endothelin-1 and Myocardial-Ischemia

Outcomes of victims of cardiac arrest or acute myocardial ischemic events have improved with advances in medical therapy. Heart failure, however, remains a leading cause of morbidity and mortality after these conditions have occurred. Clinical features may be useful for predicting patients who are at risk of developing such complications, but they lack of sensitivity and specificity. Biomarkers have been therefore suggested as means to provide relevant prognostic information. The more commonly used biomarkers after cardiovascular ischemic events, including cardiac arrest, are creatin kinases and troponins. In addition, natriuretic peptides and C-reactive protein have gained great interest and now sufficient data has been collected such to justify their clinical applicability. Finally, several other novel biomarkers, to be used after resuscitation from cardiac arrest or more generally after a myocardial ischemic event, have been anticipated. Nevertheless, the "perfect" biomarker, able to provide diagnosis and prognosis with high sensitivity and specificity does not exit. A multimarker strategy that categorizes patients based on the number of elevated biomarkers at presentation is therefore suggested.

Topics: Adrenomedullin; Arginine Vasopressin; Biomarkers; C-Reactive Protein; Cardiopulmonary Resuscitation; Creatine Kinase; Endothelin-1; Heart Arrest; Heart Failure; Humans; Immunity, Innate; Myocardial Ischemia; Natriuretic Peptides; Serum Amyloid P-Component; Troponin

The seriousness of scorpion envenomation results essentially from left cardiac function with pulmonary oedema and/or a state of shock. Adrenergic myocarditis, toxic myocarditis and myocardial ischemia are the 3 mechanisms that explain the cardiac dysfunction. Myocardial ischemia is not only due to the release of catecolamines but also the effect of the cytokines and/or neuropeptide Y on the coronary vessels. The cardiac damage can be due or enhanced by the depressive effect of the cytokines on the myocardial cells. The frequently observed hyperglycaemia only enhances the state of the already damaged myocardium.

Topics: Acidosis; Animals; beta-Thromboglobulin; Blood Platelets; Catecholamines; Cytokines; Endothelin-1; Humans; Hyperglycemia; Myocardial Ischemia; Myocarditis; Myocardium; Neuropeptide Y; Pulmonary Edema; Scorpion Stings; Scorpion Venoms; Scorpions; Shock, Cardiogenic; Stress, Physiological

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

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

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

Endothelins (ETs) are the peptides made up of 21 amino acids synthesized and released by variety of cells. Following studies revealed three isoforms of ETs-ET-1, ET-2 and ET-3. Endothelin ET-1 is known as the most potent endothelium-derived vasoconstrictor peptide identified so far. Endothelin ET-1 acts in a paracrine manner on the two types of receptors ET-A and ET-B. The former is responsible for the vascular smooth muscle constriction and the latter for vasodilation or vasoconstriction depending on the subtype of this receptor (ET-B1 or ET-B2 respectively). Endothelin receptor subtypes have been demonstrated and pharmacologically characterized in the coronary vascular bed. A good deal of experimental and clinical data has been accumulated to support an important role of endothelin-1 in ischemic heart disease. In experimental animals, exogenous ET-1 was found to cause coronary vasoconstriction and, at higher doses, ventricular fibrillation and death. The plasma levels of immunoreactive endothelin-1 were found to be increased in patients with coronary arteriosclerosis, acute myocardial infarction, and angina. The purpose of this study was to critically review the experimental and clinical data supporting the involvement of ET-1 in ischemic heart disease.

Topics: Animals; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Humans; Myocardial Ischemia; Receptors, Endothelin

Endothelin-1 and nitric oxide are the most potent factors of the endothelium-derived substances. The factors play opposite roles in regulation of cardiovascular system, and their interaction underlies the balance of vasoconstrictor and vasodilator influences on vascular tone under normal conditions. In our experiments, changes in endothelin-1 blood concentration were associated with affected production of endogenous nitric oxide. The altered interrelationships between the endothelium-derived vasoactive substances may precede pathological shifts in the cardiovascular system.

Topics: Animals; Blood Pressure; Endothelin-1; Endothelium, Vascular; Heart Rate; Hypertension; In Vitro Techniques; Muscle Contraction; Muscle Relaxation; Muscle Tonus; Myocardial Ischemia; Nitric Oxide; Nitric Oxide Synthase; Rats; Vaccination

Topics: Animals; Cell Adhesion; Chemotaxis, Leukocyte; Complement System Proteins; Cytokines; Endothelin-1; Endothelium, Vascular; Free Radicals; Humans; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Reactive Oxygen Species

Erectile dysfunction (ED) is a common problem, particularly in older men. The production of penile erection involves an interplay between autonomic nerves and locally released vasoactive mediators. Endothelin-1 (ET-1) is a peptide released from endothelium in the corpus cavernosum, which causes smooth muscle contraction. Recent studies have investigated the physiological significance of ET-1 in the control of erectile function and it may play a role in detumescence. There is also much evidence to link ET-1 to risk factors for ED. ET-1 antagonists may prove beneficial in the treatment of ED and also in prevention of long term deterioration of erectile function. These antagonists may also find a role when used in combination with agents, which are established for the treatment of ED.

Topics: Animals; Antihypertensive Agents; Bosentan; Diabetes Complications; Diabetes Mellitus; Endothelin-1; Erectile Dysfunction; Humans; Hypercholesterolemia; Hypertension; Male; Myocardial Ischemia; Neural Pathways; Nitric Oxide; Penile Erection; Risk Factors; Smoking; Sulfonamides

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

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

Since the discovery of the vasorelaxant properties of nitric oxide and the vasoconstrictor effect of endothelin-1, there have been many studies of the distribution and functional significance of these agents in various vascular beds. In the coronary and pulmonary circulation nitric oxide and endothelin-1 actions have been largely investigated in terms of an imbalance between the opposing effects of these vasoactive agents leading to pathophysiological conditions. This article review functional and immunocytochemical studies with emphasis on the ultrastructural localization of nitric oxide synthase and endothelin-1 in the coronary and pulmonary vascular beds. Localization of nitric oxide synthase (type III or I or II) has been shown in endothelial cells, smooth muscle, and perivascular nerves of the coronary and pulmonary vascular beds and in the neurons, nerve fibers, and the small granule-containing cells within cardiac ganglia. Endothelin-1 was mainly localized in subpopulations of coronary and pulmonary endothelial cells. These immunocytochemical studies provide information about the sources of nitric oxide and endothelin-1 that contribute to the vasomotor control of cardiac and pulmonary circulation under normal and pathophysiological conditions.

Topics: Animals; Coronary Circulation; Endothelin-1; Humans; Immunohistochemistry; Myocardial Ischemia; Neurons; Nitric Oxide; Nitric Oxide Synthase; Pulmonary Circulation

Cardiac myocytes and vascular endothelial cells produce endothelin-1, which increases the contractility of cardiac muscles and of vascular smooth muscles. Endothelin-1 also exerts long-term effects, such as myocardial hypertrophy, and causes cellular injury in cardiac myocytes. In heart failure, the production of endothelin-1 is markedly increased in the failing heart. Here, evidence that an endothelin receptor antagonist is a useful new drug for the treatment of heart failure is discussed. Long-term treatment with an endothelin receptor antagonist greatly improves the survival rate of animals (rat, hamster, etc.) with chronic heart failure. This beneficial effect is accompanied by amelioration of left ventricular dysfunction. The myocardial endothelin system appears to be a novel and important target for therapeutic intervention in heart failure.

Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Heart Failure; Hemodynamics; Humans; Myocardial Contraction; Myocardial Ischemia

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

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

Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide derived from vascular endothelial cells. ET-1 can also be produced by other cell types such as smooth muscle cells and cardiomyocytes. Plasma levels of ET-1 are elevated during several different cardiovascular disorders like atherosclerosis, myocardial infarction and congestive heart failure. During and following myocardial ischaemia and reperfusion, the myocardial production and release of ET-1 is stimulated and the coronary constrictor response to ET-1 is enhanced. These findings all favour a pathophysiological role for ET-1 in the development of ischaemia/reperfusion injury. Accordingly, by using different pharmacological tools (monoclonal antibody, ET converting enzyme inhibitor or ET receptor antagonists) that block the biological actions of ET-1, myocardial ischaemia/reperfusion injury has been demonstrated to be reduced in experimental animal models, in terms of both reduction in final infarct size and improved recovery of myocardial performance and coronary flow. However, some studies have shown no cardioprotective effects of ET receptor antagonists. Possible explanations for these apparently conflicting results are differences in animal species used, route and timing of drug administration, experimental protocol and chemical nature of the antagonists. The potential mechanisms underlying the cardioprotective effects of ET antagonists are discussed and include prevention of no-reflow, inhibition of ET-induced neutrophil activation, abolishment of direct pro-ischaemic actions of ET on myocytes, and interruption of interference of ET with the renin-angiotensin system.

Topics: Endothelin-1; Humans; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Peptides, Cyclic

Coronary artery disease and its sequelae remain the most important cause of morbidity and mortality in Western countries. Because the pathophysiologic characteristics of coronary artery disease are multifactorial, impairment of endothelial function featuring enhanced vasoconstriction, increased platelet vessel wall interaction, adherence of monocytes, migration and proliferation of vascular smooth muscle cells are crucially involved. Endothelial cells release numerous vasoactive substances regulating function of vascular smooth muscle and trafficking blood cells such as nitric oxide (NO), which is a potent vasodilator also inhibiting cellular growth and migration. In addition, NO possesses antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by endothelial vasoconstrictors such as angiotensin II and endothelin-1. In the blood vessel wall, the local vascular effects of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists are synergistic. ACE inhibitors diminish the conversion of angiotensin I into angiotensin II and the inactivation of bradykinin. Calcium antagonists counteract angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of NO. In hypertensive animals, long-term combination therapy with verapamil and trandolapril is particularly effective in reversing endothelial dysfunction. Further, ACE inhibitors and calcium antagonists exert beneficial vascular and complementary hemodynamic effects. Whereas ACE inhibitors inhibit the renin-angiotensin system and reduce sympathetic outflow, calcium antagonists dilate large conduit and resistance arteries. Because small vessels appear to be more dependent on extracellular Ca2+ than larger vessels, nifedipine and verapamil effectively inhibit endothelin-induced vasoconstriction in vitro and in vivo in the resistance circulation. Long-term treatment with ACE inhibitors substantially reduces morbidity and mortality rates in patients with left ventricular dysfunction after myocardial infarction; beneficial effects of verapamil in secondary prevention are confined to patients with normal left ventricular ejection fraction. In summary, long-term combination therapy of ACE inhibitors and calcium antagonists might provide beneficial effects in cardiovascular disease because they exert synergistic hemodynamic, antiproliferative, antithrombo

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Endothelin-1; Endothelium, Vascular; Humans; Hypertension; Muscle, Smooth, Vascular; Myocardial Ischemia; Nitric Oxide

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

Endothelin-1, the most potent endothelium-derived vasoconstrictor peptide identified so far, exerts multiple biologic effects that are potentially relevant for the pathogenesis of coronary atherosclerosis and ischemic heart disease. Since the discovery of the peptide, a good deal of experimental and clinical data have been accumulated to support an important role of endothelin-1 in ischemic heart disease. In experimental animals, exogenous endothelin-1 was found to cause coronary vasoconstriction and, at higher doses, ventricular fibrillation and death. Endothelin receptor subtypes have been demonstrated and pharmacologically characterized in the coronary vascular bed. The plasma levels of immunoreactive endothelin-1 were found to be increased in patients with coronary atherosclerosis, acute myocardial infarction, and angina. Given its growth-promoting and mitogenic action, endothelin-1 has also been suspected to participate in the mechanism of restenosis after PTCA. The purpose of this study was to critically review the experimental and clinical data supporting the involvement of endothelin-1 in ischemic heart disease and the results of more recent studies on the effects of endothelin-1 blockade on experimental myocardial necrosis and restenosis after PTCA.

Topics: Angioplasty, Balloon, Coronary; Animals; Coronary Vessels; Endothelin-1; Heart; Hemodynamics; Humans; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Necrosis; Platelet Aggregation; Receptors, Endothelin

Topics: Angioplasty, Balloon, Coronary; Animals; Coronary Circulation; Coronary Vessels; Endothelin-1; Humans; Myocardial Ischemia; Myocardial Reperfusion; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptor, Endothelin A; Receptors, Endothelin; Recurrence; Vasoconstriction

To explore the morphological and functional effect of selective and non-selective endothelin (ET)-receptor blockade in coronary artery disease (CAD).. Prospective randomised controlled trial.. University hospital.. 26 patients with stable CAD.. Intracoronary infusion (30 minutes) of the ET-A receptor blocker BQ-123 (40 nmol/min, group A, n = 13) alone or with the ET-B receptor blocker BQ-788 (10 nmol/min, group AB, n = 13) as well.. Fractional flow reserve (FFR), coronary flow reserve (CFR) and intramyocardial resistance (IMR) by PressureWire, mean arterial blood pressure (MAP), minimal lumen diameter (MLD) and average angiographic lumen diameter (mean LD) of the target vessel before and after intracoronary infusion of ET antagonists. Concentrations of C-terminal pro-endothelin-1 (CT-proET1) in arterial blood were determined before and after infusion.. Mean MLD, mean LD, FFR, CFR, IMR and MAP remained unaffected by ET-receptor blockade in both groups; their changes were comparable. Concentrations of CT-proET-1 increased by 6.2 (SD 5.9) pmol/l (95% CI 1.2 to 11.1 pmol/l; p = 0.022) in group A and by 4.1 (SD 4.3) pmol/l (95% CI 1.1 to 7.2 pmol/l; p = 0.014) in group AB.. We found a broad variety of individual haemodynamic responses to ET-receptor antagonists with an overall neutral effect after an infusion period of 30 minutes despite an overall effective blockade of ET-receptors. Prolonged infusion time may be needed to cause a more distinct vasomotor response.. NCT00427232.

Topics: Adult; Aged; Angina Pectoris; Antihypertensive Agents; Coronary Angiography; Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Female; Fractional Flow Reserve, Myocardial; Humans; Male; Middle Aged; Myocardial Ischemia; Oligopeptides; Peptides, Cyclic; Piperidines; Prospective Studies; Protein Precursors; Young Adult

To assess whether acute administration of 17beta-estradiol reduces pacing-induced cardiac release of endothelin-1 in female menopausal patients with coronary artery disease.. Endothelin-1 is a potent vasoactive peptide which plays a pathogenetic role in myocardial ischemia and adverse clinical events in patients with coronary artery disease. Estrogens decrease plasma levels of endothelin-1 and improve stress-induced myocardial ischemia in menopausal women with coronary artery disease.. Twenty-two postmenopausal women with angiographically proven coronary artery entered a randomized, double blinded, placebo-controlled study. Patients were sampled into the coronary sinus and aorta for endothelin-1 at baseline and after incremental pacing. After baseline study, patients were randomized to receive either sublingual 17beta-estradiol (1 mg) or placebo and underwent the sampling protocol 20 min thereafter.. 17Beta-estradiol but not placebo improved the time of onset of myocardial ischemia during pacing. The coronary sinus plasma levels of endothelin-1 were significantly reduced by estradiol administration but not by placebo, at each step of pacing protocol. The maximum reduction of endothelin-1 was noted at peak pacing (-0.18 ng/l; -0.09, -0.3; 95% CI). No changes in endothelin-1 were noted in patients allocated to placebo (-0.002 ng/l; -0.06, -0.01; 95% CI). Similarly, aorto-coronary sinus difference of endothelin-1 was significantly influenced by 17beta-estradiol administration but not by placebo.. Acute administration of 17beta-estradiol reduces pacing-induced cardiac release of endothelin-1 in postmenopausal women with coronary artery disease. This result may be related to the anti-ischemic or to a primary direct effect of the hormone upon myocyte release of the peptide, and may contribute to its anti-ischemic effect.. To assess effect of acute 17beta-estradiol administration on pacing-induced cardiac release of endothelin-1, we studied 22 female menopausal patients with coronary artery diseases. In a randomized, double-blinded, placebo-controlled study, patients were randomized to receive either sublingual 17beta-estradiol (1 mg) or placebo. Aortic and coronary sinus plasma endothelin-1 levels were evaluated at baseline, during incremental atrial pacing, and at peak pacing before and after the sublingual administration of either 17beta-estradiol or placebo. The time to the onset of myocardial ischemia during pacing was significantly increased by 17beta-estradiol vs. placebo. Moreover, coronary sinus endothelin-1 levels at peak pacing and aortic-coronary sinus changes were significantly improved by the administration of 17beta-estradiol but not by placebo. Acute administration of 17beta-estradiol reduces pacing-induced cardiac release of endothelin-1 in postmenopausal women with coronary artery disease.

Topics: Blood Pressure; Cardiac Pacing, Artificial; Double-Blind Method; Endothelin-1; Estradiol; Female; Humans; Middle Aged; Myocardial Ischemia

Off-pump coronary artery bypass grafting (CABG) is an alternative to conventional CABG using cardiopulmonary bypass. Off-pump technique reduces the complications of CABG performed with extracorporeal circulatory assistance (Lancey et al. 2000; Mack et al. 2004a,b). The object of this study was to compare peri- and postoperative time courses of vasoactive peptides - atrial natriuretic poptide (ANP), brain natriuretic poptide (BNP) and endothelin-1 (ET-1) in off-pump versus on-pump CABG. 22 patients, who underwent on-pump (group A, n = 11) or off-pump CABG (group B, n = 11) were studied. The peri- and postoperative time courses of plasma ANP and BNP were similar in both groups. A statistically significant difference between ET-1 plasma level 2 h after surgery in the group A and ET-1 plasma level 2 h after surgery in the group B (2.46 + or - 1.14 pg/ml/Ht versus 0.74 + or - 0.09 pg/ml/Ht, p < 0.0001) was found. Different CABG techniques were not associated with significant changes in peri- and postoperative plasma ANP and BNP. By contrast, plasma ET-1 significantly rose in the group A 2 h after surgery, indicating endothelial damage.

Topics: Adult; Aged; Atrial Natriuretic Factor; Coronary Artery Bypass; Endothelin-1; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain

The aim of the present study was to evaluate the effect of prolonged inhibition of beta-oxidation on glucose and lipid muscle forearm metabolism and cGMP and endothelin-1 forearm release in patients with type 2 diabetes mellitus and ischemic cardiomyopathy. Fifteen patients were randomly allocated in a double-blind cross-over parallel study with trimetazidine (20 mg tid) or placebo lasting 15 days. At the end of each period, all patients underwent euglycemic hyperinsulinemic clamps with forearm indirect calorimetry and endothelial balance of vasodilator and vasoconstricor factors. Compared with placebo, trimetazidine induced 1) an increase in insulin-induced forearm glucose uptake and glucose oxidation accompanied by a reduction in forearm lipid oxidation and citrate release and 2) a decrease of endothelin-1 release paralleled by a significant increase in forearm cGMP release. Forearm glucose oxidation significantly correlated with cGMP release (r=0.37, P<0.04), whereas forearm lipid oxidation positively correlated with endothelin-1 release (r=0.40, P<0.03). In conclusion, for the first time, we demonstrated that insulin-induced forearm glucose oxidation and forearm cGMP release were increased whereas forearm endothelin-1 release was decreased during trimetazidine treatment. Muscle's metabolic and vascular effects of trimetazidine add new interest in the use of trimetazidine in type 2 diabetic patients with cardiovascular disease.

Topics: 3-Hydroxybutyric Acid; Aged; Blood Glucose; Citric Acid; Cross-Over Studies; Cyclic GMP; Diabetes Mellitus, Type 2; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Fatty Acids, Nonesterified; Forearm; Glucose; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Male; Middle Aged; Muscle, Skeletal; Myocardial Ischemia; Oxidation-Reduction; Trimetazidine

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

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

We have demonstrated that estrogen can reduce myocardial injury in ischemia-reperfusion via activation of ATP-sensitive potassium (K(ATP)) channels. We sought to determine whether the protective effect of estrogen extends to epicardial coronary artery with attenuated vasoconstriction in patients after angioplasty by activation of such channels.. The study was designed to prospectively investigate 41 consecutive patients scheduled for elective coronary angioplasty. Pretreatment with estrogen limited myocardial ischemia during coronary occlusion and attenuated postangioplasty coronary vasoconstriction at the dilated and distal segments. An inhibitor of K(ATP) channels, glibenclamide, did not affect coronary vasomotor response, although it abolished the beneficial effect of estrogen on myocardial ischemia. Patients to whom estrogen was administered after the second balloon deflation experienced a similar magnitude of myocardial ischemia as controls but showed significantly attenuated vasoconstriction compared with controls (P=0.0001). Endothelin-1 levels from the great cardiac vein rose significantly from 1.9+/-0.4 to 3.1+/-0.6 pg/mL (P=0.001) 15 minutes after angioplasty in the control group; this was attenuated after estrogen was administered. Significant correlation was found between the changes in coronary vasomotion of the dilated segment and endothelin-1 levels (r=0.65, P<0.0001).. These results demonstrate that estrogen is protective against both myocardial ischemia and coronary vasoconstriction through different mechanisms. The myocardial effect of estrogen was abolished by glibenclamide, which suggests that the cardioprotective effect of estrogen may result from activation of K(ATP) channels. In contrast, estrogen-induced attenuated vasoconstriction is associated with an attenuated release of endothelin-1, independent of K(ATP) activation.

Topics: Adenosine Triphosphate; Angioplasty, Balloon, Coronary; Cardiotonic Agents; Chest Pain; Coronary Disease; Electrocardiography; Endothelin-1; Estrogens, Conjugated (USP); Female; Glyburide; Heart; Hemodynamics; Humans; Lactic Acid; Male; Middle Aged; Myocardial Ischemia; Myocardium; Potassium Channel Blockers; Potassium Channels; Vasoconstriction

Topics: Double-Blind Method; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Myocardial Ischemia; Pyridines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Recurrence; Tetrazoles; Treatment Outcome; Vasodilator Agents

There were controversies as to whether endothelin-1 is released after coronary angioplasty. We sought to determine whether endothelin-1 is released after coronary angioplasty and whether oestrogen administration can affect coronary vasomotor tone by reducing endothelin-1 concentrations.. The study was designed to prospectively investigate 24 consecutive patients scheduled for elective coronary angioplasty. Patients were randomized into two groups according to whether they did not (group 1, n = 12) or did (group 2, n = 12) have intracoronary treatment with oestrogen. Quantitative coronary angiography was monitored at baseline, immediately after successful angioplasty, and 15 min after the last deflation. Blood samples for measuring the levels of endothelin-1 were drawn from the ascending aorta and the coronary sinus simultaneously before angioplasty and 15 min after balloon dilatation.. The diameters of the coronary artery at the dilated segments were significantly reduced 15 min after dilation compared with those immediately after dilation in group 1 from 3.20 +/- 0.22 to 2.30 +/- 0.23 mm (P < 0.001), respectively. The vasoconstriction was significantly blunted in group 2. The endothelin-1 levels from the coronary sinus rose significantly, by 29%, 15 min after angioplasty in group 1, which was attenuated after administering oestrogen. Significant correlation was found between the changes of coronary vasomotion of the dilated segment and endothelin-1 levels (r = 0.70, P = 0.01).. Endothelin-1 is released into the coronary circulation after angioplasty, and this vasoactive substance may contribute to the occurrence of vasoconstriction. The vasoconstriction is attenuated by oestrogen by reducing the endothelin-1 levels. This finding provided a new strategy to treat coronary vasoconstriction after angioplasty.

