG) and proteasome inhibitor MG-132, and then incubated with endothelin-1 (ET) to induce hypertrophy of the cells. The ET-induced increase in the cell size was attenuated by 17-AAG pretreatment. Immunoblot analysis revealed that the c-Raf content of ET-treated cardiomyocytes was decreased in the presence of 17-AAG. An increase in phosphorylation levels of Erk1/2 and GATA4 in ET-treated cardiomyocytes was also attenuated by the 17-AAG pretreatment. Myocardial infarction was produced by ligation of the left ventricular coronary artery in rats, and then 17-AAG was intraperitoneally administered to the animals starting from the 2ndweek after coronary artery ligation (CAL). CAL-induced increases in the heart weight and cross-sectional area were attenuated by 17-AAG treatment. CAL rats showed signs of chronic heart failure with cardiac hypertrophy, whereas cardiac function in CAL rats treated with 17-AAG was not reduced. Treatment of CAL rats with 17-AAG caused a decrease in the c-Raf content and Erk1/2 and GATA4 phosphorylation levels. These findings suggest that Hsp90 is involved in the activation of the Raf/Mek/Erk pathway via stabilization of c-Raf in cardiomyocytes, resulting in the development of cardiac hypertrophy following myocardial infarction.

Topics: Animals; Cardiomegaly; Down-Regulation; Endothelin-1; Female; Heart Ventricles; HSP90 Heat-Shock Proteins; Male; MAP Kinase Signaling System; Myocardial Infarction; Myocytes, Cardiac; Rats

Previous studies suggest that granulocyte colony‑stimulating factor (G‑CSF) can promote bone marrow derived progenitor cells to mediate cardiovascular repair, potentially reversing mechanical dysfunction in chronic ischaemic heart disease and post myocardial infarction. Two models were used in the present study both using a surgical ameroid constrictor to induce arterial stenosis. The first model used the carotid artery of rabbits. They were divided into high fat diet (inducing atherosclerosis) or normal fat diet (control) groups. Each was subdivided into surgical exposure group without constrictor, ameroid constrictor receiving normal saline or receiving G‑CSF 15 µg/kg/day. Endothelial markers of endothelial nitric oxide synthase and endothelin 1 were increased by the use of ameroid constrictor in both atherosclerotic and non‑atherosclerotic mice, however were not further altered by G‑CSF. Scanning electron microscopy indicated that ameroid constrictor application altered endothelial morphology from an oval shape to a round shape and this was more prominent in the atherosclerotic compared with the non‑atherosclerotic group. G‑CSF injection increased the number of endothelial cells in all groups. The second model used the left coronary artery of pigs. They were equally divided into following groups, receiving normal saline (control), G‑CSF 2.5 µg/kg/day (low dose), 5 µg/kg/day (medium dose) and 10 µg/kg/day (high dose) for 5 days. G‑CSF at a low or high dose worsened intimal hyperplasia however at a medium dose improved it. In conclusion, G‑CSF had no effect in a rabbit carotid artery model of atherosclerosis. Its effects on the porcine heart were dose‑dependent; arterial disease worsened at a low or high dose, but improved at a medium dose.

Topics: Animals; Carotid Arteries; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Endothelin-1; Granulocyte Colony-Stimulating Factor; Heart; Male; Myocardial Infarction; Myocardial Ischemia; Nitric Oxide Synthase Type III; Rabbits; Swine; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Myocardial infarctions go along with biomechanical stress, i.e. stretching of muscle fibres, and the expression of certain marker molecules. We tested if two of those markers, endothelin-1 (ET-1) and growth differentiation factor 15 (GDF-15), can be used as immunohistochemical markers for myocardial ischaemia/infarctions. The study included experiments with an animal model, the isolated perfused Langendorff heart, as well as the investigation of human tissue samples drawn during autopsies. The overall picture of our results showed that GDF-15 is very sensitive and expressed very fast, not only as a consequence of ischaemia/infarctions, but also under other circumstances. Even an expression only caused by agony had to be discussed. ET-1, on the other hand, was less sensitive but only positive in those human cases with ischaemia/infarction that also showed typical alterations in conventional histology. Therefore, both markers did not proof to be a suitable diagnostic tool for myocardial infarctions. However, positive staining for ET-1 was also seen in rats' hearts that suffered from arrhythmias after electric shock and in the myocardium of the right ventricle in human control cases in which a right heart failure has to be discussed. Thus, especially ET-1 should be subject of further studies that focus on these pathologies.

Topics: Animals; Biomarkers; Case-Control Studies; Endothelin-1; Forensic Pathology; Growth Differentiation Factor 15; Humans; Immunohistochemistry; Models, Animal; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Rats, Wistar; Staining and Labeling

Topics: Biomarkers; Endothelin-1; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Mendelian Randomization Analysis; Myocardial Infarction; Myocardial Ischemia; Odds Ratio; Polymorphism, Single Nucleotide

To evaluate the role of adenovirus-mediated transduction human VEGF isoform 165. The whole heart weight, left heart weight, heart mass index and left heart mass index in the VEGF group were higher than those in the MI and NS group. VEGF treatment could also significantly increase cardiac function, and increase microvessel density in the infarcted area. Moreover, VEGF treatment could decrease the serum neurohumoral factors (ANP, Ag II, and TE-1), and inhibit myocardial apoptosis via TNF-α, Bax, and Bcl-2.. Adenovirus-mediated VEGF165 gene therapy could significantly improve cardiac function possibly by inducing myocardial collateral vessel development, inhibiting the apoptosis of myocardial cells, and inhibiting ventricular remodeling.

Topics: Adenoviridae; Analysis of Variance; Angiotensins; Animals; Atrial Natriuretic Factor; Disease Models, Animal; Echocardiography; Endothelin-1; Genetic Therapy; Male; Myocardial Infarction; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Ultrasonography, Doppler, Color; Vascular Endothelial Growth Factor A

The predictive value of big endothelin-1 (ET-1) for cardiovascular outcomes in myocardial infarction (MI) patients younger than 35 years old has not been characterized.. A total of 565 consecutive MI patients younger than 35 years old were studied and followed up for 37.78 ± 24.9 months.. Multivariable Cox regression analysis showed that big ET-1 was positively correlated with major adverse cardiovascular events [MACEs] (odds ratio: 3; 95% CI: 1.92-4.68; p < 0.001). The area under receiver operating characteristics curve showing the predictive value of big ET-1 on MACEs was 0.67.. The study first demonstrated that big ET-1 was an independent predictor for MACEs in MI patients younger than 35 years old.

Topics: Adult; China; Endothelin-1; Female; Humans; Kaplan-Meier Estimate; Male; Myocardial Infarction; Odds Ratio; Percutaneous Coronary Intervention; Prognosis; Regression Analysis; Risk Factors; ROC Curve; Treatment Outcome; Young Adult

Coronary artery remodelling and vasospasm is a complication of acute myocardial ischemia and reperfusion. The underlying mechanisms are complex, but the vasoconstrictor peptide endothelin-1 is suggested to have an important role. This study aimed to determine whether the expression of endothelin-1 and its receptors are regulated in the myocardium and in coronary arteries after experimental ischemia-reperfusion. Furthermore, we evaluated whether treatment with a specific MEK1/2 inhibitor, U0126, modified the expression and function of these proteins.. Sprague-Dawley rats were randomly divided into three groups: sham-operated, ischemia-reperfusion with vehicle treatment and ischemia-reperfusion with U0126 treatment. Ischemia was induced by ligating the left anterior descending coronary artery for 30 minutes followed by reperfusion. U0126 was administered before ischemia and repeated 6 hours after start of reperfusion. The contractile properties of isolated coronary arteries to endothelin-1 and sarafotoxin 6c were evaluated using wire-myography. The gene expression of endothelin-1 and endothelin receptors were measured using qPCR. Distribution and localization of proteins (pERK1/2, prepro-endothelin-1, endothelin-1, and endothelin ETA and ETB receptors) were analysed by Western blot and immunohistochemistry. We found that pERK1/2 was significantly augmented in the ischemic area 3 hours after ischemia-reperfusion; this correlated with increased ETB receptor and ET-1 gene expressions in ischemic myocardium and in coronary arteries. ETB receptor-mediated vasoconstriction was observed to be increased in coronary arteries 24 hours after ischemia-reperfusion. Treatment with U0126 reduced pERK1/2, expression of ET-1 and ETB receptor, and ETB receptor-mediated vasoconstriction.. These findings suggest that the MEK-ERK1/2 signaling pathway is important for regulating endothelin-1 and ETB receptors in myocardium and coronary arteries after ischemia-reperfusion in the ischemic region. Inhibition of the MEK-ERK1/2 pathway may provide a novel target for reducing ischemia-reperfusion damage in the heart.

Topics: Animals; Butadienes; Endothelin-1; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Male; MAP Kinase Signaling System; Myocardial Infarction; Myocardial Reperfusion Injury; Nitriles; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Vasoconstrictor Agents; Viper Venoms

Patients with ischaemic heart disease or chronic heart failure show altered levels of obestatin, suggesting a role for this peptide in human heart function. We have previously demonstrated that GH secretagogues and the ghrelin gene-derived peptides, including obestatin, exert cardiovascular effects by modulating cardiac inotropism and vascular tone, and reducing cell death and contractile dysfunction in hearts subjected to ischaemia/reperfusion (I/R), through the Akt/nitric oxide (NO) pathway. However, the mechanisms underlying the cardiac actions of obestatin remain largely unknown. Thus, we suggested that obestatin-induced activation of PI3K/Akt/NO and PKG signalling is implicated in protection of the myocardium when challenged by adrenergic, endothelinergic or I/R stress. We show that obestatin exerts an inhibitory tone on the performance of rat papillary muscle in both basal conditions and under β-adrenergic overstimulation, through endothelial-dependent NO/cGMP/PKG signalling. This pathway was also involved in the vasodilator effect of the peptide, used both alone and under stress induced by endothelin-1. Moreover, when infused during early reperfusion, obestatin reduced infarct size in isolated I/R rat hearts, through an NO/PKG pathway, comprising ROS/PKC signalling, and converging on mitochondrial ATP-sensitive potassium [mitoK(ATP)] channels. Overall, our results suggest that obestatin regulates cardiovascular function in stress conditions and induces cardioprotection by mechanisms dependent on activation of an NO/soluble guanylate cyclase (sGC)/PKG pathway. In fact, obestatin counteracts exaggerated β-adrenergic and endothelin-1 activity, relevant factors in heart failure, suggesting multiple positive effects of the peptide, including the lowering of cardiac afterload, thus representing a potential candidate in pharmacological post-conditioning.

Topics: Animals; Cardiotonic Agents; Cyclic GMP-Dependent Protein Kinases; Endothelin-1; Gene Expression Regulation; Heart Ventricles; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Nitric Oxide; Organ Culture Techniques; Papillary Muscles; Peptide Hormones; Phosphatidylinositol 3-Kinases; Potassium Channels; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Signal Transduction; Soluble Guanylyl Cyclase

The aim of the current study was to assess the link between EDN K198N SNP, ET-1 serum concentration and acute myocardial infarction (AMI) in Egyptians. The study cohort consisted of 84 patients at AMI onset and 84 age-matched healthy controls. Endothelin genotypes and concentrations were determined by sequencing and ELISA, respectively. Genotype distribution was not significantly different between AMI patients and controls (P=.8341). The mean serum ET-1 concentration of patients (13.83±0.7 pg/mL) was significantly higher than controls (7.26±0.2 pg/mL) (P<.0001). ET-1 serum concentrations did not vary significantly among various EDN genotypes in patients (P=.378) and controls (P=.6164). Hence, we conclude that EDN K198N genotypes were not related to either ET-1 concentration or incidence of early-onset AMI in Egyptians. But, AMI patients had higher ET-1 concentrations than controls.

Topics: Adult; Egypt; Endothelin-1; Female; Genetic Linkage; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Single Nucleotide

In this study, we examined whether the combination of hyperbaric oxygen (HBO) and diltiazem therapy provided a cardioprotective effect on myocardial ischemia-reperfusion injury (MIRI) rat model.. Sixty healthy Sprague-Dawley rats were randomly divided into sham, IR, diltiazem (5 mg/kg), HBO (0.25 MPa, 60 min) and combination therapy (HBO plus diltiazem) groups. MIRI model was established by ligating the left anterior descending for 30 min, followed by 60 min of reperfusion.. The results show that HBO and diltiazem preconditioning significantly improves cardiac function and myocardial infarction area, increases nitric oxide, endothelial nitric oxide synthase and ATPase (Na+-K+-ATPase and Ca2+-Mg2+-ATPase) activity and decreases levels of oxygen stress, myocardial enzymes and endothelin-1. Notably, HBO and diltiazem preconditioning significantly increased Bcl-2 protein expression and decreased Bax protein and caspase-3 mRNA expression.. These data indicate that combination therapy protected against heart MIRI by reducing oxygen stress damage, correcting energy metabolism, improving endothelial function and inhibiting cell apoptosis.

Topics: Animals; bcl-2-Associated X Protein; Caspase 3; Combined Modality Therapy; Diltiazem; Disease Models, Animal; Down-Regulation; Endothelin-1; Female; Heart; Hyperbaric Oxygenation; Ischemic Preconditioning; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Nitric Oxide; Nitric Oxide Synthase Type III; Protective Agents; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Up-Regulation

Spontaneous reperfusion (SR) was associated with better clinical outcomes and lower incidence of major adverse cardiovascular events. Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor peptide and elevated systemic ET-1 levels predict a poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI). We aimed to investigate the relationship between systemic ET-1 plasma levels and SR in a group of STEMI patients treated with a primary percutaneous coronary intervention (PCI).. We measured ET-1 levels acutely (within the first 6 h) in 33 STEMI patients with SR and 45 STEMI patients with non-SR presenting with their first STEMI who underwent primary PCI. Blood samples for ET-1 plasma level measurement were drawn after vascular puncture before angiography in the catheterization laboratory from the peripheral vein.The mean age of the patients was 56.1±13.3 years in the SR group and 57.4±11.4 years in the non-SR group. The circulating level of ET-1 was considerably higher in the non-SR patients than in the SR patients (0.81±0.2, 1.0±0.3, P=0.004). On multivariable logistic regression analysis, the ET-1 level was the only significant predictor of SR (P=0.01).The receiver operating characteristic curve analysis showed that the ET-1 level at admission is an indicator of SR, with an area under the curve of 0.62.. This study shows that in patients admitted with ST-elevation acute myocardial infarction, ET-1 plasma levels are related to angiographic SR before primary PCI.

Topics: Adult; Aged; Area Under Curve; Biomarkers; Case-Control Studies; Chi-Square Distribution; Coronary Angiography; Coronary Circulation; Coronary Vessels; Endothelin-1; Female; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Odds Ratio; Percutaneous Coronary Intervention; Predictive Value of Tests; Recovery of Function; ROC Curve; Time Factors; Treatment Outcome; Turkey

Nucleotides are released in the heart under pathological conditions, but little is known about their contribution to cardiac inflammation. The present study defines the P2Y4 nucleotide receptor, expressed on cardiac microvascular endothelial cells and involved in postnatal heart development, as an important regulator of the inflammatory response to cardiac ischemia. P2Y4-null mice displayed smaller infarcts in the left descending artery ligation model, as well as reduced neutrophil infiltration and fibrosis. Gene profiling identified inter alia endothelin-1 (ET-1) as one of the target genes of P2Y4 in ischemic heart. The reduced level of ET-1 was correlated with reduction of microvascular hyperpermeability, neutrophil infiltration, and endothelial adhesion molecule expression, and it could be explained by the decreased number of endothelial cells in P2Y4-null mice. Expression analysis of metalloproteinases and their tissue inhibitors in ischemic heart revealed reduced expression of matrix metalloproteinase (MMP)-9, reported to be potentially regulated by ET-1, and MMP-8, considered as neutrophil collagenase, as well as reduction of tissue inhibitor of MMP-1 and tissue inhibitor of MMP-4 in P2Y4-null mice. Reduction of cardiac permeability and neutrophil infiltration was also observed in P2Y4-null mice in LPS-induced inflammation model. Protection against infarction resulting from loss of P2Y4 brings new therapeutic perspectives for cardiac ischemia and remodeling.

Topics: Animals; Disease Models, Animal; Down-Regulation; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Immunohistochemistry; Mice; Mice, Knockout; Myocardial Infarction; Real-Time Polymerase Chain Reaction; Receptors, Purinergic P2; Transcriptome

In ischaemic hearts, endothelin (ET) levels are increased, and vasoconstrictor responses to ET-1 are greatly enhanced. We previously reported that ETB receptors are up-regulated in the smooth muscle layer of coronary arteries after myocardial ischaemia-reperfusion and that the MEK-ERK1/2 signalling pathway is involved in ETB receptor up-regulation. Whether ETs are directly involved in receptor regulation has not been determined. We suggest that ET-1 and ET-3 alter the expression/activity of ET receptors in coronary vascular smooth muscle cells. Vasoconstrictor responses were studied in endothelium-denuded coronary artery segments from rats that were subjected to experimental ischaemia-reperfusion or in organ-cultured segments. Post-ischaemic and cultured coronary arteries exhibited similar increased sensitivity to ET-3. ETA receptor-mediated vasoconstriction was dominant in fresh and non-ischaemic arteries. Organ culture significantly up-regulated ETB receptors and down-regulated ETA receptor expression. Co-incubation with ET-1 (1 nM) or ET-3 (100 nM) induced further down-regulation of the ETA receptor mRNA, while the function and protein level of ETA remained unchanged. ET-3 (100 nM) further up-regulated ETB receptor mRNA and proteins but abolished ETB receptor-mediated vasoconstriction, suggesting a desensitization of ETB receptors that was not observed with ET-3 (1 nM). In conclusion, ET-1, which is the most prevalent isoform in the cardiovascular system, induces down-regulation of ETA receptor expression without changing ETA or ETB receptor function or protein levels. Intermediate concentrations of ET-3 had an effect that was similar to that of ET-1, such that high concentrations of ET-3 (100 nM) up-regulated the ETB receptor at the gene and protein levels but switched off the function of the ETB receptors via desensitization.

Topics: Animals; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Endothelin-3; Gene Expression Regulation; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Organ Culture Techniques; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Time Factors; Vasoconstriction; Vasoconstrictor Agents

The purpose of this study was to explore the effect of polydatin on ventricular remodeling after myocardial infarction in coronary artery ligation rats and to elucidate the underlying mechanisms. A rat model of ventricular remodeling after myocardial infarction was established by left coronary artery ligation. Rats with coronary artery ligation were randomly divided into five groups: control, plus 40 mg/kg captopril, plus 25 mg/kg polydatin, plus 50 mg/kg polydatin, and plus 100 mg/kg polydatin. The sham-operated group was used as a negative control. Rats were administered intragastrically with the corresponding drugs or drinking water for seven weeks. At the end of the treatment, the left ventricular weight index and heart weight index were assessed. The cross-sectional size of cardiomyocytes was measured by staining myocardium tissue with hematoxylin and eosin. Collagen content was counted by Sirius red in aqueous saturated picric acid. The concentrations of angiotensin I, angiotensin II, aldosterone, and endothelin 1 in myocardium or serum were determined by radioimmunoassay. Hydroxyproline and nitric oxide concentrations and glutathione peroxidase and catalase activities in serum were measured by ultraviolet spectrophotometry. Our results showed that seven weeks of polydatin treatment resulted in a significantly reduced left ventricular weight index, heart weight index, serum concentrations of hydroxyproline and aldosterone, an increased concentration of nitric oxide as well as enhanced activities of glutathione peroxidase and catalase. Myocardial angiotensin I, angiotensin II, and endothelin 1 levels were also reduced. The cardiomyocyte cross-sectional area and collagen deposition diminished. This study suggests that polydatin may attenuate ventricular remodeling after myocardial infarction in coronary artery ligation rats through restricting the excessive activation of the renin-angiotensin-aldosterone system and inhibiting peroxidation.

Topics: Aldosterone; Animals; Antioxidants; Captopril; Collagen; Coronary Occlusion; Coronary Vessels; Endothelin-1; Glucosides; Heart Ventricles; Hydroxyproline; Hypertrophy; Male; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Nitric Oxide; Phytotherapy; Plant Extracts; Polygonum; Rats, Sprague-Dawley; Renin-Angiotensin System; Stilbenes; Ventricular Remodeling

We studied relationship between markers of endothelial dysfunction and multifocal atherosclerosis and adverse coronary events in 82 patients with non-ST segment elevation acute coronary syndrome (NSTEACS). Eighteen patients (21.9%) had adverse events during one year of observation. Patients with adverse coronary events had impaired vasodilatory, vasoconstrictive, and adhesive endothelial function. Predictors of unfavorable prognosis in NSTEACS were signs of impaired endothelium-dependent vasodilation during test with reactive hyperemia, high soluble platelet selectin and endothelin-1 levels on day 10 of the disease. Endothelin-1 and soluble platelet-endothelial cell adhesion molecule-1 had greatest predictive power relative to development of non-fatal myocardial infarction.

Topics: Acute Coronary Syndrome; Aged; Biomarkers; Coronary Circulation; Coronary Vessels; Electrocardiography; Endothelin-1; Endothelium, Vascular; Female; Humans; Hyperemia; Male; Middle Aged; Myocardial Infarction; Platelet Endothelial Cell Adhesion Molecule-1; Predictive Value of Tests; Prognosis; Vasoconstriction; Vasodilation

Takotsubo cardiomyopathy (TTC) remains a potentially life-threatening disease, which is clinically indistinguishable from acute myocardial infarction (MI). Today, no established biomarkers are available for the early diagnosis of TTC and differentiation from MI. MicroRNAs (miRNAs/miRs) emerge as promising sensitive and specific biomarkers for cardiovascular disease. Thus, we sought to identify circulating miRNAs suitable for diagnosis of acute TTC and for distinguishing TTC from acute MI.. After miRNA profiling, eight miRNAs were selected for verification by real-time quantitative reverse transcription polymerase chain reaction in patients with TTC (n = 36), ST-segment elevation acute myocardial infarction (STEMI, n = 27), and healthy controls (n = 28). We quantitatively confirmed up-regulation of miR-16 and miR-26a in patients with TTC compared with healthy subjects (both, P < 0.001), and up-regulation of miR-16, miR-26a, and let-7f compared with STEMI patients (P < 0.0001, P < 0.05, and P < 0.05, respectively). Consistent with previous publications, cardiac specific miR-1 and miR-133a were up-regulated in STEMI patients compared with healthy controls (both, P < 0.0001). Moreover, miR-133a was substantially increased in patients with STEMI compared with TTC (P < 0.05). A unique signature comprising miR-1, miR-16, miR-26a, and miR-133a differentiated TTC from healthy subjects [area under the curve (AUC) 0.835, 95% CI 0.733-0.937, P < 0.0001] and from STEMI patients (AUC 0.881, 95% CI 0.793-0.968, P < 0.0001). This signature yielded a sensitivity of 74.19% and a specificity of 78.57% for TTC vs. healthy subjects, and a sensitivity of 96.77% and a specificity of 70.37% for TTC vs. STEMI patients. Additionally, we noticed a decrease of the endothelin-1 (ET-1)-regulating miRNA-125a-5p in parallel with a robust increase of ET-1 plasma levels in TTC compared with healthy subjects (P < 0.05).. The present study for the first time describes a signature of four circulating miRNAs as a robust biomarker to distinguish TTC from STEMI patients. The significant up-regulation of these stress- and depression-related miRNAs suggests a close connection of TTC with neuropsychiatric disorders. Moreover, decreased levels of miRNA125a-5p as well as increased plasma levels of its target ET-1 are in line with the microvascular spasm hypothesis of the TTC pathomechanism.

Topics: Aged; Biomarkers; Early Diagnosis; Endothelin-1; Female; Humans; Male; MicroRNAs; Myocardial Infarction; Reproducibility of Results; Risk Factors; ROC Curve; Takotsubo Cardiomyopathy

Predicting the likely success of primary PCI to salvage potential infarcted myocardium is desirable. We compared early invasive parameters of coronary microcirculation function with the levels of circulating endothelin (ET-1) and 6-month ejection fraction after STEMI.. Forty-four STEMI patients underwent assessment of coronary flow reserve (CFR) and index of myocardial resistance (IMR) on completion of PPCI and one day later. Cardiac magnetic resonance (CMR) at 24 h and 6 months assessed ejection fraction, oedema, late gadolinium enhancement, and salvage. In patients with depressed EF, there was no difference in IMR or CFR measured immediately after PPCI compared with those with preserved EF. However, by Day 1, CFR was significantly lower in those with depressed EF [2.0(1.5-2.3) vs. 2.6(2.1-3.3), P = 0.008]. In multivariable models, higher CFR post-PPCI [EST: +8.9 (SE 3.7) per 1 CFR unit, P = 0.03] and greater increase in CFR between post-PPCI and Day 1 [EST: +8.5 (SE 3.4) per 1 CFR unit, P = 0.01] were associated with higher salvage index. Circulating endothelin levels were significantly elevated in the low EF group at both 6 and 24 h, and 24 h levels correlated with CFR.. Changes of the coronary microcirculation in the first day after PPCI are associated with 6-month ejection fraction and myocardial salvage. Depressed CFR at 24 h is associated with CMR imaging indices of MVO and haemorrhage and elevated endothelin levels.

Topics: Coronary Circulation; Coronary Occlusion; Coronary Vessels; Endothelin-1; Female; Hemorrhage; Humans; Magnetic Resonance Angiography; Male; Microcirculation; Microvessels; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Prospective Studies; Recovery of Function; Stroke Volume; Vascular Resistance

Topics: Early Diagnosis; Endothelin-1; Female; Humans; Male; Myocardial Infarction; Peptide Fragments; Risk Assessment

Endothelial dysfunction plays a major role in cardiovascular diseases, including acute myocardial infarction (AMI). However, its quantification has not been available as a clinical tool.. In a prospective international multicentre study, we analyzed the diagnostic and prognostic utility of endothelial dysfunction as quantified by C-terminal proendothelin-1 (CT-proET-1) in 658 consecutive patients presenting with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long-term for mortality.. The adjudicated final diagnosis was AMI in 145 patients (22%). The diagnostic performance of CT-proET-1 for AMI was moderate; its area under the receiver operating characteristic (ROC) curve amounted to 0.66 (95% confidence interval [CI], 0.61-0.72; P < 0.001). There was no significant increase in the AUC when CT-proET-1 was added to either cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT). Seventy four percent of patients who died during the first 24 months (n = 50) were in the fourth quartile of the CT-proET-1 presentation value (>82 pmol/L). The prognostic accuracy of CT-proET-1 regarding mortality was tantamount to that of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and outperformed cTnT and hs-cTnT both in patients with AMI and in patients without acute coronary syndrome. CT-proET-1 at presentation yielded high prognostic accuracy that was similar to that of the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores. The TIMI risk score could be significantly improved by adding CT-proET-1 (integrated discriminatory improvement [IDI] of 0.074 P = 0.004).. Use of CT-proET-1 improves risk stratification of unselected patients with suspected AMI. CT-proET-1 did not provide additional diagnostic value.

Topics: Aged; Early Diagnosis; Electrocardiography; Endothelin-1; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Prognosis; Prospective Studies; Risk Assessment; Risk Factors; ROC Curve; Survival Rate; Switzerland

Human chymase converts big endothelin (ET)-1 to 31-amino acid length ET-1 {ET-1(1-31)} that also possesses a potent vasoconstrictive action. In addition, ET-1(1-31) is an intermediate peptide, which is then readily transformed to mature ET-1 by the neutral endopeptidase 24-11. To investigate the relevance of pathophysiology of ET-1(1-31) in vivo, we have developed specific sandwich-type, enzyme-linked immunosorbent assay to measure the plasma concentration of ET-1(1-31) in healthy volunteers and patients with myocardial infarction. The plasma concentrations of ET-1(1-31) in healthy volunteers were 24.8 ± 5.2 pg/ml (n=11). ET-1(1-31) concentration in plasma was elevated in patients with acute myocardial infarction, and its elevation was several times higher and lasted longer than that of ET-1. In addition, tissue concentration of ET-1(1-31) in the myocardium from a patient with acute myocardial infarction was extremely high (12729.8 ± 2617.7 pg/mg protein). These results suggest that ET-1(1-31) may play some pathological roles in the remodeling, especially in sites where inflammatory cells produced a large amount of proteases, such as myocardial infarction.

Topics: Adult; Aged; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments

To investigate vascular endothelial impairment as a result of reperfusion therapy in patients with acute myocardial infarction (AMI).. Patients with AMI underwent reperfusion therapy (percutaneous cardiac intervention [PCI] or thrombolytic therapy) or conservative drug therapy. Healthy control subjects were recruited. Endothelial impairment was assessed via endothelial nitric oxide (NO) synthase (eNOS), NO and endothelin-1 (ET-1) levels, 24 h after reperfusion or on enrolment, as appropriate.. Patients who underwent PCI (n = 47) or thrombolytic therapy (n = 45) had significantly lower eNOS and NO levels, and higher ET-1 levels than those who received conservative drug therapy (n = 46). All patient groups had significantly lower eNOS and NO levels, and higher ET-1 levels, than controls (n = 45). There was a significant positive correlation between eNOS and NO, as well as significant negative correlations between eNOS/ET-1 and NO/ET-1 in all four groups.. Patients with AMI who underwent reperfusion therapy displayed low eNOS activity. This may result in impairment of endothelial function via downregulation of NO and upregulation of ET-1.

Topics: Adult; Aged; Animals; Case-Control Studies; Endothelin-1; Endothelium, Vascular; Female; Fibrinolytic Agents; Gene Expression Regulation; Humans; Male; Middle Aged; Myocardial Infarction; Nitric Oxide; Nitric Oxide Synthase Type III; Percutaneous Coronary Intervention

In acute myocardial infarction, left ventricular (LV) unloading reduces endothelin-1 (ET-1) release. We tested that endogenous ET-1 released during acute myocardial infarction might mediate ischemia/reperfusion (I/R) injury by stimulating increased intracellular calcium concentration, [Ca(2+)]i, and apoptosis.. Rabbits were subjected to 1 h of coronary artery occlusion followed by 3 h of reperfusion. Unloading was initiated 15 min prior to reperfusion and was maintained during reperfusion. The control group was subjected to reperfusion. Animals were treated with ET-1 receptor antagonist BQ123. In parallel, isolated rabbit cardiomyocytes subjected to simulated I/R with or without ET-1 or BQ123, intracellular Ca(2+) and cell death were assessed with flow cytometry.. LV unloading prior to reperfusion reduced myocardial ET-1 release at 2 h of reperfusion. Infarct size was reduced in unloaded and BQ123 groups versus controls. LV unloading and BQ123 treatment reduced the percentage of apoptotic cells associated with increases in Bcl-2 protein levels in ischemic regions. BQ123 reduced both ET-1-induced [Ca(2+)]i increase and cell death for myocytes subjected to stimulated I/R.. We propose that components of reperfusion injury involve ET-1 release which stimulates calcium overload and apoptosis. Intravenous ET-1 receptor blockade prior to reperfusion may be a protective adjunct to reperfusion therapy in acute myocardial infarction patients.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Calcium; Coronary Vessels; Endothelin A Receptor Antagonists; Endothelin-1; Hemodynamics; Ligation; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Peptides, Cyclic; Proto-Oncogene Proteins c-bcl-2; Rabbits

To explore the effects of ethanolic extract of Radix Scrophulariae (EERS) on ventricular remodeling in rats.. Rats with coronary artery ligation (CAL) were randomly assigned to 5 groups: CAL model; CAL plus 40 mg/kg captopril; CAL plus 60 mg/kg, 120 mg/kg, 240 mg/kg EERS. Sham operation rats were randomly assigned to 2 groups, sham-operated control and sham-operated plus 120 mg/kg EERS. The rats were orally administered with the corresponding drugs or drinking water for 14 weeks. The left ventricular weight index (LVWI) and heart weight index (HWI) were determined. Myocardium tissue was stained with hematoxylin and eosin or picric acid/Sirius red for cardiomyocyte cross-section area or collagen content measurements respectively. The concentrations of hydroxyproline (Hyp), matrix metalloproteinase 2 (MMP-2), angiotensin II (Ang II), aldosterone (ALD), endothelin 1 (ET-1), atrial natriuretic peptide (ANP), tumor necrosis factor α (TNF-α) and renin activity (RA) in myocardium or serum were determined. Real-time RT-PCR was used to detect the mRNA expressions of angiotensin converting enzyme (ACE), ET-1 and ANP.. EERS could significantly reduce the LVWI and HWI, decrease heart tissue concentrations of Hyp and collagen deposition, diminish cardiomyocyte cross-section area, reduce the tissue level of Ang II, ET-1, ANP and TNF-α. EERS could also down regulate the mRNA expression of ACE, ET-1 and ANP in myocardium.. EERS attenuates ventricular remodeling. The mechanisms may be related to restraining the excessive activation of RAAS, TNF-α and modulating some gene expressions associated with cardiac hypertrophy.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Chemical Analysis; Captopril; Cardiomegaly; Collagen; Coronary Vessels; Endothelin-1; Ethanol; Gene Expression Regulation; Hemodynamics; Hydroxyproline; Male; Matrix Metalloproteinase 2; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Organ Size; Plant Extracts; Plant Roots; Random Allocation; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Messenger; Scrophularia; Tumor Necrosis Factor-alpha; Ventricular Remodeling

To explore the relationship between endothelial nitric oxide synthase (eNOS) activity, insulin resistance and macrovascular disease in patients with acute myocardial infarction (AMI).. AMI patients were grouped according to the presence (group A, n = 49) or absence (group B, n = 48) of macrovascular disease. A healthy control group was also recruited (group C, n = 43). eNOS activity and nitric oxide (NO), endothelin-1 (ET-1), fasting plasma glucose and fasting insulin levels were compared across groups. The homeostasis model assessment of insulin resistance (HOMA- IR) was calculated in each participant and correlations between biochemical parameters were determined.. eNOS and NO levels were significantly lower in group A compared with the other groups. Conversely, ET-1 levels and the HOMA-IR were significantly higher in group A. eNOS activity and NO levels were significantly lower, and ET-1 levels and HOMA-IR were significantly higher, in group B compared with controls. Across the groups there were inverse correlations in AMI patients between eNOS and HOMAIR, NO and HOMA-IR, eNOS and ET-1, and NO and ET-1, and positive correlations between eNOS and NO, regardless of whether macrovascular disease was present.. There is a close relationship between eNOS activity and the development of insulin resistance and macrovascular disease in AMI patients.

Topics: Adult; Aged; Blood Glucose; Endothelin-1; Endothelium, Vascular; Female; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Myocardial Infarction; Nitric Oxide; Nitric Oxide Synthase Type III; Vascular Diseases

The endothelium plays a role in regulating vascular tone. Acute and dynamic changes in low-flow-mediated constriction (L-FMC) and how it changes with regard to traditional flow-mediated dilatation (FMD) have not been described. We aimed to investigate the changes in brachial artery L-FMC following percutaneous coronary intervention (PCI) and during recovery from non-ST-segment elevation myocardial infarction (NSTEMI).. FMD was performed in accordance with a previously described technique in patients before and after PCI and in the recovery phase of NSTEMI, but in addition, L-FMC data were acquired from the last 30 s of cuff inflation. About 135 scans were performed in 96 participants (10 healthy volunteers and 86 patients). Measurement of brachial L-FMC was reproducible over hours. L-FMC was greater among patients with unstable vs. stable coronary atherosclerosis (-1.33 ±1.09% vs. -0.03 ± 1.26%, P < 0.01). Following PCI, FMD reduced (4.43 ± 2.93% vs. 1.66 ± 2.16%, P < 0.01) and L-FMC increased (-0.33 ± 0.76% vs. -1.63 ± 1.15%, P = 0.02). Furthermore, during convalescence from NSTEMI, L-FMC reduced (-1.37 ± 1.19% vs. 0.01 ± 0.82%, P = 0.02) in parallel with improvements in FMD (2.54 ± 2.19% vs. 5.15 ± 3.07%, P < 0.01).. Brachial L-FMC can be measured reliably. Differences were observed between patients with stable and unstable coronary disease. L-FMC was acutely increased following PCI associated with reduced FMD and, in the recovery from NSTEMI, L-FMC reduced associated with increased FMD. These novel findings characterize acute and subacute variations in brachial L-FMC. The pathophysiological and clinical implications of these observations require further study.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Analysis of Variance; Angioplasty, Balloon, Coronary; Biomarkers; Brachial Artery; Cytokines; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Myocardial Infarction; Ultrasonography; Vasoconstriction; Vasodilation

High endothelin-1 (ET-1) levels have been linked to poor clinical outcomes after ST-segment elevation myocardial infarction (STEMI). Vasoconstriction of the coronary microcirculation seems to be the underlying mechanism. The aim of the study was to assess the effect of ET-1 on microvascular integrity, infarct size, left ventricular ejection fraction (LVEF) and myocardial salvage in evolving myocardial infarction (MI).. We measured ET-1 levels acutely (6-24h) in 127 patients presenting with their first STEMI. Contrast-enhanced cardiac magnetic resonance (ce-CMR) was performed in 94 patients within 1 week to assess microvascular obstruction (MO), infarct size and LVEF. A myocardial salvage index (MSI) was defined as the percentage of at-risk angiographic area without necrosis on the ce-CMR.. Mean age was 60.9 ± 11.8 years and 98 (77%) were males. Median ET-1 level within the first 24h was 6.8 pg/mL (25(th) -75(th) percentile range: 5.4-8.5 pg/mL). Patients with ET-1 concentrations over the median presented higher percentage of MO (77.7% for ET-1>6.8 pg/mL vs. 16.6% for ET-1 ≤ 6.8 pg/mL, P<.001) and lower MSI values (13.8 ± 26% for ET-1>6.8 pg/mL vs. 37.4 (26%) for ET-1 ≤ 6.8 pg/mL, P=.02). ET-1 levels did not show a significant association with infarct size (P=.11) and LVEF (P=.16). Multivariate analysis found ET-1 to be a significant predictor of MO (OR=2.78; CI 95% 1.16-6.66; P=.021) and MSI ≤ Percentile 25 (OR=1.69, CI 95% 1.01-2.81; P=.04).. High ET-1 levels after myocardial infarction are associated with the presence of microvascular obstruction and lower myocardial salvage index.

Topics: Aged; Angioplasty, Balloon, Coronary; Biomarkers; Capillaries; Electrocardiography; Endothelin-1; Female; Humans; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Myocardium; Prognosis; Prospective Studies; ROC Curve; Stroke Volume; Ventricular Function, Left

Topics: Biomarkers; Capillaries; Coronary Disease; Endothelin-1; Humans; Magnetic Resonance Imaging; Monitoring, Physiologic; Myocardial Infarction; Myocardium; Prognosis; Radiography; Stroke Volume

Chronic myocardial ischaemia (CMI) has become an important cause of heart failure (HF). The aim of this study was to examine the effects of sarco-endoplasmic reticulum calcium ATPase (SERCA2a) gene transfer in large HF animal models induced by CMI.. HF was induced in mini pigs by proximal left anterior descending coronary (LAD) ameroid constrictors. After confirmation of myocardial perfusion defects and cardiac function impairment, animals were divided into 4 groups (each including 4 animals): the HF group; the HF+enhanced green fluorescent protein (EGFP) group; the HF+SERCA2a group; and sham animals as a control group, rAAV1-EGFP and rAAV1-SERCA2a were injected intramyocardially to animals of the HF+EGFP and HF+SERCA2a groups separately. Sixty days after gene transfer, expressions of SERCA2a were examined, cardiac functions and changes of serum inflammatory and neuro-hormonal factors were determined. The results demonstrated that 60 days after gene transfer, LVEF, Ev/Av and +/- dp/dtmax of the HF+SERCA2a group increased significantly (P < 0.05), along with an increase in SERCA2a protein expression (P < 0.05) compared with the HF/HF+EGFP groups. Serum concentrations of inflammatory and neuro-hormonal factors were also decreased in the HF+SERCA2a group (P < 0.05).. Restoration of SERCA2a in myocardium of HF model induced by CMI could significantly improve cardiac function, suggesting its potential therapeutic significance in CMI-related heart failure.

Topics: Adenoviridae; Angiotensin II; Animals; Disease Models, Animal; Endothelin-1; Fluorescent Dyes; Gene Transfer Techniques; Genetic Therapy; Green Fluorescent Proteins; Heart Failure; Interleukin-6; Male; Myocardial Infarction; Myocardium; Natriuretic Peptide, Brain; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Stroke Volume; Swine; Swine, Miniature; Tumor Necrosis Factor-alpha

Hypoxia-inducible factor-1alpha (HIF-1α) expression promotes angiogenesis and can influence stem cell engraftment. We investigated the effect of stable over-expression of constitutively active HIF-1α on cardiosphere-derived cell (CDC) engraftment and left ventricular function. CDCs were transduced with a lentivirus expressing a constitutively active mutant of human HIF-1α (LVHIF-1α). Two million male rat CDCs were injected into the infarct following ligation of the mid-LAD in female syngeneic rats. Left ventricular ejection fraction (EF) and circumferential strain were measured by echocardiography at 1 and 4 weeks post-MI in the following groups: PBS group (n = 7), CELL group (n = 7), and CELL-HIF group (n = 7). HIF-1α, VEGF, endothelin-1 expression, and CDC engraftment were measured by quantitative PCR. At 30 days, EF was unchanged in the CELL-HIF group (p = NS), increased in the CELL group (p = 0.025), and decreased in the PBS group (p = 0.021), but engraftment was similar (2.4% ± 3.3% vs 1.7% ± 0.8%, p = NS). Mean circumferential strain of the infarcted region was unchanged in the CELL-HIF group, but improved in the CELL group (p = 0.02). Endothelin-1 and VEGF expression were higher in HIF-CDCs exposed to hypoxia, compared with non-transduced CDCs. HIF-1α expression in CDCs blunted the beneficial functional effects of CDC transplantation, suggesting that paracrine factor balance may play an important role in cardiac regeneration.

Topics: Analysis of Variance; Animals; Cell Proliferation; Disease Models, Animal; Endothelin-1; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Myocardial Contraction; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Neovascularization, Physiologic; Paracrine Communication; Rats; Rats, Inbred WKY; Spheroids, Cellular; Stroke Volume; Time Factors; Transfection; Vascular Endothelial Growth Factor A; Ventricular Function, Left

Hyperuricemia is associated with cardiovascular disease, but it is usually considered a marker rather than a risk factor. Previous studies using uric acid-lowering drugs in normouricemic animals are not suitable to answer the effect of hyperuricemia on ventricular remodeling after myocardial infarction. The purpose of this study was to determine whether hyperuricemia adversely affects ventricular remodeling in infarcted rats with elevated uric acid. Male Wistar rats aged 8 wk were randomly assigned into either vehicle, oxonic acid, oxonic acid + allopurinol, oxonic acid + benzbromarone, oxonic acid + ABT-627, or oxonic acid + tempol for 4 wk starting 24 h after ligation. Postinfarction was associated with increased oxidant production, as measured by myocardial superoxide, isoprostane, xanthine oxidase activity, and dihydroethidium staining. Compared with normouricemic infarcted rats, hyperuricemic infarcted rats had a significant increase of superoxide production (1.7×) and endothelin-1 protein (1.2×) and mRNA (1.4×) expression, which was associated with increased left ventricular dysfunction and enhanced myocardial hypertrophy and fibrosis. These changes were all prevented by treatment with allopurinol. For similar levels of urate lowering, the uricosuric agent benzbromarone had no effect on ventricular remodeling. In spite of equivalent hyperuricemia, the ability of both ABT-627 and tempol to attenuate ventricular remodeling suggested involvement of endothelin-1 and redox pathways. Hyperuricemia is associated with unfavorable ventricular remodeling probably through a superoxide and endothelin-1-dependent pathway. Uric acid lowering without inhibition of superoxide and endothelin-1 may not have an effect on remodeling. Chronic administration of allopurinol, ABT-627, and tempol is associated with attenuated ventricular remodeling.

Topics: Allopurinol; Analysis of Variance; Animals; Antioxidants; Atrasentan; Biomarkers; Cyclic N-Oxides; Dinoprost; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Fibrosis; Gout Suppressants; Hypertrophy, Left Ventricular; Hyperuricemia; Isoprostanes; Male; Myocardial Infarction; Myocardium; Oxidative Stress; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; RNA, Messenger; Spin Labels; Superoxides; Time Factors; Up-Regulation; Uric Acid; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling; Xanthine Oxidase

Endothelin-1 (ET-1), circulating endothelial cells (CEC) and endothelial progenitor cells (EPC) are well-known modulators of endothelial function with important cardiac effects after an acute myocardial infarction. However, the relationship between them has never been assessed. The objective of the present study was to establish the relationship between ET-1, CEC, and EPC concentrations after ST-elevation myocardial infarction (STEMI).. Endothelin-1, CEC, and EPC levels were measured in 61 patients presenting with a first STEMI. Samples were withdrawn acutely 6-24h and 1week after admission. Assessments included reperfusion outcomes (angiography), left ventricular ejection fraction (echocardiography), and 30-day mortality.. Mean age was 60.6±12.6years and 45 (74%) were males. Higher ET-1 plasma levels were associated with lower EPC count after 1week (7.45±2.53pg/ml if EPCs in the first quartile vs 5.72±1.49pg/ml if EPCs in the fourth quartile; P=0.04). In contrast with CEC and EPC count, higher ET-1 concentrations on admission were associated with Killip≥2 (9.92±2.01pg/ml vs 7.32±2.13pg/ml; P<0.001), post-reperfusion thrombolysis in myocardial infarction (TIMI) <3 (8.65±2.86pg/ml vs 5.87±1.93pg/ml; P=0.002), myocardial blush grade (MBG) <3 (7.46±2.48pg/ml vs 5.99±2.01pg/ml; P=0.004) and higher 30-day mortality (10.29±2.02pg/ml vs 6.57±2.20pg/ml; P=0.005).. In STEMI patients, high ET-1 levels on admission predict a lower EPC mobilization after 1week. Endothelin-1 provides better clinical, angiographic and echocardiographic information for prognosis than do CEC and EPC concentrations.

Topics: Acute Disease; Aged; Angiography; Biomarkers; Echocardiography; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardium; Risk Factors; Time Factors; Treatment Outcome

Ghrelin is a novel growth hormone-releasing peptide, which has been shown to exert beneficial effects on ventricular remodeling. In this study, we investigated whether ghrelin could decrease vulnerability to ventricular arrhythmias in rats with myocardial infarction and the possible mechanism. Twenty-four hours after ligation of the anterior descending artery, adult male Sprague-Dawley rats were randomized to ghrelin (100 μg/kg) and saline (control group) for 4 weeks. Sham animals underwent thoracotomy and pericardiotomy, but not LAD ligation. Myocardial endothelin-1 (ET-1) levels were significantly elevated in saline-treated rats at the border zone compared with sham-operated rats. Myocardial connexin43 (Cx43) expression at the border zone was significantly decreased in saline-treated infarcted rats compared with sham-operated rats. Ghrelin significantly decreased the inducibility of ventricular tachyarrhythmias compared with control group. Arrhythmias sores during programmed stimulation in saline-treated rats were significantly higher than scores in those treated with ghrelin. The electrophysiological improvement of fatal ventricular tachyarrhythmias was accompanied with increased immunofluorescence-stained Cx43, myocardial Cx43 protein and mRNA levels in ghrelin treated rats. We also shown that ghrelin significantly decreased tissue ET-1 levels at the infarcted border zone. Thus, ghrelin showed the protective effect on ventricular arrhythmias after myocardial infarction. Although the precise mechanism by which ghrelin modulates the dephosphorylation of Cx43 remains unknown, it is most likely that the ghrelin increased expression of Cx43 through the inhibition of ET-1.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Connexin 43; Coronary Vessels; Disease Models, Animal; Electrocardiography; Endothelin-1; Gene Expression; Ghrelin; Ligation; Male; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA, Messenger; Ventricular Remodeling

Topics: Angioplasty, Balloon, Coronary; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Artery Disease; Endothelin-1; Female; Humans; Inflammation; Inflammation Mediators; Male; Myocardial Infarction; Ventricular Function, Left

The purpose of this study was to evaluate the influence of zafirlukast (Z), quercetin (Q) and their combination on baroreflex sensitivity (BRS), endothelin-1 (E1) plasma concentration and the severity of ventricular arrhythmias (VA) occurring during myocardial infarction (MI). In anaesthetized Wistar rats, MI was induced by ligation of the left anterior descending coronary artery (CAL). Animals were divided into the five groups: I--sham-operated (SO); II--CAL; III--CAL+Z (0.25 mg/kg intraperitoneally 1 hour prior and 12-24 hour after CAL); IV--CAL+Q (1.5 mg/kg by i.v. injection after anesthesia and every 24 hour during 72 hour); V--CAL+Z+Q as above. CAL after 1 hour was accompanied by high incidence of VA associated with a significant mortality (68% at 72 hour) as compared with SO rats. In survived rats BRS was greatly attenuated (0.44 +/- 0.08 ms/mmHg) vs. SO animals (0.92 +/- 0.14 ms/mmHg, p < 0.05) that correlated to increase E1 plasma concentration (9.2 +/- 0.6 pg/ml) vs. SO rats (2.9 +/- 0.4 pg/ml, p < 0.001). Q did not influence markedly on the severity of VA or rats mortality, while Z and Z+Q decreased mortality in rats in compare to II group of animals (from 68%-42% and 30%), increased the reduced BRS resulting from MI (+38.5% and +55.4%, p < 0.05) and blunted the increase of E1 (-34.8% and -43.5% respectively, p < 0.05). Our results suggested a possible beneficial combine action of Z and Q on MI.

Topics: Animals; Antioxidants; Arrhythmias, Cardiac; Baroreflex; Drug Therapy, Combination; Endothelin-1; Indoles; Leukotriene Antagonists; Male; Myocardial Infarction; Phenylcarbamates; Quercetin; Rats; Rats, Wistar; Severity of Illness Index; Sulfonamides; Tosyl Compounds

No-reflow after primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI) is associated with poor prognosis. Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor that might aggravate reperfusion injury. The aim of our study was to assess the relationship between systemic ET-1 levels and the occurrence of no-reflow as well as to evaluate the prognostic value of ET-1 in a high-risk STEMI population.. We examined 128 consecutive patients undergoing primary PCI in acute STEMI <12 hours after symptom onset. Endothelin-1 was assessed before and immediately after primary PCI. Patients were categorized into 2 groups defined by the median ET-1 level on admission. No-reflow was assessed by 3 different methods after PCI: angiographic Thrombolysis in Myocardial Infarction (TIMI) flow and myocardial blush grade, electrocardiographic ST-resolution, and microvascular obstruction (MO) measured by cardiac magnetic resonance imaging (MRI). The primary clinical end points were mortality and major adverse cardiovascular events. Clinical follow-up was conducted after a median of 19 months.. Patients with angiographically (TIMI flow < or =2 or TIMI flow 3 with final myocardial bush grade < or =2 after PCI), electrocardiographically (ST-resolution <30%), and MRI- (presence of MO) detected no-reflow had significantly higher ET-1 levels on admission. At multivariable logistic regression analysis, ET-1 levels on admission were the only significant predictor of MRI-detected no-reflow (P = .03) together with left ventricular ejection fraction (P = .002). An elevated ET-1 level > or = the median on admission was a significant predictor of long-term mortality.. Endothelin-1 on admission is associated with no-reflow and increased long-term mortality in a high-risk STEMI population reperfused by primary PCI.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Endothelin-1; Female; Humans; Image Enhancement; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; No-Reflow Phenomenon; Prognosis; Prospective Studies; ROC Curve

Epidemiologic studies showed that men treated with statins appear to have a lower incidence of sudden death than men without statins. However, the specific factor for this remained disappointingly elusive. We assessed whether pravastatin enhanced connexin43 expression after myocardial infarction through attenuation of endothelin-1. Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to vehicle, pravastatin, mevalonate, bosentan, or a combination of pravastatin and mevalonate or pravastatin and bosentan for 4 wk. Myocardial endothelin-1 levels were significantly elevated in vehicle-treated rats at the border zone compared with sham-operated rats. Myocardial connexin43 expression at the border zone was significantly decreased in vehicle-treated infarcted rats compared with sham-operated rats. Attenuated connexin43 expression was blunted after administration of pravastatin, as assessed by immunofluorescence analysis, Western blotting, and real-time quantitative RT-PCR of connexin43. Bosentan enhanced connexin43 amount in infarcted rats and did not have additional beneficial effects on pravastatin-treated rats. Arrhythmic scores during programmed stimulation in vehicle-treated rats were significantly higher than scores in those treated with pravastatin. In contrast, the beneficial effects of pravastatin-induced connexin43 were abolished by the addition of mevalonate and a protein kinase C inducer. In addition, the amount of connexin43 showed significant increase after addition of bisindolylmaleimide, implicating that protein kinase C is a relevant target in endothelin-1-mediated connexin43 expression. Thus chronic use of pravastatin after infarction, resulting in enhanced connexin43 amount by attenuation of mevalonate-dependent endothelin-1 through a protein kinase C-dependent pathway, may attenuate the arrhythmogenic response to programmed electrical stimulation.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blotting, Western; Bosentan; Cardiac Pacing, Artificial; Connexin 43; Disease Models, Animal; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Fluorescent Antibody Technique; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Maleimides; Mevalonic Acid; Myocardial Infarction; Myocardium; Pravastatin; Protein Kinase C; Protein Kinase Inhibitors; Rats; Rats, Wistar; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides; Time Factors; Ultrasonography

We tested whether shock wave (SW) offers additional benefits in improving left ventricular (LV) function after acute myocardial infarction (AMI) in rabbits receiving SW-treated autologous bone marrow-derived mononuclear cells (BMDMNCs) transplantation.. Saline (750 microL; group 2), BMDMNCs (1.0 x 10(7); group 3), or preimplant SW-treated BMDMNCs (group 4) were implanted into the infarct area of male rabbits 15 minutes after left coronary artery ligation, whereas eight rabbits without AMI served as controls (group 1; n = 8 per group). The results showed that in infarct area of LV, protein expressions of Cx43 and cytochrome C in mitochondria and endothelial nitric oxide synthase mRNA expression were lower in group 2 than in other groups, and decreased in group 3 as compared with groups 1 and 4 (all p values < 0.01). Conversely, mRNA expressions of endothelin-1 and matrix metalloproteinase-9, mitochondrial oxidative stress, and total fibrotic area were higher in group 2 than in other groups (all p values < 0.05). Furthermore, 6-month LV function by 2-D echo/angiogram showed significant impairment in group 2 than in other groups and in group 3 than in groups 1 and 4 (all p values < 0.005).. Application of SW-treated autologous BMDMNCs is superior to BMDMNCs alone for preserving LV function after AMI.