Topics: Angioplasty, Balloon, Coronary; Aorta; Blood Pressure; Coronary Artery Disease; Coronary Vessels; Electrocardiography; Endothelin-1; Estrogens; Female; Humans; Lactates; Male; Middle Aged; Myocardial Ischemia; Prospective Studies; Sinus of Valsalva; Vasoconstriction

Increased plasma concentrations of endothelin-1 (ET-1) and big endothelin-1 (big ET-1) have been reported in patients with end-stage renal failure (ESRD). In the present study, which included hemodialysis (HD) patients with (n = 21) and without (n = 32) ischemic heart disease, the putative association between plasma levels of ET-1 and big ET-1 and ischemic heart disease and the influence of the dialysis procedure on ET concentrations was investigated. This study also examined in an additional five HD patients without cardiac disease whether intravenously infused ET-1 and big ET-1 (0.2, 1, and 4 pmol/kg per min, each dose for 20 min) preserve their vasoactive potency and whether exogenous big ET-1, which in healthy humans is converted in the kidney, is still converted to ET-1 in ESRD. HD patients with ischemic heart disease demonstrated higher plasma levels of ET-1 and big ET-1 than HD patients without this disorder, and HD reduced plasma ET-1 and big ET-1 concentrations. In HD patients, the big ET-1 infusion, resulting in a 1.5-fold increase in plasma ET-1, caused a more marked and prolonged rise in mean arterial BP than ET-1 (20% versus 13%, P = 0.0001) and a slightly smaller but more prolonged decrease in estimated splanchnic blood flow than ET-1 (37% versus 44%, P = 0.02). Furthermore, big ET-1 lowered heart rate by 9% (P = 0.01) but ET-1 did not. Plasma half-lives of ET-1 and big ET-1 were longer in HD patients than in healthy humans. Thus, ET-1 and big ET-1 preserve their vasoactive potency, and circulating big ET-1 is still converted to active ET-1 in ESRD. Consequently, the increased plasma levels of ET-1 and big ET-1 noted in HD patients, especially in patients with ischemic heart disease, might play a role in the development of uremic cardiovascular complications.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Endothelin-1; Endothelins; Female; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Myocardial Ischemia; Osmolar Concentration; Protein Precursors; Reference Values; Renal Dialysis; Splanchnic Circulation; Time Factors

A variety of vascular effects have been ascribed to 17 beta-oestradiol. These effects may partially explain the reduced incidence of cardiovascular disease found in post-menopausal women on oestrogen replacement therapy.. To evaluate the effects of 2 mg sublingual 17 beta-oestradiol on exercise capacity, exercise-induced myocardial ischaemia and circulating levels of endothelin-1 in post-menopausal women with stable coronary artery disease.. Twelve post-menopausal women, mean age 61 (range 52-72) years, with angiographically verified significant coronary artery disease, were randomly assigned to 2 mg of sublingual 17 beta-oestradiol, 2.5 mg of buccal nitroglycerine and to placebo in a double-blind cross-over study design with at least 2 days between each of the study arms. Antianginal medications, with the exception of beta-blockers, were discontinued before investigation. All study patients underwent a maximal bicycle exercise test 30 min after drug intake. Blood was withdrawn immediately before and up to 8 h after medication for analyses of circulating levels of oestradiol and endothelin-1.. The mean serum levels of oestradiol increased from a control level of 72 +/- 28 pmol.l-1 to 3557 +/- 1731 pmol.l-1 after 30 min and to 5028 +/- 3971 pmol.l-1 after 60 min with a gradual decline thereafter. Sublingual 17 beta-oestradiol did not induce any improvement in exercise duration when compared with nitroglycerin and placebo (500 +/- 112 s, 505 +/- 107 s, 498 +/- 157 s), and did not influence time to onset of ST-segment depression (358 +/- 89 s, 436 +/- 93 s, 384 +/- 116 s). The plasma levels of endothelin-1 did not change after administration of 17 beta-oestradiol, nitroglycerin or placebo.. No effects of exercise capacity, exercise-induced acute ischaemia, or plasma levels of endothelin-1 were found after a single dose of 2 mg 17 beta-oestradiol in post-menopausal women with documented coronary artery disease.

Topics: Administration, Sublingual; Coronary Disease; Cross-Over Studies; Double-Blind Method; Electrocardiography; Endothelin-1; Estradiol; Estrogen Replacement Therapy; Exercise Test; Female; Humans; Middle Aged; Myocardial Ischemia; Nitroglycerin; Postmenopause; Treatment Outcome

Indexes of myocardial ischemia and vasoconstrictive hormonal release were evaluated in order to investigate the difference between essential hypertension and hypertension during chronic renal failure.. Arterial hypertension induces several cardiovascular alterations that reflect themselves either on the heart and/or on the coronary blood flow enhancing the cardiovascular risk. Since chronic renal failure can influence the neuroendocrine response, various mechanisms involved in hypertension during chronic renal failure are still unclear. High endothelin 1 (ET-1) levels have been found both in arterial hypertension and during chronic renal failure. Interestingly, either ET-1 or catecholamines seem also to be implied in the pathogenesis of myocardial ischemia.. 20 hypertensive uremic and 20 essentially hypertensive patients underwent echocardiographic wall motion and wall thickening analysis performed at baseline and immediately after the end of exercise. Simultaneously, myocardial perfusion was evaluated by 99mTc-MIBI-SPECT. In addition, plasma norepinephrine and ET-1 concentrations were measured at baseline and at peak exercise.. The segmental radionuclide analysis showed a greater ischemic degree in hypertensive uremic patients. Yet, we were able to identify one or more regions of the left ventricle in which both systolic thickening measurements and wall motion after exercise were impaired. After exercise, wall thickening impairment was correlated with both wall motion abnormalities (r = 0.72, p < 0.01) and MIBI ischemic grade (r = 0.82, p < 0.001). Basal and after-exercise plasmatic norepinephrine and endothelin levels were higher in hypertensive uremic than in essentially hypertensive patients. Moreover, there was a significant correlation between increments in norepinephrine concentration and MIBI perfusion defects, and between the increment in ET-1 concentration and both MIBI perfusion defects, or kinetic alterations assessed by wall motion as well as by wall thickening.. This is the first cross-sectional study in which a higher degree of myocardial ischemia has been observed in hypertensive uremic patients combined with an enhanced plasma release of both norepinephrine and ET-1. This phenomenon may contribute to enhance the cardiovascular risk of these patients.

Topics: Aged; Cross-Sectional Studies; Echocardiography; Endothelin-1; Exercise Test; Female; Hemodynamics; Humans; Hypertension; Hypertension, Renal; Image Interpretation, Computer-Assisted; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Norepinephrine; Tomography, Emission-Computed, Single-Photon

Marjoram (Origanum majorana L.) is an herb traditionally used as a medicine in different countries, as Morocco and Iran, because of its beneficial cardiovascular effects. Some studies suggest that these effects are due, at least in part, to the presence of phenolic compounds such as rosmarinic acid (RA) and luteolin.. To analyze the possible cardiprotective effects of a marjoram extract (ME) reducing myocardial damage after coronary ischemia-reperfusion (IR) and its possible antihypertensive effects reducing the response of aorta segments to the vasoconstrictors noradrenaline (NA) and endothelin-1 (ET-1).. Male Wistar rats (300g) were used. After sacrifice, the heart was immediately removed and mounted in a perfusion system (Langendorff). The aorta was carefully dissected and cut in 2 mm segments to perform vascular reactivity experiments.. In the heart, ME perfusion after IR reduced heart rate and prevented IR-induced decrease of cardiac contractility, possibly through vasodilation of coronary arteries and through the upregulation of antioxidant markers in the myocardium that led to reduced apoptosis of cardiomyocytes. In the aorta, ME decreased the vasoconstrictor response to NA and ET-1 and exerted a potent anti-inflammatory and antioxidant effect. Neither RA nor 6-hydroxi-luteolin-O-glucoside, major compounds of this ME, were effective in improving cardiac contractility after IR or attenuating vasoconstriction to NA and ET-1 in aorta segments.. In conclusion, ME reduces the myocardial damage induced by IR and the contractile response to vasoconstrictors in the aorta. Thus, it may be useful for the treatment of cardiovascular diseases such as myocardial infarction and hypertension.

Topics: Animals; Aorta; Calcium Channel Agonists; Calcium Channels; Endothelin-1; Glyburide; Male; Myocardial Ischemia; Norepinephrine; Origanum; Plant Extracts; Rats; Rats, Wistar; Reperfusion Injury; Vasoconstriction

In this study, we investigated whether increased renin angiotensin aldosterone system (RAAS) activation and endothelin-1 levels are related to coronary artery calcium (CAC) score, total plaque volume (TPV), high risk plaque, hyperemic myocardial blood flow (MBF) and coronary microvascular dysfunction (CMD).. After correction for baseline characteristics, including RAAS inhibiting therapy, renin associated positively with CAC score and TPV, but not with hyperemic MBF (p < 0.01; p = 0.02 and p = 0.23). Patients with high risk plaque displayed higher levels of renin (mean logarithmic renin 1.25 ± 0.43 vs. 1.12 ± 0.35 pg/ml; p = 0.04), but not endothelin-1. Compared to no or non-obstructive CAD patients, renin was significantly elevated in obstructive CAD patients but not in CMD patients (mean logarithmic renin 1.06 ± 0.34 vs. 1.23 ± 0.36; p < 0.01 and 1.06 ± 0.34 vs. 1.16 ± 0.41 pg/ml; p = 0.65). Endothelin-1 did not differ between the three patient groups.. Our report provides evidence that RAAS activity measured by renin concentration is elevated in patients with coronary atherosclerosis and high risk plaque but not in patients with CMD, whereas endothelin-1 is not related to either.

Topics: Aged; Chest Pain; Coronary Angiography; Coronary Artery Disease; Cross-Sectional Studies; Endothelin-1; Female; Fractional Flow Reserve, Myocardial; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardial Perfusion Imaging; Plaque, Atherosclerotic; Predictive Value of Tests; Prospective Studies; Renin; Renin-Angiotensin System

The polysaccharide (OJP1), extracted from the root of Ophiopogon japonicus, is a well-known traditional Chinese medicine used to treat cardiovascular diseases. The present study was set up to investigate the cardioprotective effect of OJP1 on isoproterenol (ISO)-induced myocardial ischemia injury in rats. Results showed that pretreatment with OJP1 (100, 200 and 300 mg/kg) significantly reduced ISO-induced ST-segment elevation and the heart index, attenuated the levels of marker enzymes (AST, LDH, CK and CK-MB), along with a significantly enhanced the activities of ATPases. Moreover, pretreatment with OJP1 not only enhanced the activities of SOD, GPx and CAT in serum and myocardium, but also decreased the level of MDA. The biochemical and histopathological analysis also showed that OJP1 can alleviate the myocardial injury induced by ISO. Taken together, our results indicated that oral administration of OJP1 offered significant cardioprotective effect against the damage induced by ISO through enhancement of endogenous antioxidants.

Topics: Animals; Antioxidants; Biomarkers; Ca(2+) Mg(2+)-ATPase; Cardiotonic Agents; Catalase; Electrocardiography; Endothelin-1; Glutathione Peroxidase; Isoproterenol; Malondialdehyde; Myocardial Ischemia; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Ophiopogon; Organ Specificity; Polysaccharides; Rats, Sprague-Dawley; Serum Albumin, Human; Sodium-Potassium-Exchanging ATPase; Superoxide Dismutase

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD).. Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10-0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10-4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; -3.0 units in Duke Exercise Treadmill Score; -5.8 to -0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status.. We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina.. ClinicalTrials.gov: NCT03193294.

Topics: Coronary Artery Disease; Endothelin-1; Humans; Microvascular Angina; Myocardial Ischemia; Vasoconstriction

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

This study was aimed at evaluating whether transient dipyridamole-induced myocardial ischemia in hypertensive patients reflects on endothelin-1 plasma levels by comparing normotensives and hypertensives with or without stable angina. Endothelin-1 plasma levels were assessed in baseline conditions and after provocative stress test by dipyridamole. Four groups of ten age- and sex-matched subjects were retrospectively considered among patients referred for chest pain evaluation and submitted to high-dose Dipyridamole Echocardiographic-Scintigraphic combined test (DES). On the basis of DES results we considered: (1) control normotensives subjects; (2) essential hypertensives (for both groups negative result of DES); (3) essential hypertensives with stable angina; and (4) normotensives with stable angina (for both groups concordant DES detection of myocardial ischemia). Our data showed a marked post-DES increase of endothelin-1 plasma levels in hypertensives with stable angina (mean levels = 16.50 ± 4.19 pg/ml p < 0.001 vs. baseline = 9.05 ± 1.37 pg/ml) and a minor increase in stable angina pts (mean levels = 8.3 ± 1.75 pg/ml p < 0.01 vs. baseline = 6.74 ± 0.61 pg/ml) whereas non significant increase was observed both in control (mean levels = 5.09 ± 0.83 pg/ml p = n.s. vs. baseline = 4.91 ± 1.04 pg/ml) and hypertensives groups (mean levels = 6.34 ± 1.72 pg/ml p = n.s. vs. baseline = 5.95 ± 1.04 pg/ml). ET-1 involvement in hypertension-related ischemic heart disease patho-physiology appears to be considered.

Topics: Adult; Dipyridamole; Echocardiography; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged; Myocardial Ischemia; Myocardial Perfusion Imaging; Retrospective Studies

Topics: Endothelin-1; Endothelins; Humans; Hypertension; Myocardial Ischemia

Endothelin-1 (ET-1) is synthesized primarily by endothelial cells. ET-1 administration in vivo enhances the cardiac sympathetic afferent reflex and sympathetic activity. Previous studies have shown that sympathetic hyperactivity promotes malignant ventricular arrhythmia (VA). The aim of this study was to investigate whether ET-1 could activate the left stellate ganglion (LSG) and promote malignant VA. Twelve male beagle dogs who received local microinjections of saline (control,

Topics: Animals; Arrhythmias, Cardiac; Cells, Cultured; Cytokines; Disease Models, Animal; Dogs; Electrocardiography; Endothelial Cells; Endothelin-1; Humans; Inflammation Mediators; Male; Myocardial Ischemia; Nerve Growth Factors; Receptor, Endothelin A; Signal Transduction; Stellate Ganglion; Sympathetic Nervous System

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

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 role of endothelium in the progression of atheromasic disease has already been demonstrated. Endothelin-1 (ET-1) is released from endothelial cells during acute and chronic vascular damage and it appears to be the strongest vasoconstrictor agent known.The aim of this study is to investigate the amount of endothelial damage in patients with unstable angina (UA), as defined by serum levels of ET-1, to verify a possible correlation with increased ischaemic damage by evaluation of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and interleukin 8 (IL-8) levels.Serum levels of ET-1, IL-8 and NT-proBNP obtained from 10 patients affected by low-risk UA were compared to those belonging to eight healthy subjects. In order to compare the laboratory data pertaining to the two populations, a Student's t-test and a Mann-Whitney U test were performed.Levels of ET-1, IL-8 and NT-proBNP in samples of peripheral blood of patients affected by UA were significantly elevated, compared with those of the control group. The linear correlation analysis demonstrated a positive and significant correlation between levels of ET-1 and IL-8, between levels of ET-1 and NT-proBNP, and between levels of IL-8 and NT-proBNP in subjects affected by UA.Early elevated levels of ET-1, IL-8 and NT-proBNP in patients with UA show a coexistence between ischaemic insults and endothelial damages. A positive and significant linear correlation between levels of ET-1 and IL-8, between levels of ET-1 and NT-proBNP, and between levels of IL-8 and NT-proBNP confirms that an increased ischaemic insult is correlated to inflammation signs and endothelium damage signs.In patients with UA, ischaemia is always associated with a systemic immuno-mediated activity induced by acute endothelial damage. We suggest early administration of ET-1-selective receptor blockers and anti-inflammatory drugs.

Topics: Acute Disease; Adult; Angina, Unstable; Endothelial Cells; Endothelin-1; Endothelium; Female; Humans; Immunologic Factors; Inflammation; Interleukin-8; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Peptide Fragments

To observe the effects of electroacupuncture (EA) at different acupoints on apoptosis-related serum and expression of microRNA (miRNA) in rats with myocardial ischemia, so as to explore its mechanism of action.. A total of 48 male Wistar rats were randomly divided into a normal group, a model group, a Neiguan group and a acupoint compatibility group, 12 rats in each group. Isoprenaline hydrochloride (ISO) with a daily dose of 2 mg/kg was subcutaneously injected for 14 days to establish the myocardial ischemia model in the model group, Neiguan group and acupoint compatibility group. Rats in the normal group were subcutaneously injected with an equal volume of normal saline. After modeling, rats in the Neiguan group were treated with EA at "Neiguan" (PC 6), while rats in the acupoint compatibility group were treated with EA at "Guanyuan" (CV 4), "Zusanli" (ST 36) and "Neiguan" (PC 6). Rats in the normal group and model group were treated with immobilization, once day for 21 days. The contents of creatine kinase-MB (CK-MB), vascular cell adhesion molecule-1 (VCAM-1) and endothelin-1 (ET-1) in serum were detected by enzyme-linked immunosorbent assay (ELISA); apoptosis index (AI) of myocardial cells was detected by TUNEL method; the expressions of miRNA-1, miRNA-133, miRNA-208 and miRNA-499 were detected by real-time PCR method.. Compared with the normal group, the serum CK-MB, VCAM-1 and ET-1 were significantly increased in the model group, Neiguan group and acupoint compatibility group (all P < 0.01), and the apoptosis index was significantly increased (all P < 0.01). The CK-MB, VCAM-1 and ET-1 in the Neiguan group and acupoint compatibility group were significantly lower than those in the model group (all P < 0.01); the AI was reduced, which was more significant in the acupoint compatibility group (P < 0.05). Compared with the normal group, the expression of miRNA-133 was reduced (P < 0.01) and those of miRNA-208, miRNA-1 and miRNA-499 were significantly increased in the model group (all P < 0.01). Compared with the model group, the expression of miRNA-133 was increased (both P < 0.01) and that of miRNA-208, miRNA-1 and miRNA-499 were significantly reduced (all P < 0.01) in the Neiguan group and acupoint compatibility group. Compared with the Neiguan group, the expression of miRNA-133 was increased (P < 0.01) and those of miRNA-208, miRNA-1 and miRNA-499 were significantly reduced in the acupoint compatibility group (P < 0.01, P < 0.05).. EA at acupoints, especially acupoint compatibility group, could effectively prevent and treat myocardial ischemia, and the protective effect is possibly correlated to the double regulation on increasing the expression of miRNA-133 and inhibiting the expression of miRNA-1, miRNA-208, miRNA-499.

Topics: Acupuncture Points; Animals; Apoptosis; Disease Models, Animal; Electroacupuncture; Endothelin-1; Humans; Male; MicroRNAs; Myocardial Ischemia; Myocytes, Cardiac; Rats; Rats, Wistar

Type 2 diabetes (DMT2) combined with ischemic heart disease (IHD) promotes the occurrence and development of coronary atherosclerosis. We aimed to provide a theoretical basis for improving patient prognosis through analyzing expression of plasma brain natriuretic peptide (BNP), endothelin-1 (ET 1), and matrix metalloproteinase 9 (MMP-9).. Enzyme-linked immunosorbent assay (ELISA) was used to detect BNP, ET-1, and MMP-9 levels in 50 patients with DMT2 only (group A), 47 patients with IHD only (group B), 43 patients with comorbid (both) IHD and DMT2 (group C), and 50 health controls (group D). Group C was further divided into single-branch lesion group, double-branch lesions group, and triple-branch lesion group according to coronary angiography, or cardiac function grade II, III, and IV group according to cardiac function, and their BNP, ET-1, and MMP-9 levels were compared.. Compared with group D, TG, diastolic, and systolic blood pressure were all significantly elevated in groups A, B, and C. Group C exhibited obviously higher glycosylated hemoglobin than group A. Gensini score in group C was markedly higher than in group B. Compared with group D, BNP, ET-1, and MMP-9 levels were all increased in groups A, B, and C. Group C showed higher levels of BNP, ET-1, and MMP-9 than group A and B. BNP, ET-1, and MMP-9 levels in the triple-branch lesions group were higher than in the single-branch lesions group and double-branch lesions group. The cardiac function grade IV group presented higher levels of BNP, ET-1, and MMP-9 than did the grade II and III groups. BNP, ET-1, and MMP-9 showed a positive correlation to each other.. BNP, ET-1, and MMP-9 may participate in the occurrence and development of comorbid DMT2 and IHD. They are important objective indicators for evaluating severity and prognosis of patients with comorbid DMA2 and IHD.

Topics: Adult; Aged; Biomarkers; Coronary Artery Disease; Diabetes Mellitus, Type 2; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Heart Function Tests; Humans; Male; Matrix Metalloproteinase 9; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Prognosis

Calcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide. We investigated the ameliorating effect of CGRP in myocardial ischemia induced by endothelin-1 (ET-1), with special emphasis on myocardial microvascular hemodynamics and levels of energy-related metabolites.. The Langendorff preparations of rat isolated heart were perfused at a constant flow rate. Microvascular blood flow was also visualized in the anterior epicardium of the left ventricle by means of an intravital fluorescence microscope system. Energy-related metabolite contents in the myocardium were measured by means of (31)P-magnetic resonance spectroscopy ((31)P-MRS).. Intracoronary bolus injections of CGRP caused dose-dependent decreases in coronary perfusion pressure (CPP) in the hearts exposed to ET-1 (30 pmol). The vasodilator potency of CGRP was about 10,000-fold greater than that of nitroglycerin and 1,000-fold greater than that of isobutylmethylxanthine. Vasodilation of the small-sized arterioles (10-40 μm in diameter) in response to CGRP (100 pmol) was confirmed by direct microscopic observation. After ET-1 (30 pmol) plus vehicle administration, high energy phosphates (phosphocreatine (PCr), ATP) were markedly reduced (p<0.05). CGRP administration significantly (p<0.05) attenuated the anaerobic changes in the myocardium (decrease in PCr) and macrohemodynamic alterations (increase in CPP, decrease in dP/dt etc.) induced by ET-1.. We conclude that CGRP effectively confers hemodynamic and metabolic protections to isolated beating hearts against ET-1-induced myocardial ischemia.

Topics: 1-Methyl-3-isobutylxanthine; Adenosine Triphosphate; Animals; Calcitonin Gene-Related Peptide; Cardiotonic Agents; Endothelin-1; Heart Rate; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Magnetic Resonance Spectroscopy; Microvessels; Myocardial Contraction; Myocardial Ischemia; Myocardium; Nitroglycerin; Perfusion; Phosphocreatine; Phosphorus Isotopes; Rats; Rats, Wistar; Time Factors; Vasodilation

Topics: Aged; Endothelin-1; Female; Heart Failure; Humans; Male; Myocardial Ischemia; Polymorphism, Genetic; Ventricular Function, Left

In 44 patients with ischemic heart disease (IHD) and 35 healthy subjects we studied cascade mechanism of platelets activation by von Willebrand factor (vWF), and interrelationship of platelet aggregation, level of vWF, and endothelial dysfunction. The latter was estimated by severity of vasoconstriction determined basing on endothelin-1 levels. Quantitative assessment of platelet aggregation revealed differences in aggregation capacity between healthy subjects and patients with IHD. Of particular importance was absence of spontaneous aggregation in healthy subjects. It was shown that in IHD patients influence of vWF resulted in augmentation and convergence of activating signal. Positive correlation was found in patients with IHD between elevation of levels of vWF, endothelin-1, and spontaneous and induced platelet aggregation activity. Interrelationship was revealed between character of IHD course and degree of elevation of the studied markers.

Topics: Biomarkers; Blood Coagulation; Blood Platelets; Endothelin-1; Endothelium, Vascular; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation; Platelet Function Tests; Prognosis; Statistics as Topic; Thrombosis; von Willebrand Factor

Endothelin ET(B) receptors mediate under normal physiological conditions vasorelaxation in coronary arteries. However, vasocontractile ET(B) receptors appear in coronary arteries of ischemic heart disease patients. Interestingly, organ culture of isolated coronary arteries also induces upregulation of vasocontractile ET(B) receptors. This study examines the early time course and mechanism behind upregulation of contractile ET(B) receptors in isolated rat coronary arteries during short-term organ culture.. Coronary artery segments were mounted in wire-myographs and incubated in physiological saline solution. Contractions were measured after exposure to the specific ET(B) receptor agonist Sarafotoxin 6c (S6c) and the endogenous agonists endothelin-1 and endothelin-3. Protein localization and levels of ET(B) and phosphorylated-extracellular-signal-regulated-kinase-1/2 (ERK1/2) were examined by immunohistochemistry.. Fresh arteries showed negligible vasoconstriction to S6c. However, incubation for only 4 and 7h increased S6c contractions two- and seven-fold, respectively. Furthermore, 7h incubation enhanced vasocontractile responses to endothelin-3 and increased ET(B) receptor density in vascular smooth muscle cells. ERK1/2 was activated rapidly after start of incubation. Moreover, incubation with either the transcriptional inhibitor actinomycin D or the mitogen-activated-protein kinase kinase 1/2 (MEK1/2) inhibitor U0126 attenuated contractile ET(B) receptor upregulation. U0126 attenuated ET(B) receptor protein levels after 24 h of incubation.. Coronary arteries rapidly upregulate vasocontractile ET(B) receptors during organ culture via transcriptional mechanisms and MEK-ERK1/2 signalling. This model may mimic the mechanisms seen in ischemic conditions. Furthermore, these findings have important experimental implications in tissue bath experiments lasting for more than 4h.