Topics: Animals; Bone Marrow Cells; Bone Marrow Transplantation; Cells, Cultured; Connexin 43; Cytochromes c; Disease Models, Animal; Endothelin-1; Fibrosis; Gene Expression Regulation; High-Energy Shock Waves; Male; Matrix Metalloproteinase 9; Mitochondria, Heart; Myocardial Infarction; Myocardium; Nitric Oxide Synthase Type III; Oxidative Stress; Rabbits; Recovery of Function; RNA, Messenger; Time Factors; Transplantation, Autologous; Ventricular Function, Left

We investigated the effect of BQ-123, a selective endothelin-A (ET(A)) receptor antagonist in ischemia-reperfusion (IR) induced myocardial infarction (MI) with and without endothelin-1 (ET-1) challenge. MI was produced in rats by occlusion of left anterior descending coronary artery for 40 min and reperfusion for 120 min. ET-1 was administered immediately prior to coronary occlusion whereas vehicle or BQ-123 was administered 20 min after the occlusion. IR control group exhibited marked hemodynamic changes along with significant impairment of left ventricular functions. In addition, oxidative stress was increased, as evidenced by marked reduction in the activities of antioxidants and cardiac injury markers in myocardium. Furthermore, light microscopic and ultrastructural changes revealed myocardial necrosis, edema and inflammation. Prior administration of ET-1 acts synergistically with IR injury and further aggravates the impairment of ventricular functions, increased percent infarct area and decreased antioxidant levels. However, treatment with BQ-123 (1 mg/kg, IV) with or without ET-1 caused significant improvement in cardiac functions, percent infarct area, decreased malonaldehyde level, restored myocardial enzymes activities and maintained the redox status of the myocardium as compared to IR control group. Further, histopathological and ultrastructural studies reconfirmed the protective action of BQ-123. The results of present study suggest that ET-1 acting via ET(A) receptor may exaggerate myocardial damage produced by IR injury and selective blockade of ET(A) receptor by BQ-123 might offer potential cardioprotective action.

Topics: Animals; Antioxidants; Cardiotonic Agents; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Hemodynamics; Male; Malondialdehyde; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Oxidative Stress; Peptides, Cyclic; Rats; Rats, Wistar; Receptor, Endothelin A; Ventricular Function, Left

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Coronary Circulation; Diabetes Mellitus; Endothelin-1; Humans; Hyperalgesia; Hypertension, Pulmonary; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Myocardial Infarction; Pneumonia; Receptors, Tumor Necrosis Factor; Syndrome

Although the acute administration of ATP-sensitive potassium (K(ATP)) channel agonists provides a neuroprotection, it is unclear whether similar benefits are found by modulating sympathetic innervation in chronic settings after myocardial infarction. We assessed whether K(ATP) channel agonists can attenuate the sprouting of cardiac sympathetic nerves after infarction. Male Wistar rats after ligating coronary artery were randomized to either saline, nicorandil, pinacidil, glibenclamide, or a combination of 1) nicorandil and glibenclamide or 2) pinacidil and glibenclamide for 4 wk. To elucidate the role of mitochondrial K(ATP) channels in modulating nerve growth factor, 5-hydroxydecanoate was assessed in an in vitro model. The measurement of myocardial norepinephrine levels revealed a significant elevation in saline-treated infarcted rats compared with sham-operated rats, consistent with excessive sympathetic innervation. Excessive sympathetic innervation was blunted after giving the rats either nicorandil or pinacidil, compared with saline, as assessed by the immunohistochemical analysis of tyrosine hydroxylase, growth associated protein-43, and neurofilament and Western blot analysis and real-time quantitative RT-PCR of nerve growth factor. The arrhythmic scores during programmed stimulation in the saline- or glibenclamide-treated infarcted rats were significantly higher than those of rats treated with K(ATP) channel agonists. In contrast, the beneficial effects of nicorandil and pinacidil were abolished by administering either glibenclamide or 5-hydroxydecanoate. The sympathetic hyperinnervation after infarction is attenuated by the activation of mitochondrial K(ATP) channels. The chronic use of mitochondrial K(ATP) channel agonists after infarction may attenuate the arrhythmogenic response to programmed electrical stimulation.

Topics: Animals; Arrhythmias, Cardiac; Echocardiography; Endothelin-1; Glyburide; Heart; Hypoglycemic Agents; Male; Myocardial Infarction; Nerve Growth Factor; Nicorandil; Norepinephrine; Pinacidil; Potassium Channels; Rats; Rats, Wistar; RNA, Messenger; Sympathetic Nervous System; Vasodilator Agents

Our aim was to investigate the involvement of the endothelin (ET) system in the cardiovascular consequences of intermittent hypoxia (IH).. Obstructive sleep apnea (OSA) syndrome is an important risk factor for cardiovascular morbidity. Chronic IH, a major component of OSA, is thought to be responsible for most of the cardiovascular complications occurring during OSA, but the underlying mechanisms remain to be determined.. Chronic IH was applied in rats genetically prone to develop hypertension (spontaneous hypertensive rats [SHR]) and their normotensive controls. The cardiovascular effects were assessed in vivo and in Langendorff perfused hearts. Hypoxia inducible factor (HIF)-1 activity and targeting of the myocardial ET-1 gene and activation of the ET system were investigated using tissue chromatin immunoprecipitation, enzyme-linked immunoadsorbent assay, immunostaining, and Western blotting.. Chronic IH enhanced hypertension development and infarct size in SHR compared with that seen in control rats. This was accompanied by an increase in myocardial big ET-1, ET-1, and ET-A receptor expression and by an enhanced coronary vascular reactivity to ET-1 in SHR only. Myocardial HIF-1 activity was increased, and HIF-1 was shown to be linked to the promoter of the myocardial ET-1 gene after chronic IH only. Moreover, administration of bosentan, a mixed ET receptor antagonist, during chronic IH prevented both the increase in blood pressure and in infarct size.. In SHR, activation of the ET system, mediated by HIF-1 activity, is responsible for the enhanced susceptibility to chronic IH and for its associated cardiovascular consequences leading to hypertension and ischemic injury. Furthermore, the beneficial effects of bosentan suggest exploring ET antagonists as possible therapeutic tools in OSA.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Disease Models, Animal; Endothelin-1; Genetic Predisposition to Disease; Heart; Hypertension; Hypoxia; Hypoxia-Inducible Factor 1; Male; Myocardial Infarction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sleep Apnea, Obstructive; Sulfonamides

Congestive heart failure (CHF) causes lung remodelling with thickening of the alveolar septa and proliferation of myofibroblasts (MYF). Endothelin-1 (ET-1) is increased in CHF and may contribute to this process. CHF was induced in rats by myocardial infarction. After three weeks there was lung remodelling with thickening of alveolar septa and increases in 5'-bromodeoxyuridine uptake and vimentin expression (P < 0.05). The mitogenic and protein synthesis response of MYF to ET-1 (10 nM) were assessed by H-thymidine and H-leucine incorporation respectively. The mitogenic response in CHF (19.0 +/- 3.0%, mean +/- SEM) was less than for sham rats (35 +/- 5.4%, P < 0.05). This was associated with a lower production of ET-1 by CHF MYF (15.15 +/- 5.67 fmol/ml) compared to sham (33.66 +/- 13.22 fmol/ml; P < 0.05). Additionally, protein expression of ETA (0.36 +/- 0.038 AU) and ETB receptors (0.24 +/- 0.075 AU) were reduced in CHF compared to shams (0.65 +/- 0.086 AU and 0.81 +/- 0.21 AU respectively; P < 0.05). There is a downregulation of the ET system of lung MYF in CHF with reduced proliferation in response to ET-1. This may represent a protective adaptation to counteract lung remodelling in response to chronic exposure to high levels of ET-1.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Down-Regulation; Endothelin-1; Fibroblasts; Heart Failure; Lung; Male; Myocardial Infarction; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B

Topics: Animals; Endothelin-1; Heart-Assist Devices; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion; Myocardial Stunning

Ghrelin is a newly discovered peptide as an endogenous ligand for the growth hormone secretagogue receptor, and has been demonstrated to exert beneficial effect in the cardiovascular system. In the present study, we investigated whether ghrelin administration could inhibit cardiac neural remodeling and sympathetic hyperinnervation after myocardial infarction. Sprague-Dawley rats underwent coronary ligation to induce myocardial infarction and receiving ghrelin chronically (100 microg/kg s.c., twice daily) or saline control for 4 weeks after onset of ischemia. Four weeks after treatment, rats were sacrificed. We examined the expression of nerve growth factor and never markers as well as the mRNA expressions of inflammatory mediators in the infarcted border and non-infarcted left ventricular free wall. We also examined the NF-kappaBp65 protein and I-kappaBalpha protein levels by Western blot analysis. Compared to the control group, ghrelin administration significantly decreased the density of nerve fibers with positive immunostaining for GAP43 and TH, and decreased NGF mRNA and protein levels in the infarcted border and the non-infarcted area. Ghrelin also significantly suppressed interleukin-1beta, tumor necrosis factor-alpha, and endothelin-l mRNA expression, and inhibited NF-kappaB activation. In conclusion, treatment with ghrelin inhibited neural remodeling and sympathetic hyperinnervation, the process that may be associated with the inhibition of proinflammatory response and NGF signaling.

Topics: Animals; Endothelin-1; Gene Expression Regulation; Ghrelin; Inflammation; Interleukin-1beta; Male; Myocardial Infarction; Nerve Growth Factor; NF-kappa B; Protein Transport; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Sympathetic Nervous System; Tumor Necrosis Factor-alpha

Endothelin-1 (ET-1) promotes vasoconstriction and cell proliferation, and has been implicated in hypertension and coronary artery disease. Our aim was to analyse the role of the ET-1 gene (EDN1) in the risk for atherosclerosis/myocardial infarction (MI) in a population with smoking as the prevalent risk factor.. The study included 316 patients with early onset MI (<55 years old). All were male with at least one diseased coronary vessel. Denaturing high performance liquid chromatography (DHPLC), single-strand conformation analysis (SSCA), and direct sequencing were used to search for DNA variants in the five EDN1 exons and the promoter region. To determine the association of EDN1 polymorphisms with MI, we genotyped the patients and controls (n=350) and compared the allele and genotype frequencies between groups.. We found six common nucleotide changes: -1394 (T/G) and -974 C/A (promoter), +120 ins/del A (exon 1, 5' UTR), 568 A/G (exon 3, E106E), 844 G/T (exon 5, K198N), and 1617 T/C (exon 5, 3' UTR). No rare EDN1-variants specific to the MIpatients were found. None of the EDN1 polymorphisms were significantly associated with early-onset MI in our population. The two promoter polymorphisms were in linkage disequilibrium with K198N, but no haplotype was associated with MI risk.. In our population, the EDN1 variation did not contribute to early-onset MI.

Topics: Adult; Age of Onset; Aged; Atherosclerosis; Case-Control Studies; DNA Mutational Analysis; Endothelin-1; Exons; Female; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Smoking

Matrix Gla protein (MGP) expression is increased in cardiac hypertrophy, but the precise mechanisms regulating its expression are unknown. Here we characterized the effect of pressure overload and myocardial infarction in vivo as well as mechanical stretch and hypertrophic agonists in vitro on MGP expression. When angiotensin II (Ang II) was administered by osmotic minipumps, left ventricular (LV) MGP mRNA levels increased significantly from 6 h to 2 weeks, whereas intravenous arginine(8)-vasopressin increased LV MGP mRNA levels within 4 h. During post-infarction remodeling process, MGP mRNA levels were elevated at 24 h (1.3-fold, p<0.05) and the maximal increase was observed at 4 weeks (2.8-fold, p<0.01). Ang II increased MGP mRNA levels 20% (p<0.05) in neonatal rat cardiac myocytes and 40% (p<0.05) in cardiac fibroblasts, whereas endothelin-1 decreased MGP mRNA levels 30% (p<0.01) in myocytes and had no effect in fibroblasts. Cyclic mechanical stretch resulted in reduction of MGP gene expression in both cardiac myocytes and fibroblasts. These results demonstrate that MGP is rapidly upregulated in response to cardiac overload well before the development of LV hypertrophy and post-infarction remodeling process. Our results also suggest that Ang II may be involved in mediating load-induced activation of MGP expression.

Topics: Angiotensin II; Animals; Animals, Newborn; Arginine Vasopressin; Calcium-Binding Proteins; Cells, Cultured; Endothelin-1; Extracellular Matrix Proteins; Fibroblasts; Gene Expression Regulation; Hypertrophy, Left Ventricular; Male; Matrix Gla Protein; Myocardial Contraction; Myocardial Infarction; Myocytes, Cardiac; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; RNA, Messenger; Stress, Mechanical; Up-Regulation

Thromboxane A2 (TXA2) is a key mediator of platelet activation and aggregation, and an important mediator of platelet-induced coronary artery constriction. We sought to investigate whether baseline plasma levels of TXA2 are associated with coronary no-reflow after primary percutaneous coronary intervention (PPCI).. A total of 47 consecutive patients (age, 62.5 +/- 12.7; male sex, 76.6%) admitted to our hospital for a first ST-segment elevation myocardial infarction and undergoing PPCI within 12 h of onset of symptoms were enrolled. Admission TXA2 plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). Angiographic no-reflow was defined as a final TIMI flow of

Topics: Angioplasty, Balloon, Coronary; Biomarkers; Coronary Angiography; Coronary Circulation; Electrocardiography; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Myocardial Infarction; No-Reflow Phenomenon; Risk Assessment; Thromboxane A2; Treatment Outcome

It has been verified that adenosine can attenuate myocardial no-reflow. However, the effects of adenosine on adenosine triphosphate-sensitive K+ (KATP) channel and endothelin-1 (ET-1) are unknown.. Forty mini-swines were randomized into 5 study groups: 8 in the control group, 8 in the adenosine pretreatment group, 8 in the glibenclamide (K(ATP) channel blocker)-treated group, 8 in the adenosine and glibenclamide-pretreated group and 8 in the sham-operated group. An acute myocardial infarction and reperfusion model was created with three-hour occlusion of the left anterior descending coronary artery followed by a one-hour reperfusion.. Compared with the control group, adenosine significantly decreased the area of no-reflow (myocardial contrast echocardiography: from 78.5 +/- 4.5% to 20.7 +/- 4.1%, pathological means: from 82.3 +/- 1.9% to 21.5 +/- 4.3% of ligation area, respectively; all P < 0.01), reduced necrosis size from 98.5 +/- 1.3% to 75 +/- 4.7% of ligation area, P < 0.05). It also decreased plasma ET-1 and myocardial tissue ET-1. However, glibenclamide abrogated the protective effect of adenosine.. The beneficial effect of adenosine on myocardial no-reflow could be due to its effect on ET-1 via the activation of K(ATP) channel.

Topics: Adenosine; Animals; Coronary Circulation; Disease Models, Animal; Echocardiography; Endothelin-1; Injections, Intravenous; KATP Channels; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Radioimmunoassay; Random Allocation; Swine; Swine, Miniature; Treatment Outcome; Vasodilator Agents

The aim of this study was to test the hypothesis that after an acute myocardial infarction, endothelin-1 release with subsequent calcium overload is a mediator of myocardial reperfusion injury, which can be inhibited, in part, by left ventricular unloading immediately before reperfusion. We recently have reported that left ventricular unloading before reperfusion reduces infarct size after acute myocardial infarction. However, the biologic mechanisms of infarct salvage in unloaded hearts subjected to ischemia/reperfusion remain undefined.. Twelve pigs were subjected to 1 hour of left anterior descending coronary artery occlusion followed by 4 hours of reperfusion. A left ventricular assist device was initiated 15 minutes before reperfusion and maintained during reperfusion (assist device group, n = 6). A control group (n = 6) was subjected to reperfusion alone. Infarct size, endothelin-1 plasma levels, intracellular calcium levels, and apoptosis were analyzed in both groups.. At reperfusion, left ventricular unloading significantly decreased left ventricular end-diastolic and end-systolic pressures. Infarct size, expressed as a percentage of zone at risk, was also significantly reduced by 54% in the group with the left ventricular assist device compared with controls. Support with a left ventricular assist device reduced endothelin-1 release from the heart at 15 minutes, 30 minutes, and 1 hour of reperfusion. Myocardial release of endothelin-1 was significantly correlated with infarct size at 15 minutes of reperfusion (r = 0.79; P = .008). Left ventricular unloading caused a significant reduction of calcium overload and of the percentage of apoptotic cells in the ischemic region.. Our findings suggest that endothelin-1 release and calcium overload are important mediators of reperfusion injury and that they can be significantly reduced by left ventricular unloading before coronary artery reperfusion during myocardial infarction.

Topics: Animals; Apoptosis; Calcium; Coronary Circulation; Endothelin-1; Hemodynamics; In Situ Nick-End Labeling; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Sus scrofa; Ventricular Function, Left

We tested the hypothesis that unloading the left ventricle with intra-aortic balloon counter-pulsation just prior to reperfusion provides infarct salvage compared with left ventricular (LV) unloading postreperfusion or reperfusion alone.. Previous reports demonstrated infarct salvage with complete LV unloading with an LVAD prior to reperfusion; however, partial LV unloading using intra-aortic balloon pumps (IABPs) has not been evaluated.. Twenty-eight Yorkshire pigs were subjected to 1 hr of left anterior descending artery occlusion and 4 hr of reperfusion. An IABP was inserted and activated just prior to reperfusion (IABP-Pre), or 15 min after reperfusion (IABP-Post), or not at all (control).. At baseline, the hemodynamic data were similar in the three groups. Myocardial infarct size expressed a percentage of zone at risk in control animals was 44.9% +/- 4.8%, IAPB-Pre group 20.9% +/- 5.1% (P < 0.05 compared to control), and IABP-Post group 33.2 +/- 6.1% (P = 0.16 vs. control group). There was a correlation between transcardiac endothelin-1 release at 15 min postreperfusion and infarct size (r = 0.59).. LV unloading with an IABP prior to reperfusion reduces the extent of myocardial necrosis in hearts subjected to 1 hr of left anterior descending artery occlusion and 4 hr of reperfusion compared with either reperfusion alone or LV unloading after reperfusion. Inhibition of myocardial ET-1 release by LV unloading may be a significant mechanism of myocardial protection. These data suggest that in high-risk STEMI patients, IABP unloading prior to reperfusion might be more beneficial than IABP placement postreperfusion.

Topics: Angioplasty, Balloon, Coronary; Animals; Coronary Circulation; Disease Models, Animal; Endothelin-1; Heart-Assist Devices; Hemodynamics; Intra-Aortic Balloon Pumping; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Necrosis; Swine; Time Factors; Ventricular Function, Left

It has been verified that carvedilol can attenuate myocardial no-reflow. However, the effects of carvedilol on adenosine triphosphate-sensitive K(+) (K(ATP)) channel and endothelin-1 (ET-1) are unknown. Forty mini-swines were randomized into 5 study groups: 8 control, 8 carvedilol pretreatment, 8 glibenclamide (K(ATP) channel blocker)-treated, 8 carvedilol and glibenclamide-pre-treated and 8 sham-operated. An acute myocardial infarction(AMI) and reperfusion model was created with a three-hour occlusion of the left anterior descending coronary artery followed by one-hour reperfusion. Compared with the control group, carvedilol significantly decreased the area of no-reflow (myocardial contrast echocardiography: from 78.5+/-4.5% to 24.9+/-4.1%, pathological means: from 82.3+/-1.9% to 25.8+/-4.3% of ligation area, respectively; all p < 0.01) and reduced necrosis size from 98.5+/-1.3% to 74.4+/-4.7% of ligation area, p < 0.05). It also decreased plasma ET-1 and myocardial tissue ET-1. However, glibenclamide abrogated the protective effect of carvedilol. The beneficial effect of carvedilol on myocardial no-reflow could be due to its effect on ET-1 via the activation of the K(ATP) channel.

Topics: Animals; Antihypertensive Agents; Carbazoles; Carvedilol; Disease Models, Animal; Endothelin-1; Glyburide; Hypoglycemic Agents; KATP Channels; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Potassium Channel Blockers; Propanolamines; Swine; Swine, Miniature

17beta-Estradiol (E2) has been shown to exert antiarrhythmic effect after myocardial infarction; however, the mechanisms remain unclear. This study was performed to determine whether E2 exerts beneficial effects through attenuated sympathetic hyperreinnervation after infarction. Two weeks after ovariectomy, female Wistar rats were assigned to coronary artery ligation or sham operation. Twenty-four hours after coronary ligation, rats underwent one of five treatments: 1) sc vehicle treatment (control), 2) sc E2 treatment, 3) sc E2 treatment + tamoxifen (a potent estrogen receptor antagonist), 4) bosentan (an endothelin receptor blocker), or 5) sc E2 treatment + bosentan and followed for 4 wk. Myocardial endothelin-1 and norepinephrine levels at the remote zone revealed a significant elevation in control infarcted rats, compared with sham-operated rats, which is consistent with sympathetic hyperinnervation after infarction. Sympathetic hyperinnervation was blunted after giving the rats either E2 or bosentan, assessed by immunohistochemical analysis of tyrosine hydroxylase, growth-associated protein 43 and neurofilament, and Western blotting and real-time quantitative RT-PCR of nerve growth factor. Arrhythmic scores during programmed stimulation in E2-treated infarcted rats were significantly lower than in control-infarcted rats. Addition of bosentan did not have additional beneficial effects, compared with rats treated with E2 alone. The beneficial effect of E2 on sympathetic hyperinnervation was abolished by tamoxifen. Our data indicated that E2 has a role for sympathetic hyperinnervation after infarction, probably through an endothelin-1-depedent pathway. Chronic administration of E2 after infarction may attenuate the arrhythmogenic response to programmed electrical stimulation.

Topics: Animals; Bosentan; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Estradiol; Estrogen Antagonists; Estrogens; Female; GAP-43 Protein; Myocardial Infarction; Nerve Growth Factor; Nerve Regeneration; Norepinephrine; Ovariectomy; Rats; Rats, Wistar; Sulfonamides; Sympathetic Nervous System; Tamoxifen; Tyrosine 3-Monooxygenase

The resveratrol-induced cardiac protection was studied in Zucker obese rats. Rats were divided into five groups: group 1, lean control; group 2, obese control (OC); group 3, obese rats treated orally with 5 mg kg(-1) day(-1) of resveratrol (OR) for 2 wk; group 4, obese rats received 10% glucose solution ad libitum for 3 wk (OG); and group 5, obese rats received 10% glucose for 3 wk and resveratrol (OGR) during the 2nd and 3rd wk. Body weight, serum glucose, and insulin were measured, and then hearts were isolated and subjected to 30 min of ischemia followed by 120 min of reperfusion. Heart rate, coronary flow, aortic flow, developed pressure, the incidence of reperfusion-induced ventricular fibrillation, and infarct size were measured. Resveratrol reduced body weight and serum glucose in the OR compared with the OC values (414 +/- 10 g and 7.08 +/- 0.41 mmol/l, respectively, to 378 +/- 12 g and 6.11 +/- 0.44 mmol/l), but insulin levels were unchanged. The same results were obtained for the OG vs. OGR group. Resveratrol improved postischemic cardiac function in the presence or absence of glucose intake compared with the resveratrol-free group. The incidence of ventricular fibrillation and infarct size was reduced by 83 and 20% in the OR group, and 67 and 16% in the OGR group, compared with the OC and OG groups, respectively. Resveratrol increased GLUT-4 expression and reduced endothelin expression and cardiac apoptosis in ischemic-reperfused hearts in the presence or absence of glucose intake. Thus the protective effect of resveratrol could be related to its direct effects on the heart.

Topics: Animals; Antioxidants; Apoptosis; Blood Glucose; Blood Pressure; Electrocardiography; Endothelin-1; Glucose Transporter Type 4; Heart Rate; In Situ Nick-End Labeling; In Vitro Techniques; Insulin; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Obesity; Rats; Rats, Zucker; Resveratrol; Signal Transduction; Stilbenes

Mid-regional pro-adrenomedullin (MR-proADM) and endothelin-1 have been shown to predict mortality of patients with acute myocardial infarction. However, the prognostic value of both biomarkers in predicting long-term clinical events after acute myocardial infarction remains unclear.. In a prospective study, 30 patients suffering from acute ST elevation myocardial infarction or non-ST elevation myocardial infarction were enrolled. Measurements of MR-proADM and CT-pro-endothelin-1 (CT-proET-1) were performed at initial presentation, 2 or 3 days and 4 months after acute myocardial infarction. Long-term clinical events (e.g., recurrent myocardial infarction, percutaneous transluminal coronary angioplasty, aorto-coronary venous bypass or cardiogenic shock) were documented over a period from the 4th until the 10th month.. Both MR-proADM and CT-proET-1 were able to differentiate patients with subsequent long-term clinical events (n=11) from those without (n=19). At the time of acute myocardial infarction, median MR-proADM level of the event group was 0.69 nmol/L as compared to 0.59 nmol/L of the no-event group (p=0.036). A difference was still observed after 3 days (event group median 0.66 nmol/L; no-event group median 0.57 nmol/L; p=0.022). Accordingly, median CT-proET-1 level was 72.9 pmol/L in the event group as compared to a median of 54.4 pmol/L in patients in the no-event group (p=0.009) 3 days after acute myocardial infarction. Within the acute phase, patients with MR-proADM levels > or =0.67 nmol/L were 3 times more likely (relative risk 2.8; 95% confidence interval 1.2-6.9; p=0.042) to suffer from a future clinical event. The area under the curve (AUC) was 0.71 (95% confidence interval 0.51-0.86; p=0.046). After 3 days, patients with CT-proET-1 levels > or =57 pmol/L were 6 times more likely (relative risk 5.9; 95% confidence interval 0.9-40.4; p=0.036) to suffer from a future clinical event. The AUC was 0.76 (95% confidence interval 0.55-0.90; p=0.015).. Elevated levels of MR-proADM and CT-proET-1 during the acute phase of myocardial infarction may predict an adverse long-term clinical outcome.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Endothelin-1; Female; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Prospective Studies

Topics: Antiphospholipid Syndrome; Coronary Vessels; Electrocardiography; Endothelin-1; Female; Humans; Microvascular Angina; Myocardial Infarction; Risk Factors

This study investigated whether selective endothelin (ET) type A (ET(A)) or nonselective ET(A)/ET(B) receptor blockade exerted antiarrhythmic effects through attenuated sympathetic reinnervation after infarction. Twenty-four hours after ligation of the left anterior descending artery, male Wistar rats received either vehicle, ABT-627 (selective ET(A) receptor antagonist), bosentan (nonselective ET(A)/ET(B) receptor antagonist), or hydralazine for 4 wk. The measurement of myocardial ET-1 levels at the remote zone revealed a significant increase in vehicle-treated infarcted rats compared with sham-operated rats, consistent with increased activities of ET-1 after infarction. Sympathetic nerve function changes assessed by the norepinephrine content of myocardium and the dialysate and plasma dihydroxyphenylglycol levels were parallel to ET-1 levels. Immunohistochemical analysis for tyrosine hydroxylase, growth-associated protein 43, and neurofilament also confirmed the change of nerve function. This was accompanied with a significant upregulation of nerve growth factor protein expression and mRNA in the vehicle-treated infarcted rats, which reduced after the administration of either ET(A) or ET(A)/ET(B) blockade to a similar extent. The beneficial effects of ET receptor antagonists on sympathetic nerve function and structures were dissociated from their blood pressure-lowering effect because ET receptor antagonists and hydralazine reduced arterial pressure similarly. Arrhythmic severity during programmed stimulation in ET receptor antagonists-treated rats was significantly lower than that in vehicle-treated infarcted rats. Our data indicate that the ET system, especially via ET(A) receptors, plays an important role in attenuating sympathetic reinnervation after infarction. Independent of their hemodynamic effects, a chronic use of either ET(A) or ET(A)/ET(B) antagonists may modify the arrhythmogenic response to programmed electrical stimulation.

Topics: Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Atrasentan; Blotting, Western; Bosentan; Cardiac Pacing, Artificial; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; GAP-43 Protein; Hemodynamics; Hydralazine; Immunohistochemistry; Male; Methoxyhydroxyphenylglycol; Myocardial Infarction; Myocardium; Nerve Growth Factor; Neurofilament Proteins; Norepinephrine; Polymerase Chain Reaction; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Sulfonamides; Sympathetic Nervous System; Time Factors; Tyrosine 3-Monooxygenase; Up-Regulation

To observe the effects of Xuefu Zhuyu Capsule (XFZYC), a compound traditional Chinese herbal medicine, on endothelin-1 (ET-1) release in myocardium and vascular endothelium and nitric oxide (NO)/nitric oxide synthase (NOS) system of swines after acute myocardial infarction (AMI) and reperfusion, and to explore the action mechanisms of XFZYC in improving the endothelium function.. Forty-five Yorkshire swines were randomized into 3 groups: sham-operated group, untreated group and XFZYC-treated group. A Yorkshire swine model of reperfusion in AMI was established by ligation of left anterior descending coronary artery for 90 min followed by 2 h relaxation. The content of serum ET-1 and NO was measured by radioimmunoassay before and after AMI and after reperfusion, respectively. Twenty-four hours after operation, all Yorkshire swines underwent diagnostic coronary angiography to delineate coronary arteries. The expressions of ET-1 and endothelial nitric oxide synthase (eNOS) in myocardial tissue of ischemic area were quantified with Western blotting. Microvessel density of the implanting sites was assessed by using HE staining.. Compared with the untreated group, the levels of serum ET-1 after AMI and reperfusion were significantly decreased in XFZYC-treated group (P<0.01), while the NO levels after AMI and reperfusion in XFZYC-treated group were significantly increased (P<0.01). There was no significant difference in diagnostic coronary angiography between XFZYC-treated group and untreated group (P=0.253). Western blotting showed that the level of ET-1 in ischemic area in XFZYC-treated group was lower than that in the untreated group (P<0.01), while the eNOS protein expression in XFZYC-treated group was higher than that in the untreated group (P<0.01). The results of HE staining and microvessel density analysis of the implanting sites all showed that the degree of telangiectasis was reduced, the cardiac muscle damage was improved, and the density of capillaries was increased obviously in XFZYC-treated group as compared with the untreated group.. The endothelium injury may be one of the important mechanisms for no-reflow phenomenon. XFZYC may reduce the no-reflow by protecting endothelium cells.

Topics: Animals; Capsules; Drugs, Chinese Herbal; Endothelin-1; Endothelium, Vascular; Female; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type III; Phytotherapy; Random Allocation; Swine

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

The goals of this study were to determine the source of circulating endothelin-1 (ET-1) and interleukin-6 (IL-6) in acute myocardial infarction (MI) and to study the effects of coronary reperfusion (CR) on plasma levels of ET-1 and IL-6.. We serially measured plasma concentrations of ET-1 and IL-6 at different sampling sites before and after CR in patients with acute MI. A femoral vein (FV) catheter, a Swan-Ganz catheter, and a femoral artery (FA) catheter were placed in 25 patients with acute MI who were admitted within 12 hours after onset. For the measurement of ET-1 and IL-6 concentrations, blood samples from the FV, right atrium (RA), pulmonary artery (PA), and FA were collected before and 1 hour, 8 hours, and 24 hours after CR therapy. In 5 of the 25 patients, blood samples were collected through a coronary sinus (CS) catheter. We also assessed the gradient across 3 vascular beds (systemic, pulmonary, and coronary) as indices of the net release of ET-1 and IL-6 from those vascular beds. The maximal serum creatine kinase (CK) levels were assessed as an index of myocardial necrosis.. ET-1 levels were higher in the FV than in the RA, PA, or FA. On CR, ET-1 levels peaked after 1 hour and returned to baseline by 24 hours. Calculated net release of ET-1 from the systemic vascular bed (ET-1 at FV-ET-1 at FA) was the highest among the 3 vascular beds. Plasma ET-1 levels correlated with hemodynamic parameters. Plasma IL-6 levels were similar among different sampling sites, whereas calculated net release of IL-6 from the coronary vascular bed was the highest among the 3 vascular beds. IL-6 levels increased throughout 24 hours after coronary reperfusion and closely correlated with maximal CK levels.. The present study suggests that, in acute MI, the major source of ET-1 maintaining baseline plasma levels is the systemic vascular bed and that the ET-1 levels presumably reflect the congestion. ET-1 levels peaked 1 hour after CR. IL-6 increased for 24 hours after CR. The major source of IL-6 is the coronary vascular bed. Only a slight correlation was observed between plasma ET-1 and IL-6 levels.

Topics: Blood Vessels; Endothelin-1; Female; Humans; Interleukin-6; Male; Myocardial Infarction; Myocardial Reperfusion; Time Factors

Endothelin-1 is elevated in heart failure (HF) and after acute myocardial infarction (AMI) and gives prognostic information on mortality. Another part of its precursor, C-terminal pro-endothelin-1 (CT-proET-1), is more stable in circulation and ex vivo. We investigated the cardiovascular prognostic value post-AMI of CT-proET-1 and compared it to N-terminal pro-B-type natriuretic peptide (NTproBNP), a marker of death and HF.. We measured plasma CT-proET-1 and NTproBNP in 983 consecutive post-AMI patients (721 men, mean age 65.0 +/- [SD] 12.2 years), 3 to 5 days after chest pain onset.. There were 101 deaths and 49 readmissions with HF during follow-up (median 343, range 0-764 days). C-terminal pro-endothelin-1 was raised in patients with death or HF compared to survivors (median [range] [pmol/L], 119.0 [14.0-671.0] vs 73.0 [4.6-431.0], P < .0001). Using a Cox proportional hazards logistic model, log CT-proET-1 (HR 6.82) and log NTproBNP (HR 2.62) were significant independent predictors of death or HF (along with age, sex, history of AMI, and therapy with beta-blockers). The areas under the receiver operating curve for CT-proET-1, NTproBNP, and the logistic model with both markers were 0.76, 0.76, and 0.81 respectively. Findings were similar for death and HF as individual end points.. The endothelin system is known to be activated post AMI. C-terminal pro-endothelin-1 is a powerful predictor of adverse outcome, along with NTproBNP. CT-proET-1 may represent a clinically useful marker of prognosis after AMI.

Topics: Aged; Comorbidity; Endothelin-1; Female; Humans; Logistic Models; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Protein Precursors; Risk Assessment; ROC Curve; Survival Analysis

It has been verified that nicorandil can attenuate myocardial no-reflow. However; the effects of nicorandil on endothelial junctions and Endothelin-1 (ET-1) are unknown.. 40 mini-swines randomized into 5 study groups: 8 in control, 8 nicorandil pretreatment, 8 in glibenclamide (KATP channel blocker)-treated, 8 in nicorandil and glibenclamide-pretreated and 8 in sham-operated. Acute myocardial infarction and reperfusion model was created with three-hour occlusion of the left anterior descending coronary artery followed by one-hour reperfusion.. In control group, plasma ET-1 significantly increased, ET-1 or VE-cadherin level in the reflow and no-reflow myocardium was significantly higher or lower than that in normal myocardium. Compared with the control group, nicorandil significantly decreased plasma ET-1 and myocardial tissue ET-1, maintained VE-cadherin level. However, glibenclamide abrogated the protective effect of nicorandil.. The beneficial effect of nicorandil on endothelial junctions could be due to its effect on ET-1 via the activation of KATp channel.

Topics: Animals; Antigens, CD; Cadherins; Coronary Vessels; Disease Models, Animal; Endothelial Cells; Endothelin-1; Glyburide; Injections, Intravenous; Intercellular Junctions; KATP Channels; Ligation; Myocardial Infarction; Myocardium; Nicorandil; No-Reflow Phenomenon; Potassium Channel Blockers; Research Design; Swine; Swine, Miniature; Vasodilator Agents

Oxidative stress may play a causative role in myocardial ischemia-reperfusion injury. However, it is a relatively understudied aspect regarding an optimal timing of antioxidant intervention during ischemia-reperfusion. The present study investigates the effect of different treatment regimens of Salvia miltiorrhiza (SM) herb extracts containing phenolic compounds that possess potent antioxidant properties on postischemic myocardial functional recovery in the setting of global myocardial ischemia and reperfusion. Langendorff-perfused rat hearts were subjected to 40 min of global ischemia at 37 degrees C followed by 60 min of reperfusion, and were randomly assigned into the untreated control and 2 SM-treated groups (n = 7 per group). In treatment 1 (SM1), 3 mg/mL of water soluble extract of SM was given for 10 min before ischemia and continued during ischemia through the aorta at a reduced flow rate of 60 microL/min, but not during reperfusion. In treatment 2 (SM2), SM (3 mg/mL) was given during the first 15 min of reperfusion. During ischemia, hearts in the control and SM2 groups were given physiological saline at 60 microL/min. The SM1 treatment reduced the production of 15-F2t-isoprostane, a specific index of oxidative stress-induced lipid peroxidation, during ischemia (94 +/- 20, 43 +/- 6, and 95 +/- 15 pg/mL in the coronary effluent in control, SM1, and SM2 groups, respectively; p < 0.05, SM1 vs. control or SM2) and postponed the onset of ischemic contracture. However, SM2, but not the SM1 regimen, significantly reduced 15-F2t-isoprostane production during early reperfusion and led to optimal postischemic myocardial functional recovery (left ventricular developed pressure 51 +/- 4, 46 +/- 4, and 60 +/- 6 mmHg in the control, SM1, and SM2 groups, respectively, at 60 min of reperfusion; p < 0.05, SM2 vs. control or SM1) and reduced myocardial infarct size as measured by triphenyltetrazolium chloride staining (26% +/- 2%, 22% +/- 2%, and 20% +/- 2% of the total area in the control, SM1, and SM2 groups, respectively, p < 0.05, SM2 vs. control). It is concluded that S. miltiorrhiza could be beneficial in the treatment of myocardial ischemic injury and the timing of administration seems important.

Topics: Animals; Antioxidants; Dinoprost; Drugs, Chinese Herbal; Endothelin-1; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Organ Size; Oxidative Stress; Plant Extracts; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Salvia miltiorrhiza; Time Factors; Ventricular Function, Left

Myocardium undergoes functional changes in the infarcted region primarily due to ischemia. Following myocyte functional alterations of the noninfarcted myocardium are caused by remodelling and hypertrophy. We have monitored and compared changes in the electrocardiographical (ECG) image after coronary artery occlusion (CAO, n=5) and intracoronary endothelin-1 (ET-1, n=3) administration during a 6-month period. In 3 dogs, the CAO was repeated 6 months after the first occlusion. Signal-averaged ECG (SA ECG) was recorded before the operation and 10 days, 1 month, 3 months and 6 months after myocardial infarction (MI). The modified Wigner distribution was used for spectrotemporal analysis of the SA ECG. Eight-hour Holter monitoring was performed in each dog before and after experimental MI. Spectrotemporal representations of the QRS complex were stabilized after the first 1-month period in the group of dogs after CAO. The same results were also observed after the repeated CAO. No arrhythmias were recorded 9 days after CAO. The spectrotemporal representations of the QRS complex after intracoronary ET-1 administration were not stabilized during the whole observed period. Very few arrhythmic events were recorded by Holter monitoring already 3 days after intracoronary ET-1 injection. Experimental MI induced by CAO caused a changed ECG image, which was stable from 1 month after MI induction till the end of the monitoring. However, the ECG image after ET-1 administration was not stable during the whole observed period. No arrhythmic events were recorded in either group 3 months postoperatively that could be caused by healthy myocardial status before the experimental MI induction. In clinical practice, however, ischemic heart disease usually precedes the MI. Arrhythmogenic substrate could thus be a consequence of combination of healthy status of the myocardium before MI and MI itself.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Disease Models, Animal; Dogs; Electrocardiography, Ambulatory; Endothelin-1; Heart; Myocardial Infarction; Risk Factors; Signal Processing, Computer-Assisted; Time Factors

Adiponectin, an adipocyte-derived protein, has cardioprotective actions. We elucidated the role of the adiponectin receptors AdipoR1 and AdipoR2 in the effects of adiponectin on endothelin-1 (ET-1)-induced hypertrophy in cultured cardiomyocytes, and we examined the expression of adiponectin receptors in normal and infarcted mouse hearts. Recombinant full-length adiponectin suppressed the ET-1-induced increase in cell surface area and [(3)H]leucine incorporation into cultured cardiomyocytes compared with cells treated with ET-1 alone. Transfection of small interfering RNA (siRNA) specific for AdipoR1 or AdipoR2 reversed the suppressive effects of adiponectin on ET-1-induced cellular hypertrophy in cultured cardiomyocytes. Adiponectin induced phosphorylation of AMP-activated protein kinase (AMPK) and inhibited ET-1-induced ERK1/2 phosphorylation, which were also reversible by transfection of siRNA for AdipoR1 or AdipoR2 in cultured cardiomyocytes. Transfection of siRNA for alpha(2)-catalytic subunits of AMPK reduced the inhibitory effects of adiponectin on ET-1-induced cellular hypertrophy and ERK1/2 phosphorylation. Effects of globular adiponectin were similar to those of full-length adiponectin, and siRNA for AdipoR1 reversed the actions of globular adiponectin. Compared with normal left ventricle, expression levels of AdipoR1 mRNA and protein were decreased in the remote, as well as the infarcted, area after myocardial infarction in mouse hearts. In conclusion, AdipoR1 and AdipoR2 mediate the suppressive effects of full-length and globular adiponectin on ET-1-induced hypertrophy in cultured cardiomyocytes, and AMPK is involved in signal transduction through these receptors. AdipoR1 and AdipoR2 might play a role in the pathogenesis of ET-1-related cardiomyocyte hypertrophy after myocardial infarction.

Topics: Adiponectin; Angiotensin II; Animals; Cardiomegaly; Cells, Cultured; Endothelin-1; Endothelins; Image Processing, Computer-Assisted; Immunohistochemistry; Myocardial Infarction; Myocytes, Cardiac; Neurotransmitter Agents; Norepinephrine; Rats; Rats, Sprague-Dawley; Receptors, Adiponectin; Receptors, Cell Surface; RNA, Messenger; RNA, Small Interfering; Transfection; Tumor Necrosis Factor-alpha

Objective of the work is to determine the relation of G8002 polymorhism in endothelin 1 gene to the incidence of diabetes mellitus (DM), ischemic disease of lower limbs (ID LL) and myocardial infarction (MI) at the patients with heart failure. METHODICS: There were observed 224 patients, 176 males, 48 females, average age 55 +/- 12 years, NYHA II/III/IV 82/131/11, average EF LK 25 +/- 7 %, diagnosis ischemic heart disease (IHD) 133, dilatation cardiomyopathy (DCMP) 91.. Patients with IHD had higher incidence of hypertension (p < 0.0007), diabetes mellitus (p < 0.00007) and hyperlipoproteinemy (p < 0.0006) than patients with DCMP. Patients with IHD who experienced MI had a difference in the distribution of G8002A genotypes for endothelin 1 gene: G 0.718 and A 0.282 alleles vs ischemic patients without MI G 0.882 and A 0.118 (p < 0.05) alleles. Ischemic patients with DM had G allele in 0.67 and A 0.33 unlike ischemic patients without DM G allele 0.791 and A 0.209 (p < 0.03). Ischemic patients with synchronous ID LL had G allele in 0.718 and A 0.282 vs ischemic patients without ID LL G allele 0.882 and A 0.118 (p < 0.0004). At the patients with DCMP there was not found a difference in G8002A genotype and the presence of DM or ID LL.. At the patients with heart failure on the basis of ischemic heart disease there was found a difference in endothelin G8002A genotype distribution depending on other accessory diseases. There was more frequently present an A allele and less present G allele in the ischemic patients with DM, who had experienced MI or ID LL than in the ischemic patients without these diseases. Genotype with A allele is connected with higher risk of all accessory diseases.

Topics: Alleles; Diabetes Mellitus; Endothelin-1; Female; Genetic Predisposition to Disease; Genotype; Heart Failure; Humans; Ischemia; Leg; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Polymorphism, Genetic

Both angiotensin receptor antagonists and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to attenuate cardiomyocyte hypertrophy after myocardial infarction. Whether combination treatment may be superior to either drug alone on cardiomyocyte hypertrophy remains unclear. After ligation of the left anterior descending artery, rats were randomized to both, one, or neither of the angiotensin receptor antagonists olmesartan (0.01, 0.1, 1, and 2 mg.kg-1.day-1) and HMG-CoA reductase inhibitor pravastatin (5 mg.kg-1.day-1) for 4 wk. Each drug, when given alone, decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone when compared with vehicles. However, compared with either drug alone, combined olmesartan and pravastatin prevent cardiomyocyte hypertrophy to a larger extent, which was further confirmed by downregulation of the left ventricular atrial natriuretic peptide mRNA. The myocardial endothelin-1 levels at the border zone were 6.5-fold higher (P<0.0001) in the vehicle group compared with the sham group, which can be inhibited after pravastatin administration. Combination treatment significantly attenuated cardiomyocyte hypertrophy in a dose-dependent manner, although tissue endothelin-1 levels remained stable in combination groups of different olmesartan doses. Measurements of the arrhythmic score mirrored those of cardiomyocyte hypertrophy. Dual therapy with pravastatin and olmesartan, which produced an additive reduction in cardiomyocyte hypertrophy and cardiac fibrosis after myocardial infarction through different mechanisms, decreases the propensity of the heart to arrhythmogenesis. Pravastatin administration provided favorable ventricular remodeling, probably through decreased tissue endothelin-1 level. In contrast, olmesartan-related attenuated cardiomyocyte hypertrophy is independent of endothelin-1 pathway.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin-1; Gene Expression Regulation; Heart Ventricles; Hemodynamics; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy, Left Ventricular; Imidazoles; Male; Myocardial Infarction; Pravastatin; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Tetrazoles; Ventricular Remodeling

We previously observed that pulmonary hypertension secondary to myocardial infarction (MI) in swine is characterized by elevated plasma endothelin (ET) levels and pulmonary vascular resistance (PVR). Consequently, we tested the hypothesis that an increased ET-mediated vasoconstrictor influence contributes to secondary pulmonary hypertension after MI and investigated the involvement of ET(A) and ET(B) receptor subtypes. Chronically instrumented swine with (MI swine; n = 25) or without (normal swine; n = 19) MI were studied at rest and during treadmill exercise (up to 4 km h(-1)), in the absence and presence of the ET(A) antagonist EMD 122946 or the mixed ET(A)/ET(B) antagonist tezosentan. In normal swine, exercise caused a small decrease in PVR. ET(A) blockade had no effect on PVR at rest or during exercise. Conversely, ET(A)/ET(B) blockade decreased PVR but only during exercise (at 4 km h(-1), from 3.0 +/- 0.1 to 2.3 +/- 0.1 mmHg min l(-1); P

Topics: Animals; Blood Pressure; Consciousness; Endothelin Receptor Antagonists; Endothelin-1; Female; Hemodynamics; Hypertension, Pulmonary; Male; Myocardial Infarction; Physical Conditioning, Animal; Pulmonary Circulation; Pyridines; Receptors, Endothelin; Rest; Swine; Tetrazoles; Vasoconstriction; Vasodilator Agents

To evaluate the effect of adenosine on endothelin-1 (ET-1) after acute myocardial infarction (AMI) and reperfusion and explore the possible mechanism of no-reflow.. Twenty-four mini-swine were randomized into three study groups: control group (n=8), adenosine treated group (n=8), and sham-operated group (n=8). The mini-swine in the groups were subjected to 3 hours of coronary occlusion, followed by 60 minutes of reperfusion except those in the sham-operated group. The levels of ET-1 in blood sample, normal, infracted reflow and no-reflow myocardium were evaluated by radioimmuno-assay (RIA). The gene expressions of ET-1 in normal, infracted reflow and no-reflow myocardium were quantified by reverse transcription-polymerase chain reaction.. In both control group and adenosine group, compared with that at the baseline, ET-1 in blood sample significantly increased at 5 minutes and 180 minutes of left anterior descending coronary artery occlusion, as well as 5 and 60 minutes of reperfusion (all P < 0.01). In adenosine group, the levels of ET-1 were significantly lower than those in the control group (P < 0.05, P < 0.01). In both control group and adenosine group, compared with that in normal myocardium, ET-1 levels in both infarcted reflow and no-reflow myocardium significantly increased (both P < 0.01), with the level of ET-1 in no-reflow myocardium significantly higher than that in infarcted reflow myocardium (P < 0.01). In adenosine group, the level of ET-1 in infarcted reflow myocardium was significantly lower than that in the control group (P < 0.01). In both control and adenosine groups, compared with that in normal myocardium, the gene expression of ET-1 in infarcted reflow myocardium was significantly up-regulated (P < 0.01), while that of ET-1 in. no-reflow myocardium significantly down-regulated (P < 0.01). In adenosine group, the level of ET-1 in infarcted reflow myocardium was significantly lower than that in the control group (P < 0.01).. The endothelium injury may be one of the important mechanisms for no-reflow phenomenon. Adenosine cay prevent endothelium from injury to reduce no-reflow.

Topics: Adenosine; Animals; Disease Models, Animal; Endothelin-1; Female; Male; Myocardial Infarction; Myocardial Reperfusion; Swine; Swine, Miniature

Endothelin (ET) levels are elevated in congestive heart failure secondary to myocardial infarction (MI) and correlate well with the severity of pulmonary hypertension (PH), suggesting that the ET peptide could contribute to the pathophysiology of venous PH. Alterations of pulmonary vasoreactivity to ET after MI and the respective roles of the ET(A) and ET(B) receptors (ET(A)-R and ET(B)-R) have never been evaluated, to our knowledge. MI was induced in rats. Three weeks later, small pulmonary resistance arteries were mounted on a microvascular myograph. Cumulative concentration-response curves to ET-1 and sarafotoxin 6c (S6c) were performed. Response to ET was also assessed in the presence of ET-R antagonists. Heterodimerization of receptors was evaluated by immunoprecipitation of the ET(B)-R, followed by western blotting for the expression of the ET(A)-R. Maximal vasoconstriction and sensitivity to ET-1 were similar in sham and MI with values of 88 +/- 3.9% and 80 +/- 3.8%, respectively. The response to S6c was similarly less in both sham (67 +/- 5.7%) and MI groups (60 +/- 6.6%). When administered alone, the ET(A)-R antagonist (10 nM A-147627.1) and the ET(B)-R antagonist (1 microM A-192621.1) had no significant effect. However, their combination markedly reduced vaso-constriction (52 +/- 5.3%; P < 0.001). The endothelial and medial distribution of ET-Rs was similar in sham and MI groups. In vitro studies demonstrated co-immunoprecipitation of the ET(A)-R and ET(B)-R. Vasoconstriction of isolated resistance pulmonary arteries to ET agonists is not altered after MI. Dual antagonism results in optimal blockade of vasoconstriction, possibly because the ET(A)-R and ET(B)-R can form functional heterodimers.

Topics: Animals; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Lung; Myocardial Infarction; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction; Viper Venoms

No-reflow after a primary percutaneous coronary intervention (PCI) is associated with a high incidence of left ventricular (LV) failure and a poor prognosis. Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor peptide and an important modulator of neutrophil function. Elevated systemic ET-1 levels have recently been reported to predict a poor prognosis in patients with acute myocardial infarction (AMI) treated by primary PCI. We aimed to investigate the relationship between systemic ET-1 plasma levels and no-reflow in a group of AMI patients treated by primary PCI.. A group of 51 patients (age 59+/-9.9 years, 44 males) with a first AMI, undergoing successful primary or rescue PCI, were included in the study. Angiographic no-reflow was defined as coronary TIMI flow grade < or =2 or TIMI flow 3 with a final myocardial blush grade < or =2. Blood samples were obtained from all patients on admission for ET-1 levels measurement. No reflow was observed in 31 patients (61%). Variables associated with no-reflow at univariate analysis included culprit lesion of the left anterior coronary descending artery (LAD) (67 vs. 29%, P=0.006) and ET-1 plasma levels (3.95+/-0.7 vs. 3.3+/-0.8 pg/mL, P=0.004). At multivariable logistic regression analysis, ET-1 was the only significant predictor of no-reflow (P=0.03) together with LAD as the culprit vessel (P=0.04).. ET-1 plasma levels predict angiographic no-reflow after successful primary or rescue PCI. These findings suggest that ET-1 antagonists might be beneficial in the management of no-reflow.