Topics: Animals; Butadienes; Coronary Vessels; Dactinomycin; Disease Models, Animal; Endothelin-1; Endothelin-3; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocardial Ischemia; Nitriles; Organ Culture Techniques; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Time Factors; Transcription, Genetic; Up-Regulation; Vasoconstriction; Vasoconstrictor Agents; Viper Venoms

Topics: Animals; Endothelin-1; Humans; Myocardial Ischemia; Rats

Endothelin-1 (ET-1) increases in the ischemically induced ventricular fibrillation (VF) swine model of cardiac arrest and affects outcome by potentially attenuating the hemodynamic response to epinephrine. Fifty-one swine underwent percutaneous left anterior descending occlusion. Seven minutes postonset of ischemic VF, cardiopulmonary resuscitation (CPR) was initiated. If VF persisted after 3 shocks, 1 mg of epinephrine was given. ET-1 (collected at baseline and every 5 min until VF onset) was assayed with ELISA. Bayesian multivariate logistic regression analysis compared peak ET-1 levels with the binary outcome of a positive coronary perfusion pressure response of >20 mmHg following epinephrine. Sixteen animals (31%) failed to achieve a positive response. Restoration of spontaneous circulation (ROSC) was observed in 1/16 (6.3%) of epinephrine nonresponders and 20/35 (57.1%) of epinephrine responders (P = 0.0006). The median peak ET-1 level was 2.71 pg/mL [interquartile range (IQR) 1.06-4.40] in nonresponders and 1.69 pg/mL (IQR 0.99-2.35) in responders. ET-1 levels were inversely associated with epinephrine response with a median posterior odds ratio (OR) of a coronary perfusion pressure response of 0.72 (95% confidence interval [CI] 0.48-1.06) for each one-unit increase in ET-1 and a probability that the associated OR is <1 of 0.95. Peak ET-1 levels predict a lack of a hemodynamic response to epinephrine during treatment of cardiac arrest during ischemic VF.

Topics: Animals; Disease Models, Animal; Endothelin-1; Epinephrine; Heart Arrest; Hemodynamics; Male; Myocardial Ischemia; Swine; Ventricular Fibrillation

In order to explore the scientific connotation of "Fangzhengduiying (formula corresponding to pattern types)", "Qiyinliangxuzheng (Qi and Yin deficiency pattern)" of myocardial ischemia rat model and GC-TOF/MS based metabonomic method were used for comparing the effects of Sheng-mai injection, Salvia injection and propranolol in the present study. After data processing and pattern recognition, Sheng-mai injection showed better efficacy than the other two drugs in accordance with not only visual observation from PLS-DA scores plots but also the number of abnormal endogenous compounds restored to the normal level. Further studies showed that Sheng-mai injection could normalize the level of plasma endothelin-1, the index related to cardiovascular diseases and sleep disorders, which verified the results of metabonomics. Finally, the regulated metabolites and related metabolic pathways were analyzed, and it was supposed that the effects of Sheng-mai injection involved in the alternation of energy metabolism, lipid metabolism, amino acids metabolism, and so on. These findings provided scientific evidence to Shengmai "Fang" used for "Qi and Yin deficiency pattern" correspondingly, indicating that metabonomics has great potential in traditional Chinese medical research, which provides a novel approach and way to modernization of traditional Chinese medicine.

Topics: Animals; Anti-Arrhythmia Agents; Drug Combinations; Drugs, Chinese Herbal; Endothelin-1; Gas Chromatography-Mass Spectrometry; Injections; Male; Medicine, Chinese Traditional; Metabolomics; Myocardial Ischemia; Panax; Plants, Medicinal; Propranolol; Qi; Rats; Rats, Sprague-Dawley; Salvia; Schisandraceae; Yin Deficiency

Myocardial ischaemia activates cardiac sympathetic afferents leading to chest pain and reflex cardiovascular responses. Previous studies have shown that a brief period of myocardial ischaemia increases endothelin in cardiac venous plasma draining ischaemic myocardium and that exogenous endothelin excites cutaneous group III and IV sensory nerve fibres. The present study tested the hypothesis that endogenous endothelin stimulates cardiac afferents during ischaemia through direct activation of endothelin A receptors (ET(A)Rs). Nerve activity of single unit cardiac sympathetic afferents was recorded from the left sympathetic chain or rami communicates (T(2)-T(5)) in anaesthetized cats. Single fields of 38 afferents (CV = 0.25-3.86 m s(-1)) were identified in the left or right ventricle with a stimulating electrode. Five minutes of myocardial ischaemia stimulated all 38 cardiac afferents (8 Adelta, 30 C-fibres) and the responses of these 38 afferents to chemical stimuli were further studied in the following protocols. In the first protocol, injection of endothelin 1 (ET-1, 1, 2 and 4 microg) into the left atrium (LA) stimulated seven ischaemically sensitive cardiac afferents in a dose-dependent manner. Second, BQ-123, a selective ET(A)R antagonist, abolished the responses of nine afferents to 2 microg of ET-1 injected into the left atrium and attenuated the ischaemia-related increase in activity of eight other afferents by 51%. In contrast, blockade of ET(B) receptors caused inconsistent responses to exogenous ET-1 as well as to ischaemia. Furthermore, in the absence of ET(A)R blockade, cardiac afferents responded consistently to repeated administration of ET-1 (n = 7) and to recurrent myocardial ischaemia (n = 7). Finally, using an immunocytochemical staining approach, we observed that ET(A) receptors were expressed in cardiac sensory neurons in thoracic dorsal root ganglia. Taken together, these data indicate that endogenous endothelin contributes to activation of cardiac afferents during myocardial ischaemia through direct stimulation of ET(A) receptors likely to be located in the cardiac sensory nervous system.

Topics: Animals; Cats; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Electrophysiology; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Fluorescent Antibody Technique; Ganglia, Spinal; Heart; Immunohistochemistry; Male; Myocardial Ischemia; Nerve Fibers, Unmyelinated; Neurons, Afferent; Sympathetic Nervous System

Endogenous vasopressors, including endothelin-1 (ET-1), have been shown to be elevated in patients following resuscitation from out-of-hospital cardiac arrest and are likely a physiologic response to global ischaemia. The importance of ET-1 in the setting of arrest and resuscitation has not been established. Prior work has demonstrated that ET-1 increases significantly after coronary occlusion. The purpose of this study was to assess changes in ET-1 following induction of ischaemia and VF.. VF was induced in 30 anesthetized and instrumented swine by balloon occlusion of the LAD. Blood was collected from the right atrium at baseline and at 5 min intervals following LAD occlusion until VF occurred. After 7 min of VF, resuscitation was attempted in accordance with guidelines. ET-1 and matrix metalloproteinase-9 (MMP-9), a measure of infarct size, were measured using ELISA.. ET-1 and MMP-9 levels increased significantly from baseline within 20 min of occlusion of the LAD. Animals that could not be resuscitated had a higher ET-1 (p=0.031) at VF onset but similar ischaemia time (time to VF) and MMP-9, reflecting infarct size. An ET-1 level >4 pg/ml had a likelihood ratio of 4 for predicting resuscitation failure.. Elevated levels of ET-1 during acute ischaemia predict resuscitation failure independent of the time to VF. This finding may be due to the known effect of ET-1 on coronary vascular resistance or ventricular compliance, resulting in early ischemic contracture.

Topics: Animals; Cardiopulmonary Resuscitation; Disease Models, Animal; Endothelin-1; Male; Matrix Metalloproteinase 9; Myocardial Ischemia; Predictive Value of Tests; Swine; Time Factors; Treatment Outcome; Ventricular Fibrillation

The aim of this study was to investigate whether the previously reported anti-arrhythmic effect of endothelin-1 (ET-1) is mediated by degranulation of cardiac mast cells prior to myocardial ischaemia.. Male Sprague-Dawley rats received either ET-1 (1.6 nmolxkg(-1)) in the presence or absence of disodium cromoglycate (DSCG; 20 mgxkg(-1)xh(-1)) prior to coronary artery occlusion (CAO). In separate experiments rats were given compound 48/80 (50 microgxkg(-1)) to compare the effects of ET-1 with those of a known mast cell degranulator. Ischaemia-induced ventricular arrhythmias were detected through continuous monitoring of a lead I electrocardiogram. After 30 min of CAO, the hearts were removed and mast cell degranulation determined by histological analysis. A parallel series of sham groups were performed to determine the direct effects of ET-1 and compound 48/80 on mast cell degranulation in the absence of ischaemia.. ET-1 and compound 48/80 both exerted profound anti-arrhythmic effects, significantly reducing the total number of ventricular ectopic beats (P < 0.001) and the incidence of ventricular fibrillation (P < 0.05). These anti-arrhythmic effects were abolished by concomitant DSCG infusion prior to CAO. In sham animals ET-1 and compound 48/80 both induced mast cell degranulation (P < 0.001), an effect which was abolished by DSCG, confirming their ability to induce degranulation of mast cells.. These results demonstrate for the first time that when given prior to ischaemia ET-1 mediates its anti-arrhythmic effects, at least in part, via cardiac mast cell degranulation.

Topics: Animals; Anti-Arrhythmia Agents; Blood Pressure; Cell Degranulation; Cromolyn Sodium; Disease Models, Animal; Electrocardiography; Endothelin-1; Heart Rate; Histamine Release; Injections, Intravenous; Male; Mast Cells; Myocardial Ischemia; p-Methoxy-N-methylphenethylamine; Rats; Rats, Sprague-Dawley; Ventricular Fibrillation; Ventricular Premature Complexes

Xinmailong, a compound extracted from Periplaneta americana, is used for the treatment of cardiovascular diseases. This study investigated the effects of Xinmailong on myocardial hypoxia-inducible factor-1alpha (HIF-1alpha) and plasma endothelin-1(ET-1) levels in neonatal rats with asphyxia and explored the protection mechanism of Xinmailong in hypoxia-ischemic myocardial injury.. Seven-day-old Sprague-Dawley rats were randomly divided into three groups (n=30 each): sham-operated, asphyxia, Xinmailong-treated asphyxia. Each group was randomly subdivided into three groups according to the observed time points: 6 hrs, 24 hrs and 72 hrs. Xinmailong (5 mg/kg) was intraperitoneally injected to the rats in the Xinmailong-treated group five minutes before asphyxia. Myocardial HIF-1alpha expression, and plasma ET-1 and creatine kinase (CK) levels were measured. The histopathologic changes of the myocardium were observed by hematoxylin-eosin staining.. Four rats died in the asphyxia group while only one died in the Xinmailong-treated group during the experiment. The plasma ET-1 and CK levels as well as myocardial HIF-1alpha expression increased at 6 hrs, reached a peak at 24 hrs, and declined at 72 hrs after asphyxia in the asphyxia group, being higher than that in the sham-operated group (P<0.01). Myocardial ischemia was observed in the three time points, and cell necrosis occurred at 24 hrs after asphyxia in the asphyxia group. Myocardial HIF-1alpha expression was positively correlated with plasma ET-1 levels (r=0.876, P<0.01). In the Xinmailong-treated group, plasma levels of CK and ET-1 as well as myocardial HIF-1alpha expression were significantly lower than those in the asphyxia group (P<0.01). Myocardial ischemia was alleviated and no cell necrosis was found in the Xinmailong-treated group.. Asphyxia leads to increase in myocardial HIF-1alpha expression and plasma levels of ET-1 and CK. Xinmailong can reduce the myocardial expression of HIF-1alpha and decrease plasma ET-1 levels, thus alleviating hypoxia-ischemic myocardial injury.

Topics: Animals; Animals, Newborn; Asphyxia; Creatine Kinase; Endothelin-1; Female; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Male; Myocardial Ischemia; Myocardium; Periplaneta; Rats; Rats, Sprague-Dawley

Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease.. Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ETA) and type B (ETB), and angiotensin type 1 (AT1) and type 2 (AT2) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro pharmacology.. ETA and, to a lesser extent, ETB receptor staining was observed in the healthy vascular smooth muscle cells. The level of ETB receptor expression was higher in patients undergoing CABG surgery (250% +/- 23%; P < 0.05) and in the patients with angina pectoris (199% +/- 6%; P < 0.05), than in the healthy controls (100% +/- 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ETB receptor agonist sarafotoxin S6c, compared to healthy controls (P < 0.05). No such difference was found for the ETA receptors. AT1 and, to a lesser extent, AT2 receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT1 receptor expression was higher in both the angina pectoris (128% +/- 25%; P < 0.05) and in the CABG patients (203% +/- 41%; P < 0.05), as compared to the healthy controls (100% +/- 25%). The increased AT1 receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s).. The results demonstrate, for the first time, upregulation of ETB and AT1 receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.

Topics: Aged; Angina Pectoris; Angiotensin II; Angiotensin II Type 2 Receptor Blockers; Arteries; Blotting, Western; Case-Control Studies; Coronary Artery Bypass; Dose-Response Relationship, Drug; Endothelin-1; Humans; Imidazoles; Immunohistochemistry; Middle Aged; Muscle, Smooth, Vascular; Myocardial Ischemia; Myography; Pyridines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Endothelin A; Receptor, Endothelin B; Subcutaneous Tissue; Up-Regulation; Vasoconstriction; Vasoconstrictor Agents; Viper Venoms

Endothelin-1 and norepinephrine are involved in myocardial ischemia/reperfusion injury. The aim of this study was to investigate the role of endogenously generated endothelin-1 in ischemia/reperfusion-induced norepinephrine overflow and cardiac dysfunction using a nonselective prototype of endothelin-converting enzyme (ECE) inhibitor, phosphoramidon, and a selective ECE inhibitor, SM-19712 (4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl]benzenesulfonamide, monosodium salt). According to the Langendorff technique, isolated Sprague-Dawley rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Phosphoramidon and SM-19712 were perfused 30 min before ischemia and during reperfusion. Endothelin-1 level in left ventricle was increased by ischemia/reperfusion. This increase in left ventricular endothelin-1 level was suppressed by treatment with SM-19712. SM-19712 significantly improved ischemia/reperfusion-induced cardiac dysfunction such as decreased left ventricular developed pressure and dP/dt(max) and increased left ventricular end diastolic pressure. In addition, this agent suppressed excessive norepinephrine overflow in the coronary effluent from the post-ischemic heart. In contrast, treatment with phosphoramidon further enhanced left ventricular endothelin-1 level and norepinephrine overflow, and significantly worsened cardiac dysfunction after ischemia/reperfusion. These responses such as exaggerated norepinephrine overflow and the cardiac dysfunction observed after ischemia/reperfusion were markedly suppressed in the presence of a selective endothelin ET(A) receptor antagonist, ABT-627 [2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid]. These findings indicate that cardiac endothelin-1 production is enhanced by ischemia/reperfusion, and this endogenously increased endothelin-1 is involved in post-ischemic norepinephrine overflow and cardiac dysfunction via the activation of endothelin ET(A) receptors.

Topics: Animals; Aspartic Acid Endopeptidases; Atrasentan; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Glycopeptides; Male; Metalloendopeptidases; Myocardial Ischemia; Myocardial Reperfusion Injury; Norepinephrine; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sulfonamides; Sulfonylurea Compounds

Endothelin(ET)-1 (ET-1) increases after myocardial infarction and may have effects on myocardial function. ET-1 has also been shown to affect the action potential (AP) which may be arrhythmogenic and predispose to ventricular fibrillation (VF). The effects of ET-2 and ET-3 are uncertain. We hypothesized that the ETs increase during acute ischemia and that plasma levels are predictive of ischemically induced VF. Thirty-four domestic swine underwent balloon occlusion of the proximal LAD coronary artery. Occlusion was confirmed angiographically. Venous samples were collected from the right atrium at baseline and at 5 min intervals for 30 min or until VF induction. ET-1, ET-2, and ET-3 were measured using ELISA. Changes in plasma concentrations were assessed using repeated measures ANOVA with Dunnett's. A p < 0.05 was considered statistically significant. All animals had angiographic evidence of successful proximal LAD occlusion. ET-1 levels were significantly increased from a baseline at 20 min and remained elevated during 30 min of occlusion. ET-2 and ET-3 levels did not change from baseline values (figure, mean +/- SE). VF occurred in 60% of animals. Peak ET-1 values were not significantly different between VF and non-VF animals (6.2 +/- 2.2 vs. 4.8 +/- 2.3 pg/mL). No single ET-1 value had a VF predictive value >50%. There is a significant increase in ET-1 level within 20 min of acute myocardial ischemia. Despite known effects of ET-1 on the AP, this increase did not correlate with the occurrence of VF.

Topics: Action Potentials; Acute Disease; Animals; Balloon Occlusion; Biomarkers; Coronary Angiography; Endothelin-1; Endothelin-2; Endothelin-3; Gene Expression Regulation; Myocardial Ischemia; Predictive Value of Tests; Swine; Time Factors; Ventricular Fibrillation; Ventricular Premature Complexes

Topics: Antioxidants; Endothelin-1; Heart; Humans; Myocardial Ischemia; Oxidative Stress

EPO (erythropoietin) has recently been shown to have protective actions upon the myocardium; however, the direct effects of EPO upon cardiac contractile and secretory functions are unknown and the signalling mechanisms are not well defined. In the present study, we provide the first evidence of direct cardiac contractile actions of EPO. In isolated perfused Sprague-Dawley rat hearts, a 30 min infusion of EPO significantly increased contractility in a dose-dependent fashion (maximal change 18+/-2% with 1 unit/ml EPO; P<0.005 compared with vehicle). Perfusate ET-1 (endothelin-1) increased transiently during EPO infusion, and the ET(A/)ET(B) antagonist bosentan abolished the inotropic response to EPO. BNP (B-type natriuretic peptide) secretion (28+/-8%; P<0.05) and nuclear transcription factor GATA-4 DNA-binding activity (51%; P<0.05) were both significantly increased by EPO and blocked by bosentan. In a model of global ischaemic injury, delivery of 1 unit/ml EPO during reperfusion significantly attenuated creatine kinase release (28+/-12%; P<0.05) and significantly improved contractile recovery (P<0.001), independent of ET(A) blockade. Apoptotic indices [assessed by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling)/cleaved caspase-3-positive cells] were significantly decreased (P<0.01) by 1 unit/ml EPO during reperfusion alone, coincident with significantly increased phosphorylation of myocardial JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3). Thus EPO directly enhances cardiac contractility and BNP secretion and alleviates ischemia/reperfusion injury via ET-1-dependent and -independent mechanisms respectively.

Topics: Animals; Apoptosis; Bosentan; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Erythropoietin; Heart; Humans; Janus Kinase 2; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Natriuretic Peptide, Brain; Perfusion; Phosphorylation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; STAT3 Transcription Factor; Stimulation, Chemical; Sulfonamides

The hypothesis was tested that endothelin-1 (ET-1)-induced superoxide (O(2)(-)) generation mediates post-ischemic coronary endothelial injury, that ischemic preconditioning (IPC) affords endothelial protection by preventing post-ischemic ET-1, and thus O(2)(-), generation, and that opening of the mitochondrial ATP-dependent potassium channel (mK(ATP)) triggers the mechanism of IPC. Furthermore, the study was aimed at identifying the source of O(2)(-) mediating the endothelial injury. Langendorff-perfused guinea-pig hearts were subjected either to 30 min ischemia/35 min reperfusion (IR) or were preconditioned prior to IR with three cycles of either 5 min ischemia/5 min reperfusion or 5 min infusion/5 min washout of mK(ATP) opener diazoxide (0.5 mM). Coronary flow responses to acetylcholine (ACh) served as a measure of endothelium-dependent vascular function. Myocardial outflow of ET-1 and O(2)(-) and functional recoveries were followed during reperfusion. NADPH oxidase and xanthine oxidase (XO) activities were measured in cardiac homogenates. IR augmented ET-1 and O(2)(-) outflow and impaired ACh response. All these effects were attenuated or prevented by IPC and diazoxide, and 5-hydroxydecanoate (a selective mK(ATP) blocker) abolished the effects of IPC and diazoxide. Superoxide dismutase and tezosentan (a mixed ET-1-receptor antagonist) mimicked the effects of IPC, although they had no effect on the ET-1 generation. IR augmented also the activity of NADPH oxidase and XO. Apocynin treatment, that resulted in NADPH oxidase inhibition, prevented XO activation and O(2)(-) generation in IR hearts. The inhibition of XO, either by allopurinol or feeding the animals with tungsten-enriched chow, prevented post-ischemic O(2)(-) generation, although these interventions had no effect on the NADPH activity. In addition, the post-ischemic activation of NADPH oxidase and XO, and O(2)(-) generation were prevented by IPC, tezosentan, thenoyltrifluoroacetone (mitochondrial complex II inhibitor), and tempol (cell-membrane permeable O(2)(-) scavenger). In guinea-pig heart: (i) ET-1-induced O(2)(-) generation mediates post-ischemic endothelial dysfunction; (ii) IPC and diazoxide afford endothelial protection by attenuating the ET-1, and thus O(2)(-) generation, and the mK(ATP) opening triggers the protection; (iii) the NADPH oxidase maintains the activity of XO, and the XO-derived O(2)(-) mediates the endothelial injury, and (iv) ET-1 and O(2)(-) (probably of mitochondrial o

Topics: Animals; Endothelin-1; Endothelium, Vascular; Enzyme Activation; Enzyme Inhibitors; Guinea Pigs; Ischemic Preconditioning, Myocardial; Mitochondria, Heart; Myocardial Ischemia; Myocardium; NADPH Oxidases; Superoxides; Xanthine Oxidase

Large burns cause systemic inflammation and myocardial depression. We hypothesized that small burns affect cardiac tolerance to ischemia, and that tumor necrosis factor alpha (TNFalpha) signaling through endothelin-1 (ET) and nuclear factor kappa B (NF kappaB) are associated.. Mice were randomly assigned to four groups: burn (caused by boiling water on <2% of the body surface area), sham, burn+etanercept (TNFalpha blocker) treatment and sham+etanercept treatment. Twenty-four hours later, hearts were isolated and subjected to global ischemia followed by reperfusion. Additional hearts and burned skin lesions were sampled to evaluate expression of TNFalpha (immunoblotting) and endothelin-1 (radioimmunoassay). A NF kappaB-luciferase reporter mouse was used to evaluate NF kappaB activation.. Baseline cardiac function before ischemia (BI) was only negligibly influenced by burn or etanercept, but was reduced by burn+etanercept. Burn markedly impaired post-ischemic left ventricular function and increased infarct size in comparison with sham-treated mice. Cardiac, but nut cutaneous, expression of TNFalpha was increased in burned mice, while cardiac NF kappaB and endothelin-1 were not influenced. TNFalpha blockade reduced the detrimental effects of burn on cardiac tolerance to ischemia.. Small cutaneous burns, that did not influence baseline heart function, impaired the tolerance to ischemia. This effect may be mediated through TNFalpha, but does not involve signaling through NF kappaB or endothelin-1.