Topics: Angioplasty, Balloon, Coronary; Coronary Circulation; Endothelin-1; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Prognosis; Regression Analysis

The AMPD1 gene C34T polymorphism has previously been associated with prolonged survival in small cohorts of heart failure (HF) and coronary artery disease patients. This study aimed to corroborate the association of the AMPD1 C34T polymorphism with survival in larger myocardial infarction (MI) and HF cohorts.. Genotypes were obtained for 935 post-MI (PMI) and 433 patients with established HF, with median follow-up times of 5.4 and 3.1 years, respectively. At admission, cardiac function was assessed by nuclear ventriculography (PMI) and echocardiography (HF) and plasma cardiac neurohormones were assayed.. Differences in mortality by AMPD1 genotype did not achieve significance, either for the overall HF (P = .07) or the overall PMI group (P = .28), but AMPD1 genotype predicted mortality in patients of both cohorts with a history of MI (HxMI). In contrast to previous studies, the mutant T allele was associated with poorer outcome. Mortality in HF HxMI patients was significantly different between genotype groups (n = 144, mortality CC 56.5%, CT/TT 77.8%, P = .027), but not in patients without HxMI. In PMI patients, the association of genotype with survival in the HxMI subgroup trended toward significance (n = 147, mortality CC 29.8%, CT/TT 45.5%, P = .093). Multivariate analysis of combined PMI and HF cohorts showed that HxMI patients with CT/TT genotype were at greater risk than all other groups (P < .001).. This study suggests that AMPD1 C34T genotype is not a predictor of survival in heart disease patients, except possibly those with HxMI.

Topics: Aged; Aldosterone; AMP Deaminase; Angiotensin II; Atrial Natriuretic Factor; Endothelin-1; Epinephrine; Female; Genotype; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Natriuretic Peptide, Brain; Norepinephrine; Polymorphism, Genetic; Proportional Hazards Models; Retrospective Studies

Left ventricular dysfunction in swine with a recent myocardial infarction (MI) is associated with neurohumoral activation, including increased catecholamines and endothelin (ET). Although the increase in ET may serve to maintain blood pressure and, hence, perfusion of essential organs such as the heart and brain, it could also compromise myocardial perfusion by evoking coronary vasoconstriction. In the present study, we tested the hypothesis that endogenous ET contributes to perturbations in myocardial O2 balance during exercise in remodeled myocardium of swine with a recent MI. For this purpose, 26 chronically instrumented swine (10 with and 16 without MI) were studied at rest and while running on a treadmill at 1-4 km/h. After MI, plasma ET increased from 3.2 +/- 0.4 to 4.9 +/- 0.3 pM (P < 0.05). In normal swine, blockade of ETA (by EMD-122946) or ETA-ETB (by tezosentan) receptors resulted in an increase in coronary venous PO2, i.e., coronary vasodilation at rest, which decreased during exercise. In contrast, neither ETA nor ETA-ETB receptor blockade resulted in coronary vasodilation in swine with MI. Coronary vasoconstriction to intravenous ET-1 infusion in awake resting swine was blunted after MI. To investigate whether factors released by cardiac myocytes contributed to decreased vascular responsiveness to ET, we performed ET-1 dose-response curves in isolated coronary arterioles (70-200 microm). Vasoconstriction to ET-1 in isolated arterioles from MI swine was enhanced. In conclusion, the vasoconstrictor influence of endogenous as well as exogenous ET on coronary circulation in vivo is reduced. Because the response of isolated coronary arterioles to ET is increased after MI, the reduced vasoconstrictor influence in vivo suggests modulation of ET receptor sensitivity by cardiac myocytes, which may serve to maintain adequate myocardial perfusion.

Topics: Animals; Arterioles; Coronary Circulation; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Male; Myocardial Infarction; Oxygen; Pyridines; Sus scrofa; Tetrazoles; Vasoconstriction; Vasodilator Agents

In vitro studies have demonstrated that endothelin-1 (ET-1) given before myocardial ischaemia may evoke a preconditioning (PC)-like cardioprotective effect. The first aim of this study was to investigate whether administration of ET-1 before ischaemia exerts cardioprotection against ischaemia/reperfusion injury in vivo and to determine involvement of the ET-1 receptor subtype. The second aim was to examine the role of mitochondrial ATP-sensitive K+ channels (mitoK(ATP)) as a mediator of this cardioprotection. Anaesthetised open-chest Wistar rats were subjected to 30 min of coronary artery occlusion followed by 2 h reperfusion (I/R). In protocol I, the first group was subjected to I/R only (control, n=10). In the second (n=10) group, PC was elicited by three 5 min cycles of coronary artery occlusion, separated by 5 min reperfusion before I/R. The third (n=6) and fourth (n=7) groups were given ET-1 intravenous (i.v.) during three 5 min infusion periods separated by 5 min before I/R. The fourth group was in addition given the ET(A) receptor antagonist LU 135252 5 min before the infusions of ET-1. In protocol II, the first group was I/R control as in protocol I (n=8). The second (n=6), third (n=7) and fourth (n=7) groups were given ET-1 as in protocol I. The third group was in addition given the nonselective K(ATP) channel antagonist glibenclamide (Glib) 30 min before the ET-1 infusions and the fourth group the selective mitoK(ATP) channel antagonist 5-hydroxydecanoic acid (5-HD) 5 min before I/R. There were no significant differences in MAP or heart rate between the groups during I/R. In protocol I, PC reduced IS compared to the control group (10+/-3 vs 35+/-5%, P<0.01). Infusion of ET-1 also reduced IS (to 14+/-3%, P<0.05 vs control). The ET(A) receptor antagonist blocked the reduction in IS induced by ET-1 (IS 47+/-8% after LU+ET-1; P< 0.05 vs ET-1). In protocol II, Glib and 5-HD abolished the cardioprotective effect induced by ET-1 (IS 48+/-7% after Glib+ET-1 and 42+/-5% after ET-1+5-HD vs 18+/-4% after ET-1 alone; P<0.05). In conclusion, administration of ET-1 before ischaemia resulted in a PC-like cardioprotective effect. This effect is mediated via the ET(A) receptor and activation of mitoK(ATP) channels.

Topics: Animals; Electrocardiography; Endothelin-1; Hemodynamics; Ischemic Preconditioning, Myocardial; Male; Membrane Proteins; Myocardial Infarction; Myocardial Reperfusion Injury; Phenylpropionates; Potassium Channels; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Reperfusion Injury

Topics: Endothelin-1; Humans; Myocardial Infarction; Predictive Value of Tests; Prognosis; Vasoconstriction

The link between increased circulating level of endothelin (ET)-1 and adverse clinical outcomes after acute myocardial infarction (AMI) has been established. Current studies demonstrate that reperfusion therapy by either thrombolysis or primary percutaneous coronary intervention (PCI) can salvage myocardium, improving survival of AMI patients. However, whether reperfusion therapy by primary PCI can prevent the adverse effect of ET-1 on clinical outcomes in patients after AMI remains unclear. Therefore, this study examined the predictive value of circulating ET-1 levels on 30-day outcomes in ST-segment elevated AMI treated with primary PCI.. We conducted a prospective cohort study of 186 consecutive patients with ST-segment elevated AMI of onset < 12 h who underwent primary PCI. Blood samples for plasma concentration of ET-1 were collected in the catheterization laboratory following vascular puncture. Patients were classified into a high group (group 1, ET-1 level >or= 0.632 pg/mL, n = 93) and a low group (group 2, ET-1 level < 0.632 pg/mL, n = 93) according to the median value of ET-1 after AMI. Univariate analysis demonstrated that the 30-day composite major adverse clinical outcomes (MACO) [advanced Killip score >or= 3], severe congestive heart failure (CHF) [New York Heart Association functional class 4], and 30-day mortality were strongly associated with high ET-1 level (>or= 0.632 pg/mL; p < 0.0001), unsuccessful reperfusion (final Thrombolysis in Myocardial Infarction flow

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Endothelin-1; Female; Humans; Logistic Models; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; Prospective Studies; Risk Assessment; Stroke Volume

The aim of the present study was to investigate the relationship between plasma concentrations of endothelin (ET)-1 and clinical outcome (including mortality) and left ventricular (LV) systolic function in acute myocardial infarction (AMI).. The study group comprised 110 consecutive first-AMI patients who were successfully reperfused by primary coronary intervention. Plasma ET-1 concentrations were evaluated 24 h from onset and the patients were divided into 2 groups according to the median value, either a high group (H group: > or = 2.90 pg/ml plasma ET-1; n = 55) or low group (L group: < 2.90 pg/ml plasma ET-1; n = 55). Major complications and LV systolic function were monitored in the 2 groups. Both highly sensitive C-reactive protein (hs-CRP) and brain natriuretic peptide (BNP) showed a significant positive correlation with ET-1 (BNP: r = 048, p < 0.0001, hs-CRP: r = 0.43, p < 0.001). Chronic stage left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume index (LVEDVI) were significantly poorer in the H group (LVEF: 51+/-15% vs 60+/-13%, p = 0.003, LVEDVI: 74+/-19 ml/m2 vs 66+/-14 ml/m2, p < 0.05). There were significantly more major complications in the H group than in the L group (cardiogenic shock: 18% vs 5%, p = 0.04; cardiac death: 13% vs 0%, p < 0.01).. In the setting of AMI, plasma ET-1 concentrations may be closely related to LV systolic dysfunction and poor patient outcome, including mortality.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Biomarkers; Endothelin-1; Female; Humans; Male; Middle Aged; Myocardial Infarction; Treatment Outcome

Reactive oxygen species induce formation of 15-F(2t)-isoprostane (15-F(2t)-IsoP), a specific marker of in vivo lipid peroxidation, which is increased after myocardial ischemia and during the subsequent reperfusion. 15-F(2t)-IsoP possesses potent bioactivity under pathophysiological conditions. However, it remains unknown whether 15-F(2t)-IsoP, by itself, can influence myocardial ischemia-reperfusion injury (IRI). Adult rat hearts were perfused by the Langendorff technique with Krebs-Henseleit (KH) solution at a constant flow rate of 10 ml/min. 15-F(2t)-IsoP (100 nM), SQ-29548 (1 microM, SQ), a thromboxane receptor antagonist that can abolish the vasoconstrictor effect of 15-F(2t)-IsoP, 15-F(2t)-IsoP + SQ in KH, or KH alone (vehicle control) was applied for 10 min before induction of 40 min of global ischemia followed by 60 min of reperfusion. During ischemia, saline (control), 15-F(2t)-IsoP, 15-F(2t)-IsoP + SQ, or SQ in saline was perfused through the aorta at 60 microl/min. 15-F(2t)-IsoP, 15-F(2t)-IsoP + SQ, or SQ in KH was infused during the first 15 min of reperfusion. Coronary effluent endothelin-1 concentrations were significantly higher in the group treated with 15-F(2t)-IsoP than in the control group during ischemia and also in the later phase of reperfusion (P < 0.05). Infusion of 15-F(2t)-IsoP increased release of cardiac-specific creatine kinase, reduced cardiac contractility during reperfusion, and increased myocardial infarct size relative to the control group. SQ abolished the deleterious effects of 15-F(2t)-IsoP. 15-F(2t)-IsoP exacerbates myocardial IRI and may, therefore, act as a mediator of IRI. 15-F(2t)-IsoP-induced endothelin-1 production during cardiac reperfusion may represent a mechanism underlying the deleterious actions of 15-F(2t)-IsoP.

Topics: Animals; Blood Pressure; Creatine Kinase; Creatine Kinase, MB Form; Dinoprost; Endothelin-1; Heart; In Vitro Techniques; Isoenzymes; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents

We performed a cohort study of 392 postmenopausal women who had coronary disease to assess whether baseline serum endothelin-1 level predicts angiographic disease progression, nonfatal myocardial infarction, or death. Angiographic progression was defined as the annualized change in minimal lumen diameter of all qualifying lesions for each patient. Twenty-nine patients died or had a myocardial infarction during follow-up. Each picogram per milliliter increase in endothelin-1 was associated with a 1.8-fold increased risk of death or myocardial infarction. After adjustment for potential confounders, endothelin-1 remained a predictor of clinical events but was not correlated with angiographic progression.

Topics: Aged; Biomarkers; Coronary Angiography; Coronary Disease; Disease Progression; Endothelin-1; Female; Humans; Middle Aged; Myocardial Infarction; Postmenopause; Predictive Value of Tests; Randomized Controlled Trials as Topic

Adequate wound healing and scar formation is an essential response to myocardial infarction (MI), and fibroblasts are primary cellular components regulating the process. How fibroblast functions are altered post-MI and to what extent these abnormalities persist in vitro is not well understood. Accordingly, we isolated myocardial fibroblasts from MI and non-MI (remote) regions at 7 days post-MI (n=35) and from the free wall and septum of unoperated control C57BL/6 mice (n=14). Proliferation was increased 182+/-28% in MI, but not in remote, fibroblasts compared with unoperated controls (P=0.01). Migration decreased 61+/-8%, adhesion to laminin decreased 79+/-8%, adhesion to collagen IV increased 196+/-27%, and collagen synthesis increased 169+/-24% in fibroblasts isolated from the MI region (all P<0.05). Migration, adhesion, and collagen synthesis changes were similar in remote fibroblasts, and the phenotypic differences were maintained through passage four. Transforming growth factor beta1 (TGFbeta1) is a bioactive molecule that has been shown to affect fibroblast function. Stimulation of unoperated control fibroblasts with 10 ng/ml TGFbeta(1) increased proliferation 137+/-7% (P=0.03 vs. unstimulated), increased adhesion to collagen IV 149+/-6% (P<0.01), and increased collagen I levels 187+/-10% (P=0.01). TGFbeta1 may, therefore, explain some of the changes in post-MI fibroblast phenotype. These data demonstrate for the first time region specific alterations in post-MI fibroblast biology that are maintained in vitro. Additionally, our model provides a novel in vitro template for examining the cellular mechanisms of wound healing and scar formation post-MI.

Topics: Angiotensin II; Animals; Autoantibodies; Cell Adhesion; Cell Movement; Cell Proliferation; Collagen; Discoidin Domain Receptors; Endothelin-1; Female; Fibroblasts; Heart Ventricles; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Receptor Protein-Tyrosine Kinases; Receptors, Mitogen; Transforming Growth Factor beta; Transforming Growth Factor beta1

To investigate the effect of coronary microemboliation (CME) on coronary microvascular injury and myocardial endothelin-1 (ET-1) level.. CME was induced in 10 miniswines by selective infusion of microspheres (45 microm) into left anterior descending artery (LAD). The ET-1 level in coronary sinus was measured with radioimmunoassay. The microvascular integrity indicator CFR was measured by Doppler flow wire in LAD at baseline and after infusion of microspheres.. Compared to the baseline, CFR decreased significantly with different doses of microspheres. ET-1 level increased significantly with doses of 5 x 10(4) and peaked with 10 x 10(4), and progressively decreased from doses of 12 x 10(4) to 15 x 10(4) microspheres. There was negative correlation between ET-1 and CFR (r=-0.31, P=0.02).. The extent of microvascular injury is not linearly related to the extent of microembolization, but it is closely associated with myocardial ET-1 level.

Topics: Animals; Coronary Vessels; Disease Models, Animal; Embolism; Endothelin-1; Female; Male; Myocardial Infarction; Swine; Swine, Miniature

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

Elevations in endothelin-1 (ET-1) and inflammatory cytokines may impair myocardial reperfusion through the induction of microvascular constriction or obstruction; however, the generation of these factors close to the site of lesion rupture is unknown.. Coronary sinus (CS) and aortic blood was sampled during angioplasty for acute myocardial infarction (AMI) or stable angina to assess the local release of ET-1, interleukin-1beta, interleukin-6, tumor necrosis factor-alpha and C-reactive protein following atherosclerotic plaque rupture. Transthoracic echocardiography documented left ventricular function in AMI. ET-1 levels were higher in CS than in aortic blood in AMI (3.0 +/- 0.3 pmol/L vs 2.6 +/- 0.3 pmol/L, P =.04), but not in stable angina (1.7 +/- 0.2 pmol/L vs 1.5 +/- 0.3 pmol/L, P = NS). CS ET-1 levels were also higher in AMI than in stable angina (3.0 +/- 0.3 pmol/L vs 1.7 +/- 0.2 pmol/L, P =.002), and correlated with left ventricular dysfunction (R(2) = 0.51, P =.02). In contrast, C-reactive protein levels were higher in CS than in aortic blood only in stable angina (2.3 +/- 0.4 mg/L vs 1.8 +/- 0.3 mg/L, P =.01). Similarly, CS tumor necrosis factor-alpha was higher in stable angina than in AMI (6.0 +/- 1.4 pg/mL vs 2.5 +/- 0.9 pg/mL, P =.02).. Local myocardial release of ET-1 is highest in AMI, where it relates to the extent of myocardial dysfunction. Although local inflammation is a component of stable coronary artery disease, it does not appear acutely enhanced in AMI.

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; C-Reactive Protein; Cytokines; Endothelin-1; Female; Humans; Inflammation; Male; Middle Aged; Myocardial Infarction; Myocardium; Ventricular Function, Left

To explore the protective effect of morphine and its mechanism on acute myocardial ischemia/reperfusion (AMIR) injury in rats, by the method of detecting calcitonin gene-related peptide (CGRP) and endothelin-1 (ET-1) levels, as well as myocardial infarct size.. Forty SD rats were randomly divided into four groups: ischemia/reperfusion group (n=10), morphine preconditioning group (n=10), morphine and naloxone hydrochloride group (n=10), and normal controls (n=10). The animal model of AMIR was established in rats. The left anterior descending branch (LAD) of rat coronary was tied and un-tied. Animals were then sacrificed and hearts were harvested to determine myocardial infarct size by 2, 3, 5-triphenyl tetrazolium chloride (TTC). Radioimmunoassay was used to detect CGRP and ET-1 levels in plasma, and routine method was used to measure creatine kinase isoenzyme (CK-MB) in serum.. Plasma ET-1 and CGRP levels were increased significantly than that in normal controls in acute myocardial infarction (AMI) at 10 minutes of LAD tied (all P<0.01). Plasma ET-1 and CK-MB levels in morphine preconditioning group in AMIR at 45 hours of reperfusion were decreased significantly as compared with that in the same group in AMI at 10 minutes, and myocardial infarct size decreased significantly (all P<0.01), while, plasma CGRP levels were markedly increased. Significant differences in those parameters were found between morphine preconditioning group and morphine combined with naloxone hydrochloride group (all P<0.01).. Intravenous morphine has protective effects on AMI by increased plasma CGRP level, decreased plasma ET-1 level, and reduced myocardial infarct size.

Topics: Animals; Calcitonin Gene-Related Peptide; Disease Models, Animal; Endothelin-1; Female; Ischemic Preconditioning, Myocardial; Male; Morphine; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Random Allocation; Rats; Rats, Sprague-Dawley

In vivo models of myocardial infarction induced by coronary artery ligation (CAL) in rats usually suffer from high early mortality and a low rate of induction. This study investigated the time course initiation of chronic myocardial infarction (CMI) in albino rats and the possibility of reducing early mortality rate due to myocardial infarction by modification of the surgical technique. CAL was carried out by passing the suture through the epicardial layer around the midway of the left anterior descending coronary artery including a small area of the myocardium to avoid mechanical damage to the heart geometry. In addition, the role of endothelin-1 (ET-1) in rat heart with congestive heart failure was critically assessed. Time course initiation experiments were designed by sacrificing the animals at different time intervals and by carrying out physiological, biochemical, histopathological, electron microscopical and immunohistochemical studies. Specific markers of myocardial injury, viz. cardiac troponin-T (cTnT), high sensitivity C-reactive protein, lactate dehydrogenase and fibrinogen were measured at different time points. Serum marker enzymes and activities of lysosomal hydrolases were found to be elevated on the eighth day post-ligation. Histopathological studies demonstrated focal areas showing fibrovascular tissue containing fibroblasts, collagenous ground substance and numerous small capillaries replacing cardiac muscle fibers. Transmission electron micrographs exhibited mitochondrial changes of well-developed irreversible cardiac injury, viz. swelling, disorganization of cristae, appearance of mitochondrial amorphous matrix densities, significant distortion of muscle fibers and distinct disruption of the intercalated discs. Immunoblotting studies confirmed the presence of alpha 2-macroglobulin which supported the inflammatory response. The severity of the CMI was inferred by the measurement of the level of ET-1 in plasma and left ventricle which was significantly higher in the CMI rats than in the sham-operated rats. Immunohistochemical studies at different time intervals showed that there was a significant immunoexpression of ET-1 on the eighth day post-ligation. This study conclusively showed that ligation of left anterior descending artery minimized mortality and ET-1 was expressed during CMI.

Topics: alpha-Macroglobulins; Animals; Biomarkers; Blood Pressure; Blotting, Western; C-Reactive Protein; Disease Models, Animal; Electrocardiography; Electrophoresis, Polyacrylamide Gel; Endothelin-1; Heart Failure; Hydrolases; Immunohistochemistry; Kinetics; L-Lactate Dehydrogenase; Ligation; Lysosomes; Male; Mitochondria, Heart; Myocardial Infarction; Rats; Rats, Wistar; Severity of Illness Index; Troponin T

Topics: Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Humans; Myocardial Infarction; Ventricular Remodeling

Aims To evaluate whether plasma endothelin-1 (ET-1) is extracted or produced through the heart in patients with acute myocardial infarction (AMI), and the relationship between transcardiac extraction of plasma ET-1 and left ventricular (LV) remodelling. Methods and results We measured the plasma level of ET-1 in the aortic root (Ao) and coronary sinus (CS) in 48 consecutive patients, who received successful revascularization and enalapril, for a first anterior AMI. In the acute phase the plasma ET-1 level was significantly higher both in the Ao and the CS compared to the control subjects. However, the plasma ET-1 level was significantly lower in the CS than in the Ao in the acute phase and after 1 month. There were significant correlations between transcardiac extraction of ET-1 in the acute phase and LV ejection fraction and LV end-diastolic volume index (LVEDVI) after 1 month. Stepwise multivariate analysis showed that maximal creatine phosphokinase and transcardiac extraction of plasma ET-1 during the acute phase were independently and positively correlated with the absolute change in LVEDVI after 1 month. Conclusions These results indicate that elevated circulating ET-1 is extracted through the heart in patients with a first anterior AMI and that the extracted ET-1 plays a significant role in modulating post-infarct LV remodelling.

Topics: Atrial Natriuretic Factor; Endothelin-1; Female; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Prospective Studies; Ventricular Remodeling

Recently it was demonstrated that treatment with a nonselective endothelin (ET) receptor antagonist significantly reduces myocardial infarct size, which suggests a major role for ET in tissue repair following myocardial infarction (MI). Tissue repair and remodeling found at the site of MI are mainly attributed to myofibroblasts (myoFbs), which are phenotypically transformed fibroblasts that express alpha-smooth muscle actin. It is unclear whether myoFbs generate ET peptides and consequentially regulate pathophysiological functions de novo through expression of the ET-1 precursor (prepro-ET-1), ET-converting enzyme-1 (ECE-1), a metalloprotease that is required to convert Big ET-1 to ET-1 and ET receptors. To address these intriguing questions, we used cultured myoFbs isolated from 4-wk-old MI scar tissue. In cultured cells, we found: 1) expression of mRNA for ET precursor gene (ppET1), ECE-1, and ETA and ETB receptors by semiquantitative RT-PCR; 2) phosphoramidon-sensitive ECE-1 activity, which converts Big ET-1 to biologically active peptide ET-1; 3) expression of ETA and ETB receptors; 4) elaboration of Big ET-1 and ET-1 peptides in myoFb culture media; and 5) upregulation of type I collagen gene expression and synthesis by ET, which was blocked by bosentan (a nonselective ETA- and ETB receptor blocker). These studies clearly indicated that myoFbs express and generate ET-1 and receptor-mediated modulation of type I collagen expression by ET-1. Locally generated ET-1 may contribute to tissue repair of the infarcted heart in an autocrine/paracrine manner.

Topics: Animals; Aspartic Acid Endopeptidases; Blotting, Western; Cells, Cultured; Collagen Type I; Culture Media; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Gene Expression; Male; Metalloendopeptidases; Myocardial Infarction; Myocardium; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger

Proinflammatory cytokines are capable of modulating cardiovascular function by a various mechanisms. The aim of the study was to evaluate the influence of the selected cytokines: tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (L-6), endothelin 1 (ET-1) on the remodeling of the heart in patients with congestive heart failure (1-year follow-up). The study was made in 45 patients with congestive heart failure treated in the Department of Cardiology. Of these, 31 were men aged from 44 to 77 and 14 were women aged from 48 to 79. Ischaemic heart disease was diagnosed in 22 patients and ischaemic heart disease and hypertension in 10 patients, dilated cardiomyopathy was diagnosed in 6 patients and postinflammatory cardiomyopathy in 7 patients. Blood samples for determination of TNF-alpha, IL-1, IL-2, IL-6, ET-1, aldosterone, catecholamines, brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) levels were obtained prior to the treatment and in 3 and 6 and 12 month follow-up. At the same time were estimated: NYHA functional class, structure, systolic and diastolic left ventricle function of the heart using echocardiography and 24-hour ECG Holter monitoring (HR, supraventricular and ventricular arrhythmias). TNF-alpha, IL-1, IL-2, IL-6, ET-1, aldosterone, catecholamines, BNP and ANP plasma levels were determined with radioimmunological assay. In patients with progression of congestive heart failure (worsening of NYHA class and ejection fraction of left ventricle) the plasma concentrations of TNF-alpha and ET-1 significantly increased in following observations. In this group patients we determined a correlation between ejection fraction of the left ventricle and serum concentration of TNF-alpha and ET-1. In patients with improving of NYHA functional class and ejection fraction of left ventricle the plasma concentrations of cytokines were not altering. In all patients the plasma concentration of TNF-alpha correlated with ANP and BNP concentrations.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathy, Dilated; Catecholamines; Cytokines; Echocardiography; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Heart Valve Diseases; Humans; Hypertension; Interleukin-1; Interleukin-2; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Radioimmunoprecipitation Assay; Severity of Illness Index; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Remodeling

Reactive cardiomyocyte hypertrophy after myocardial infarction (MI) is an important risk factor for arrhythmias. Endothelin (ET)-1 has been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on ventricular hypertrophy during remodeling after MI and whether the attenuated hypertrophic effect was via reduced regional ET-1 expression. After ligation of the anterior descending artery, male Wistar rats were randomized to either vehicle, pravastatin, mevalonate, or a combination of the two drugs for 4 weeks. Sham operation served as controls. Pravastatin decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone. The myocardial ET-1 levels at the border zone were 6.3-fold higher (P < 0.0001) in the vehicle group compared with sham group. The increased regional ET-1 levels can be inhibited after pravastatin administration. Immunohistochemical analysis confirmed the localization of ET-1 mainly in the cardiomyocytes. This was paralleled by a 9.8 +/- 2.3-fold upregulation of preproET-1 mRNA assessed by real-time quantitative reverse transcription-polymerase chain reaction in the vehicle-treated rats, which reduced after administering pravastatin. Cardiomyocyte sizes at the border zone correlated positively with regional ET-1 levels (P = 0.001). Arrhythmic scores during programmed stimulation were significantly higher in the vehicle group than in the pravastatin-treated group (3.0 +/- 1.3 vs. 1.3 +/- 1.0, P < 0.0001). In contrast, pravastatin-induced effects were reversed by the addition of mevalonate, implicating 3-hydroxy-3-methyglutaryl-CoA reductase as the relevant target. The results of the present study suggest that the pravastatin administration after infarction can reduce the inducibility of ventricular arrhythmias as a result of attenuated cardiomyocyte hypertrophy probably through decreased tissue ET-1 level, which is linked to mevalonate metabolism.

Topics: Animals; Anti-Arrhythmia Agents; Cardiomyopathy, Hypertrophic; Cell Size; Cholesterol; Endothelin-1; Heart Ventricles; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Lipids; Male; Myocardial Infarction; Myocytes, Cardiac; Pravastatin; Rats; Rats, Wistar; RNA, Messenger; Up-Regulation; Ventricular Remodeling

Exposure of rats to hyperoxia before organ harvesting protected their isolated hearts against global ischaemia-reperfusion injury in a previous study. The present study investigates whether hyperoxia influences vasomotor function and regional ischaemia of the heart. Isolated rings of the thoracic aorta were obtained from rats immediately or 24 h after in vivo exposure to 60 min of hyperoxia (>95% O2), and the in vitro dose-response to phenylephrine (PHE), prostaglandin F2alpha (PGF2alpha) and endothelin-1 (ET-1), acetylcholine (Ach) and sodium nitroprusside (SNP) was assessed. Hyperoxia in vivo increased the relaxation of aortic rings to Ach and SNP, while it delayed contraction to PHE. The effect was more evident when the vessels were harvested immediately rather than 24 h after hyperoxic exposure. In separate experiments rat hearts were isolated immediately after hyperoxia, buffer-perfused, and subjected to 30 min of regional ischaemia and reperfused for 120 min. Infarct size was determined by triphenyl tetrazolium chloride staining. Hyperoxia significantly reduced infarct size. In normoxic controls 23.0 +/- 8.3% of the area at risk was infarcted, while in hyperoxic animals infarct size was 14.8 +/- 5.6% of the area at risk (P = 0.012). Exposure of rats to hyperoxia modifies the vasomotor response of isolated aortic rings, and reduces the infarct size of isolated rat heart. These novel aspects of hyperoxic treatment require further studies to explore the potential of its clinical application.

Topics: Animals; Aorta, Thoracic; Blood Pressure; Coronary Circulation; Dinoprost; Endothelin-1; Heart Rate; Hyperoxia; Male; Myocardial Infarction; Nitroprusside; Phenylephrine; Rats; Rats, Sprague-Dawley; Rats, Wistar; Vasoconstriction; Vasodilation; Vasodilator Agents; Ventricular Function

Intervention with selective endothelin (ET)A receptor antagonists within 24h after myocardial infarction (MI) in rats has been reported to aggravate left ventricular (LV) remodeling. In contrast, beneficial effects are reported when initiation of treatment is delayed 7 days or more after MI. However, bosentan, a mixed ET(A)/ET(B) receptor antagonist with low affinity for the ET receptors, has been shown to exert beneficial effects independent of the time point of initiation of treatment after MI. The aim of the present study was to investigate to what extent early intervention with a mixed ET(A)/ET(B) receptor antagonist with higher affinity at the ET receptors (SB 209670) would also exert beneficial effects on postinfarction LV remodeling. After ligation of the left coronary artery, rats were randomized to treatment with SB 209670 (6.25 mg x kg(-1) SC b.i.d., n = 10) or vehicle (n = 12) for 26 days, starting 48h after MI. Treatment with SB 209670 adversely affected the postinfarction remodeling process causing further dilatation of the LV (LV end-diastolic diameter: 10.4+/-0.5 vs 9.1+/-0.2 mm; LV end-systolic diameter: 8.5+/-0.4 vs 7.2+/-0.2 mm, P < 0.05). However, SB 209670 did not significantly affect infarct size, compensatory cardiac hypertrophy, nor the myocardial mRNA levels of procollagen type I and III, and prolyl 4-hydroxylase and lysyl oxidase, 2 important enzymes affecting collagen secretion, stability and functionality. In addition, SB 209670 had no significant effects on LV collagen cross-linking or extent of fibrosis. Thus, our data demonstrate that early intervention with a potent, mixed ET(A)/ET(B) receptor antagonist after MI may promote dilatation of the LV without significant alterations of infarct size and extracellular matrix composition. Our data support the notion that the timing of initiation of ET receptor antagonism after MI is critical and that potent ET receptor antagonists may be harmful during the first few days after MI.

Topics: Animals; Cardiomegaly; Collagen; Echocardiography; Endothelin Receptor Antagonists; Endothelin-1; Extracellular Matrix; Fibrosis; Gene Expression; Heart; Heart Failure; Hemodynamics; Indans; Male; Myocardial Infarction; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Although it is generally accepted that endurance training improves cardiac function after myocardial infarction the sub-cellular mechanisms are uncertain. The present study reports the effects of aerobic endurance training on myocardial mass, myocyte dimensions, contractile function, Ca2+ handling, and myofilament responsiveness to Ca2+ in cardiomyocytes from healthy and failing rat hearts.. Adult female Sprague-Dawley rats ran on a treadmill 1.5 h/day, 5 days a week for 8 weeks. Exercise intervals alternated between 8 min at 85-90% of V(O(2max)) and 2 min at 50-60%. Training started 4 weeks after ligation of the left coronary artery (TR-INF, n=11) or sham operation (TR-SHAM, n=6). Sedentary animals (SED-SHAM, n=6; SED-INF, n=13) were controls.. After 6 weeks V(O(2max)) in TR-INF and TR-SHAM leveled off 65% above sedentary controls. In TR-SHAM, left and right ventricle weights were approximately 25% higher than in SED-SHAM, myocytes were approximately 13% longer; width remained unchanged. At physiological stimulation frequencies, relative myocyte shortening was markedly higher whereas peak systolic [Ca2+] and t(1/2) of Ca2+ transient decay were 10-20% lower, indicating higher Ca2+ sensitivity in cardiomyocytes from trained rats, compared to respective controls. In TR-INF the left and right ventricular weights, and myocyte length and width were 15, 23, 12, and 20% less than in SED-INF. Endurance training significantly increased the myocardial SR Ca2+ pump (SERCA-2) and sarcolemmal Na+-Ca2+-exchanger (NCX) protein levels to the extent that TR-INF did not differ from SED-SHAM.. This is the first study to show that aerobic endurance training attenuates the ventricular and cellular hypertrophy in failing hearts. Furthermore, training consistently restores contractile function, intracellular Ca2+ handling, and Ca2+-sensitivity in cardiomyocytes from rats with myocardial infarction.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Western; Calcium; Calcium-Transporting ATPases; Cell Size; Cells, Cultured; Echocardiography; Electric Stimulation; Endothelin-1; Female; Insulin-Like Growth Factor I; Models, Animal; Myocardial Contraction; Myocardial Infarction; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium-Calcium Exchanger

In the uncomplicated course of myocardial infarction (MI), the level of endothelin-1 (ET-1) comes to be increased beginning from day 1 and remains the same during the acute phase of the disease and gets decreased during the subacute phase. In MI presenting with parietal thrombosis, left ventricular aneurism, the level of ET-1 increases during the first period of 24 hours, increasing further toward the end of the acute phase, there being no decrease in the subacute phase. In MI presenting with pericardial effusion, an increase in the level of ET-1 is seen during the first period of 24 hours of the disease with no rise being recordable in peptide concentration during the acute and subacute phases. There is a positive correlation between the level of ET-1 and size of the heart cavities in the systole and diastole, pressure in the pulmonary artery, and a negative one with indices for the systolic function.

Topics: Endothelin-1; Female; Heart Aneurysm; Humans; Male; Middle Aged; Myocardial Infarction; Pericardial Effusion; Thrombosis

The interaction between the cardioprotective effect of endothelin (ET) receptor blockade and nitric oxide (NO) during ischemia-reperfusion injury was investigated. Anesthetized pigs were subjected to 45 (protocol 1) or 30 min (protocol 2) coronary artery ligation and 4 h reperfusion. In protocol 1, five groups were given vehicle, the ET(A) receptor antagonist LU-135252 (LU), the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine (L-NNA), L-NNA in combination with LU, or L-NNA in combination with the NO precursor L-arginine (L-Arg) and LU intravenously before ischemia. In protocol 2, two groups were given vehicle or L-NNA. In protocol 1, the infarct size (IS) was 79 +/- 5% of the area at risk in the vehicle group and 93 +/- 2% in the L-NNA group. LU reduced the IS to 43 +/- 7% (P < 0.001). The cardioprotective effect of LU was abolished in the presence of L-NNA (IS 76 +/- 6%), whereas addition of L-Arg restored its cardioprotective effect (IS 56 +/- 2%; P < 0.05 vs. vehicle and L-NNA + LU groups). In protocol 2, the IS was 49 +/- 6% in the vehicle group and 32 +/- 4% in the L-NNA group (P = not significant). Myocardial ET-like immunoreactivity (ET-LI) increased in the vehicle group of protocol 1. ET-LI in the ischemic-reperfused myocardium was lower in the groups given LU (P < 0.01) and L-NNA + L-Arg + LU (P < 0.05) but not in the group given L-NNA + LU compared with the vehicle group. These results suggest that the cardioprotective effect of the ET(A) receptor antagonist is mediated via a mechanism related to NO.

Topics: Animals; Blood Pressure; Coronary Circulation; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Female; Heart Rate; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Phenylpropionates; Pyrimidines; Receptor, Endothelin A; Survival Rate; Swine

Hypoxia-inducible factor (HIF)-1alpha is an important transcriptional factor that activates the gene expression of glycolytic enzymes, which are activated as compensation for impaired beta-oxidation of fatty acid in the failing heart. We reported that cardiac endothelin (ET)-1 expression is markedly increased in heart failure. The mechanism, however, is unknown. Because we found an HIF-1alpha binding site in the 5'-promoter region of the ET-1 gene, we hypothesized that HIF-1alpha is involved in this mechanism.. In rat cardiomyocytes, luciferase assay and electrophoretic mobility shift assay showed that HIF-1alpha transcriptionally activates ET-1 gene expression by direct interaction with the predicted DNA binding site in the 5'-promoter region. HIF-1alpha mRNA and ET-1 mRNA in the failing heart increased during the aggravation of heart failure in vivo in animal models, ie, rats with myocardial infarction and hamsters with cardiomyopathy. In cultured cardiomyocytes treated with a mitochondrial inhibitor, HIF-1alpha mRNA and ET-1 mRNA were markedly increased with activated glycolysis, and antisense oligonucleotide for HIF-1alpha largely inhibited the increased gene expression of ET-1.. The present study revealed a novel molecular mechanism of upregulation of myocardial ET-1 in heart failure, indicating that induction of HIF-1alpha to stimulate glycolysis as an adaptation in heart failure against impaired energy metabolism alternatively causes an elevation of cardiac ET-1 gene expression as a maladaptation.

Topics: Adenosine Triphosphate; Animals; Binding Sites; Cells, Cultured; Cobalt; Cricetinae; DNA-Binding Proteins; DNA, Antisense; Endothelin-1; Energy Metabolism; Gene Expression Regulation; Hemodynamics; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Luciferases; Mitochondria; Myocardial Infarction; Myocardium; Nuclear Proteins; Promoter Regions, Genetic; Protein Binding; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Regulatory Sequences, Nucleic Acid; RNA, Messenger; Transcription Factors

We hypothesized that myocardial infarction induces regional and temporal differences in endothelin-1 (ET-1), atrial natriuretic peptide (ANP), and insulin-like growth factor-1 (IGF-1) gene expression that correlate with left ventricular (LV) wall stress. Echocardiography and LV pressure measurements were performed in coronary artery-ligated or sham-operated rats. Gene expression was measured by competitive RT-PCR in the infarct, border zone, and remote area and in regionally isolated cardiomyocytes. ET-1 and IGF-1 expression was highest in the infarcted myocardium, whereas ANP expression was highest in noninfarcted myocardium. For all genes, remote area expression was highest after 7 days. At 42 days, ANP maintained maximum expression, ET-1 decreased to 50% of peak levels, and IGF-1 was normalized. Cardiomyocyte expression followed the same pattern as in the myocardium except for a markedly lower IGF-1 expression. Diastolic wall stress was the best hemodynamic variable to predict ET-1 and ANP expression in the remote area. We conclude that ET-1, ANP, and IGF-1 are expressed in different patterns in the infarcted heart in relation to time, functional regions, cellular distribution, and mechanical load.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Diastole; Disease Models, Animal; Endothelin-1; Female; Gene Expression; Heart Ventricles; Hemodynamics; Insulin-Like Growth Factor I; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stress, Mechanical; Ventricular Function, Left

Studies of congestive heart failure (CHF) in man and in experimental CHF have demonstrated elevated circulating levels of endothelin (ET). In order to examine whether there are concomitant ET receptor alterations, the vasomotor effects of endothelin-1 (ET-1) and sarafotoxin 6c (S6c) were examined in endothelium-intact and -denuded isolated mesenteric arteries from rats with CHF. CHF was induced by ligation of the left anterior descending coronary artery. Vasomotor responses were studied using small mesenteric arteries (approx. 250 microm in diameter, determined after normalisation). The antagonists IRL2500 and FR139317 were used in order to characterise the ET-1-induced response. In mesenteric arteries with intact endothelium, ET-1-induced contractions were more potent in CHF as compared to sham (pEC(50) 9.6+/-0.2 and 9.1+/-0.1, respectively, P<0.01). In endothelium-denuded arteries, there was no difference in potency of ET-1 between CHF and sham arteries, or in maximum contraction. In the presence of IRL2500, a selective ET(B)-receptor antagonist, ET-1 was more potent in endothelium-denuded arteries of CHF rats, while this difference was not seen in sham arteries. S6c had no consistent contractile or dilatory effect in CHF and sham rats. The results indicate that the enhanced contractile effects of ET-1 noted in CHF might be due to an attenuated endothelial function and that inhibition of smooth muscle cell ET(B) receptors increase the effects of contractile ET(A) receptors in CHF rats.

Topics: Animals; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Failure; Male; Mesenteric Arteries; Myocardial Contraction; Myocardial Infarction; Potassium; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Vasoconstrictor Agents; Viper Venoms

To investigate the effects of endothelin blockade initiated immediately after the onset of myocardial infarction on survival and left ventricular remodeling, treatment with the nonselective receptor antagonist TAK-044 (n = 22) or saline (n = 19) for 3 weeks was initiated immediately after coronary ligation in rats. The 24-h survival rate was significantly lower in the TAK-044 group than in the saline group. The systolic blood pressure 24 h after the onset of myocardial infarction was similar in the saline and TAK-044 groups, although it was significantly lower in the TAK-044 group during the 3-week protocol. Heart weight/tibial length was significantly increased in the TAK-044 group compared with the saline group. As all deaths in the TAK-044 group occurred within 24 h after myocardial infarction, we performed additional experiments using a separate group of rats 12-16 h after myocardial infarction. Plasma and myocardial endothelin-1 levels were significantly increased, and a bolus injection of TAK-044 significantly reduced left ventricular dP/dtmax in these rats that had had a myocardial infarction compared with sham-operated rats. Endothelin receptor blockade initiated immediately after the onset of myocardial infarction may deteriorate acute-phase survival and left ventricular remodeling. Inhibition of the positive inotropic action of endothlin-1 may partially explain the increased 24-h mortality.

Topics: Animals; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Male; Myocardial Infarction; Peptides, Cyclic; Rats; Rats, Wistar; Receptors, Endothelin; Ventricular Remodeling

Cardiac endothelin-1 (ET-1) levels and ET receptor expression are increased in congestive heart failure (CHF). In order to determine whether this results in increased responsiveness of ET-A or ET-B receptors to ET-1, we evaluated the contractile effects of ET-1 in isolated papillary muscles isolated from hearts of control rats and from rats 4 weeks post myocardial infarction (MI) having received no therapy or chronic quinapril therapy. The ET-1 dose-response was biphasic in normal muscles. The use of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 revealed that the initial decrease in tension was the result of ET-B receptor stimulation. Blockade of nitric oxide (NO) production with L-NAME abolished the initial decrease in tension. MI resulted in CHF that was partially reversed by quinapril. In MI, the positive inotropic effects of ET-1 were enhanced due to the loss of the initial ET-B receptor mediated decrease in tension, as well as an increase in the positive inotropic effects of ET-A receptors. This was associated with an increase in ET-A and ET-B receptor mRNA and a decrease in cardiac ecNOS protein. Four weeks of therapy with quinapril attenuated the positive inotropic effects of ET-1 and prevented the increase in ET-A receptor mRNA. Although quinapril did not restore the effects of ET-B receptor stimulation or prevent the increase in ET-B mRNA, it did restore cardiac ecNOS protein expression. Thus, the inotropic response to ET-1 is biphasic due to an overall positive inotropic effect of ET-A receptor stimulation and an ET-B receptor mediated decrease in contractility at low ET-1 concentrations which appears to be mediated by cardiac ecNOS (NO). In post-MI CHF, responsiveness to ET-A receptors increases and the ET-B mediated negative inotropic response is lost despite an increase in both receptor subtypes. Quinapril therapy attenuates these effects and normalises cardiac ecNOS protein.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Binding, Competitive; Body Weight; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; Isoquinolines; Kinetics; Male; Muscles; Myocardial Contraction; Myocardial Infarction; Myocardium; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oligopeptides; Organ Culture Techniques; Organ Size; Papillary Muscles; Peptides, Cyclic; Piperidines; Protein Binding; Quinapril; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrahydroisoquinolines; Time Factors; Vasoconstrictor Agents; Viper Venoms

To observe the dynamic variations of blood lipids and circulatory endocrine factors in acute myocardial infarction(AMI) patients.. We determined plasma levels of ET-1, ANP, insulin and serum lipids on the 1st, 3rd, 7th and 14th day in 41 patients with acute myocardial infarction.. The serum levels of TC, LDL-C obviously decreased from the 3rd to the 7th day, and gradually elevated on the 14th day. The serum level of TG elevated gradually and showed significant difference after one week. HDL-C had no significant difference. The levels of ET-1 and insulin increased to highest level on the 1st day and decreased gradually since then. However, ANP reached the highest value on the 3rd day, and decreased markedly in fourteen days later. On the 1st day, only the concentration of insulin was negatively related with serum levels of TC, LDL-C(r = -0.376, -0.388, respectively, P < 0.05). The concentrations of blood lipids weren't related with circulatory endocrine factors during other phases.. The primary characteristics of blood lipids dynamic variations are the decrement of TC, LDL-C and the increment of TG during acute phase of AMI. Meanwhile, the concentrations of ET-1, ANP and insulin present dynamic variations and may effect the metabolism of blood lipids through some cytokines.

Topics: Aged; Atrial Natriuretic Factor; Cholesterol, LDL; Endothelin-1; Female; Humans; Insulin; Male; Middle Aged; Myocardial Infarction; Triglycerides

Clinical heart failure, often the result of myocardial infarction, may be preceded by a period of compensated left ventricular impairment. There is substantial need for an experimental model that reflects this human condition. In sheep, coronary artery ligation produced consistent left ventricular anteroapical myocardial infarctions resulting in chronic (5 wk), stable hemodynamic changes compared with sham controls, including reductions in ejection fraction (51 +/- 2 vs. 30 +/- 5%, P < 0.001), cardiac output (6.3 +/- 0.2 vs. 5.1 +/- 0.2 l/min, P < 0.01), and arterial pressure (93 +/- 2 vs. 79 +/- 3 mmHg, P < 0.001), and increases in cardiac preload (left atrial pressure, 3.3 +/- 0.1 vs. 8.3 +/- 1.3 mmHg, P < 0.001). These changes were associated with acute and sustained increases in plasma concentrations of atrial natriuretic peptide (ANP; 5 wk, 11 +/- 2 vs. 27 +/- 5 pmol/l, P < 0.001), brain natriuretic peptide (BNP; 3 +/- 0.2 vs. 11 +/- 2 pmol/l, P < 0.001), and amino-terminal pro-brain natriuretic peptide (NT-BNP; 17 +/- 3 vs. 42 +/- 12 pmol/l, P < 0.001). Significant correlations were observed between plasma levels of the natriuretic peptides (ANP, day 7 to week 5 samples; BNP and NT-BNP, day 1 to week 5 samples) and changes in left ventricular volumes and ejection fraction. In contrast, renin activity, aldosterone, catecholamines, and endothelin were not chronically elevated postinfarction and were not related to indexes of ventricular function. Coronary artery ligation in sheep produces the pathological, hemodynamic, and neurohormonal characteristics of compensated left ventricular impairment secondary to myocardial infarction. Plasma concentrations of the cardiac natriuretic peptides are sensitive markers of left ventricular dysfunction. This is a reproducible model that reflects the clinical condition and should prove suitable for investigating the pathophysiology of, and experimental therapies in, early left ventricular dysfunction.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Coronary Vessels; Disease Models, Animal; Endothelin-1; Epinephrine; Female; Hemodynamics; Ligation; Myocardial Infarction; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Neuropeptides; Norepinephrine; Peptide Fragments; Renin; Sheep; Ventricular Dysfunction, Left

A comparative analysis of the content of the soluble form of cell adhesion protein P-selectin in the blood plasma of patients with acute myocardial infarction (AMI), massive atherosclerosis (MA) and primary pulmonary hypertension (PPH), investigation of the relationship between plasma content of P-selectin and known markers of platelets and endothelial cells activation, preliminary assessment of the prognostic value of P-selectin determination.. This study included 16 patients with AMI, 20 patients with MA, 21 patients with PPH and 18 healthy donors. The follow-up was 1-5 years. End-points in the group of patients with AMI were recurrent acute coronary syndrome and coronary artery by-pass operation, in the group with MA--thrombotic complications (acute coronary syndrome, ischemic stroke) and in the group with PPH--death. P-selectin was measured by ELISA and platelet factor 4 (PF4), thromboxane B2 (TXB2), endothelin-I and stable prostacyclin metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) by means of commercial ELISA kits.. Mean level of P-selectin in blood plasma of patients with AMI (1 day) (361 +/- 18 ng/ml), MA (410 +/- 31 ng/ml) and PPH (627 +/- 83 ng/ml) was increased in comparison with the group of healthy donors (269 +/- 12 ng/ml) (everywhere p < 0.001). In AMI, P-selectin was increased on day 1 only, on days 2, 3 and 10-14 of the disease the level of P-selectin was significantly lower than on day 1 and did not differ from the control level in the group of donors. In patients with MA a significant correlation was detected between plasma content of P-selectin and platelet activation marker PF4 (r = 0.606, P = 0.007) and in patients with PPH between the content of P-selectin and another platelet activation marker TXB2 (r = 0.622, p = 0.013). However, no correlation was found in PPH patients between the content of P-selectin and markers of endothelial activation and/or damage (endothelin-1 and 6-keto-PGF1 alpha). Difference in the concentration of P-selectin in patients with or without end-points during the follow-up period was detected in patients with AMI (353 +/- 14 ng/ml and 451 +/- 24 ng/ml, p = 0.009) and PPH (477 +/- 58 ng/ml and 927 +/- 184 ng/ml, p = 0.017) but not with MA (426 +/- 37 ng/ml and 361 +/- 24 ng/ml, p = 0.295).. The level of P-selectin in plasma was increased in patients with acute thrombosis (AMI, 1 day) as well as in patients without clinical signs of thrombosis but with a massive injury of the vasculature (MA and PPH). The increase of P-selectin was, presumably, caused by its secretion from activated platelets since its concentration in plasma correlated with platelet concentration but not endothelial activation markers. Preliminary data indicate that blood plasma soluble P-selectin may be considered as a potential prognostic marker in AMI and PPH.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Arteriosclerosis; Biomarkers; Blood Coagulation; Blood Vessels; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Myocardial Infarction; P-Selectin; Platelet Activation; Platelet Factor 4; Prognosis; Solubility; Thromboxane B2

To elucidate the effect of selective endothelin ET(A)- and mixed ET(A/B)-receptor antagonists on endothelial vasomotor dysfunction in rats with heart failure after myocardial infarction (MI).. Vasoreactivity and superoxide anion formation were determined in aortic rings from Wistar rats 12 weeks after extensive MI (>46% of left ventricle) compared to sham-operated animals. Rats were either treated with the selective ET(A)-receptor antagonist LU 135252 (30 mg/kg/day), the mixed ET(A/B)-receptor antagonist Bosentan (100 mg/kg/day) or placebo.. In MI rats, the concentration-response curve of the endothelium-dependent, nitric oxide-mediated relaxation induced by acetylcholine was significantly shifted to the right and the maximum relaxation was attenuated. Long-term treatment with both ET antagonists significantly improved acetylcholine-induced relaxation in MI rats. LU 135252 was more effective than Bosentan. Endothelium-independent relaxations induced by sodium nitroprusside as well as endothelin- and phenylephrine-induced contractions were similar in all groups of rats. Plasma renin activity and aortic superoxide formation, which were enhanced in rats with heart failure, were normalized by LU 135252, but not by Bosentan treatment.. Long-term treatment with ET-receptor antagonists improves endothelial vasomotor dysfunction in rats with chronic MI. This mechanism may essentially contribute to the beneficial effects of ET receptor blockade in heart failure.