Topics: Animals; Blood Pressure; Burns; Cell Communication; Coronary Circulation; Endothelin-1; Immunoblotting; Male; Mice; Mice, Inbred C57BL; Myocardial Ischemia; NF-kappa B; Random Allocation; Skin; Tumor Necrosis Factor-alpha

This study compared lipids, the product of lipid peroxidation malondialdehyde (MDA), the acute phase reactant high-sensitive C-reactive protein (hsCRP), endothelin-1 (ET-1), P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) between healthy controls, subjects with ischemic heart disease (IHD) and type 2 diabetes mellitus (DM) subjects who did not perform coronary artery bypass graft (CABG) surgery as well as type 2 DM subjects who performed CABG. HbA1c, lipids, MDA, hsCRP, ET-1, P-selectin, ICAM-1, and VCAM-1 levels were significantly higher in the diabetic groups than in either healthy controls or IHD subjects. In the diabetic groups, there was a negative association among hsCRP and HDL-C. ET-1, ICAM-1 levels, and TAG were positively correlated, as do the association between P-selectin, VCAM-1, and HbA1c%. Also a positive relation was found among hsCRP levels and ICAM-1, as well as MDA and ET-1. P-selectin and ICAM-1 were significantly positively correlated. This study indicates that increased level of oxidative stress marker, proinflammatory markers, and their downstream effectors adhesion molecules occur in type 2 DM.

Topics: Adult; Analysis of Variance; C-Reactive Protein; Cell Adhesion Molecules; Cholesterol, HDL; Coronary Artery Bypass; Diabetes Mellitus, Type 2; Endothelin-1; Humans; Intercellular Adhesion Molecule-1; Male; Malondialdehyde; Middle Aged; Myocardial Ischemia; P-Selectin; Triglycerides; Vascular Cell Adhesion Molecule-1

Peroxisome proliferator-activated receptors (PPARs), key transcriptional regulators of lipid and energy metabolism in cardiomyocytes, have recently been proposed to modulate cardiovascular pathophysiological responses in experimental models. However, there is little information about the functional activity of PPARs in human heart failure.. To investigate PPAR-alpha and -gamma expression and activity, and the association with ET-1 production and fibrosis, in cardiac biopsies from patients with end-stage heart failure due to ischemic cardiomyopathy (ICM) in comparison and from non-failing donor hearts. All samples were obtained during cardiac transplantation.. Morphological analysis (by Masson trichrome and image analysis) did not detect fibrosis in the left atrium from non-failing donors (NFLA) or from ICM patients (FLA). However, left ventricles from failing hearts (FLV) contained a greater number of fibrotic areas (NFLA: 3.21+/-1.15, FLA: 1.63+/-0.83, FLV: 14.5+/-3.45%; n = 9, P<0.05). By RT-PCR, preproET-1 expression was similar in the non-failing and failing atrium but was significantly higher in the ventricles from failing hearts (NFLA: 1.00+/-0.06, FLA: 1.08+/-0.11, FLV: 1.74+/-0.19; n = 9, P<0.05). PPAR-alpha and PPAP-gamma mRNA (by RT-PCR) and protein (by Western blot) levels were higher in the ventricles from failing hearts compared with the atrium from failing and non-failing hearts. Electrophoretic mobility shift assays showed that PPAR-alpha and PPAP-gamma were not activated in the ventricles (NFLA: 1.00+/-0.11, FLA: 1.89+/-0.24, FLV: 0.95+/-0.07; n = 9, P<0.05).. These data suggest that PPAR-alpha and PPAP-gamma are selectively activated in the atria from ICM patients and might be functionally important in the maintenance of atrial morphology.

Topics: Adolescent; Adult; Biopsy; Blotting, Western; Case-Control Studies; Child; Endothelin-1; Female; Fibrosis; Gene Expression; Heart Atria; Heart Failure; Humans; Male; Middle Aged; Myocardial Ischemia; PPAR alpha; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

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

Enhanced external counterpulsation (EECP) significantly augments diastolic blood flow and has been postulated to improve endothelial function by increased shear stress. We examined the effects of EECP on plasma nitric oxide and endothelin-1 (ET-1) levels. Plasma nitrate and nitrite (NOx) and ET-1 levels were measured serially in 13 patients with coronary artery disease who received 1-hour daily treatments of EECP over 6 weeks. During the course of EECP therapy, plasma NOx progressively increased and plasma ET-1 progressively decreased. After 36 hours of EECP, there was a 62 +/- 17% increase in plasma NOx compared with baseline (43.6 +/- 4.3 vs 27.1 +/- 2.6 micromol/L, p <0.0001) and a 36 +/- 8% decrease in plasma ET-1 (76.7 +/- 9.5 vs 119.5 +/- 8.5 pg/L, p <0.0001). At 3 months after completion of EECP, NOx remained 12 +/- 11% above baseline (p = 0.002), and ET-1 remained 11 +/- 10% below baseline (p = 0.0068). Our data provides neurohormonal evidence to support the hypothesis that EECP improves endothelial function.

Topics: Adult; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Counterpulsation; Endothelin-1; Female; Humans; Male; Myocardial Ischemia; Nitric Oxide; Oxygen; Treatment Outcome

Endothelin (ET)-1 and norepinephrine (NE) are involved in myocardial ischemia/reperfusion injury. We investigated the role of ET-1 in ischemia/reperfusion-induced NE overflow and cardiac dysfunction using a selective ET(A) receptor antagonist (ABT-627), a selective ET(B) receptor antagonist (A-192621), and the spotting lethal (sl) rat, which carries a naturally occurring deletion in the ET(B) receptor gene.. According to the Langendorff technique, isolated hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. In Sprague-Dawley rat hearts, ischemia/reperfusion-induced cardiac dysfunctions such as decreased left ventricular developed pressure and coronary flow and increased left ventricular end-diastolic pressure were worsened by treatment with A-192621. This agent enhanced excessive NE overflow in the coronary effluent from the postischemic heart. In contrast, treatment with ABT-627, in the absence or presence of A-192621, significantly improved postischemic cardiac dysfunction and markedly suppressed NE overflow to the same extent. Postischemic cardiac dysfunction and NE overflow in the heart of ET(B) receptor-deficient homozygous (sl/sl) rats were highly observed compared with cases in wild-type rats, and exaggerated responses to ischemia/reperfusion in sl/sl rats were abolished by ABT-627 treatment. Exogenously applied ET-1 produced severe cardiac dysfunction and a significant increase in NE overflow in a dose-dependent manner, but these responses were markedly suppressed in the presence of 5-N-ethyl-N-isopropyl-amiloride, an inhibitor of the Na+/H+ exchanger (NHE).. Pharmacological blockade or genetic deficiency of ET(B) receptors is detrimental to the postischemic heart, and exaggerated cardiac pathology under the above conditions is mediated by ET(A) receptor activation. ET(A)/NHE-mediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.

Topics: Amiloride; Animals; Animals, Genetically Modified; Atrasentan; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Gene Deletion; In Vitro Techniques; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Norepinephrine; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; Ventricular Pressure

In this study we assessed whether serum endothelin-1 levels were associated with indexes of disease severity in unstable angina, including troponin I, C-reactive protein, and transient myocardial ischemia. Endothelin-1 levels were higher in patients who had transient myocardial ischemia and in those who had 3-vessel disease on angiography but were not significantly correlated with levels of C-reactive protein and troponin I.

Topics: Aged; Angina, Unstable; Biomarkers; C-Reactive Protein; Electrocardiography, Ambulatory; Endothelin-1; Female; Humans; Male; Myocardial Ischemia; Prospective Studies; Severity of Illness Index; Troponin

Topics: Angina Pectoris; Endothelin-1; Exercise; Humans; Myocardial Ischemia; Placebos; Simvastatin

NO plays an important role in the compensatory increase in coronary flow conductance against myocardial ischemia, and NO bioavailability is impaired in various diseases. We tested the hypothesis that, when NO production is inhibited, vasoconstrictor signals from the ischemic myocardium are unmasked. We investigated the involvement of endothelin type A (ETA) receptors in the transduction of the constrictor signal. To detect coronary vasoactive signals derived from ischemic myocardium, we used a bioassay system in which an isolated rabbit coronary microvessel (detector vessel, DV) was placed on beating myocardium perfused by the left anterior descending coronary artery (LAD) of an anesthetized open-chest dog (n = 38). The DV was pressurized to 60 cmH2O throughout the experiment and observed with an intravital microscope equipped with a floating objective. After the intrinsic tone of the DV was established, vehicle (n = 7), Nomega-nitro-L-arginine (L-NNA, 100 micromol/l; n = 13), L-NNA + BQ-123 (a selective ETA receptor blocker, 1 micromol/l; n = 7), or BQ-123 alone (1 micromol/l; n = 7) was superfused onto the DV. Thereafter, the LAD of the beating heart was occluded. Coronary occlusion produced significant dilation of the DV by 10 +/- 4%. When L-NNA was applied, the DV significantly constricted by 12 +/- 5% in response to LAD occlusion, and BQ-123 abolished the vasoconstriction. Pretreatment with BQ-123 alone produced an enhancement of the ischemia-induced dilation. We conclude that ischemic myocardium releases transferable vasomotor signals that produce coronary microvascular constriction during the blockade of NO production and the constrictor signal is mediated by ETA receptors.

Topics: Animals; Coronary Vessels; Dogs; Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; In Vitro Techniques; Male; Microcirculation; Myocardial Ischemia; Nitric Oxide; Nitroarginine; Peptides, Cyclic; Rabbits; Receptor, Endothelin A; Signal Transduction; Vasoconstriction

The purpose of this study was to investigate the effects of bosentan, a mixed endothelin receptor A and B subtype antagonist, on myocardial ischemia-reperfusion injury and to explore the influence of the timing of bosentan administration on its cardioprotective effects. Adult rat hearts were perfused by the Langendorff technique with Krebs-Henseleit solution (KH) at a constant flow rate at 10 mL/min. Global myocardial ischemia was induced by stopping KH perfusion for 40 min, and this was followed by 60 min of reperfusion. Hearts were randomized to 1 of 3 experimental groups (n = 7 each): untreated control; treatment with bosentan 1 micromol/L 10 min prior to, during 40 min global ischemia, and for 15 min of reperfusion (BOS); or treatment with bosentan 1 micromol/L after 15 min of reperfusion (BOS-R). We observed that BOS-R, but not the BOS treatment regimen, significantly reduced the release of cardiac-specific creatine kinase and postischemic myocardial infarct size (P < 0.05 vs. control) without affecting myocardial contractility. Left ventricular developed pressure in the BOS group was significantly (P < 0.01) lower than that in the control group throughout reperfusion. It is concluded that pharmacologically delayed antagonism of endothelin-1 during reperfusion attenuates postischemic myocardial injury. Endothelin-1 antagonist application during early reperfusion may exacerbate postischemic myocardial dysfunction.

Topics: Animals; Bosentan; Creatine Kinase; Creatine Kinase, MB Form; Drug Administration Schedule; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Heart; Isoenzymes; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rats; Sulfonamides; Time Factors; Ventricular Pressure

To explore the relationship between expression of endothelin in heart and ischemia.. Using the RT-PCR method, we enquiry changes of ET-1 RNA after 60min ischemia in hearts of rats.. Although the two group appear positive, they are different significantly, which indicate that ischemia may lead to the increase of ET-1 mRNA.. The experiment, therefore, pave a way for immunochemical study.

Topics: Animals; Endothelin-1; Female; Image Processing, Computer-Assisted; Male; Myocardial Ischemia; Myocardium; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

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

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

The aims of this study were to determine if endothelin-1 (ET-1) under normal and ischaemic conditions exhibits a direct arrhythmogenic effect that is independent of its ability to cause coronary vasoconstriction, and to determine the contribution of the ET(A) and ET(B) receptor subtype. ET(A/B) (with ET-1) and ET(A) (ET-1 in the presence of BQ-788) receptor activation resulted in a significant reduction in both epi- and endocardial monophasic action potential duration (MAPD(90)). ET(A) receptor activation reduced both epi- and endocardial effective refractory period (ERP). This MAPD(90) and ERP shortening were associated with a reduction in coronary flow, myocardial contractility and induction of ventricular fibrillation (VF) during ERP measurement. The ET(B) agonist sarafotoxin (S6c) had no marked, or concentration-dependent, effect on MAPD(90), ERP, myocardial contractility or induction of arrhythmias. Neither ET-1 nor S6c, given prior to coronary artery occlusion, significantly changed the ischaemia-induced dispersion of MAPD(90), ERP or the % incidence of VF. In conclusion, neither ET(A) nor ET(B) receptor stimulation has a direct arrhythmogenic effect in isolated rabbit hearts under normal or ischaemic conditions. The ET-1-induced arrhythmogenic effect observed in nonischaemic hearts is likely to be the result of the associated coronary vasoconstriction caused by ET(A) receptor stimulation resulting in myocardial ischaemia.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Circulation; Disease Models, Animal; Endocardium; Endothelin B Receptor Antagonists; Endothelin-1; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Oligopeptides; Pericardium; Piperidines; Rabbits; Receptor, Endothelin A; Receptor, Endothelin B; Ventricular Fibrillation; Viper Venoms

To examine if the decline in post-ischemic hyperemic flow after repeated brief periods of myocardial ischemia is accompanied by augmented cardiac release of the vasoconstrictors endothelin-1 (ET-1) and norepinephrine (NE).. Mid-LAD (left anterior descending coronary artery) was occluded for 10 min with 30 min intervals a total of four times in six anesthetized pigs. Blood from the anterior interventricular coronary vein was drained through a shunt to the right atrium to facilitate blood sampling. Plasma concentrations of ET-1 and NE were repeatedly measured in arterial and coronary venous blood to estimate cardiac vasoconstrictor release.. Plasma concentrations of ET-1 and NE remained unaltered, but cardiac release of both vasoconstrictors rose briefly during reperfusion due to the hyperemia. However, release declined progressively after repeated periods of ischemia and reperfusion and amounted to 53% (NE) and 17% (ET-1) of initial release after the fourth period of ischemia.. The decline in post-ischemic hyperemia after repeated brief periods of myocardial ischemia is not accompanied by a progressive accentuation of cardiac ET-1 and NE release.

Topics: Analysis of Variance; Animals; Biomarkers; Coronary Circulation; Disease Models, Animal; Endothelin-1; Female; Hemodynamics; Hyperemia; Male; Myocardial Ischemia; Norepinephrine; Random Allocation; Recurrence; Risk Factors; Sensitivity and Specificity; Statistics, Nonparametric; Swine; Time Factors; Vasoconstrictor Agents

The endothelin-1 (ET-1) is known to cause myocardial ischemia; however, whether this effect is entirely dependent on vasoconstriction is uncertain. The aim of this study was to characterize the myocardial ischemia after the intracoronary administration of endothelin-1, and compare it with that induced by coronary stenosis. In the left anterior descending coronary artery of 15 dogs, a mild inflow reduction (30%) was produced for 10 minutes using intracoronary endothelin-1 (46 +/- 33 pmol/min) or coronary stenosis. The hearts were rapidly cross-sectioned at short axial plane and freeze-clamped within 120 milliseconds using a specially developed device to visualize and quantify the area of ischemia (%IA) with NADH fluorescence photography. The %IA was larger in the endothelin-1 group than in the stenosis group (66 +/- 23 versus 18 +/- 18, P = 0.0005); furthermore, the ischemia was transmural in the ET-1 group, but limited to subendocardium in the stenosis group. ET-1 increased the coronary arterial resistance especially in subepicardial region and produced smaller ischemic foci in microcirculation. The mechanism of larger ischemia produced by ET-1 might depend on pro-ischemic effects on myocytes and vasoconstriction of the coronary microcirculation, predominantly in the subepicardium in vivo.

Topics: Animals; Coronary Circulation; Dogs; Endothelin-1; Fluorescence; Hemodynamics; Myocardial Ischemia; NAD

Altered Na(+)/Ca(2+) exchanger (NCX) protein expression or activity is thought to contribute to various aspects of cardiac pathology. In guinea pig ventricular myocytes, NCX-mediated Ca(2+) entry is almost entirely responsible for Ca(2+) overload during hypoxia-reoxygenation. Because Ca(2+) overload is a common initiator of apoptosis, the purpose of this study was to test the hypotheses that NCX activity is critically involved in initiating apoptosis after hypoxia-reoxygenation and that hypoxia-reoxygenation-induced apoptosis can be modulated by changes in NCX protein expression or activity. An NCX antisense oligonucleotide was used to reduce NCX protein expression in cultured adult guinea pig ventricular myocytes. Caspase-3 activation and cytochrome c release were used as markers of apoptosis. Hypoxia-reoxygenation-induced apoptosis was significantly decreased in antisense-treated myocytes compared with untreated control or nonsense-treated myocytes. Pretreatment of cultured myocytes for 24 h with either endothelin-1 or phenylephrine was found to increase both NCX protein expression and evoked NCX activity as well as enhance hypoxia-reoxygenation-induced apoptosis. Control experiments demonstrated that endothelin-1 and phenylephrine did not induce apoptosis on their own nor did they enhance the apoptotic response in a model of Ca(2+)-dependent, NCX-independent apoptosis. Additional control experiments demonstrated that the NCX antisense oligonucleotide did not alter the apoptotic response of myocytes to either H(2)O(2) or isoproterenol. Taken together, these data suggest that the NCX has a critical and specific role in the initiation of apoptosis after hypoxia-reoxygenation in guinea pig myocytes and that hypoxia-reoxygenation-induced apoptosis is quite sensitive to changes in NCX activity.

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Animals; Apoptosis; Cells, Cultured; Endothelin-1; Female; Guinea Pigs; Heart Ventricles; Hydrogen Peroxide; Hypoxia; Isoproterenol; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocytes, Cardiac; Oligonucleotides, Antisense; Oxidants; Oxygen; Phenylephrine; Sodium-Calcium Exchanger

Myocardial bridging (MB) is associated with clinical and metabolic evidence of ischaemia. In the present study, we aimed to evaluate the extent of atherosclerosis and endothelial dysfunction in patients with MB. The study population consisted of 15 patients with MB [9 women (60%), aged 56 +/- 9 years] and 14 control subjects [8 women (57%), aged 54 +/- 10 years]. All patients underwent coronary angiography. The femoral artery and coronary sinus endothelin-1 (ET-1) and nitric oxide (NOx) plasma levels were measured before and after right atrial pacing in all subjects. Also, intravascular ultrasonography was performed in 13 patients with MB. With right atrial pacing, coronary sinus ET-1 levels increased significantly in patients with MB compared with baseline levels (5.77 +/- 6.76 versus 11.32 +/- 9.40 pg/ml, p < 0.05). The coronary sinus ET-1 levels remained unchanged in controls with pacing (3.99 +/- 4.00 versus 4.19 +/- 7.15 pg/ml, p > 0.05). There was no significant difference between the two groups according to the increase in NOx levels with atrial pacing. Ten (77%) of the 13 patients had plaque formation in the segments proximal to the bridge with an area stenosis of 37 +/- 21% (12% to 75%). In patients with MB, post-pacing levels of coronary sinus ET-1 correlated significantly with the cross-sectional area of the plaque (r = 0.65, p = 0,04). Increased ET-1 levels and the pathological data of intravascular ultrasonography may be associated with endothelial dysfunction and atherosclerosis development in patients with MB. The presence of atherosclerosis in the proximal segments to the bridge may contribute to the myocardial ischaemia detected in these patients.

Topics: Case-Control Studies; Coronary Vessel Anomalies; Endothelin-1; Female; Heart-Assist Devices; Humans; Male; Middle Aged; Myocardial Ischemia; Nitric Oxide; Ultrasonography

To investigate the cardiac protective effects of ghrelin in rat with myocardial injury induced by isoproterenol (ISO).. Rats were subcutaneously injected ISO 40 mg/kg/d with or without ghrelin 1 or 10 nmol/kg/d for 2 d. Hemodynamic parameters including mean arterial blood pressure and left ventricular pressure were measured at 12 h after the last injection with ISO and/or ghrelin. Plasma lactate dehydrogenase (LDH) activity, plasma and myocardial contents of malondialdehyde (MDA), and conjugated diene were measured. Plasma ghrelin and endothelin-1 levels were assayed using radioimmunoassay methods. Endothelin-1 and ghrelin mRNA were determined using RT-PCR.. About 45 % (5/11) of rats after treatment with ISO alone died during experimental periods. However, no rats died after administration with ghrelin 10 nmol/kg/d (0/11, P<0.05). Ghrelin also obviously ameliorated the hemodynamic disturbance in rats induced by ISO. The plasma LDH activity, contents of myocardial and plasma MDA, and conjugated diene level in plasma in ISO+G10 nmol/kg/d group were decreased by 28 %, 34 %, 73 %, and 38 % compared with those of ISO group (all P<0.01) respectively. ISO-induced endothelin-1 mRNA over-expression was inhibited and endothelin-1 level in plasma were inhibited by ghrelin 1 and 10 nmol/kg/d. The ghrelin levels in plasma and ghrelin mRNA in myocardium were increased in the rats after injection of ISO. The plasma ghrelin level was further increased after ghrelin administration.. Ghrelin has a protective effect against ISO-induced myocardial injury.

Topics: Animals; Cardiotonic Agents; Endothelin-1; Ghrelin; Isoproterenol; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocardial Ischemia; Myocardium; Peptide Hormones; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger

Endothelin-1 (ET-1) probably plays an important role in myocardial damage in acute ischemia. Coronary sinus ET-1 and its precursor big endothelin-1 (big ET-1) levels and also tissue levels of preproendothelin-1 mRNA (ET-1 mRNA) were investigated in an in vivo canine ischemia-reperfusion model in nine consecutive mongrel dogs, surviving 30-minute ligation of the left descending coronary artery followed by a 90-minute reperfusion period. Samples were collected before and at the end of ischemia and during reperfusion. ET-1 and big ET-1 were obtained by immunoprecipitation and detected by western blotting. The ET-1 mRNA level was assessed by reverse transcription-polymerase chain reaction. During ischemia the plasma ET-1 levels and big ET-1 levels did not change significantly, while the myocardial ET-1 mRNA level decreased to 57.8%. During reperfusion an increase of the coronary sinus ET-1 and big ET-1 levels was observed (control versus reperfusion, 90 minutes; ET-1, 15.2 +/- 4.18 fmol/mL versus 23.2 +/- 5.23 fmol/mL, P < 0.01; big ET-1, 14.7 +/- 5.9 fmol/mL versus 27.2 +/- 7.1 fmol/mL, P < 0.001). Simultaneously, the ET-1 mRNA level increased by 322% relative to the ischemic and by 214% relative to the baseline level. The decrease of ET-1 mRNA during ischemia may be due to degradation and decreased metabolism in the hypoxic cells locally. The elevation of the ET-1 mRNA level during reperfusion indicates rapid big ET-1 synthesis. This was confirmed by the increases in big ET-1 and ET-1 plasma levels. This latter can be associated with the generation of reperfusion arrhythmias or other complications of acute myocardial infarction.

Topics: Animals; Blotting, Western; Disease Models, Animal; Dogs; Endothelin-1; Female; Gene Expression Regulation; Immunoprecipitation; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

Increased intrapericardial levels of endothelin-1 (ET-1) induce myocardial ischemia and concomitant release of the purine metabolites adenosine (ADO), inosine (INO) and hypoxanthine (HXA) into the pericardial fluid. However, the potential modulatory role of nitrogen monoxide in compensating the ET-1-induced ischemic stress is not fully elucidated. The pericardial elevations of purine metabolite concentrations in the pericardial fluid after ET-1 administration (150 pmol/kg intrapericardially) were measured in the in situ dog heart with (n = 6) or without (n = 5) systemic nitrogen monoxide synthase blockade (30 mg/kg (G)-nitro-L-arginine methyl ester, followed by 6 mg/min intravenously). After control sampling, three consecutive pericardial infusate samples (ET1, ET2, ET3) were obtained for purine metabolite determinations (high-performance liquid chromatography-ultraviolet). It was found that intrapericardial ET-1 elevated the pericardial purine metabolite concentrations significantly in both groups. No significant differences were detected between the control and (G)-nitro-L-arginine methyl ester-treated groups in ischemic changes of pericardial ADOmax (+3.27 +/- 1.13 microM versus +1.84 +/- 0.56 microM), INOmax (+15.21 +/- 2.3 microM versus +12.09 +/- 4.04 microM) and HXAmax (+16.34 +/- 2.98 microM versus +17.09 +/- 5.22 microM) levels and in the maximal ST elevations (0.43 +/- 0.05 mV versus 0.61 +/- 0.08 mV). The hemodynamic variables did not change with ET-1 administration. In conclusion, systemic nitrogen monoxide synthase blockade does not aggravate the ET-1-induced acute myocardial ischemia and the release of purine metabolites, suggesting that endogenous nitrogen monoxide is not a supplementary factor to purine metabolites in this type of coronary adaptive responses.