Topics: Acetylcholine; Analysis of Variance; Animals; Aorta; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Failure; In Vitro Techniques; Male; Myocardial Infarction; Nitroprusside; Oxygen; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Renin; Sulfonamides; Superoxide Dismutase; Vasoconstrictor Agents; Vasodilator Agents

The relative efficacy of endothelin-A (ET(A)) receptor blockade versus combined ET(A)-ET(B) receptor blockade in chronic heart failure (CHF) is still largely unknown.. We compared, in a rat model of CHF (coronary ligation), the hemodynamic and structural effects of 1 month of treatment with the ET(A) antagonist ABT-627 (5 mg x kg(-1) x d(-1)), the ET(B) antagonist A-192621 (30 mg x kg(-1) x d(-1)) or a combination of the 2 drugs. Doses were chosen for their capacity to block the pressor response to ET-1 (for ET(A) blockade) or the depressor responses to sarafotoxin S6c or ET-1 (for ET(B) blockade). ET(A) and combined ET(A)-ET(B) blockade reduced systolic blood pressure to the same extent, whereas ET(B) blockade had no effect. In contrast, only combined ET(A)-ET(B) blockade significantly reduced heart rate. Both ET(A) and combined ET(A)-ET(B) blockade, but not ET(B) blockade alone, increased left ventricular (LV) fractional shortening and wall thickening and reduced LV end-diastolic pressure, as well as LV end-diastolic and end-systolic volumes. However, all treatments (including ET(B) blockade) decreased LV collagen accumulation.. The chronic blockade of both ET(A) and ET(B) receptors improved systemic hemodynamics, as well as LV function and remodeling, to the same extent as ET(A) receptor blockade alone. However, only combined ET(A)-ET(B) receptor blockade decreased heart rate. Whether this differential effect on heart rate affects the long-term outcome after treatment with ET(A) or mixed ET(A)-ET(B) antagonists in CHF remains to be determined.

Topics: Animals; Atrasentan; Blood Pressure; Collagen; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Myocardial Infarction; Myocardium; Pyrrolidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Ventricular Function, Left

Endothelium-derived nitric oxide (NO) and endothelin (ET)-1 interact to regulate vascular tone. In congestive heart failure (CHF), the release and/or the activity of both factors is affected. We hypothesized that the increased ET-1 production associated with CHF may result in a reduced smooth muscle sensitivity to NO. The aim of this study was to evaluate the effects of a chronic treatment with the ET(A)-receptor (ET receptor A) antagonist LU-135252 (LU) on cerebrovascular reactivity to sodium nitroprusside (SNP) in the rat infarct model of CHF. Rats were subjected to coronary artery ligation and were treated for 4 wk with placebo (n = 24) or LU (50 mg. kg(-1). day(-1), n = 29). CHF was associated with a decreased (P < 0.05) efficacy of SNP to induce relaxation of isolated middle cerebral arteries. Furthermore, neither NO synthase inhibition with N(omega)-nitro-L-arginine (L-NNA) nor endothelial denudation affected the efficacy of SNP. Thus the endothelium no longer influences smooth muscle sensitivity to SNP. LU treatment, however, normalized (P < 0.05) smooth muscle sensitivity to SNP. Sensitivity of ET-1-induced contraction was increased in CHF only in the presence of L-NNA, whereas contraction induced by ET(B) receptor (receptor B) stimulation was increased (P < 0.05) in endothelium-denuded vessels. LU treatment restored these changes in reactivity and revealed a significant endothelium-dependent ET(B)-mediated relaxation after NO synthase inhibition. In conclusion, CHF decreases and uncouples cerebrovascular smooth muscle sensitivity to SNP from endothelial regulation. The observation that chronic ET(A) blockade restored most of the changes associated with CHF suggests that activation of the ET-1 system importantly contributes to the alteration in vascular reactivity observed in experimental CHF.

Topics: Animals; Cerebral Arteries; Electrocardiography; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Myocardial Infarction; Nitroarginine; Nitroprusside; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; Vasoconstrictor Agents; Vasodilation; Viper Venoms

Endothelin-1 (ET-1) has been implicated as a mediator of increased vascular tone during development of heart failure post-myocardial infarction (MI). In the present study, expression and pharmacology of ET-1 and its receptors were studied in small mesenteric arteries from rats at 5 and 12 weeks after coronary artery ligation for induction of MI, or sham-operation. In vessels from sham-operated and 5 week post-MI rats preproET-1mRNA, immunoreactive (ir) ET-1, ET(B) receptor mRNA and irET(B) receptor were confined to the endothelium, while ET(A) receptor mRNA was distributed throughout the media. At 12 weeks post-MI, preproET-1 and irET(A) receptor localization was similar but ET(B) receptor mRNA and immunoreactivity were detectable in the media, as well as the endothelium. The ET-1 concentration-response curve (CRC) was progressively shifted to the right in pressurized third generation mesenteric arteries from 5 and 12 week post-MI rats relative to sham-operated rats, with no change in the maximum. The ET(A) receptor antagonist BQ-123 (10(-6) M) induced a rightward shift of the ET-1 CRC in all vessels. Desensitization of ET(B) receptors, by exposure to SRTX S6c (3x10(-8) M), had no effect on the ET-1 CRC in vessels from 5 week post-MI or sham-op rats but induced a leftward shift in vessels from 12 week post-MI rats. These results identify the endothelium as the primary site of ET-1 synthesis in small arteries and the ET(A) receptor as mediating the effects of ET-1 in these vessels. However, ET(B) receptor expression increases in vascular smooth muscle post-MI and is linked to mechanisms that inhibit the contractile response to ET-1.

Topics: Animals; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Gene Expression Regulation; In Vitro Techniques; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Myocardial Infarction; Peptides, Cyclic; Potassium Chloride; Protein Precursors; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Survival Analysis; Up-Regulation; Vasoconstriction; Viper Venoms

To test the hypothesis that calcium antagonists protect the myocardium from reperfusion-induced damage by local myocardial mechanisms just at the time of reperfusion, the myocardioprotective effects of the dihydropyridine clevidipine were investigated, taking advantage of its ultrashort-acting effect. Pigs were subjected to 45 min of myocardial ischemia by occlusion of the left anterior descending coronary artery followed by 4 h of reperfusion. Either clevidipine (0.3 nmol/kg/min, n = 6) or the corresponding amount of vehicle (n = 6) was administered to the ischemic myocardium by retrograde coronary venous infusion over a 30-min period starting 10 min before reperfusion. Hemodynamic variables (heart rate, left ventricular systolic and end-diastolic pressure, max dP/dt, and mean arterial blood pressure) as well as coronary blood flow were measured throughout the experiment. At the end of reperfusion, the area at risk (percentage of left ventricle) was determined by infusion of Evans blue into the left atrium, and the infarct size, by triphenyl tetrazolium chloride (TTC) staining. The plasma level of endothelin-like immunoreactivity (ET-LI) was analyzed in blood from the aorta and the anterior coronary vein before ischemia and at different times during reperfusion. The area at risk was similar in the vehicle and the clevidipine groups. The infarct size, expressed as a percentage of the area at risk, was 80 +/- 9.2 in the vehicle group, whereas it was significantly reduced to 51 +/- 9.2% in the clevidipine group (p < 0.01). Clevidipine did not influence any of the hemodynamic variables measured throughout the study. A nonsignificant trend toward decreased total ET-LI overflow during 4-h reperfusion was observed in the clevidipine-treated pigs compared with vehicle-treated ones (5.3 +/- 1.4 vs. 7.1 +/- 3.4 pmol). These results demonstrate that, in this model of ischemia/reperfusion-induced myocardial infarction, clevidipine reduced the damage to the myocardium when given in association with reperfusion. The local administration of the compound together with its short blood half-life shows that clevidipine reduces reperfusion-induced damage by local mechanisms within the ischemic tissue rather than by peripheral mechanisms.

Topics: Animals; Calcium; Calcium Channel Blockers; Coronary Circulation; Endothelin-1; Female; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Pyridines; Swine

We describe the pharmacological characteristics of SM-19712 (4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl] benzenesulfonamide, monosodium salt). SM-19712 inhibited endothelin converting enzyme (ECE) solubilized from rat lung microsomes with an IC50 value of 42 nM and, at 10 - 100 microM, had no effect on other metalloproteases such as neutral endopeptidase 24.11 and angiotensin converting enzyme, showing a high specificity for ECE. In cultured porcine aortic endothelial cells, SM-19712 at 1 - 100 microM concentration-dependently inhibited the endogenous conversion of big endothelin-1 (ET-1) to ET-1 with an IC50 value of 31 microM. In anesthetized rats, either intravenous (1-30 mg/kg) or oral (10-30 mg/kg) administration of SM-19712 dose-dependently suppressed the pressor responses induced by big ET-1. In acute myocardial infarction of rabbits subjected to coronary occlusion and reperfusion, SM-19712 reduced the infarct size, the increase in serum concentration of ET-1 and the serum activity of creatinine phosphokinase. The present study demonstrates that SM-19712 is a structurally novel, nonpeptide, potent and selective inhibitor of ECE, and SM-19712 is a valuable new tool for elucidating the pathophysiological role of ECE.

Topics: Acute Disease; Animals; Aspartic Acid Endopeptidases; Disease Models, Animal; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Glycopeptides; Lung; Male; Metalloendopeptidases; Myocardial Infarction; Pressoreceptors; Rabbits; Rats; Rats, Sprague-Dawley; Substrate Specificity; Sulfonamides; Sulfonylurea Compounds; Swine

Whilst endothelin (ET) receptor antagonism has been evaluated in post-myocardial infarction (MI) remodeling, endothelin-converting enzyme (ECE) inhibition has not been determined. In the study reported here female Sprague-Dawley rats underwent coronary artery ligation, then were randomized 24 h post-MI to either no therapy (control) or 7 days therapy with the highly selective ECE inhibitor, FR901533 (Fujisawa, Osaka, Japan) 100 mg/kg/day, by continuous subcutaneous infusion. Echocardiography [fractional shortening (FS), internal dimensions and relative wall thickness (RWT)] and invasive hemodynamics were performed before sacrifice on day 8, with subsequent cardiac immunohistochemistry. Plasma concentrations of ET-1 and big ET-1 (39 AA) were determined by enzyme-linked immunosorbent assay (ELISA). ECE inhibitor-treated rats [n = 6, infarct size (IS) 37 +/- 2%) were compared to control rats with similar size MI (n = 8, IS 38 +/- 3%). Values for sham-operated rats were: RWT 0.49 +/- 0.02; left ventricular end-diastolic diameter (LVEDD) 6.2 +/- 0.5 mm; left ventricular end-systolic diameter (LVESD) systolic3.5 +/- 0.5 mm; blood pressure (SBP) 119 +/- 4 mmHg; heart rate 340 +/- 21 bpm; and left ventricular end-diastolic pressure (LVEDP) 12 +/- 2 mmHg, FS 46 +/- 4%. ECE inhibition was confirmed by increased big ET-1 to ET-1 ratio (0.23 +/- 0.06 vs 0.05 +/- 0.02, ECE inhibitor vs control, p < 0.05). ECE inhibitor increased RWT (0.43 +/- 0.03 vs 0.35 +/- 0.02, p < 0.05) contributed to by reduced left ventricular (LV) internal dimensions (EDd 7.5 +/- 0.4 vs 7.9 +/- 0.3 mm, ESd 5.2 +/- 0.5 vs 5.6 +/- 0.3 mm, ECE inhibitor vs control respectively). There were also trends in ECE inhibitor rats to increased FS (31 +/- 4 vs 29 +/- 2%), decreased SBP (99 +/- 4 vs 104 +/- 4 mmHg), heart rate (355 +/- 28 vs 385 +/- 12 bpm) and LVEDP (23 +/- 2 vs 25 +/- 1 mmHg), all p = NS, ECE inhibitor vs control. Immunoreactive cardiac collagen I peptide was unchanged by ECE inhibitor, however, alpha-smooth muscle actin, a marker of myofibroblast activation, was decreased in the infarct zone of ECE inhibitor rats (35 +/- 4 vs 46 +/- 3%, ECE inhibitor vs control, p < 0.05). This study concludes that selective ECE inhibitor with FR901533 reduces the conversion of big ET-1 to ET-1 in post-MI rats and improves some parameters of cardiac remodeling early post-MI. However, longer-term studies are needed fully to assess the therapeutic potential of ECE inhibitor post-MI and in heart failure.

Topics: Animals; Aspartic Acid Endopeptidases; Echocardiography; Endothelin-1; Endothelin-Converting Enzymes; Female; Hemodynamics; Immunohistochemistry; Metalloendopeptidases; Myocardial Infarction; Protease Inhibitors; Rats; Rats, Sprague-Dawley; Tetracyclines; Ventricular Function, Left

Estrogen may increase the long-term survival of women who have suffered from a myocardial infarction (MI). We examined the acute and chronic influence of estrogen on MI in the rat left coronary artery ligation model.. Female Sprague-Dawley rats (10 to 12 weeks, n=93), divided into 3 groups (rats with intact ovaries, ovariectomized rats administered 17beta-estradiol [17beta-E(2)] replacement, and ovariectomized rats administered placebo 2 weeks before MI), were randomized to left coronary artery ligation (n=66) or sham-operated (n=27) groups. Ten to 11 weeks after MI, rats were randomly assigned to either (1) assessment of left ventricular (LV) function and morphometric analysis or (2) measurement of cardiopulmonary mRNA expression of preproendothelin-1 and endothelin A and B receptors. Acutely, estrogen was associated with a trend toward increased mortality. Infarct size was increased in the 17beta-E(2) group compared with the placebo group (42+/-2% versus 26+/-3%, respectively; P:=0.01). Chronically, wall tension was normalized through a reduction in LV cavity size with estrogen treatment (419+/-41 mm Hg/mm for 17beta-E(2) versus 946+/-300 mm Hg/mm for placebo, P:=0.039). In the LV, there was a 2.5-fold increase in endothelin B mRNA expression after MI in placebo-treated rats (P:=0.004 versus sham-operated rats) that was prevented in the 17beta-E(2) group (P:=NS versus sham-operated rats).. These results suggest that estrogen is detrimental at the time of MI or early post-MI period, resulting in an increased size of infarct or infarct expansion, but chronically, it can normalize wall tension and inhibit LV dilatation, which may in turn lead to increased long-term survival. Regulation of the endothelin system, particularly the expression of the endothelin B receptor, may contribute to these estrogenic effects.

Topics: Animals; Disease Models, Animal; Endothelin-1; Estradiol; Estrogen Replacement Therapy; Female; Myocardial Infarction; Ovariectomy; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Ventricular Remodeling

We employed cDNA microarrays representing 4000 distinct sequences to profile changes in gene expression in a rodent model of heart disease, namely, progression to heart failure after myocardial infarction. Differential gene expression in the left ventricle was examined at 4-week intervals over a 12-week period after coronary artery ligation in rats. Over this time course, insulin-like growth factor-binding protein-3 (IGFBP-3) was found to have a greater expression than in nondiseased tissues. We then employed quantitative real-time PCR to analyze gene expression in neonatal rat cardiac myocytes that had been treated with recombinantly expressed IGFBP-3 to examine a number of transcriptional responses designed to reflect the heart failure phenotype. The IGFBP-3 protein was shown to induce transcription of atrial natriuretic factor (ANF) and beta-myosin heavy chain (B-MHC). Analysis of conditioned media taken from IGFBP-3-treated cardiac myocyte cultures demonstrated an increase in ANF protein as well as in protein synthesis, as determined by metabolic incorporation of a radiolabeled amino acid. However, transcriptional changes of troponin-1, endothelin-1, or angiotensin-II by IGFBP-3 were not observed.

Topics: Angiotensin II; Animals; Animals, Newborn; Atrial Natriuretic Factor; Cells, Cultured; Coronary Vessels; Disease Models, Animal; Disease Progression; Endothelin-1; Gene Expression Profiling; Gene Expression Regulation; Heart Ventricles; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Myocardial Infarction; Myocardium; Myosin Heavy Chains; Nonmuscle Myosin Type IIB; Oligonucleotide Array Sequence Analysis; Rats; RNA, Messenger; Transforming Growth Factor beta; Troponin I

The aim of this work was to investigate the influence of endothelin on myocardial ischemia and reperfusion in anaesthetized dogs. Animals were submitted to left thoracotomy and 120 min of left anterior descending coronary occlusion, followed by 180 min of reperfusion. Arterial blood pressure and electrocardiogram (ECG) were recorded in order to analyze heart rate (HR)-pressure product and production of ectopic beats. Infarcted areas were identified by a macroscopic staining method and infarct size was expressed as percentage of risk zone. To inhibit the effects of endothelin in a group of animals, we administered intravenously an endothelin synthesis inhibitor (phosphoramidon) and in another group, an endothelin-1 A receptor blocker (BQ-123). Phosphoramidon decreased the HR-pressure product during reperfusion period, and both, phosphoramidon and BQ-123 decreased infarct size by 40% and the number of ventricular ectopic beats by 88% and 68%, respectively, as compared to the saline treated dogs. In conclusion, endothelin seems to play a deleterious role on the myocardium submitted to ischemia and reperfusion.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Coronary Disease; Dogs; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Glycopeptides; Injections, Intravenous; Myocardial Infarction; Myocardial Reperfusion; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Endothelin; Ventricular Fibrillation; Ventricular Premature Complexes

There is accumulating evidence that endothelin-1 plays an important role in vascular pathophysiology. Our objective was to examine whether molecular variations at the endothelin-1 locus were involved in susceptibility to myocardial infarction and variation in blood pressure. The entire coding sequence and 1.4 kb of the 5' flanking region were screened. Five polymorphisms were detected, which were genotyped in the ECTIM (Etude Cas-Témoin de l'Infarctus du Myocarde) Study, a multicenter study comparing 648 male patients who had survived a myocardial infarction and 760 population-based controls. The polymorphisms were not associated with myocardial infarction, nor did they contribute to blood pressure levels in the population at large. However, a G/T polymorphism predicting an Lys/Asn change (ET1/C198) strongly interacted (P<0.001) with body mass index in the determination of blood pressure levels. There was a steeper increase of blood pressure with body mass index in carriers of the T allele than in GG homozygotes. As a consequence, the T allele was associated with an increase of blood pressure in overweight subjects (body mass index >/=26 kg/m2), while no significant effect was observed in lean subjects (body mass index <26 kg/m2). To determine whether this finding could be replicated, the ET1/C198 was genotyped in the Glasgow Heart Scan Study, a population-based study including 619 men and 663 women. Subjects homozygous for the T allele had higher resting blood pressure levels than others (P<0.05). A similar interaction between the T allele and body mass index was observed on the maximum blood pressure achieved during a treadmill exercise test (P<0.001). In conclusion, results from 2 independent studies suggest that the ET1/C198 polymorphism is associated with blood pressure levels in overweight people.

Topics: Adult; Alleles; Analysis of Variance; Blood Pressure; Body Mass Index; Cross-Sectional Studies; Endothelin-1; Female; Genetic Predisposition to Disease; Genotype; Heart Rate; Homozygote; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Transcription, Genetic

We measured plasma concentrations of vasoactive peptides in 32 patients with acute myocardial infarction and evaluated their value as markers of left ventricular dysfunction. Plasma levels of atrial natriuretic peptide (ANP), the N-terminal fragment of proANP (NT-proANP), B-type natriuretic peptide (BNP) and endothelin-1 were measured serially by radioimmunoassays. The infarct size was estimated from the creatine kinase MB release curve. Coronary angiography and left ventricular cineangiography were performed in all patients during hospitalization and 6 months later in 15 patients. Myocardial infarction caused an increase in vasoactive peptides, the highest values for ANP (36.5+/-6.79 pmol/l), NT-proANP (1130+/-170 pmol/l) and endothelin-1 (9.72+/-0.68 pmol/l) being found on admission and those for BNP (56.0+/-7.13 pmol/l) on Day 2. Plasma levels of natriuretic peptides were dependent on infarct size, its location and degree of myocardial dysfunction and that of BNP also on infarct artery patency. Plasma endothelin-1 level was higher in patients with TIMI 3 than TIMI 0-2 flow. Plasma vasoactive peptides remained elevated during the 6-month follow-up period and they were dependent on the degree of myocardial dysfunction. BNP measured on any day of hospitalization showed the best correlation with ejection fraction measured during the acute phase of infarction or at 6 months. The results show that BNP is the best indicator of left ventricular dysfunction after myocardial infarction and its reliability is not dependent on the time point of measurement.

Topics: Analysis of Variance; Atrial Natriuretic Factor; Creatine Kinase; Endothelin-1; Female; Humans; Isoenzymes; Male; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; Regression Analysis; Time Factors; Ventricular Dysfunction, Left

An elevated plasma level of endothelin-1 was reported in several cardiovascular conditions including unstable angina pectoris and myocardial infarction. The present study was designed to evaluate the time course of the endothelin-1 release in unstable angina pectoris and to assess its relationship to the development of myocardial infarction and coronary vessel occlusion. The cohort studied included 32 patients with the clinical diagnosis of unstable angina pectoris who had been admitted to the coronary care unit and subsequently underwent coronary angiography (group A). Fourteen patients with chronic stable angina pectoris referred to routine diagnostic coronary angiography served as the control group (group B). A significant difference in the endothelin-1 plasma level was found between both groups, the values being 10.2 +/- 5.3 and 6.0 +/- 3.1 pg/ml (p < 0.01), respectively. There were, however, no significant differences between the following subdivisions of group A: patients with and without subsequent myocardial infarction; those with angiographically documented occlusion of at least one major branch of the coronary artery and no occlusion; and finally, those with persisting symptoms of angina pectoris and with favorable response to treatment. Neither was there any difference found among the subgroups differing in the time interval between the onset of chest pain and blood sampling. The time course of endothelin plasma concentrations showed elevated values lasting for more than 96 h after the index episode of prolonged chest pain. No correlation with the subsequent clinical course could be inferred. Thus, plasma endothelin level was elevated in patients with unstable angina pectoris and myocardial infarction and the increase persisted for several days after the onset of symptoms.

Topics: Adult; Aged; Angina, Unstable; Biomarkers; Coronary Angiography; Endothelin-1; Female; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Reference Values; Sensitivity and Specificity; Time Factors

The study was designed to assess temporal changes in atrial natriuretic peptide (ANP) and endothelin-1 (ET) concentrations in patients hospitalized for acute myocardial infarction (AMI) and their relationships to cardiac performance determined by radionuclide ventriculography.. 20 patients with first AMI were studied. Blood samples were drawn within the first 4-18 h, after 18-24 h, and on days 2, 3 and 6. Plasma concentrations of ANP and ET were measured in blood samples taken simultaneously. Radionuclide ventriculography was performed on the day of discharge to determine left-ventricular ejection fraction (LVEF), left-ventricular end-diastolic volume index, end-systolic volume index and left-ventricular stroke volume index.. Median concentrations of ET decreased from 2.15 pmol/l on admission to 1.45 pmol/l at discharge (32%, p < 0.001). Median ANP rose from 29 to 79 pg/ml (172%, p < 0.001). The increment in ANP and the decrease in ET concentrations from admission to discharge was inversely correlated (r = -0.81, p < 0.005). ANP was inversely correlated to LVEF (r = -0.82, p < 0.001) and to the end-systolic volume index at discharge (r = -0.73, p < 0.003).. Dynamic and inverse fluctuations in ET and ANP occur within the 1st week of AMI. The magnitude of endocrine activation in the ANP-ET system seems to reflect an impairment in the left-ventricular systolic performance.

Topics: Atrial Natriuretic Factor; Endothelin-1; Female; Follow-Up Studies; Hospitalization; Humans; Male; Middle Aged; Myocardial Contraction; Myocardial Infarction; Radioimmunoassay; Radionuclide Ventriculography; Stroke Volume; Ventricular Function, Left

The hemodynamic effects of enalapril, an angiotensin-converting enzyme inhibitor, BQ-123, a selective ETA receptor antagonist, and bosentan, a nonselective ETA and ETB receptor antagonist, were studied in dogs 4 weeks after myocardial infarction (MI) produced by ligation of the left anterior descending coronary artery. Reduced arterial pressure and total peripheral resistance after administration of analapril, BQ-123, and bosentan revealed that both the renin-angiotensin system and endothelin participate in maintenance of cardiovascular function in chronic MI.

Topics: Animals; Antihypertensive Agents; Bosentan; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hemodynamics; Male; Myocardial Infarction; Peptides, Cyclic; Receptor, Endothelin A; Receptor, Endothelin B; Renin-Angiotensin System; Structure-Activity Relationship; Sulfonamides

We have previously reported that production of endothelin (ET)-1 is markedly increased in failing hearts of rats with chronic heart failure (CHF). It was also reported that the production of angiotensin II (Ang II) is increased in the failing heart. In this study we investigated both converting enzymes of the ET-1 system and the angiotensin system. We used left coronary artery-ligated rats as a model of CHF. The peptide level of ET-1 in the left ventricle (LV) was markedly higher in CHF rats than in control rats. In the LV, expression of preproET-1 mRNA was also markedly higher in CHF rats than in controls. The expression of endothelin-converting enzyme (ECE)-1 mRNA in the rats with CHF was similar to that in controls. Therefore, we believed that the increase in ET-1 production in the failing heart originated from an increase in preproET-1 production rather than increase in ECE. The expression of angiotensin-converting enzyme (ACE) mRNA in failing hearts of CHF rats was significantly higher than that of the sham-operated rats. The expression of angiotensinogen mRNA in failing hearts of these CHF rats was slightly higher than that of the sham-operated rats. This study suggests that there is a difference in the role of peptide synthesis between the ECE system and the ACE system in rats with CHF.

Topics: Angiotensinogen; Animals; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Enzyme Induction; Heart Failure; Hemodynamics; Male; Metalloendopeptidases; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger

Endothelin is a very potent vasoconstrictor peptide produced by the vascular endothelium. Several studies have shown that the endothelin system is activated in various cardiovascular conditions, including myocardial infarction, heart failure and pulmonary hypertension. The known actions of the endothelin-1 isoform suggest that it may be an important mediator in several of the pathophysiological manifestations of heart failure. Data on the potential value of endothelin antagonists in heart failure are reviewed.

Topics: Endothelin-1; Endothelins; Endothelium, Vascular; Heart Failure; Humans; Hypertension, Pulmonary; Myocardial Infarction

The pulmonary vascular bed is a major site for endothelin-1 (ET-1) clearance. A reduced clearance could contribute to the increase in circulating ET-1 levels found in heart failure (HF). We therefore evaluated the effect of HF on pulmonary ET-1 clearance and on plasma ET-1 concentrations.. Rats with myocardial infarction (n=24) were compared with sham-operated rats (n=22). The lungs were isolated and perfused at a constant flow rate of 10 mL/min. Pulmonary ET-1 clearance was measured by the single-bolus indicator-dilution technique with 125I-labeled ET-1. Infarct rats developed HF with mild pulmonary hypertension. ET-1 extraction was reduced by HF from 63+/-1.5% to 41+/-4.5% (mean+/-SEM, P<0.001). Mixed venous (MV) and aortic ET-1 levels doubled with HF. There was a plasma ET-1 gradient across the lungs of sham rats (MV-aortic levels, 0.21+/-0.12 pg/mL) but not in lungs of HF rats (0.01+/-0.17 pg/mL). Plasma ET-1 levels correlated closely and inversely with ET-1 extraction (P<0.001).. HF is associated with reduced pulmonary ET-1 clearance that contributes to the increase in circulating levels.