Topics: Adaptation, Physiological; Adenosine; Animals; Disease Models, Animal; Dogs; Endothelin-1; Enzyme Inhibitors; Hemodynamics; Hypoxanthine; Inosine; Myocardial Ischemia; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pericardium; Purines

Myocardial ischemia-reperfusion is associated with increased production of endothelin-1 (ET-1). Moreover, exogenous ET-1 has arrhythmogenic properties. Our aim was to investigate the correlation between endogenous ET-1, big ET-1 levels and epicardial monophasic action potential duration during myocardial ischemia-reperfusion in anesthetized dogs. Thirty-minute myocardial ischemia was followed by a 90-minute reperfusion period in 18 mongrel dogs. The total incidence of ventricular fibrillation (VF) during ischemia and reperfusion was 11.1% and 33.3%, respectively. During ischemia, the monophasic action potential duration at 90% repolarization (MAPD90) decreased significantly (control versus ischemia, 30 minutes, 224.7 +/- 7.1 ms versus 173.8 +/- 7.6 ms; P < 0.05), while during reperfusion a significant prolongation of MAPD90 was observed (ischemia, 30 minutes versus reperfusion, 30 minutes, 173.8 +/- 7.6 ms versus 249.7 +/- 9.9 ms, P < 0.05). During reperfusion ET-1 and big ET-1 levels increased significantly in the coronary sinus and femoral artery (control versus reperfusion, 90 minutes: coronary sinus ET-1, 15.1 +/- 1.4 fmol/mL versus 22.3 +/- 1.1 fmol/mL; big ET-1, 14.7 +/- 1.9 fmol/mL versus 27.4 +/- 2.3 fmol/mL; P < 0.05). The ET-1 concentration increased to a higher level during ischemia in dogs with VF compared with dogs surviving ischemia-reperfusion (non-VF versus VF: control, 15.1 +/- 1.3 versus 15.2 +/- 1.3; ischemia, 30 minutes, 17.6 +/- 1.2 fmol/mL versus 22 +/- 1.6 fmol/mL; P < 0.05), demonstrating a trend of correlation between endothelin levels and development of VF (P = 0.07). ET-1 and big ET-1 levels increased during reperfusion and in the VF group during ischemia; however, there was no correlation between endothelin levels and MAPD90.

Topics: Action Potentials; Animals; Disease Models, Animal; Dogs; Endothelin-1; Female; Male; Myocardial Ischemia; Myocardial Reperfusion; Pericardium; Protein Precursors; Time Factors; Up-Regulation; Ventricular Fibrillation

Topics: Acute Disease; Aged; Aged, 80 and over; C-Reactive Protein; E-Selectin; Endothelin-1; Female; Heart Failure; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Neurotransmitter Agents; Norepinephrine; P-Selectin; Pulmonary Edema; Sympathomimetics; Tumor Necrosis Factor-alpha

Circadian rhythms have long been recognized to occur in many biologic phenomena, including secretion of hormones as well as autonomic nervous system. There is increasing evidence that circadian rhythms have been also found in cardiovascular events, for example, myocardial infarction, sudden cardiac death as well as stroke have shown a circadian pattern of the distribution. Transient myocardial ischemia, detected by ambulatory ST segment monitoring, is also unevenly distributed during the day. The pathophysiology and the mechanism underlying these variations are the focus of much investigation, while it is not full understood up to date. Heart rate, blood pressure, neural and humoral vasoactive factors such as plasma norepinephrine levels and renin activity, and probably also contractility are increased in the morning hours, indicating that increase in myocardial oxygen demand contribute importantly to the increased prevalence of ischemia in the morning. Our recent study found that circadian rhythm of ischemic threshold detected by repetitive exercise treadmill tests in patients with chronic coronary artery disease is also apparently associated with levels of plasma ET-1. This information should enable better understanding as well as treatment on patients on circadian variation of cardiovascular events.

Topics: Cardiovascular Agents; Circadian Rhythm; Endothelin-1; Exercise Test; Humans; Models, Cardiovascular; Myocardial Ischemia

The combining of molecular biology and physiology is essential for the further development of cardiovascular medicine, and DNA microarray is a useful tool for assessing multiple gene expressions. A canine DNA microarray has been designed and tested. Approximately 60 cardiovascular-related genes were cloned from newly developed canine cDNA libraries and spotted on slides. Using the arrays, the gene expression profiles of canine myocardium in were analyzed 2 protocols: (1). ischemic myocardium by 50% reduction of the coronary blood flow, and (2). necrotic myocardium caused by coronary artery ligation. Three hours after 50% flow reduction, cardiovascular-related genes, including ecto-5'-nucleotidase, endothelin-1, PAI-1, and AT receptors, exhibited rapid alteration and there were many more altered genes than with the complete coronary occlusion. Irreversible ischemic damage without necrosis more strongly affected gene expressions in surviving myocardium than in fatally damaged myocardium. The canine DNA microarray is a useful tool for assessing the precise molecular events following changes in the pathophysiological conditions of the heart.

Topics: 5'-Nucleotidase; Animals; Coronary Circulation; Dogs; Endothelin-1; Gene Expression Profiling; Myocardial Ischemia; Necrosis; Oligonucleotide Array Sequence Analysis; Plasminogen Activator Inhibitor 1; Receptors, Angiotensin

Although beta-blockers can not be used for the treatment of vasospastic angina, the effect of beta-blockers with vasorelaxant property on coronary vasospasm remains uncertain. In this study, we evaluated the effect of betaxolol, a new beta-blocker with calcium antagonistic property, as an additional therapy on vasospastic angina (VSA) with anginal attacks on effort. We enrolled 12 patients with VSA and anginal attacks with ST segment depression during exercise stress test. All patients received 1.25-5 mg of betaxolol for 3 months. Treadmill exercise stress test and adenosine triphosphate stress thallium-201 myocardial scintigraphy were performed before and 3 months after the onset of the betaxolol treatment. The other drugs including calcium antagonists, nitrates and nicorandil were continued. No patients experienced the exacerbation of angina during the betaxolol treatment. Exercise time to chest pain (317.5+/-72.1-454.2+/-75.5 s, P<0.01) and maximal ST segment depression (1.67+/-0.67-1.16+/-0.46 mm, P<0.01) obtained by exercise stress test, the defect score (8.6+/-2.7-5.3+/-2.1, P<0.01), the extent score (14.8+/-5.8-8.8+/-4.6%, P<0.01), the severity score (17.5+/-7.3-11.3+/-5.2, P<0.01) and washout rate (31.4+/-5.6-37.6+/-5.0%, P<0.01) obtained by the scintigraphy were improved by betaxolol. Our results suggest that betaxolol increases regional myocardial blood flow and improves exercise capacity in patients with VSA. Betaxolol may become a drug for a new potential therapy for VSA.

Topics: Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Antagonists; Aged; Betaxolol; Biomarkers; Blood Pressure; Calcium Channel Blockers; Coronary Circulation; Coronary Vasospasm; Drug Evaluation; Electrocardiography; Endothelin-1; Endothelium, Vascular; Exercise; Exercise Test; Exercise Tolerance; Female; Heart Conduction System; Heart Rate; Humans; Male; Middle Aged; Motor Activity; Myocardial Ischemia; Nitric Oxide; Oxygen Consumption; Severity of Illness Index; Treatment Outcome; Vasoconstriction; Vasodilation

There is epidemiologic evidence that the prognosis of patients with nonischemic heart failure is better than that for patients with ischemic heart failure. In addition, studies have revealed that patients with ischemic heart failure show a poorer response to medical therapy. However, the pathophysiologic difference between ischemic and nonischemic heart disease is unclear. To clarify this point, we measured atrial natriuretic peptide, brain natriuretic peptide, angiotensin II, endothelin (ET)-1. interleukin-1beta interleukin-6. tumor necrosis factor (TNF)-alpha soluble TNF receptor I, and soluble TNF receptor II concentrations in plasma and pericardial fluid in patients with ischemic or nonischemic heart disease undergoing cardiac surgery. The pericardial ET-1 concentration in patients with ischemic heart disease was statistically greater than that in patients with nonischemic heart disease (about 1.5-fold), although no difference was found in the plasma ET-1 concentration. These findings suggest that the production and secretion of ET-1 from the myocardium in patients with ischemic heart disease are augmented to a greater extent than in patients with nonischemic heart disease. This result may lead to a greater understanding of the pathophysiology of ischemic heart disease.

Topics: Angiotensin II; Atrial Natriuretic Factor; Endothelin-1; Growth Substances; Humans; Myocardial Ischemia; Myocardium; Natriuretic Peptide, Brain; Pericardial Effusion; Prognosis; Receptors, Tumor Necrosis Factor

Endothelin (ET)-1 levels were analyzed in patients who underwent elective coronary stenting. There was a significant increase in systemic ET-1 levels immediately after the procedure, which is probably a marker of endothelial dysfunction that is associated with arterial injury. However, there was no association between ET-1 levels and in-stent restenosis in humans.

Topics: Aged; Blood Vessel Prosthesis Implantation; Endothelin-1; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Myocardial Ischemia; Predictive Value of Tests; Prospective Studies; Stents

The contrasting pattern of cardiac inotropy induced by human peptide endothelin-1 (ET-1) has not been satisfactorily explained. It is not clear whether ET-1 is primarily responsible for increased myocardial ET-1 expression and release with resultant inotropic effects, or for the induction of myocardial hypertrophy and heart failure. There are at least two subtypes of endothelin receptors (ET(A) and ET(B)) and the inotropic effects of ET-1 differ depending on the receptor involved. Along with some other groups, we reported significant subtype-ET(B) endothelin receptor down-regulation in human cardiac cells preincubated with endothelin agonists (Drímal et al. 1999, 2000). The present study was therefore designed to clarify the subtype-selective mechanisms underlying the inotropic response to ET-1 and to its ET(B)-selective fragment (8-21)ET-1 in the isolated rat heart. The hearts were subjected to (1-21)ET-1 and to (8-21)ET-1, or to 30 min of stop-flow ischemia followed by 40 min of reperfusion, both before and after selective blockade of endothelin receptors. The present study revealed that both peptides, ET-1 and its (8-21)ET-1 fragment, significantly reduced coronary blood flow in nmolar and higher concentrations. The concomitant negative inotropy and chronotropy were marked after ET-1, while the infusion of the ET-1(8-21) fragment produced a slight but significant positive inotropic effect. Among the four endothelin antagonists tested in continuous infusion only the non-selective PD145065 and ET(B1/B2) selective BQ788 (in molar concentrations) slightly reduced the early contractile dysfunction of the heart induced by ischemia, whereas ET(A)-selective PD155080 partially protected the rat heart on reperfusion.

Topics: Amino Acid Sequence; Animals; Coronary Circulation; Dioxoles; Endothelin-1; Endothelins; Heart; Heart Failure; Heart Rate; Humans; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Oligopeptides; Peptide Fragments; Perfusion; Piperidines; Rats; Rats, Wistar; Ventricular Function, Left; Ventricular Pressure

It has been shown that the adenosine concentration in the pericardial fluid of the normal heart is higher by one order of magnitude than that of the venous plasma. A further increase in the pericardial adenosine concentration was also demonstrated in myocardial ischaemia or hypoxia. It was proposed that pericardial nucleoside levels may represent the interstitial concentrations of the adenine nucleosides. An experimental model was designed to determine the intrapericardial concentrations of adenosine, inosine and hypoxanthine during coronary spasm provoked by intracoronary administration of endothelin-1 (ET-1; 0.08+/-0.02 nmol/g of myocardial tissue). In the in situ dog heart (n=10), adenosine, inosine and hypoxanthine concentrations were determined by HPLC in fluid samples collected from the closed pericardial sac before and after ET-1 administration, and from the systemic arterial blood. Systemic blood pressure, heart rate and standard ECG were registered continuously. We found that the nucleoside concentrations in the infusate samples increased significantly during coronary spasm [adenosine, 1.49+/-0.44 compared with 0.37+/-0.07 microM (P<0.05); inosine, 27.43+/-11.51 compared with 0.47+/-0.11 microM (P<0.05); hypoxanthine, 21.17+/-6.49 compared with 4.91+/-1.24 microM (P<0.05)], while a significant decrease in blood pressure and an elevation in ECG ST segments were observed. The levels of the purine metabolites did not change in the systemic blood. The data indicate that changes in adenine nucleoside levels measured in pericardial infusate samples reflect activation of coronary metabolic adaptation in this model of spastic ischaemia, and that pericardial nucleoside levels may characterize alterations in interstitial adenine nucleoside concentrations.

Topics: Adenosine; Animals; Coronary Vasospasm; Dogs; Endothelin-1; Hypoxanthine; Inosine; Models, Animal; Myocardial Ischemia; Pericardium; Vasoconstrictor Agents

This study aims to investigate the role of endothelin-1 (ET-1) in the genesis of acute ischaemic arrhythmias. In anaesthetized cats and rats receiving continuous monitor of electrocardiogram and arterial blood pressure, the ischaemic arrhythmias during 60-min myocardial ischaemia elicited by the occlusion of the left anterior descending coronary artery (LAD) were analysed. To prevent the putative arrhythmic effects of endogenous ET-1, ET(A) receptor antagonist BQ610 (1.5-6.0 nmol/kg) was intracoronary injected just before LAD occlusion in cats, and preproET-1 mRNA antisense oligodeoxynucleotide (AS-ODN; 30-90 nmol/kg) was intravenously injected 2 h before LAD occlusion in rats. The results showed that BQ610 dose-dependently decreased the incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF), and the numbers of ventricular ectopic beats (VEBs). At the dose of 6.0 nmol/kg, the incidence of VT decreased significantly from 33.3% in normal saline (NS) control group to zero (P<0.01), and total VEBs decreased significantly from 831+/-162 to 158+/-51 (P<0.05). In rats receiving ET-1 AS-ODN, plasma ET-1 decreased significantly after 2 h, and remained stable at 30 min of LAD occlusion. However, in rats receiving the control, NS or sense ODN, plasma ET-1 remained unchanged after administration, but increased significantly during LAD occlusion. The ischaemic arrhythmias were dose-dependently suppressed in the presence of ET-1 AS-ODN. At the dose of 90 nmol/kg, the incidence of VT decreased significantly from 100% in both the control groups to 30%. The numbers of single VEBs, consecutive VEBs, VT and total VEBs were also significantly decreased, from 60+/-15 in NS group to 19+/-12, 11+/-3 to 2+/-2, 155+/-41 to 11+/-11, and 239+/-49 to 35+/-25 respectively. In the present cat and rat models of coronary artery occlusion, antagonism of either ET(A) receptors or endogenous ET-1 synthesis prevented the ischaemic arrhythmias, indicating that ET-1 is possibly an important promotive factor in the genesis of acute ischaemic arrhythmias.

Topics: Acute Disease; Animals; Arrhythmias, Cardiac; Blood Pressure; Cats; Electrocardiography; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Male; Myocardial Ischemia; Oligonucleotides, Antisense; Oligopeptides; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

To study the molecular mechanism of effect of Sini Decoction (SND) on myocardial endothelin (MET) in myocardial ischemic rats.. Sprague-Dawley rats were randomly divided into 3 groups, the normal control group, the ischemia group and the SND group. Myocardial ischemia was produced by pituitrin in the latter two groups. The content, immunohistochemical assay and gene expression of MET-1 were determined in all the three groups and compared.. The content of MET in the SND group was significantly lower than that in the ischemia group (P < 0.01). Immunohistochemical examination showed that MET-1 was mainly located at the cardiac muscle cells and vascular endothelial cells with the grey scale obviously lower in the ischemia group than that in the control group and the SND group (P < 0.01). While RT-PCR showed that the grey scale of PCR product band in the ischemia group was significantly higher than that in the other two groups (P < 0.01).. SND could significantly lower MET content, it may be related to the effect of SND in inhibiting MET-1 gene expression and protein synthesis.

Topics: Animals; Drugs, Chinese Herbal; Endothelin-1; Female; Male; Myocardial Ischemia; Myocardium; Phytotherapy; Pituitary Hormones, Posterior; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger

The effects of four anti-sense oligodeoxynucleotides (AS-ODNs) against rat or human preproendothelin-1 mRNA on ischemic arrhythmias in anesthetized rats were studied. AS-ODN (60 nmol/kg) or control (normal saline; sense-ODN, and scrambled-ODN, 60 nmol/kg) was injected 2 h before acute myocardial ischemia elicited by the occlusion of the left anterior descending coronary artery. Arrhythmias during 60-min ischemia were assessed, and plasma endothelin-1 was determined with an endothelin-1-specific radioimmunoassay system. The results showed that anti-senses against human preproendothelin-1 mRNA were anti-arrhythmic without significant impact on hemodynamics, whereas two against rat preproendothelin-1 mRNA and the three controls failed to be anti-arrhythmic. In human antisense groups, both the incidence of reversible ventricular fibrillation and the mortality were decreased to zero. The incidences of ventricular tachycardia and salvos were significantly decreased from almost 100% in the controls to < or =30% (p < 0.01), the arrhythmia score from an average of approximately 3.6 to 0 and 0.7, respectively (p < 0.01 versus controls), and the total ventricular ectopic beats from an average of 307-338 to < 40 (p < 0.01). The human AS-ODNs led to less plasma endothelin-1, which was associated with suppressed ischemic arrhythmias in this rat model, indicating a contributory role of endothelin-1 in ischemic arrhythmias. Conversely, considering the two- or three-base mismatches between the human AS-ODNs and rat preproendothelin-1 mRNA, and the failure of the rat AS-ODNs in suppressing arrhythmias, the possibility could not be excluded that human endothelin-1 AS-ODNs acted via an undetermined pathway other than endothelin-1.

Topics: Amino Acid Sequence; Animals; Arrhythmias, Cardiac; Endothelin-1; Endothelins; Hemodynamics; Humans; Male; Molecular Sequence Data; Myocardial Ischemia; Oligodeoxyribonucleotides, Antisense; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger

Endothelin-1 (ET-1), a potent vasoconstrictor, is released in response to several inflammatory cytokines after heart transplantation. The present study correlated patterns of myocardial ET-1 expression in heart biopsies with acute rejection, post-transplantation ischemic injury, and subsequent development of coronary vasculopathy.. Patterns of myocardial ET-1 expression were evaluated in 47 heart transplant recipients at 3 months after transplant. Transplant vasculopathy was documented by coronary angiography at 2 years after transplant. Expression of ET-1 was tabulated for both blood vessels and the interstitium. Vascular ET-1 expression was positive in 7/17 (41%) of patients with greater than grade 2 (International Society Heart Lung Transplant) rejection compared with 3/30 (10%) of patients with grade 0 and grade 1A rejection (P=0.02). Compared with patients with negative interstitial ET-1 expression (n=22), patients with positive interstitial ET-1 expression (n=25) had higher incidence of post-transplantation ischemic injury (52% versus 9%, P=0.002), lower mean episodes of acute rejection (> or = grade 2) during the first 3 months of transplant (1.09+/-0.66 versus 1.86+/-1.6, P=0.048), and more common vasculopathy at 2 years (50% versus 15%, P=0.02), and they tended to have worse survival (83.2% versus 100%, P=0.058).. Vascular ET-1 expression is likely to be associated with acute rejection. Interstitial ET-1 expression, however, is more likely to be associated with post-transplantation ischemic injury and subsequent development of coronary vasculopathy.

Topics: Coronary Angiography; Coronary Disease; Coronary Vessels; Endothelin-1; Graft Rejection; Heart Transplantation; Humans; Middle Aged; Myocardial Ischemia; Myocardium; Survival Rate; Treatment Outcome

The effect of endothelin (ET)-1 on cardiac energetics is not fully understood.. In isolated, coronary-perfused rat hearts, we measured left ventricular contractility index (E(max)), pressure-volume area (PVA), and myocardial oxygen consumption (MVO(2)) before and after administration of ET-1 (1x10(-)(9) mol/L). ET-1 increased E(max) by 48+/-16% (P<0.01) and the total MVO(2) by 24+/-11% (P<0.01). The MVO(2)-PVA relations were linear both before and after ET-1 (r>0.99). ET-1 shifted MVO(2)-PVA upward, increasing the MVO(2) intercept by 24+/-13%. At the same time, ET-1 decreased the slope (S), with 1/S (contractile efficiency) being 46+/-5% before and 56+/-5% after ET-1 (P<0.01). ET-1-induced increases in E(max) and in contractile efficiency were abolished by an ET(A) receptor blocker (S-0139) but not by an ET(B) blocker (BQ-788). Although high [Ca(2+)] perfusion increased E(max) and the intercept to the same extent as ET-1, it did not change S. N(G)-Nitro-L-arginine (an inhibitor of nitric oxide synthase) increased the coronary perfusion pressure as much as ET-1, but S again remained unchanged. Dimethylamyloride (Na(+)/H(+) exchanger inhibitor) partially blocked the positive inotropic effect of ET-1 but not the ET-1-induced increase in the contractile efficiency.. Agonistic effects of ET-1 on the ET(A) receptor economized the chemomechanical conversion efficiency of the left ventricular unit myocardium by a mechanism independent of the Na(+)/H(+) exchanger. This unique oxygen-saving effect of ET-1 may play an adaptive role in the failing myocardium, in which local accumulation of ET-1 is present.

Topics: Amiloride; Animals; Antihypertensive Agents; Caffeic Acids; Cardiotonic Agents; Drug Interactions; Endothelin-1; Heart; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Oleanolic Acid; Oligopeptides; Oxygen; Perfusion; Piperidines; Rats; Rats, Sprague-Dawley

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

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

There is growing evidence that hypertriglyceridemia exacerbates ischemic injury. We tested the hypothesis that triglycerides impair myocardial recovery from low-flow ischemia in an ex vivo model and that such an effect is related to endothelin-1. Hyperglycemic (glucose concentration = 12 mmol/l) and hyperinsulinemic (insulin concentration = 1.2 micromol/l) isolated rat hearts were perfused with Krebs-Henseleit buffer (PO(2) = 670 mmHg, pH 7.4, 37 degrees C) added with increasing triglycerides (0, 1,000, 2,000, and 4,000 mg/dl, n = 6-9 rats/group). Hearts were exposed to 60 min of low-flow ischemia (10% of basal coronary flow), followed by 30 min of reperfusion. We found that increasing triglycerides impaired both the diastolic (P < 0.005) and systolic (P < 0.02) recovery. The release of endothelin-1 during reperfusion increased linearly with triglyceride concentration (P = 0.0009). Elevated triglycerides also increased the release of nitrite and nitrate (NO(x)), the end products of nitric oxide, up to 6 micromol/min. Trimetazidine (1 micromol) further increased NO(x) release, blunted endothelin-1 release, and protected myocardial function during recovery. We conclude that high triglyceride levels impair myocardial recovery after low-flow ischemia in association with endothelin-1 release. The endothelium-mediated effect of triglycerides on both contractile recovery and endothelin-1 release is prevented by 1 microM trimetazidine.

Topics: Animals; Dose-Response Relationship, Drug; Endothelin-1; Glucose; Heart Rate; Hyperglycemia; Hyperinsulinism; In Vitro Techniques; Insulin; Male; Myocardial Ischemia; Myocardial Reperfusion; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Recovery of Function; Reperfusion Injury; Triglycerides; Trimetazidine; Vasodilator Agents; Ventricular Function, Left

Atrial pacing (AP) procedure was carried out in 11 cardioischemic patients to reproduce tachycardia-induced myocardial ischemia. Six control subjects underwent the same procedure until the maximum pacing rate was reached. During the procedure, endothelin-1 (ET-1) and plasma lactate levels were measured in the coronary sinus and in the aortic root. In all the patients, atrial pacing provoked electrocardiographic signs and metabolic evidence of myocardial ischemia and a significant decrease (p<0.001) in left ventricular ejection fraction. At AP-induced ischemia, coronary sinus (17.31 +/- 4.20 pg/mL) and arterial (9.60 +/- 3.31 pg/mL) ET-1 plasma levels were significantly different (p<0.001) in the patients. On the contrary, at maximum pacing rate, no significant difference (p=0.186) emerged between coronary sinus (9.72 +/- 1.09 pg/mL) and arterial (8.95 +/- 0.75 pg/mL) plasma ET-1 levels in the control group. These results suggest that, in cardioischemic patients, tachycardia can induce the coronary endothelium to release significant amounts of ET-1.

Topics: Adult; Cardiac Pacing, Artificial; Case-Control Studies; Coronary Circulation; Endothelin-1; Humans; Lactic Acid; Male; Middle Aged; Myocardial Ischemia

We have shown previously that a small bolus dose of endothelin-1, given intravenously before coronary occlusion, exerts a marked antiarrhythmic effect in anaesthetised rats. The aim of the current study was to determine whether or not this is due to a direct effect of endothelin-1 on the heart by assessing the antiarrhythmic effect of endothelin-1 against occlusion-induced arrhythmias in rat isolated hearts. Rat isolated hearts were perfused in Langendorff mode (constant flow) and subjected to coronary artery occlusion for 30 min. Coronary perfusion pressure and a surface electrocardiogram (ECG) were monitored throughout the experiment. In the first series of studies, the effects of three 5-min infusions of endothelin-1 (0.1-10 nM), given prior to coronary occlusion, were assessed. A second series of hearts was given a single bolus dose of endothelin-1 (10 pmol) 5 min prior to ischaemia. A third series of experiments was performed using a modified (low K+) Krebs Henseleit solution to increase the incidence of ischaemia-induced ventricular fibrillation (VF). In these hearts, endothelin-1 (0.1 or 2 pmol) was administered as a bolus injection 5 min before ischaemia. Infusion of endothelin-1 prior to ischaemia did not modify the incidence or severity of arrhythmias at any of the concentrations used. Bolus administration of endothelin-1 (10 pmol) in hearts perfused with Kreb's Henseleit solution containing normal K+ (4.4 mM) was found to cause a small rise in coronary perfusion pressure, with no preceding depressor response. Under these conditions, endothelin-1 exerted only a very moderate reduction in arrhythmias, by reducing the arrhythmia count in the 21-30-min post-occlusion period. Furthermore, in hearts perfused with low K+ solution, bolus injection of endothelin-1, in a dose that either had no effect on coronary perfusion pressure (0.1 pmol) or produced a significant vasodilator effect with no significant pressor effect (2 pmol), had no effect on ventricular fibrillation. Thus, in concentrations that are sufficient to exert effects on the coronary vasculature, endothelin-1 fails to modify arrhythmias in an isolated heart preparation. These results suggest that the antiarrhythmic effects of endothelin-1 previously observed in vivo are not due to a direct effect on either the myocardium or the coronary blood vessels.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Dose-Response Relationship, Drug; Endothelin-1; Heart; In Vitro Techniques; Male; Myocardial Ischemia; Perfusion; Potassium; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Time Factors; Ventricular Fibrillation

Little is known about the long-term impact of cardiac transplantation on activity and modifications of endothelin (ET)-1 system, vascular endothelial growth factor (VEGF), and mitochondrial metabolism and morphology in patients with ischemic cardiomyopathy (ICM) versus dilated cardiomyopathy (DCM). Messenger RNA (mRNA) expression levels of ET-1, endothelin converting enzyme (ECE)-1, VEGF-C, carnitine palmitoyltransferase (CPT)-1, and carnitine acetyltransferase (CARAT), as well as the number of normal, edematous, and degenerated mitochondria were assessed in left ventricular biopsies of 21 patients with DCM and 20 with ICM (New York Heart Association class III-IV) before and up to 3 months after cardiac transplantation. Cardiac samples of donated, nonfailing hearts served as controls (n=10). In cardiac biopsies of both ICM and DCM patients, ET-1, VEGF-C, CPT-1, and CARAT mRNA were up-regulated, whereas ECE-1 mRNA was down-regulated (P<0.05). Degenerated mitochondria had the highest number in both groups, followed by normal and edematous mitochondria. After cardiac transplantation, in ICM patients impaired gene expression levels decreased to, or below, normal levels, and the number of normal mitochondria increased (P<0.05). In implanted hearts of DCM patients, however, up-regulated ET-1 transcript levels persisted and the number of normal mitochondria decreased, whereas the number of degenerated mitochondria increased (P<0.05), and edematous mitochondria remained unchanged in number. These results show that cardiac transplantation corrects the impaired hemodynamic and echocardiographic parameters in both groups, whereas in DCM, the molecular pathology of ET-1 system and mitochondria persists. Therefore, it is more likely that these changes are the cause rather than a consequence of DCM.

Topics: Adult; Cardiomyopathy, Dilated; Carnitine O-Acetyltransferase; Carnitine O-Palmitoyltransferase; Endothelial Growth Factors; Endothelin-1; Female; Heart Transplantation; Humans; Male; Microscopy, Electron; Middle Aged; Mitochondria, Heart; Myocardial Ischemia; Reverse Transcriptase Polymerase Chain Reaction; Vascular Endothelial Growth Factor C

To examine the role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning induced by prostaglandins in isolated guinea pig hearts.. The isolated guinea pig hearts were perfused in a Langendorff model. The heart rate, coronary flow, left ventricular pressure, and its first derivatives (+/-dp/dt(max)) were recorded and the calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) and 6-keto-PGF(1 alpha) were measured.. Endothelin-1 (200 pmol in 1 mL K-H buffer) reduced the left ventricular developed pressure and its first derivatives (+/-dp/dt(max)), heart rate, and coronary flow. Preconditioning with two cycles of 5-min global ischemia and 5-min reperfusion attenuated endothelin-1 induced myocardial injury, and concentrations of both CGRP and 6-keto-PGF(1alpha) in the coronary effluent were markedly raised in the preconditioning periods. Pretreatment with capsaicin, which depletes endogenous CGRP, abolished the elevated level of CGRP concomitantly with loss of the cardioprotection induced by ischemic preconditioning. CGRP(8-37) (100 nmol/L), a selective CGRP1 receptor antagonist, also abolished the protective effects of ischemic preconditioning. After pretreatment with indometacin (10 micromol/L), an inhibitor of cyclooxygenase, the protective effects of ischemic preconditioning were abolished and the release of 6-keto-PGF1alpha was no longer elevated. Pretreatment with indometacin abolished the elevated level of CGRP in the coronary effluent.. Endogenous prostaglandins are involved in the protective effects of ischemic preconditioning, and the beneficial effects of prostaglandins are mediated by CGRP in the guinea pig heart.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Capsaicin; Coronary Circulation; Cyclooxygenase Inhibitors; Endothelin-1; Guinea Pigs; Heart Rate; In Vitro Techniques; Indomethacin; Ischemic Preconditioning, Myocardial; Male; Myocardial Ischemia; Peptide Fragments; Protective Agents

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

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

The aim of the present study was to test whether oral dosing of an endothelin (ET) receptor antagonist was able to reduce restenosis in the model of stent-induced restenosis. After pigs underwent coronary artery catheterization they were randomly allocated either to controls or to treatment with the ET receptor antagonist BSF 208075. Thirty-seven pigs underwent percutaneous transluminal coronary angioplasty plus stent implantation; seven animals died of ventricular fibrillation due to procedure-related myocardial ischaemia. From the 30 surviving animals coronary arteries were sampled after 6 weeks of oral treatment with 10 mg/kg/day BSF 208075 or vehicle and histologically evaluated. Stent implantation had no effect on total coronary artery diameter, and media thickness was virtually identical in the two groups. However, neointimal thickness in the group treated with the ET receptor antagonist was significantly reduced, resulting in a significantly larger total coronary artery lumen in the treated group. As in the setting of stent implantation neither 'recoil' nor scar-related vascular remodelling can occur, this result allows the conclusion of a significant antiproliferative effect of ET receptor antagonism in pig coronary arteries.

Topics: Angioplasty, Balloon; Angioplasty, Balloon, Coronary; Animals; Coronary Artery Disease; Coronary Restenosis; Endothelin Receptor Antagonists; Endothelin-1; Male; Models, Animal; Myocardial Ischemia; Propionates; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Stents; Swine

We hypothesized that exercise training preserves endothelium-dependent relaxation, lessens receptor-mediated constriction of coronary resistance arteries, and reduces myocardial contractile dysfunction in response to ischemia. After 10 wk of treadmill running or cage confinement, regional and global indexes of left ventricular contractile function were not different between trained and sedentary animals in response to three 15-min periods of ischemia (long-term; n = 17), one 5-min bout of ischemia (short-term; n = 18), or no ischemia (sham-operated; n = 24). Subsequently, coronary resistance vessels ( approximately 106 +/- 4 microm ID) were isolated and studied using wire myographs. Maximal ACh-evoked relaxation was approximately 25, 40, and 60% of KCl-induced preconstriction after the long-term, short-term, and sham-operated protocols, respectively, and was similar between groups. Maximal sodium nitroprusside-evoked relaxation also was similar between groups among all protocols, and vasoconstrictor responses to endothelin-1 and U-46619 were not different in trained and sedentary rats after short-term ischemia or sham operation. We did observe that, after long-term ischemia, maximal tension development in response to endothelin-1 and U-46619 was blunted (P < 0.05) in trained animals by approximately 70 and approximately 160%, respectively. These results support our hypothesis that exercise training lessens receptor-mediated vasoconstriction of coronary resistance vessels after ischemia and reperfusion. However, training did not preserve endothelial function of coronary resistance vessels, or myocardial contractile function, after ischemia and reperfusion.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Carbon Dioxide; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Hemodynamics; Hydrogen-Ion Concentration; Myocardial Contraction; Myocardial Ischemia; Nitroprusside; Oxygen; Partial Pressure; Physical Conditioning, Animal; Potassium Chloride; Rats; Time Factors; Vasoconstriction; Vasoconstrictor Agents

Endothelin-1 (ET-1) induces severe pathologic conditions such as coronary spasm followed by vasospastic angina pectoris and acute myocardial infarction. The related pathophysiologic mechanisms have remained obscure. Endothelin-1 receptor (ET(A) and ET(B)) is reported to couple with several types of G protein-involved pathways that participate in phospholipase C activation and atrial myofibrils organization into sarcomeric units. Here we demonstrate that ET-1 induces histologic and pathologic dysfunction in the rabbit myocardium and that such pathologic events are prevented by the Rho-kinase inhibitor fasudil. Although the bolus injection of ET-1 (1.4 nmol/kg) via the auricular vein of the rabbit induced only transient T-wave elevation, irreversible, severe histologic changes were observed in papillary muscles of the ventricle, and multifocal myocardial necrosis with infiltration of neutrophils and macrophages in the left ventricle occurred. Oral administration of fasudil (10 mg/kg) significantly reduced the occurrence of myocardial injury determinants, whereas conventional Ca2+ channel blockers (nifedipine, diltiazem) and a K+ channel opener (nicorandil; 10 mg/kg, p.o. each) showed a lesser or no effect on such determinants. These results suggest that ET-1 induces severe myocardial dysfunction based not only on the occurrence of vasospastic ischemia but also on its direct effects on the myocardium.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Cell Movement; Diltiazem; Electrocardiography; Endothelin-1; Enzyme Inhibitors; Heart Ventricles; Macrophages; Male; Microscopy; Myocardial Ischemia; Necrosis; Neutrophils; Nicorandil; Nifedipine; Papillary Muscles; Rabbits; Random Allocation; Vasodilator Agents

Only scarce information is available on the activity and modifications of the cardiac endothelin (ET)-1 system in heart failure due to ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. The activity of the ET-1 system was investigated by measuring cardiac ET-1 and big ET-1 formation and quantifying cardiac mRNA for prepro-ET-1 (ppET-1), ET-converting enzyme-1, and ET(A) and ET(B) receptors both in myocardium and in isolated myocytes using Northern blot, reverse transcription-polymerase chain reaction, and in situ hybridization in 22 patients with DCM and 20 with ICM who underwent cardiac transplantation and in 7 potential heart transplant donors (nonfailing hearts). Notwithstanding a similar increase of plasma ET-1 in the 2 groups, cardiac ET formation, mRNA levels for ppET-1, and ET(A) and ET(B) receptors were higher on both the myocardium and isolated myocytes from ICM than on those from DCM hearts (P<0.001 for all). ppET-1 and ET-converting enzyme-1 mRNAs were expressed on myocytes and endothelial and interstitial cells in ICM, whereas in DCM and nonfailing hearts they were mainly expressed on nonmyocyte cells. In both ICM and DCM, the ET(A) mRNA signal was expressed on both myocytes and nonmyocyte cells, whereas ET(B) mRNA was almost exclusively localized on nonmyocyte cells. ET(A)- and ET(B)-specific receptor binding was increased on both myocytes and cardiac membranes, showing a positive correlation with left ventricular ejection fraction in ICM (r=0.78 and 0.70) but not in DCM patients. The present results show that human ventricular myocytes express all of the components of the ET-1 system, which is selectively upregulated in ICM patients and appears to be functionally important in the maintenance of cardiac function.

Topics: Adult; Aged; Aspartic Acid Endopeptidases; Cardiac Output, Low; Cardiomyopathy, Dilated; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Female; Humans; Male; Metalloendopeptidases; Middle Aged; Myocardial Ischemia; Myocardium; Protein Precursors; Radioligand Assay; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Up-Regulation

To analyze three-dimensional activation patterns of ventricular arrhythmias induced by endothelin-1 in comparison with ischemia-induced tachycardias.. Following AV node ablation, sixty pin electrodes containing four bipoles each were inserted into both ventricles of ten foxhounds. Using a computerized mapping system, this would allow to simultaneously record 240 endo-, epi- and midmyocardial electrograms for reconstruction of the three-dimensional activation pattern. In five dogs, endothelin-1 was infused into the LAD at 60 pmol/min. In another five animals, the LAD was ligated. During the following 40 min, all ventricular arrhythmias were recorded for subsequent analysis. Furthermore, left ventricular conduction times during constant pacing and local effective refractory periods at eight left ventricular sites were determined before and after either intervention.. Endothelin-1 had no significant effect on conduction time and refractoriness, whereas ligation prolonged both parameters significantly. Endothelin-1 as well as ligation induced multiple mono- and polymorphic nonsustained ventricular tachycardias. Endothelin-1-induced arrhythmias were exclusively based on focal mechanisms, whereas during ligation, macroreentrant mechanisms were involved in the maintenance of tachycardias in 29% of episodes.. The differences in the effects of endothelin-1 and LAD ligation on electrophysiologic properties and the difference in the mechanism of induced ventricular tachycardias support the hypothesis that, apart from vasoconstrictive properties, endothelin-1 exerts an intrinsic arrhythmogenic effect.

Topics: Animals; Body Surface Potential Mapping; Dogs; Endothelin-1; Heart Block; Myocardial Ischemia; Ventricular Dysfunction

Elevated urinary albumin excretion (UAE) is a predictor of cardiovascular disease, and one possible explanation is that elevated UAE reflects a generalized vascular dysfunction. The present study tests whether the plasma concentrations of the two main endothelial vasoactive substances (nitric oxide and endothelin-1 [ET-1]) are changed in clinically healthy subjects with elevated UAE (>6.6 microg/ min-the 90th percentile in the background population) and to test associations between these concentrations and systemic blood pressure. Twenty-seven subjects with elevated UAE were compared with 46 matched controls with normoalbuminuria. Plasma concentration of ET-1 was measured using an ELISA method and plasma concentration of nitrate/nitrite using a photometric method. Twenty-four-hour blood pressure was measured using a portable recorder (TM-2421). No significant differences in the concentrations of nitrate/nitrite and ET-1 were found between the groups, e.g. 21 (10-105) vs. 18 (11 -152) (p=0.33) and 0.98 (0.58 1.95) vs. 1.10 (0.54 -1.50) (p = 0.27), respectively. However, plasma nitrate/nitrite was significantly positively correlated to systolic and diastolic blood pressure in subjects with normoalbuminuria but not in subjects with elevated UAE. In contrast, plasma ET-1 concentration was significantly positively correlated to systolic blood pressure only in subjects with elevated UAE. In conclusion, elevated UAE is not associated with changed plasma concentrations of endothelial vasoactive substances in clinically healthy subjects. However, nitrate/nitrite is positively correlated to BP only in subjects with normoalbuminuria, and ET-1 is positively correlated to BP only in subjects with elevated UAE.

Topics: Aged; Albuminuria; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Endothelin-1; Endothelium, Vascular; Female; Humans; Longitudinal Studies; Male; Middle Aged; Myocardial Ischemia; Nitrates; Nitric Oxide; Nitrites; Reference Values; Risk Factors

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, which may also elicit severe ventricular arrhythmias. The aims of our study were to compare the effects of total left anterior descending coronary artery (LAD) occlusion to intracoronary (ic.) ET-1 administration and to investigate the pathomechanism of ET-1 induced arrhythmias in 3 groups of anesthetized, open-chest mongrel dogs. In group A (n=10) a total LAD occlusion was carried out for 30 min, followed by a 60 min reperfusion period. In groups B and C ET-1 was administered into LAD for 30 min at a rate of 30 pmol/min (n=6) and 60 pmol/min (n=8). Epi- and endocardial monophasic action potential (MAP) recordings were performed to detect electrophysiologic changes and ischemia Blood samples for lactate measurements were collected from the coronary sinus (CS) and from the femoral artery. Infrared imaging was applied to follow epimyocardial heat emission changes. At the end of the ET-1 infusion period coronary blood flow (CBF) was reduced significantly in groups B and C (deltaCBF30MIN B: 21+/-2%, p<0.05; C: 35+/-2%, p<0.05), paralleled by a significant epimyocardial temperature decrease in group C (deltaT30MIN: -0.65+/-0.29 degrees C, p<0.05). Two dogs died of ventricular fibrillation (VF) in the reperfusion period in group A. Ventricular premature contractions and non-sustained ventricular tachycardic episodes appeared in group B, whereas six dogs died of VF in group C. Significant CS lactate level elevation indicating ischemia was observed only in group A from the 30th min occlusion throughout the reperfusion period (control vs. 30 min: 1.3+/-0.29 vs. 2.2+/-0.37 mmol/l, p<0.05). Epi- and endocardial MAP durations (MAPD90) and left ventricular epicardial (LV(EPI)) upstroke velocity decreased significantly in group A in the occlusion period. ET-1 infusion significantly increased LV(EPI) MAPD90 in group B and both MAPD90-s in group C. In conclusion, ischemic MAP and CS lactate changes were observed only in group A. Although ET-1 reduced CBF significantly in groups B and C, neither MAP nor lactate indicated ischemic alterations. ET-1 induced major ventricular arrhythmias appeared before signs of myocardial ischemia developed, though reduced CBF presumably contributed to sustaining the arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Dogs; Endothelin-1; Myocardial Contraction; Myocardial Ischemia; Regional Blood Flow

Topics: Animals; Arrhythmias, Cardiac; Dogs; Endothelin-1; Heart Ventricles; Myocardial Ischemia

The metabolic changes, possible myocardial damage, and influence on the vascular endothelium during off-pump coronary artery bypass grafting have been investigated.. Coronary sinus and arterial blood samples were obtained before coronary arterial occlusion, after 10 minutes of ischemia, and after 1 and 10 minutes of reperfusion in 9 patients who had an anastomosis performed to the left anterior descending coronary artery off-pump bypass. The mean ischemic time was 14 +/- 1 minutes. The arteriovenous difference in lactate decreased during ischemia to reach a minimum at 1 minute of reperfusion (-0.15 +/- 0.06 micromol/L compared to 0.21 +/- 10 micromol/L before ischemia; p < 0.01). Myocardial lactate extraction decreased from 14.2 +/- 6.8 micromol/min before ischemia to -10.9 +/- 6.5 micromol/min after 1 minute of reperfusion (p < 0.01). Simultaneously, the arteriovenous difference in 6-keto-PGF(1alpha), the stable metabolite of prostacyclin, decreased from -30 +/- 26 pg/mL to -258 +/- 80 pg/mL at 1 minute of reperfusion (p < 0.05), and the 6-keto-PGF(1alpha) extraction over the heart decreased -556 +/- 466 pg/min to -18,560 +/- 5,683 pg/min (p < 0.01).. The localized myocardial ischemia associated with these procedures causes changes in the myocardium and endothelial influence. Coronary bypass surgery performed on the beating heart may not be superior in preventing cardiac ischemia and endothelial disturbance, compared with conventional bypass surgery.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Coronary Artery Bypass; Endothelin-1; Epoprostenol; Humans; Lactates; Male; Middle Aged; Myocardial Ischemia; Myocardium; Nitric Oxide

Endothelial injury plays critical roles in acute and chronic complications after percutaneous transluminal coronary angioplasty (PTCA). We investigated coronary endothelial injury and the release of vasoactive substances induced by PTCA. We examined 44 patients with ischemic heart disease who underwent elective PTCA to isolated stenotic lesions in left coronary arteries. Eleven patients received balloon angioplasty (BA), 14 percutaneous transluminal rotational atherectomy (PTRA), and 19 stent implantation. Blood samples were drawn from the coronary sinus immediately before and after as well as 4 hr and 24 hr after PTCA. Plasma levels of endothelin (ET) 1, angiotensin (ANG) II, von Willebrand factor (vWF), and thrombomodulin (TM) were measured. Seven control subjects who underwent diagnostic coronary angiography (CAG) were used as controls. In all patients, ET-1 levels in the coronary sinus blood significantly increased immediately after PTCA. ANG II levels and vWF activity showed significant increases 4 hr after PTCA. Changes in levels of these markers were similar among the BA, PTRA, and stent groups. TM levels were elevated in all groups of patients, including those simply undergoing diagnostic CAG. Changes in ET-1, ANG II, and vWF levels in the coronary sinus reflect coronary endothelial injury induced by PTCA.

Topics: Aged; Angioplasty, Balloon, Coronary; Angiotensin II; Atherectomy, Coronary; Coronary Vessels; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Stents; Thrombomodulin; Treatment Outcome; von Willebrand Factor

Reperfusion injury may affect the cardiac NO and endothelin production. We investigated whether 20 min of total ischemia followed by 40 min of reperfusion can induce apoptosis in a Langendorff model of retrogradely perfused rat hearts (37 degrees C; paced at 300/'), and we attempted to correlate these findings with measured tissue NO and ET-1 levels.. An apoptosis detection system was utilized which catalytically incorporates fluorescein-12-dUTP at the 3'-OH DNA ends using the principle of the TUNEL assay, with direct visualization of the labeled DNA. ET-1 was measured by radioimmunoassay and NO3/NO2 by ion pairing HPLC on C18 reverse phase columns.. None of the postischemic (n = 6) nor of the control perfused (90 min, n = 6) hearts showed signs of apoptosis, while those exposed to longer ischemia (40 min) and reperfusion (2 h) confirmed the presence of apoptotic cells. Myocardial ET-1 concentrations were 4.8 +/- 1.0 versus 8.3 +/- 2.5 pg/100 mg (control vs. ischemic hearts, respectively; mean +/- SD; p < 0.05). Myocardial NO contents showed no differences.. These data suggest that the time window of apoptosis with detectable DNA fragmentation exceeds 20 min of global total ischemia and 40 min of reperfusion, a model frequently used for inducing myocardial stunning. While NO was not increased in postischemic hearts, increased ET-1 levels indirectly argue for a role of ET-1 as inducer of apoptosis, but only at a later stage of reperfusion.