Topics: Animals; Cardiac Output, Low; Endothelin-1; Lung; Male; Metabolic Clearance Rate; Myocardial Infarction; Rats; Rats, Wistar

The key role of endothelin-1 (ET-1) has been recognised in patients with ischaemic heart disease. However, the serial changes of ET-1 during both brief and prolonged ischaemia-reperfusion are poorly known. Serial changes of plasma ET-1 were measured during myocardial stunning (MS) and acute myocardial infarction (AMI). The effects of magnesium (Mg), diltiazem and a MAC-1 inhibitor on the plasma ET-1 were elucidated. Forty-nine swine underwent brief (8 min) or prolonged (50 min) coronary artery occlusion followed by reperfusion. ET-1 plasma concentration was measured by ELISA at prespecified time points. The occlusion was associated with a decline of ET-1 followed by a significant increase during the reperfusion. Mg as well as diltiazem similarly affected the plasma ET-1 by reducing ET-1 release during the first hour of the reperfusion period. MAC-1 inhibition was also associated with decreases of ET-1. Ability of Mg, diltiazem and leumedins to decrease the ET-1 plasma level may have direct clinical implications for the use of these agents in patients with coronary artery disease.

Topics: Animals; Diltiazem; Endothelin-1; Female; Leucine; Macrophage-1 Antigen; Magnesium; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Stunning; Swine

There is little information available regarding local vasomotor regulating processes in chronic heart failure. In this study, we tested the hypothesis that chronic heart failure impaired the endothelial function, and long term captopril treatment might reverse endothelial activity through tissue endothelin (ET) pathway.. Forty Sprague-Dawley rats were divided into 4 groups including 15 rats in each of the sham-operated with or without captopril-treated groups and 5 rats in each of large infarcted with or without captopril-treated groups.. Concentration-response curves obtained in aortic rings without endothelium revealed no difference in nitroprusside-induced relaxation. With endothelium, rightward shifting was noted only in the untreated large infarct group during acetylcholine-induced relaxation. As compared to the non-treated group, plasma ET-1 concentrations were lower in the captopril-treated with or without large infarct groups. However, endothelin-like immunoreactivity in endothelial cells and cytoplasma of smooth muscle cells of the media of the aorta were lower only in the non-treated large infarct group.. Endothelial function was impaired in the chronic heart failure model. Coverting enzyme inhibitor might improve endothelial function through the Local endothelin pathway.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Captopril; Endothelin-1; Hemodynamics; Male; Myocardial Infarction; Random Allocation; Rats; Rats, Sprague-Dawley; Ventricular Dysfunction, Left

Plasma endothelin (ET) concentrations are increased in heart failure. The aims of the present study were to investigate to what extent cardiac ET mRNA expression is induced in ischemic heart failure and whether there may be compensatory downregulation of myocardial mRNA levels for the ETA and ETB receptor subtypes.. In rats with ischemic heart failure (left ventricular end-diastolic pressure > 15 mmHg) due to left coronary artery ligation. Northern blot analyses were performed on mRNA isolated from cardiac tissues.. A substantial upregulation was revealed in all chambers of the failing hearts. Up to 27-fold upregulation (mean 10.6 +/- 4.0, P = 0.002) of left ventricular ET-1 mRNA levels was measured 1 week after myocardial infarction, whereas only a modest upregulation was detected after 6 weeks (mean 2.7 +/- 0.5, P < 0.05). Ribonuclease protection assay revealed 2.8 +/- 0.4-fold higher levels of ET-1 mRNA in the left ventricular area subjected to myocardial infarction compared to the non-infarcted tissue after 1 week. Left ventricular ET-1 mRNA correlated significantly with left ventricular end-diastolic pressure after 1 week (r2 = 0.86, P = 0.007). The ETA and ETB receptor mRNA levels tended to increase 1 week after myocardial infarction although these changes were not statistically significant.. Cardiac ET-1 mRNA levels are increased in ischemic heart failure and correlate significantly with left ventricular end-diastolic pressure 1 week after myocardial infarction. The increase in cardiac ET-1 mRNA is not accompanied by a decrease in ET receptor mRNA.

Topics: Animals; Blotting, Northern; Endothelin-1; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Rats; Rats, Wistar; Receptors, Endothelin; RNA, Messenger; Stroke Volume

Controversy currently exists regarding the use of diltiazem in the treatment of acute myocardial infarction (AMI). due to conflicting results from clinical trials and animal studies. The purpose of this project was to evaluate the changes in the hemostatic profile during AMI following low dose intracoronary diltiazem infusion. Fourteen Yorkshire swine underwent thoracotomy and 50 min LAD occlusion, followed by 3 h of reperfusion. The first group (n = 8) received 2.5 mg of diltiazem intracoronary at a rate of 5.6 micrograms kg min-1 at the onset of reperfusion. The second group (n = 6) received 0.9% saline intracoronary at the onset of reperfusion and served as the control. The dynamics of plasma antithrombin-III (AT-III), Protein C, total Protein S, fibronectin, endothelin-1 (ET-1), and the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1a) were determined at baseline, then twice during occlusion and finally three times during reperfusion. Diltiazem infusion resulted in diminished ET-1 (34.5%), fibronectin (23.2%), and TxB2 (35.6%); and elevated Protein C (29.3%) when compared with controls. We conclude that intracoronary diltiazem favorable influences hemostasis during AMI in swine. The cardioprotective effects of diltiazem during AMI may be related to the improved hemostatic profile and the reduced incidence of thrombotic complications in such patients.

Topics: Animals; Calcium Channel Blockers; Diltiazem; Disease Models, Animal; Eicosanoids; Endothelin-1; Female; Fibronectins; Hemostasis; Infusions, Intra-Arterial; Myocardial Infarction; Swine

The goal of this study was to test the hypothesis that chronic myocardial infarction potentiates agonist-induced constrictor responses of rat skeletal muscle arterioles in vivo. Eight weeks after we performed coronary artery ligation or sham (control) surgery, the spinotrapezius muscle was prepared for direct visualization of the microcirculation. Diameter of third-order arterioles (40.7 +/- 0.5 microns) to topical suffusion of angiotensin II (ANG II; 0.1-10 nM), arginine vasopressin (AVP; 0.1-10 nM), endothelin-1 (ET-1; 1.0-100 pM), and the thromboxane analog U-46619 (1.0-100 nM) was measured in both groups. Myocardial-infarcted rats exhibited enhanced arteriolar constrictor responses to ANG II and AVP compared with the responses in controls. In contrast, ET-1- and U-46619-induced constrictor responses were similar in control and myocardial-infarcted rats. Additional experiments explored the impact of NG-monomethyl-L-arginine (L-NMMA; 0.1 mM) on arteriolar reactivity. In control animals, L-NMMA potentiated ANG II- and AVP-induced vasoconstriction, achieving values similar to those observed in myocardial-infarcted rats. L-NMMA did not alter vasoconstrictor responses in rats with chronic myocardial infarction. These observations suggest that enhanced agonist-induced vasoconstriction during heart failure may reflect a loss of nitric oxide-mediated modulation of arteriolar tone.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Arginine Vasopressin; Arterioles; Coronary Vessels; Endothelin-1; Hemodynamics; Male; Muscle, Skeletal; Muscle, Smooth, Vascular; Myocardial Infarction; omega-N-Methylarginine; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Reference Values; Thromboxane A2; Time Factors; Vasoconstriction; Vasoconstrictor Agents

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

We sought to assess the effects of second-hand smoke (SHS) and gender on infarct size in young rats exposed in utero or in the neonatal to adolescent period, or both.. We previously demonstrated that exposure to SHS increases infarct size in a rat model of ischemia and reperfusion, with a dose-response relation. These results are consistent with epidemiologic studies demonstrating that SHS increases risk of death from heart disease.. Thirty-one pregnant female rats were randomly divided into two groups: those exposed to SHS and a control group (non-SHS). After 3 weeks, each rat had given birth to 10 to 12 rats. One hundred one neonatal rats were divided into four groups according to exposure to SHS in utero (SHSu) and randomized to SHS exposure in the neonatal to adolescent period (SHSna). After 12 weeks, all rats were subjected to 17 min of left coronary artery occlusion and 2 h of reperfusion.. Birth mortality was higher in the SHSu group than in the non-SHSu group (11.9% vs. 2.8%, p < 0.001). Body weight of neonatal rats at 3 and 4 weeks in the two SHSu groups was lower than that of rats in the two non-SHSu groups (p < 0.001). Exposure to SHSna increased endothelin-1 levels in plasma (p = 0.001). In all 70 young rats who survived the neonatal period, infarct size (Infarct mass/Risk area x 100%) was greater in the SHSna groups than in the non-SHSna groups (p = 0.005) and in the male groups than in the female groups (p < 0.001).. Exposure to SHS in the neonatal to adolescent period and male gender increased myocardial infarct size in a young rat model of ischemia and reperfusion. These results are consistent with epidemiologic studies demonstrating that SHS increases the health risk to neonates and adolescents.

Topics: Angiotensin II; Animals; Animals, Newborn; Body Weight; Endothelin-1; Female; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Pregnancy; Prenatal Exposure Delayed Effects; Random Allocation; Rats; Rats, Sprague-Dawley; Risk Factors; Sex Factors; Tobacco Smoke Pollution

Left ventricular dilatation after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of this study was to investigate the role of endothelin-1 (ET-1) in ventricular dilatation and the effects of chronic endothelin receptor blockade by a mixed ET(A) and ET(B) receptor blocker (bosentan) on the circulating and cardiac endothelin systems.. Three hours after coronary ligation or sham operation, bosentan (100 mg x kg body wt(-1) x d(-1)) or placebo was given by gavage. Seven days and 8 weeks after surgery, hemodynamic and left ventricular volume studies were performed. Acute bosentan treatment (7 days) had no effects on hemodynamic parameters and early left ventricular dilatation. In the rats with large infarcts, chronic bosentan treatment (8 weeks) versus placebo reduced left ventricular systolic pressure (116+/-2 versus 125+/-3 mm Hg, P<.05) and arterial pressure (93+/-2 versus 103+/-3 mm Hg, P<.05), improved stroke volume index (0.69+/-0.06 versus 0.52+/-0.04 mL/kg, P<.05), and prevented in part the rightward shift of the pressure-volume curve. Chronic bosentan treatment also decreased ET-1 levels (390+/-33 versus 475+/-22 pg/g tissue, P<.05) and density of ET-1 receptors (262+/-24 versus 346+/-31 fmol/mg protein, P<.05) in left ventricular myocardium.. In the present study, a mixed ET(A) and ET(B) receptor antagonist (bosentan) partially prevented left ventricular dilatation and improved hemodynamics, suggesting that endothelin plays a role in left ventricular remodeling after myocardial infarction. Supporting this hypothesis, we show inhibitory effects of bosentan on the peripheral and myocardial endothelin system.

Topics: Animals; Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Endothelin-1; Female; Heart Ventricles; Hemodynamics; Hypertrophy, Left Ventricular; Myocardial Infarction; Rats; Rats, Wistar; Receptors, Endothelin; Sulfonamides; Time Factors

To investigate whether circulating endothelin-1 (Et-1) may be related to the increased incidence and severity of ischaemic heart disease in type 2 diabetes mellitus, we compared the concentrations in type 2 diabetic patients and in non-diabetic patients with coronary artery disease (CAD) angiographically documented. Plasma levels of Et-1 were determined in 34 type 2 diabetic patients with CAD (16 with stable angina, 6 with unstable angina, 12 with previous myocardial infarction) and in 19 nondiabetic patients with CAD (4 with stable angina, 5 with unstable angina, 10 with previous myocardial infarction). Fifteen diabetic patients without CAD and 9 healthy volunteers served as control subjects. In the type 2 diabetic patients, the mean Et-1 levels were 3.19 +/- 1.61 pmol/l in those with stable angina, 3.58 +/- 1.92 pmol/l in those with unstable angina, 4.24 +/- 2.53 pmol/l in those with myocardial infarction. These values were not significantly different one another, nor from the values obtained from type 2 diabetic controls (3.64 +/- 2.13 pmol/l). In the non-diabetic patients, the mean Et-1 levels were 3.92 +/- 0.73 pmol/l in those with stable angina, 4.35 +/- 1.67 pmol/l in those with unstable angina, 4.33 +/- 1.66 pmol/l in those with myocardial infarction. These values were not significantly different one another, but significantly higher than those obtained from healthy controls (2.07 +/- 0.67 pmol/l; P < 0.001). No significant differences were found in Et-1 levels between diabetic and non-diabetic patients with stable, unstable angina and previous myocardial infarction. In contrast, a statistically significant difference was found in Et-1 levels between diabetic and non-diabetic control subjects (P < 0.05). In conclusion, similar raised concentrations of Et-1 in diabetic and non-diabetic patients with stable, unstable angina and previous myocardial infarction do not support the hypothesis that higher levels of Et-1 in diabetic patients are responsible for the increased incidence of CAD in diabetes mellitus. However, the raised Et-1 levels found in diabetic patients in the absence of CAD strongly suggest that a generalised endothelial dysfunction, documented in our study by increased levels of Et-1, most probably precedes subsequent cardiovascular diseases.

Topics: Aged; Analysis of Variance; Angina Pectoris; Blood Pressure; Diabetes Mellitus, Type 2; Endothelin-1; Female; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Reference Values

Occlusion of the diseased coronary artery in humans causes acute myocardial infarction, survivors of which have a high risk for the development of chronic heart failure. Cardiac myocytes and vascular endothelial cells produce endothelin-1 (refs 2-4), which increases the contractility of cardiac muscle and of vascular smooth muscle cells. Endothelin-1 also exerts long-term effects such as myocardial hypertrophy, and causes cellular injury in cardiac myocytes. Production of endothelin-1 is markedly increased in the myocardium of rats with heart failure, and acute application of an endothelin-receptor antagonist decreases myocardial contractility in such rats, indicating that myocardial endothelin-1 may help to support contractility of the failing heart. But we report here that the upregulated myocardial endothelin system may contribute to the progression of chronic heart failure, because long-term treatment with an endothelin-receptor antagonist greatly improved the survival of rats with chronic heart failure. This beneficial effect was accompanied by significant amelioration of left ventricular dysfunction and prevention of ventricular remodelling, in which there is usually an increase in the ventricular mass and cavity enlargement of the ventricle.

Topics: Animals; Cardiac Output, Low; Cardiomegaly; Endothelin Receptor Antagonists; Endothelin-1; Heart Ventricles; Hemodynamics; Male; Myocardial Infarction; Myocardium; Peptides, Cyclic; Rats; Receptor, Endothelin A; RNA, Messenger; Survival Analysis; Time Factors

The use of calcium antagonists and magnesium (Mg) in the treatment of acute myocardial infarction is controversial. We compared changes in hemostasis during acute myocardial infarction after either low-dose intracoronary Mg or diltiazem infusion in 20 Yorkshire swine undergoing thoracotomy and coronary artery occlusion for 50 min, followed by 3 h of reperfusion. The first group received MgSO4 (250 mg), delivered at the onset of reperfusion, the second group received diltiazem (2.5 mg) at the beginning of reperfusion. Six controls received saline. Plasma antithrombin III, protein C, total protein S, fibronectin, endothelin 1, and metabolites of thromboxane and prostacyclin were measured at baseline, twice during occlusion, and three times during reperfusion. Compared to controls, Mg and diltiazem infusion diminished endothelin 1 (32.9 vs. 34.5%) and fibronectin. (21.7 vs. 23.2%), but increased protein C (31.9 vs. 29.3%). Intracoronary Mg, like diltiazem, improved hemostasis in swine.

Topics: Animals; Antithrombin III; Blood Coagulation Factors; Calcium Channel Blockers; Diltiazem; Eicosanoids; Endothelin-1; Female; Fibronectins; Hemodynamics; Magnesium; Myocardial Infarction; Myocardial Reperfusion Injury; Protein C; Protein S; Swine

There has been some debate regarding the benefit of magnesium (Mg) in the treatment of acute myocardial infarction (AMI) because of conflicting results from recent clinical trials. Several different hypotheses have been advanced to explain the cardioprotective properties of Mg, including the influence of the timing of Mg administration during AMI. This experiment was designed to assess the effect of intracoronary Mg on certain hemostatic parameters that are known to change during an AMI. Yorkshire swine underwent thoracotomy and 50 min left anterior descending artery (LAD) occlusion, followed by 3 h of reperfusion. In the early group, 250 mg of MgSO4 was delivered at the onset of reperfusion (n = 6, Mg-early group). In the second group, MgSO4 was given after 1 h of reperfusion (n = 6, Mg-late group). Six animals received saline instead of Mg and served as controls. The dynamics of plasma antithrombin-III (AT-III), protein C, total protein S, fibronectin, endothelin-1 (ET-1), as well as the stable metabolites of thromboxane (TXB2) and prostacyclin (6-keto-PGFla) were determined at baseline, twice during occlusion, and three times during reperfusion. Mg given at reperfusion onset was associated with a diminished ET-1 (32.9%), decreased fibronectin level (21.7-25.2%), and increased protein C concentrations (31.9-52.3%) when compared with both the control and late Mg group. In summary, intracoronary Mg administered at the onset of reperfusion favorably influenced hemostasis in swine. The beneficial effects of early Mg supplementation in an expanding array of clinical conditions, including AMI, may be directly related to the improved hemostatic profile in such patients.

Topics: Animals; Endothelin-1; Female; Fibronectins; Hemodynamics; Hemostasis; Magnesium Sulfate; Myocardial Infarction; Swine; Thromboxane B2; Time Factors

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

We have proposed that ischemic preconditioning in rabbit hearts is initiated by adenosine receptor stimulation resulting in activation of protein kinase C. If this theory is correct then any agonist which can activate PKC should also put the heart into a preconditioned state. This study sought to determine whether endothelin-1 (ET-1), which is known to activate protein kinase C can also mimic ischemic preconditioning. Isolated rabbit hearts experienced 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 30.3 +/- 2.5% of the risk zone. Preconditioning with 5 min global ischemia and 10 min reperfusion reduced infarct size to 5.6 +/- 0.7% (P < 0.01). Perfusion with either 10 PM ET-1 at constant coronary artery flow for 5 min in lieu of ischemia or 50 PM ET-1 with 10 nM nicardipine to block the former's coronary constructive effect was quite protective and equipotent with preconditioning. Infarction averaged 7.2 +/- 0.8% and 5.8 +/- 1.7% of the risk zone, respectively. This protection could be blocked by PD 156 707 (10 microM), a highly specific endothelin receptor antagonist. Chelerythrine (5 microM), a PKC inhibitor, also aborted protection (22.0 +/- 1.7% infarction). However, 8-(p-sulfophenyl)theophylline (100 microM), an adenosine receptor blocker, given during ET-1 administration did not block ET-1's protective effect indicating that adenosine was not involved in the effect. PD 156707 failed to block the protection from ischemic preconditioning (12.6 +/- 2.3% infarction) revealing that endothelin is not an important physiological mediator of ischemic preconditioning. We conclude that ET-1 can mimic ischemic preconditioning in isolated rabbit hearts as would be predicted since its receptors are PKC-coupled, but that endogenous endothelin contributes little to ischemic preconditioning.

Topics: Alkaloids; Animals; Benzophenanthridines; Coronary Vessels; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Female; Heart; Hemodynamics; In Vitro Techniques; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Phenanthridines; Protein Kinase C; Purinergic P1 Receptor Antagonists; Rabbits; Receptors, Endothelin; Theophylline

The potent vasoconstrictor endothelin-1 (ET) may play an important pathophysiologic role in acute myocardial infarction, but its precise effects are incompletely understood. The purpose of this study was to evaluate the interrelationships between cardiac ET-1 release and infarct size, myocardial blood flow, and ventricular function.. Fifteen closed chest dogs underwent 3 hours of coronary artery occlusion followed by 3 hours of reperfusion. Coronary sinus and aortic ET-1 levels during occlusion and after reperfusion were determined by radioimmunoassay. Left ventricular function and regional myocardial blood flow were measured by echocardiography and colored microspheres, respectively. Myocardial infarct size was determined by postmortem staining with blue dye and triphenyl tetrazolium chloride.. Coronary occlusion and reperfusion produced significant elevations of coronary sinus ET-1 (p < 0.05) and cardiac ET-1 release (p < 0.05), and a trend toward an increase in aortic ET-1 (p = 0.08). A trend toward more ET-1 release was observed in dogs with larger infarcts (p = 0.06), and in dogs with substantial no-reflow in the reperfused territory (p = 0.05). Endothelin-1 release also was associated with increased contractility in nonischemic myocardial segments (p = 0.002), and ET-1 correlated with increased global left ventricular function (p < 0.02).. In this canine model of coronary occlusion and reperfusion, greater increases in cardiac ET-1 release were observed in dogs with larger infarcts, and increased ET-1 release was associated with the no-reflow phenomenon in the reperfused territory. These data suggest that ET-1 release may have adverse consequences in acute myocardial infarction, including a reduction of myocardial blood flow in the reperfused zone after reperfusion and increased contractility in nonischemic myocardium.

Topics: Animals; Coronary Circulation; Disease Models, Animal; Dogs; Endothelin-1; Male; Myocardial Infarction; Myocardial Reperfusion; Time Factors; Ventricular Function, Left

Endothelin (ET), the most potent endogenous vasoconstrictor with mitogenic potency, is generated from its precursor big-endothelin (BET) in a proteolytic process and discussed as a pathogenetic factor in coronary artery disease and in the acute coronary syndromes. Several studies documented elevated plasma endothelin concentrations in acute myocardial infarction, but conflicting results were reported in patients with stable and unstable angina. Only few studies determined big endothelin, although it half-life and plasma concentrations are higher in comparison to endothelin. ET and BET levels (Radioimmunoassay, Biomedica GmbH, Vienna) were determined in patients with stable angina (SAP, n = 20), unstable angina (IAP, n = 12), acute myocardial infarction (AMI, n = 12) and healthy subjects (NP, n = 11). The concentrations of ET and BET (median (minimum-maximum) in fmol/ml) of the patients with stable angina (SAP: ET 0.7 (0.3-1.1); BET 1.7 (0.7-2.9)), unstable angina (IAP: ET 1.0(0.5-1.7); BET 2.5 (1.3-4.1)) and acute myocardial infarction (AMI: ET 1.2 (0.6-2.3); BET 3.6 (3.2-5.3)) showed a significant difference compared to controls (NP: ET 0.5 (0.4-0.7); BET 1.4 (1.1-1.7)) (SAP vs. NP: ET p < 0.01; BET p < 0.05; IAP and AMI vs. NP: ET and BET p < 0.001). Also, the concentrations of the peptides differed significantly dependent on the clinical severity of coronary artery disease (AMI vs. SAP: ET and BET p < 0.001; AMI vs. IAP: BET p < 0.05; IAP vs. SAP: ET p < 0.05; BET p < 0.01). Twelve of 15 patients with big endothelin concentrations over 3 fmol/ml suffered acute myocardial infarction. Seven of 12 patients with AMI showed elevated ET and BET concentrations before the increase of creatinecinase. There was no correlation between number of risk factors per patient, cholesterin and subfractions, severity of CAD classified in one-two-three-vessel disease or coronary score according to modified criteria of the American Heart Association (AHA). We conclude that in patients with coronary artery disease endothelin and big endothelin levels are elevated and related to the clinical and not to the morphological severity of coronary artery disease. Big endothelin is the more sensitive parameter in comparison to endothelin and indicates a severe course of myocardial ischemia in patients with unstable angina. The development of assays with the possibility of a quick determination of the peptides may be valuable for risk stratification of acute coronary events.

Topics: Adult; Aged; Aged, 80 and over; Angina Pectoris; Angina, Unstable; Coronary Disease; Endothelin-1; Endothelin-2; Endothelins; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Protein Precursors; Radioimmunoassay; Reference Values; Risk Factors

In vitro binding of (3-[125I]Tyr)-endothelin-1 ([125I]ET-1) and (3-[125I]Tyr)-big ET-1(1-38) ([125I]big ET-1) to plasma proteins of healthy humans, cardiac patients and normotensive and hypertensive rats was investigated by equilibrium dialysis. Binding of both tracers was similar in plasma from healthy humans, patients with congestive heart failure, and following myocardial infarction (approximately 60%), and marginally higher in rat plasmas (approximately 70%). Binding of [125I]ET-1 to human plasma could be explained by binding to human serum albumin. Endogenous plasma ET-1 levels were approximately 9 pg/ml in healthy humans, and approximately 12-16 pg/ml in cardiac patients; big ET-1 concentrations were approximately two- to threefold higher. ET-1 bound to plasma protein was partly lost in column extraction. In rat isolated perfused hearts, the coronary dilator and constrictor potency of exogenous free and albumin-bound ET-1 was similar, whereas the kinetics of endogenous ET-1 was impeded by tight binding to ET receptors. The data indicate that binding of ET-1 to plasma proteins is without effect on peptide vasoactivity, but binding to tissue receptors greatly impedes its tissue kinetics.

Topics: Animals; Blood Proteins; Endothelin-1; Endothelins; Female; Heart Failure; Humans; In Vitro Techniques; Iodine Radioisotopes; Kinetics; Male; Myocardial Contraction; Myocardial Infarction; Protein Binding; Protein Precursors; Rats; Reference Values; Serum Albumin; Serum Albumin, Bovine; Sex Characteristics; Vasoconstrictor Agents; Vasodilator Agents

Several studies have indicated that endothelin-1 (ET-1) and endothelin-3 (ET-3) are produced by different cells. Although ET-1 is produced by vascular endothelial cells, these cells do not produce ET-3. In the present study, we measured plasma concentrations of both ET-1 and ET-3 by sandwich-enzyme immunoassays which we developed recently in patients on chronic hemodialysis, age-matched normal subjects, patients with acute myocardial infarction, patients undergoing surgery, and healthy subjects before and after strenuous endurance exercise. Plasma levels of ET-1 and ET-3 were demonstrated to be altered differently in the above conditions in humans. Although the exact origin of circulating endothelins has yet to be elucidated, the different alterations of plasma levels suggest that both ET-1 and ET-3 may play different roles in physiological and/or pathophysiological responses to various conditions in humans.

Topics: Adult; Aged; Endothelin-1; Endothelins; Exercise; Female; Humans; Immunoenzyme Techniques; Intraoperative Period; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Protein Precursors; Renal Dialysis

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

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