Topics: Animals; Apoptosis; Cell Nucleus; Disease Models, Animal; Endothelin-1; Microscopy, Electron; Myocardial Ischemia; Myocardial Stunning; Myocardium; Nitric Oxide; Rats; Rats, Inbred WKY; Time Factors; Ventricular Function, Left

Topics: Animals; Arrhythmias, Cardiac; Dogs; Drug Administration Schedule; Endothelin Receptor Antagonists; Endothelin-1; Myocardial Ischemia; Phenylpropionates; Pyrimidines; Receptor, Endothelin A

The supposed direct arrhythmogenic property of endothelin-1 (ET-1) has not yet been clearly proven. Our study aimed to characterize the electrophysiological changes during left anterior descending artery (LAD) occlusion and intracoronary (i.c.) ET-1 infusion, and to differentiate between the supposed direct and ischemic arrhythmogenic actions of ET-1 in a canine model. Changes of monophasic action potential duration (MAPD90) and upstroke velocity (UV) are capable of detecting local ischemic changes. Left and right ventricular endo- (LVEND, RVEND) and epicardial (LVEP, RVEP) monophasic action potentials were recorded. MAPD90, monophasic action potential dispersion (MAPDISP) and UV were determined. In group A (n = 8) 30 min LAD occlusion was followed by a 60 min reperfusion period. In groups B and C ET-1 was administered into the LAD at rates of 30 (n = 8) and 60 pmol/min (n = 10), respectively. In group A after the LAD occlusion both MAPD90 and UV decreased significantly in the LAD region (LVEP and LVEND 18 +/- 3% and 10 +/- 1%, p < 0.05, and 65 +/- 4% and 52 +/- 8%, respectively, p < 0.05; control and 30 min values in all groups), whereas the increase in MAPDISP remained unchanged. No severe arrhythmias were noticed in this group. In group B, both MAPD90 and MAPDISP increased significantly (LVEP and LVEND 11 +/- 4% and 18 +/- 3%, p < 0.05; MAPDISP 200 +/- 40%, p < 0.05), whereas UV remained unchanged at the end of the infusion. Early afterdepolarizations (EADs) were present in three instances. In group C both MAPD90 and MAPDISP increased significantly (LVEP and LVEND 12 +/- 5% and 26 +/- 8%, respectively, p < 0.05; MAPDISP 215 +/- 30%, p < 0.05) and UV decreased slightly in the LAD region. EADs were observed in five instances. Severe arrhythmias were observed in both groups B and C. We concluded that MAP prolongation, increased MAP dispersion and development of EADs all contribute to the arrhythmogenic action of ET-1. The lack of the almost prompt decrease of UV and MAPD90 which was observed in group A in groups B and C strongly supports the probability of a direct arrhythmogenic effect of ET-1.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Coronary Vessels; Dogs; Endothelin-1; Heart; Myocardial Ischemia

Upregulation of the endothelin (ET) system, following coronary ischemia-reperfusion injury, may contribute to coronary vasospasm and congestive heart failure. Because endothelin-1 (ET-1) is rapidly cleared from the circulation, the levels of its inactive precursor big ET-1 and the ET-1/big ET-1 ratio may constitute better ways to assess the activation of the ET system in both venous and arterial beds. Anesthetized dogs (n = 6-12) were subjected to two successive coronary artery occlusions (with intervening 60 min reperfusion) over 6 h. Cardiac hemodynamics and electrocardiogram (ECG) were recorded and blood samples were drawn simultaneously from the internal thoracic artery and coronary sinus (venous blood). Under basal conditions at t = -20 min, arterial plasma levels of ET-1 and big ET-1 were 2.05 +/- 0.21 and 2.00 +/- 0.51 pg/ml (ratio: 1.00; n = 12); venous values were 2.29 +/- 0.25 and 3.14 +/- 0.77, respectively (ratio: 0.73, n = 12). Both arterial and venous plasma levels of ET-1 increased (by 46 and 56%) after 5 and 15 min of reperfusion, respectively, following the initial 120 min ischemic period compared to baseline values, and returned to near baseline values after 60 min reperfusion. Both arterial and venous values for big ET-1 increased steadily by 2.2 and 2.3 times maximum, respectively, during the initial 60 min reperfusion period; these values increased by 3.4 and 3.2 times, respectively by the end of the second 120 min reperfusion period. ET-1/big ET-1 ratios dropped to 0.39, in arterial, and 0.21, in venous plasma, at the end of the second reperfusion period. In conclusion, plasma ET-1 levels increase significantly but transiently after the first ischemic injury; the increased plasma big ET-1 levels were more pronounced in both the arterial and venous circulation along with ischemia-reperfusion injuries. These results suggest an upregulation of the ET system that was easily monitored by increased production of big ET-1. During ischemia-reperfusion injuries, the conversion to the active mature peptide ET-1 is either impaired, or ET-1 is more rapidly degraded.

Topics: Animals; Dogs; Endothelin-1; Endothelins; Female; Hemodynamics; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Protein Precursors

The aim of this study was to investigate whether the endothelin-B- (ETB) receptor agonist sarafotoxin 6c (S6c) can protect against ischaemia-induced cardiac arrhythmias. Arrhythmias were induced by a 30 min period of coronary artery occlusion in pentobarbitone-anaesthetized male rats, or in Langendorff-perfused rat hearts. Rats or rat hearts were administered a bolus dose of vehicle or S6c (0.8 nmol/kg i.v. or 10(-8) M into the coronary circulation, respectively) 5 min before the onset of ischaemia. In vivo administration of S6c significantly reduced the incidence of ventricular fibrillation (VF) from 59% to 13% and the number of premature ventricular beats. This effect was associated with a transient fall in mean arterial blood pressure. In isolated hearts, S6c reduced significantly both the incidences of ventricular tachycardia (VT) and VF while having no statistically significant effect on coronary perfusion pressure. This is the first report to show that stimulation of ETB-receptors, with a bolus dose of S6c, has an antiarrhythmic effect on rat hearts both in vivo and in vitro, suggestive of a direct effect on the myocardium.

Topics: Animals; Arrhythmias, Cardiac; Endothelin-1; Male; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Receptors, Endothelin; Viper Venoms

Circulating levels of endothelin-1 (ET-1) are elevated in a number of pathophysiological conditions. Our aim was to determine the effect of overexpression of the peptide on ET receptors in human blood vessels. Aorta and pulmonary arteries were removed from patients with dilated cardiomyopathy (CDM), ischaemic heart disease (IHD), and primary pulmonary hypertension (PPH) and compared with controls. Sections of the medial (smooth muscle) layer were incubated with [125I]ET-1 and increasing concentrations of FR139317, an endothelin-A- (ET(A)) selective antagonist. FR139317 competed for the binding of iodinated ET-1 monophasically, indicating that all vessels examined expressed ET(A)-receptors in the media. ET(B)-receptors could not be detected, either in the control vessels or in those from patients with disease. There was no change in affinity (K(D)) but there was a significant (*p < 0.05) reduction in ET(A)-receptor density (Bmax) by 20-50% in diseased tissues, compared with controls. These results suggest that ET(A)-receptors are downregulated as an adaptive response to increased levels of ET-1.

Topics: Adaptation, Physiological; Adult; Aorta; Cardiomyopathy, Dilated; Down-Regulation; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Myocardial Ischemia; Pulmonary Artery; Receptor, Endothelin A; Receptors, Endothelin

Reperfusion of ischemic rat hearts in the presence of thrombin or norepinephrine but not endothelin-1 causes the generation of inositol 1,4,5-trisphosphate (Ins 1,4,5P3) and arrhythmias. The present study investigates the effect of endothelin-1 on these responses.. Ins 1,4,5P3 generation was quantified by use of [3H] labeling and high-performance liquid chromatography as well as by mass analysis. Twenty minutes of global ischemia followed by 2 minutes of reperfusion increased [3H]Ins 1,4,5P3 from 2828+/-265 to 5033+/-650 cpm/g tissue in the presence of thrombin 2.5 IU/mL and to 4561+/-286 cpm/g tissue in response to release of norepinephrine (n=4, P<0.01) in both cases. Reperfusion in the presence of endothelin-1 alone caused no change in Ins 1,4,5P3 (2762+/-240 cpm/g tissue), but when added together with thrombin or norepinephrine, endothelin-1 reduced the Ins 1,4,5P3 responses to 2313+/-197 and 1764+/-168 cpm/g tissue, respectively (n=4, P<0.01 in both cases). Similar inhibitory interactions between endothelin-1 10 nmol/L and thrombin 2.5 IU/mL were observed under normoxic conditions in nonperfused ventricle, eliminating the possibility that excessive vasoconstriction was responsible. In parallel studies, endothelin-1 suppressed the development of reperfusion arrhythmias initiated by either thrombin (ventricular fibrillation, 75% to 39%, n=16 to 18) or norepinephrine (83% to 8%, n=12 to 22) (P<0.01 in both cases).. Inhibition of Ins 1,4,5P3 generation during myocardial reperfusion by endothelin-1 represents a novel antiarrhythmic mechanism.

Topics: Animals; Arrhythmias, Cardiac; Drug Interactions; Endothelin-1; Hemostatics; Inositol 1,4,5-Trisphosphate; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Norepinephrine; Oxygen; Phospholipids; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha; Sympathomimetics; Thrombin

Congestive heart failure (CHF) and heart transplantation (HTX) are characterized by endothelial dysfunction as indicated by elevation of markers of endothelial function, including endothelin and von Willebrand factor (vWF). However, previous studies included both patients with idiopathic dilated cardiomyopathy and ischemic heart disease; the latter condition shows endothelial dysfunction, per se. The 2 endothelial factors have different origin and may provide different information about endothelial dysfunction in CHF and after HTX caused by idiopathic dilated cardiomyopathy.. We investigated plasma endothelin and vWF, the relation between these 2 factors, and determinants of endothelin and vWF plasma levels in 32 healthy controls, 25 patients with CHF, and 22 patients who had HTX; both conditions were caused by idiopathic dilated cardiomyopathy.. Plasma endothelin was elevated in CHF (6.8 +/- 3.4 pg/mL) and after HTX (6.1 +/- 2.1) compared with healthy controls (4.0 +/- 1.0, P <.0001 for both). VWF was also elevated in CHF (1.6 +/- 0.6 U/mL) and after HTX (2.6 +/- 1.0) compared with healthy controls (1.0 +/- 0.5, P <.0001 for both). VWF was increased after HTX compared with CHF (P <.001), in contrast to similar endothelin levels in CHF and after HTX. Plasma endothelin and vWF correlated in both CHF (r = 0.65, P <.001) and HTX (r = 0.66, P <. 001) but not in controls. In CHF, New York Heart Association functional class was an independent determinant of vWF (P <.0001) and furosemide dose of endothelin (P <.0001). In cardiac transplant recipients, plasma albumin was an independent determinant of vWF (P <.01), and plasma sodium and furosemide dose were independent determinants of endothelin (P <.01).. Plasma endothelin and vWF were directly correlated in both CHF and after HTX caused by idiopathic dilated cardiomyopathy. However, the production of the 2 factors appeared to be stimulated by different mechanisms and provided different information about endothelial function, as indicated by the different determinants and different response to heart transplantation.

Topics: Adult; Biomarkers; Cardiomyopathy, Dilated; Diuretics; Endothelin-1; Endothelium, Vascular; Female; Furosemide; Heart Failure; Heart Transplantation; Humans; Male; Middle Aged; Myocardial Ischemia; Regression Analysis; Serum Albumin; Sodium; von Willebrand Factor

The aim of this study is to evaluate the role of non-selective endothelin blockade (TAK-044) in ischemic myocardial injury. Forty anesthetized rats were separated into four groups: 1) TAK-I group, after preinjection of TAK-044 (3 mg/kg), LAD was ligated for 60 min and reperfused for 60 min; 2) Saline (SAL)-I group, LAD ligation and reperfusion without TAK-044; 3) TAK-C group, sham operated TAK group; 4) SAL-C group, sham-operated SAL group. Myocardium from each group was separated and analyzed by biochemical and ultrastructural procedures. Reperfusion arrhythmia (VT) was observed in 88% of the SAL-I group, in contrast to only 36% of the TAK-I group. At the end of reperfusion, hemodynamics indicated no significant differences between these two groups. The Ca(++)-ATPase activity of sarcoplasmic reticulum (SR) was 3.9 mumoles Pi/mg protein/h (39% of SAL-C group) in the SAL-I group, while that in the TAK-I group was significantly higher at 6.1 (54%). The ratio of infarct/risk area was 58% in the SAL-I group and 36% in the TAK-I group. In the ultrastructural observations, irreversibly injured cells of the ischemic portion were reduced significantly from 35% (SAL-I group) to 14% (TAK-I group). Thus, our results indicated that endothelin blockade reduced ischemic cellular injury. The mechanism of this reduction was speculated to be a resistance to ischemic injury in the subcellular levels of the myocardium conferred by a reduction of vascular constriction and improvement of imbalance in the energy supply and demand.

Topics: Animals; Calcium-Transporting ATPases; Creatine Kinase; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Male; Myocardial Ischemia; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum; Tachycardia, Ventricular

Myocardial ischaemia followed by reperfusion during coronary artery bypass grafting (CABG) is known to result in the activation of polymorphonuclear neutrophils (PMN). The activation of PMN during ischaemia/reperfusion may be a result of their direct contact with activated endothelial cells and/or an effect of stimuli released from ischaemic myocardium. Increased expression of adhesion molecules on the PMN surface, after activation, leads to coronary capillary plugging with a subsequent decrease in blood flow. The purpose of the study was to evaluate plasma-mediated stimulation of PMN adhesion during CABG and to verify if endothelin-1 (ET-1), known to be a potent stimulus for PMN, is involved in stimulation of neutrophils adhesion mediated by integrins.. Coronary sinus, peripheral artery and peripheral venous plasma samples were taken from 11 patients undergoing coronary surgery before aortal cross-clamping, at the beginning of reperfusion and 30 min thereafter. PMN isolated from five healthy volunteers were incubated with the plasma (20 samples per patient) in the presence of saline or a specific ET-1 receptor blocker, and PMN adherence to a microtiter plate covered with a monoclonal antibody against CD 18 antigen (beta-subunit of the integrin family of adhesion molecules) was evaluated.. We have observed a significant increase in adhesion of PMN incubated in the presence of saline with the plasma taken from coronary sinus at the beginning of reperfusion (7.79+/-1.64% of adhering cells) as compared with plasma obtained before aortal cross-clamping from the same place (6.78+/-1.3%, P = 0.04) and from peripheral artery at the beginning of reperfusion (6.64+/-1.1%, P = 0.04, means +/- SEM). ET-1 receptor blocker, significantly decreased stimulation of PMN adhesion by coronary sinus plasma obtained at the beginning of reperfusion (6.7+/-1.51%, P = 0.02). Plasma levels of ET-1 (ELISA) in the samples taken from coronary sinus at the beginning of reperfusion, were higher than in samples obtained before myocardial ischaemia or 30 min after reperfusion.. We conclude, that soluble stimuli capable of stimulation of PMN adhesion are released following myocardial ischaemia during CABG and ET-1 may be involved in PMN stimulation.

Topics: Adult; Aged; Cell Adhesion; Coronary Artery Bypass; Endothelin-1; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Neutrophils; Plasma

Recently, several types of centrifugal pumps have been widely used as the main pumps for cardiopulmonary bypass (CPB). However, according to the results of our experimental studies, after cardiogenic shock, pulsatile flow was effective in maintaining the functions and microcirculations of end organs, especially those of the liver and kidney. To estimate the effectiveness of pulsatility during CPB, cytokine and endothelin and other metabolic parameters were measured in clinical pulsatile and nonpulsatile CPB cases. From March to May 1997, CPB was performed in 18 elective cases (14 ischemic and 4 valvular disease). In 9 cases, pulsatile perfusion was achieved by the Jostra HL20, which is a newly developed CPB pump (Group P). A nonpulsatile centrifugal pump was used in 9 patients (Group NP). In both groups, as chemical and metabolic mediators, interleukin-8 (IL-8), endothelin-1 (ET-1), and plasma free hemoglobin were measured before and during CPB, and 0.5, 3, 6, 9, 18 h after weaning from CPB. This pulsatile CPB pump could be very simply and easily controlled and could easily produce pulsatile flow. There were no significant differences in CPB time (CPBT), aortic cross clamp time (ACCT), mean aortic pressure, or pump flow during CPB between the both groups. The ET-1 level of Group P was significantly (p < 0.05) lower than that of Group NP 9 h after CPB weaning. The IL-8 level of Group P also showed a lower value than that of Group NP. As for plasma free hemoglobin, there were no significant differences between the groups. These results suggested that even in conventional CPB, pulsatility was effective to reduce endothelial damage and suppress cytokine activation. It may play a important role in maintaining the functions and microcirculations of end organs during CPB.

Topics: Aged; Aorta; Blood Pressure; Cardiopulmonary Bypass; Coronary Artery Bypass; Elective Surgical Procedures; Endothelin-1; Endothelium, Vascular; Female; Follow-Up Studies; Heart Valve Prosthesis Implantation; Hemoglobins; Humans; Interleukin-8; Kidney; Liver; Male; Microcirculation; Middle Aged; Myocardial Ischemia; Pulsatile Flow; Shock, Cardiogenic; Time Factors

The changes in endothelium-derived vascular regulatory factors during dobutamine (DOB)-induced myocardial ischemia (MI) were investigated in 21 patients with Kawasaki disease aged from 11 months to 18 years. They were classified into an ischemia group (8 patients) and a non-ischemia group (13 patients) based on the results of 99mTc myocardial scintigraphy and DOB stress 99mTc myocardial scintigraphy. In the ischemia group, MI was relatively mild, because there were ischemic changes on the electrocardiogram and no significant symptoms during DOB stress. Catheters were positioned near the orifice of the coronary artery (Ao) and at the coronary sinus (CS). Hemodynamics and the blood concentrations of lactic acid and endothelin-1, as well as NO3-, 6-keto-prostaglandin F1alpha, and thromboxane B2, (which are inactive metabolites of nitric oxide, prostaglandin I2 and thromboxane A2, respectively), were measured at rest and after DOB stress (maximum dose: 30 microg x kg(-1) x min(-1)). The CS/Ao ratio was determined for all parameters. The rate-pressure product, an index of work load, and the cardiac index were significantly increased by DOB stress in both groups. Coronary angiography showed no vasospasm of the epicardial coronary arteries before or after DOB stress in either group. The plasma concentrations of endothelin-1 and 6-keto-prostaglandin F1alpha were significantly increased after DOB stress in the ischemia group, but the serum concentration of NO did not increase. The lack of an increase in NO production during DOB stress may have contributed to the worsening of MI in patients with Kawasaki disease.

Topics: Adolescent; Calcinosis; Cardiomyopathies; Child; Child, Preschool; Coronary Angiography; Dobutamine; Endothelin-1; Endothelins; Female; Hemodynamics; Humans; Infant; Lactic Acid; Male; Mucocutaneous Lymph Node Syndrome; Myocardial Ischemia; Nitrates; Nitric Oxide; Prostaglandins F; Rest; Stress, Physiological; Thromboxane B2

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

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

Endothelin has both vasoconstrictor and mitogenic properties and might, therefore, play a role in the pathogenesis of acute coronary syndromes and coronary atherosclerosis. The aim of the study was to characterize the mechanisms and kinetics of cardiac endothelin-1 (ET-1) release following a local endothelial injury during PTCA (group A) and after sustained myocardial ischemia (group B). Additionally, the precision of agreement between measurements in coronary sinus and peripheral venous samples should be analyzed. In group A, elective PTCA was performed in 20 patients with stable angina pectoris and a > 70% type A stenosis. Simultaneous determinations of ET-1 from coronary venous and peripheral venous blood were done before balloon inflation and during the several hours following the last dilatation procedure. A coronary sinus study with high rate atrial pacing was performed in 20 group B patients with coronary multivessel disease. ET-1 was determined from coronary sinus and peripheral venous blood samples prior to stimulation and during several hours after cessation of pacing. Control groups were provided for both groups. The control group consisted of 10 patients with coronary angiography without PTCA for group A and 10 patients with angiographic normal coronary arteries for group B.PTCA induced an instantaneous increase of coronary sinus ET levels from 4.1 +/- 1.1 pg/ml to 13.7 +/- 2.3 pg/ml (peripheral venous 7.9 +/- 2.5 pg/ml), which was more pronounced if the target vessel was the left anterior descending artery. This peak was followed by a gradual decrease of ET-1 to the limit of normal within 6 hours. The concentrations of ET, furthermore, remained higher in the coronary sinus compared with the peripheral vein indicating a persisting cardiac release of ET. In group B, incremental atrial pacing resulted in myocardial ischemia, and a significant increase in ET-1 from 4.6 +/- 0.6 pg/ml to 13.1 +/- 2.8 pg/ml was detected in the coronary sinus samples. A persistent cardiac release of ET-1, as reflected by sustained elevated coronary sinus concentrations, was observed for up to one hour after cessation of pacing. The analysis of measurement agreement between coronary venous and peripheral venous samples revealed considerable variations of the differences between the two sampling sites indicating wide limits of agreement. Despite a significant positive correlation, our date reflecting a remarkable lack of agreement.. 1) An enhanced release of ET-1 following PTCA is mainly due to the localized endothelial injury, and the ET-1 levels remain elevated for up to hours after the mechanical stimulus. 2) A short-lasting myocardial ischemia is associated with a significant ET-1 increase. 3) For refined evaluations of release kinetics of cardiac ET-1, blood sampling from the coronary sinus seems to be essential.

Topics: Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Cardiac Pacing, Artificial; Coronary Disease; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Reference Values; Sensitivity and Specificity

We and other groups have reported that endothelin (ET)-1 expression in the heart is altered in the setting of heart diseases. We have also reported that myocardial ET-1 is involved in the progression of heart failure, and that an ET receptor antagonist improves long-term survival in heart failure (Nature 384: 353-355, 1996). However, the role of myocardial ET-2 in disease states are not known. To characterize the role of ET-2, we used a) the failing hearts of rats with heart failure caused by myocardial infarction, and b) primary cultured cardiomyocytes subjected to hypoxia. In the failing heart in vivo, ET-1 mRNA increased by 390% compared with that in the non-failing heart, while ET-2 mRNA drastically decreased by 88%. Thus, gene expression of ET-1 and ET-2 was reciprocally altered in the failing heart in vivo. In in vitro studies, reciprocal alterations in ET-1 and ET-2 gene expression were also observed in isolated primary cultured cardiomyocytes, subjected to hypoxia. Specifically, acute hypoxic stress induced a significant increase (360% of the basal level) in ET-2 mRNA expression compared with that in normoxic cells, whereas it decreased ET-1 mRNA expression by 62% in primary cultured cardiomyocytes. Although these two crucial conditions, i.e., heart failure in vivo and acute hypoxic stress in vitro, are pathophysiologically distinct from each other, reciprocal alteration of ET-1 and ET-2 gene expression was observed in both cases. To further investigate the regulatory mechanism of the altered gene expression, luciferase analysis was performed using primary cultured cardiomyocytes. ET-2 promoter, which is the 5'-flanking region of preproET-2 gene (5'ET-2), showed a marked increase in luciferase activity during acute hypoxia. In contrast, the luciferase activity of 5'ET-1 (ET-1 promoter) did not change in response to hypoxic stress. The present study suggests that there are transcriptionally distinct regulatory mechanisms for ET-1 and ET-2 expression in cardiomyocytes, and therefore this study may provide a new aspect of cardiac ET system that not only ET-1 but also ET-2 can be participated in the pathophysiological conditions.

Topics: Animals; Cell Hypoxia; Cells, Cultured; Disease Models, Animal; Endothelin-1; Endothelin-2; Endothelins; Gene Expression Regulation; Heart Failure; Hemodynamics; Male; Myocardial Ischemia; Myocardium; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger

Acute myocardial ischemia was induced by occlusion of the anterior descending of left coronary artery (LAD) in rats; the resultant arrhythmia in 1 h after LAD occlusion was evaluated. In order to prevent expression of endothelin-1 mRNA, human endothelin-1 mRNA antisense oligonucleotide (ET-1 AS-ODN) was intravenously injected 2 h before LAD occlusion. The effect of AS-ODN on plasma ET-1 concentration and the acute ischemic arrhythmia were observed. The results showed that plasma ET-1 was significantly decreased in rats pretreated with AS-ODN, and both the incidence and severity of the acute ischemic arrhythmia were decreased dose-dependently as compared with normal saline control and sense oligonucleotide control, indicating that ET-1 AS-ODN could prevent acute myocardial ischemic arrhythmia and that endogenous endothelin-1 may play an important role in the development of acute ischemic arrhythmia in rats.

Topics: Animals; Arrhythmias, Cardiac; Endothelin-1; Male; Myocardial Ischemia; Oligonucleotides, Antisense; Rats; Rats, Sprague-Dawley; RNA, Messenger

Topics: Angiotensin II; Animals; Endothelin-1; Extracellular Space; Heart; Hydroxyl Radical; Microdialysis; Myocardial Ischemia; Neuropeptide Y; Norepinephrine

Women with prior preeclampsia are characterized by hyperinsulinemia and a 2- to 3-fold excess risk of hypertension and ischemic heart disease in later life. We therefore studied whether these women present changes in pituitary, ovarian, and endothelial factors that could also affect the risk of vascular disorders. Twenty-two women with prior preeclampsia and 22 control women matched by age and body mass index were studied an average of 17 yr after delivery. Women with prior preeclampsia had elevated serum free testosterone levels (20.6 +/- 2.2 vs. 15.0 +/- 1.3 pmol/L, mean +/- SE, P = 0.03), an elevated free androgen index (3.2 +/- 0.5 vs. 1.9 +/- 0.2, P = 0.04), and an elevated free testosterone estradiol ratio (0.089 +/- 0.017 vs. 0.046 +/- 0.006, P = 0.02). The levels of insulin-like growth factor binding protein-1 decreased as expected during a 3-h oral glucose tolerance test without differences between the groups. Levels of FSH, LH, androstenedione, dehydroepiandrosterone sulfate, and endothelin-1, as well as urinary output of prostacyclin and thromboxane A2 metabolites, showed no difference between study groups. A history of preeclampsia an average of 17 yr earlier thus appears to be associated with elevated levels of testosterone, which may contribute to the increased risk of vascular morbidity in such women.

Topics: Adult; Endothelin-1; Estradiol; Female; Glucose Tolerance Test; Humans; Hypertension; Insulin; Insulin-Like Growth Factor Binding Protein 1; Myocardial Ischemia; Pre-Eclampsia; Pregnancy; Risk Factors; Testosterone

Circulating endothelin (ET)-1 is elevated in ischemia/reperfusion and may exert proischemic effects. The aim of the present study was to characterize the effects of ET-1 in rat isolated hearts using subtype-selective ET receptor antagonists, agents modulating the cytosolic Ca2+ concentration, or the activity of cGMP-dependent protein kinase.. Rat hearts perfused at constant pressure were made ischemic by reducing flow to 0.2 mL x min(-1) x g(-1), followed by reperfusion at normal pressure (each phase, 25 minutes). Drugs were infused during the ischemic phase only. Parameters monitored were extent and time-to-onset of contracture in ischemia, left ventricular developed pressure (LVDevP), coronary flow (CF), and diastolic relaxation during reperfusion. The ET(A) receptor-selective antagonist PD 155080 (50 nmol/L) reduced peak ischemic contracture (-49%) and delayed its time to onset (+56%) and improved recovery of reperfusion LVDevP (+12%), CF (+16%), and diastolic relaxation (+50%). Infusion of an ET(A)/ET(B)-nonselective antagonist, PD 142893 (200 nmol/L), had similar effects on all parameters, whereas infusion of BQ-788 (20 nmol/L), an ET(B) receptor-selective antagonist, was without effect. Exogenous ET-1 (100 pmol/L) hastened contracture and increased its extent (+23%) and reduced recovery of both LVDevP (-31%) and CF (-18%), effects that were counteracted by HOE 642 (10 micromol/L), a Na+/H+ exchange inhibitor, but not by nicardipine (30 micromol/L), a Ca2+ entry blocker; activation of cGMP-dependent protein kinase by the cell-permeable cGMP analog Sp-8-p-chlorophenylthioguanosine-3',5'-cyclic monophosphorothioate (10 micromol/L) improved function without preventing the effects of ET-1.. The data indicate that ET-1 exacerbates ischemic contracture and worsens ventricular and coronary reperfusion dysfunction by activating ET(A) receptors via a mechanism likely involving activation of Na+/H- exchange in this model.

Topics: Animals; Coronary Vessels; Cyclic GMP-Dependent Protein Kinases; Endothelin-1; Female; Heart; Heart Rate; Intracellular Membranes; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin

The aim of this study was to detect the possible release from the ischemic rabbit myocardium of a factor capable of modulating the release of endothelin-1 (ET-1) from the peripheral vasculature. Isolated rabbit hearts were perfused on a Langendorff apparatus so that part of the coronary effluent was pumped directly into the arterial supply of isolated ears. Mean ET-1 outflow from ears perfused with fresh Krebs was 4.33 +/- 0.72 pg/min; from ears perfused with coronary effluent it was 84.3% less. This still represented net ET-1 production in the ear (venous/arterial ET-1 concentration ratio (V/A) = 3.9 +/- 1.2). Myocardial ischemia (30 min) caused a large reduction in ET-1 outflow from the ears and changed net production to net loss (V/A = 0.32 +/- 0.17). Within 2 min of reperfusion the V/A had risen to 6.3 +/- 2.2 and the ET-1 outflow from the ears rose 16-fold. Neither 30-min coronary occlusion nor 2-min reperfusion altered ET-1 concentrations in the coronary effluents. After 60-min reperfusion, ET-1 concentration in coronary effluent rose by 230%. During myocardial ischemia and reperfusion there was no change in pO2, pCO2 or pH in the perfusate supplying the ears. Therefore the changes in ET-1 handling by the ear vasculature must have been induced by a transmissible factor released from the heart.

Topics: Animals; Ear, External; Endothelin-1; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Myocardial Ischemia; Myocardium; Perfusion; Rabbits; Regional Blood Flow

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

Peri-operative ischemic episodes following coronary artery bypass grafting with the internal mammary artery (IMA) are thought to be due to a vasospasm of this conduit. Endothelin-1 (ET-1) is a potent vasoconstrictor by itself and increases the response to other vasoconstrictor stimuli. This study focused on the possible role of an enhanced tissue ET-1-like immunoreactivity in the perioperative reaction of the IMA in patients with diabetes or hypercholesterolemia.. Specimens of the distal part of the IMA from 46 patients (mean age 58.5 years, four women, 42 men) were studied prospectively. Nine of those patients were diabetic and 26 had evidence of hypercholesterolemia. Another cohort of 20 IMA specimens was stained retrospectively; 10 of those biopsies were from patients that had experienced transient ischemic events peri-operatively in the myocardial area supplied by the IMA. The biopsies were examined histologically and immunohistochemically (rabbit polyclonal ET-1 antiserum, three-step avidin-biotin complex) with regard to their immunoreactivity to tissue ET-1.. An immunoreactivity to ET-1 (graded 0-3) was present in 89% of the biopsies. The reactivity was significantly higher in patients with hypercholesterolemia ( 1.92+/-0.74) when compared to controls (1.0+/-0.63) (P = 0.04). The reactivity was also increased in patients with non-insulin-dependent diabetes mellitus (2.1+/-0.79), when compared to controls (P = 0.02). Mostly transient ischemic events in the area supplied by the IMA seemed to occur more frequently when the biopsies revealed a higher immunoreactivity to ET-1. They showed an increased reactivity to ET-1 (2.27+/-0.76) compared to 10 patients with an uneventful peri-operative course (1.66+/-0.71 ) (P = 0.04).. This study provides evidence that the internal mammary artery is not a passive conduit. Vasospasm or vasoconstriction, in particular at its distal end, may occur more frequently in patients with hypercholesterolemia or diabetes, and may lead to post-operative ischemic events.

Topics: Biopsy; Cohort Studies; Coronary Circulation; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypercholesterolemia; Immunohistochemistry; Internal Mammary-Coronary Artery Anastomosis; Intraoperative Complications; Male; Mammary Arteries; Middle Aged; Myocardial Ischemia; Prospective Studies; Retrospective Studies; Vasoconstriction; Vasoconstrictor Agents

The aim of this study was to investigate the influence of endogenously released and exogenously applied endothelin-1 (ET-1) on ischaemia-induced arrhythmias.. Ischaemia was induced in pentobarbitone-anaesthetised rats by ligation of a coronary artery for 30 min. To determine the role of endogenous ET-1 in ischaemic arrhythmias, either the ETA receptor antagonist BQ123 (50 micrograms/kg/min, i.v.; n = 10) or the ETB receptor antagonist PD161721 (0.1 or 1 mg/kg i.v.; n = 10 per group) was administered before the onset of ischaemia. To assess the influence of exogenous ET-1 on arrhythmias, ET-1 (1.6 nmol/kg i.v.) was administered 5 min before ischaemia in the absence (n = 12) or presence of BQ123 (n = 10) or PD161721 (n = 10). The total number of ventricular ectopic beats (VEB's) were counted and expressed as median (Q1-Q3) and the incidence of ventricular fibrillation (VF) and ventricular tachycardia (VT) in each group was determined. Mean arterial blood pressure (MABP) and heart rate (HR) were measured.. In control animals (n = 20), the incidence of VF was 65% and the total VEB count was 2775 (1870-4041). Both BQ123 and the higher dose of PD161721 reduced the VEB count to 654 (348-1489; P < 0.05) and 782 (432-1153; P < 0.05) respectively. Only PD161721 reduced the incidence of VF (to 10%; P < 0.05). Administration of ET-1 reduced VEB's to 1530 (1204-2017); P < 0.05) and the incidence of VF to 17% (P < 0.05). Neither PD161721 nor BQ123 modified this antiarrhythmic effect of ET-1, but rather enhanced the reduction in arrhythmias. Before occlusion, ET-1 caused a transient fall in MABP (from 107 +/- 3 to 63 +/- 3 mmHg; P < 0.05). PD161721, but not BQ123, partially blocked this effect. Upon occlusion, MABP fell in control animals (from 106 +/- 4 to 67 +/- 4 mmHg at 1 min post-occlusion; P < 0.05). This was significantly attenuated by ET-1, although neither of the antagonists were able to block this effect of ET-1.. ET-1 released endogenously during ischaemia is arrhythmogenic whereas exogenous application of ET-1 may, under certain conditions, be antiarrhythmic.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Dioxins; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Male; Myocardial Ischemia; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Ventricular Premature Complexes

The vasoconstrictor effect of endothelins (ET) is mediated by endothelin A (ETA) and endothelin B (ETB) receptors. Furthermore, ETB receptor stimulation results in release of vasodilators. Hence, ETA receptor antagonists should attenuate ET-mediated vasoconstriction. The aim of the present study was to evaluate and compare the effects of BQ-123, an ETA receptor antagonist, and bosentan, an ETA and ETB receptor antagonist, on coronary vasomotor tone, left ventricular systolic function and ET-1 efflux in the presence or absence of myocardial ischaemia/reperfusion.. Isolated rat hearts were perfused using a Langendorff preparation. Global ischaemia was induced on average by 68 +/- 2% (+/- standard error of the mean) reduction of a baseline perfusion flow-rate 10 min after introduction of ET antagonists. Thirty minutes of ischaemia was followed by 30 min reperfusion. ET-1 efflux in coronary perfusate was measured by radioimmunoassay.. In non-ischaemic hearts (n = 7), BQ-123 (10(-6) M) perfusion induced a progressive decrease in coronary flow-rate compared with control group. This flow reduction persisted after wash-out of BQ-123. In contrast, bosentan (10(-5) M, n = 7) induced no change in perfusion rate. In the absence of ET antagonists (n = 16), there was a 22 +/- 6% post-ischaemic increase in perfusion flow-rate. BQ-123 (n = 5) but not bosentan (n = 12) abolished this post-ischaemic increase in flow-rate. Neither BQ-123 nor bosentan induced significant variation in force of contraction. In ischaemic hearts, ischaemia per se induced a transient decrease in force of contraction. Bosentan significantly (P < 0.05) accentuated and BQ-123 tended to accentuate (P = 0.06) this decrease in force of contraction during ischaemia. Bosentan but not BQ-123 significantly impaired the recovery of systolic function during reperfusion (P < 0.05). Both BQ-123 and bosentan perfusion increased ET-1 efflux rate to 730 +/- 188% and 315 +/- 81% respectively. This effect was abolished during ischaemia for BQ-123, but not for bosentan.. In isolated perfused rat hearts, both BQ-123 and bosentan increased ET-1 efflux, but only BQ-123 exerted vasoconstrictor effects. These results thus generated the hypothesis that: (1) ET-1 release within the coronary vascular bed may be physiologically subject to negative feedback regulation mediated via ETA receptors; (2) ETA receptor antagonists increase ET-1 efflux, which may lead to net vasoconstriction via unopposed ETB stimulation. Furthermore, the negative inotropic effects observed during ischaemia suggest that ET is critical to the maintenance of systolic function during ischaemia.

Topics: Animals; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Male; Myocardial Contraction; Myocardial Ischemia; Peptides, Cyclic; Perfusion; Rats; Rats, Inbred Strains; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Regional Blood Flow; Sulfonamides; Vasoconstriction; Ventricular Function, Left

The aim of this study was to test the hypothesis that plasma endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) concentrations in patients with ischemic heart disease are related either to myocardial ischemia or left ventricular (LV) dysfunction during dobutamine stress echocardiography. Plasma concentrations of ET-1 and ANP were measured in three patient groups. Group I (n = 21) patients had normal stress echocardiography and a resting LV ejection fraction (LVEF) of 40% or more. Group II (n = 32) had positive stress echocardiography and a resting LVEF of more than 40%. Group III (n = 18) had positive stress echocardiography with a resting LVEF of less than 40%. All three groups were subjected to thallium 201 scintigraphy and coronary angiography studies. The resting LV end-diastolic pressure was significantly higher in groups II and III than in Group I. The LVEF decreased significantly in group III compared to groups I and II. In the resting state, groups II and III had higher ET-1 concentrations than Group I (p = 0.021 and p = 0.039, respectively). The plasma ANP concentration was higher in group III than in groups I and II (p = 0.005 and p = 0.054, respectively). During peak dobutamine infusion, the ET-1 concentration dropped 8.7% from the baseline in group I, 10.2% in group II, and 10.5% in group III. The ANP concentrations were increased in all three groups but only the increase in Group II reached statistical significance. In conclusion, in patients with suspected ischemic heart disease, the concentrations of ET-1 and ANP may predict significant anatomic and functional coronary artery disease. However, ET-1 does not play a pathophysiologic role during an ischemic attack.

Topics: Adult; Aged; Atrial Natriuretic Factor; Coronary Angiography; Dobutamine; Echocardiography; Endothelin-1; Female; Hemodynamics; Humans; Male; Middle Aged; Myocardial Ischemia; Tomography, Emission-Computed, Single-Photon

Endothelin-1 (ET-1) is an endothelium-derived mediator with vasoconstrictive and mitogenic activity which stimulates vascular smooth muscle cell proliferation. The aim of this study was to evaluate ET-1 production during percutaneous transluminal coronary angioplasty (PTCA) and elective stent implantation. We hypothesized that the additional vessel wall trauma induced by stent deployment might be associated with a greater production of ET-1. To this end, ET-1 levels were measured in 18 patients undergoing PTCA and stenting (12 with left anterior descending coronary artery stenosis and 6 with circumflex artery lesion). The sampling sites were the coronary ostium and coronary sinus in basal conditions (before the procedure), during first balloon inflation, and 5, 20, 60 min after the end of first balloon inflation. At baseline, ET-1 levels were higher in the coronary sinus than in coronary ostium (1.58 +/- 0.22 vs 1.29 +/- 0.20 pg/ml, p < 0.001). During first balloon inflation, ET-1 coronary sinus levels significantly diminished with respect to the basal levels (1.08 +/- 0.32 vs 1.58 +/- 0.22 pg/ml, p < 0.001). Further significant variations of ET-1 levels were not detected neither following the first balloon inflation nor after stent deployment. In conclusion, the culprit lesion seems to produce most of ET-1 circulating in the coronary tree. This is demonstrated by higher ET-1 levels in the coronary sinus compared to coronary ostium at baseline, and even more by the significant ET-1 reduction in the coronary sinus during first balloon inflation. Despite our expectations, we did not detect any significant ET-1 increase during stent deployment.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Circulation; Coronary Disease; Endothelin-1; Humans; Male; Middle Aged; Myocardial Ischemia; Stents

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

At peak exercise, plasma endothelin-1 concentration increases in patients with effort angina as well as thallium-201 radionuclide perfusion defects; the opposite occurs in patients with normal scans and in healthy volunteers. It is concluded that exercise-induced ischemia correlates with enhanced endothelin-1 production.

Topics: Angina Pectoris; Case-Control Studies; Endothelin-1; Exercise Test; Female; Heart; Humans; Male; Middle Aged; Myocardial Ischemia; Radionuclide Imaging; Thallium Radioisotopes

The acute effect of cyclosporine A (CSA) on myocardial function after ischemia and reperfusion and the mechanism of action was investigated in isolated working guinea-pig hearts. Myocardial function was experimentally infringed by imposing short-term global ischemia and reperfusion (15 min each). External heart work (EHW), determined before and after ischemia, served as the criterion for quantitation of recovery. Control hearts were perfused with modified Krebs-Henseleit buffer, other hearts received buffer supplemented with CsA +/- an endothelin receptor antagonist or exogenous endothelin +/- an inhibitor of nitric oxide (NO) synthesis. To assess the importance of endothelial production of mediators directly, NO release in coronary effluent (continuously measured with an amperometric sensor) and release of 6-keto-prostaglandin F1, (6-keto-PGFb), a stable metabolite of prostacyclin (PGI2), were determined in non-working. Langendorff hearts. Oxidative stress during reperfusion was assessed by measuring glutathione release in coronary venous effluent. Cyclosporine A (0.8 microM) improved post-ischemic function significantly (59% recovery of EHW nu 31% for controls). At 0.08 microM. CsA was without beneficial effect (30% recovery). The endothelin (ET)A- and ETB-receptor antagonist bosentan inhibited the protective action of 0.8 microM CsA (32% recovery). Exogenous ET-1 (80 pM) improved recovery to 53%, an effect which was blocked by the inhibitor of NO-synthase, NG-nitro-L-arginine (NOLAG. 1 microM. 31% recovery. In the control group, post-ischemic NO release in coronary effluent recovered from zero to about 100% of the pre-ischemic value by 10 min. but then decreased rapidly during the subsequent 15 min of reperfusion. In hearts treated with 0.8 microM CsA, NO release stayed at 100% of the pre-ischemic value throughout reperfusion, the difference between controls and CsA-treated hearts being significant after 20 min of reperfusion. On the other hand, coronary venous release of 6-keto-PGF1a was not different between the groups. Release of glutathione during early reperfusion first 5 min) was significantly lowered (P < 0.05) to about 50% in CsA (0.8 microMI- and ET-I-treated compared with controls (8.8 nmol/min). Cyclosporine A acts as a cardioprotective agent in our model of ischemia and reperfusion, presumably by elevating the level of endogenous nitric oxide and thereby reducing oxidative stress.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antirheumatic Agents; Bosentan; Coronary Circulation; Cyclosporine; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Enzyme Inhibitors; Glutathione; Guinea Pigs; Hemodynamics; Immunosuppressive Agents; In Vitro Techniques; Male; Myocardial Ischemia; Myocardial Reperfusion; Nitric Oxide; Nitroarginine; Sulfonamides

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen involved in vascular development and angiogenesis. Recently we have observed increased VEGF expression in the normal myocardium after myocardial infarction in a rat heart. This study was designed to explore the mechanism responsible for this increase in VEGF expression. Induction of myocardial stretch in an isolated perfused Langendorff preparation by inflation of an intraventricular balloon to an end-diastolic load of 35 mmHg for 30 min resulted in a nearly sixfold increase in VEGF message level not only in the chamber subjected to stretch (left ventricle) but also in the unstretched right ventricle, thus raising the possibility of a soluble factor mediating stretch- induced induction of VEGF expression. This was further confirmed by demonstrating that coronary venous effluent collected from the stretched heart and used to perfuse isolated hearts in which no balloon was present was able to induce VEGF expression in these normal hearts. Inhibition of TGF-beta activity using a neutralizing antibody, but not antagonists/inhibitors of endothelin and angiotensin II, eliminated stretch-induced increase in VEGF expression. Staurosporine, a protein kinase C inhibitor, also blocked stretch-induced increase of VEGF expression. Measurement of TGF-beta concentration in the perfusate demonstrated increased amounts of the cytokine after myocardial stretch, and addition of TGF-beta protein to the perfusion buffer resulted in increased VEGF expression in control hearts. These results suggest that stretch-induced increase of VEGF expression in the heart is mediated at least in part by TGF-beta.

Topics: Angiotensin II; Animals; Antibodies; Catheterization; Diastole; Endothelial Growth Factors; Endothelin Receptor Antagonists; Endothelin-1; Heart; In Vitro Techniques; Lymphokines; Male; Myocardial Ischemia; Myocardium; Peptides, Cyclic; Protein Kinase C; Rats; Rats, Sprague-Dawley; RNA, Messenger; Saralasin; Staurosporine; Transcription, Genetic; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The endothelium-derived peptide endothelin-1 (ET-1) was evaluated in 14 male patients [mean age 52.74 years (SEM 1.10)] affected by coronary artery disease during a bicycle electrocardiographic stress test and dipyridamole echocardiogram. Both tests were performed before and after coronary revascularization. Fourteen healthy male subjects served as controls [mean age 53.21 years (SEM 1.63)]. Baseline plasma endothelin-1 levels were higher (P < 0.0001) in ischaemic patients [1.81 pg mL-1 (0.15, n = 14)] than in control subjects [0.61 pg mL-1 (0.03, n = 14)], but did not increase with exercise in both groups. Similar results were obtained with dipyridamole infusion. Endothelin-1 levels significantly decreased after coronary revascularization [before: mean 1.81 pg mL-1 (SEM 0.15, n = 14); after: mean 1.16 pg mL-1 (SEM 0.11), P < 0.002], without changes in the peptide response to both tests. In conclusion, elevated plasma endothelin-1 concentrations were found in patients with stable angina compared with non-ischaemic subjects. No changes were observed during exercise or dipyridamole infusion in both groups. Coronary revascularization was followed by a significant decrease in plasma endothelin-1 levels.

Topics: Adult; Angina Pectoris; Case-Control Studies; Dipyridamole; Echocardiography; Endothelin-1; Exercise Test; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardial Revascularization

Although several studies have demonstrated that nitric oxide appears to be cardioprotective and endothelin-1 (ET-1) deleterious in myocardial ischemia/reperfusion injury, their interactions in the intact heart are unknown. Therefore, coronary effluent and interstitial fluid ("transudate") levels of ET-1 and cyclic GMP, an indirect measure of nitric oxide production, were determined simultaneously in normoxic and reperfused hearts and compared with myocardial and coronary function. Rat hearts were buffer-perfused at 9 ml/min/g heart wet weight for 45 min (baseline), followed either by another 45 min of perfusion (normoxia), or 15 min of total global ischemia and 30 min reperfusion. Hearts received, from 42-90 min, either vehicle, the inhibitor of nitric oxide formation NG-nitro-L-arginine (L-NNA; 200 micromol/l), the nitric oxide donor S-nitroso-N-acetyl-DL-penicillamine (SNAP; 200 micromol/l), or the ET receptor antagonist PD 142893 (200 nmol/l). Both mediators were released preferentially into the vascular lumen which resulted in similar luminal and interstitial concentrations of cyclic GMP, but three-fold higher levels of ET-1 in tissue because of the higher effluent than transudate flow rate. L-NNA increased the release of ET-1 and worsened coronary function, whereas SNAP had opposite effects. On reperfusion, considerable functional impairment was observed, although levels of cyclic GMP both in the vascular and tissue compartment were not reduced, but even increased. Reperfusion functional impairment was aggravated after inhibiting the synthesis of nitric oxide, whereas SNAP restored cardiac and coronary function close to pre-ischemic level. Deterioration of function corresponded with an increased level, and improvement with a decreased level of intersitial ET-1 at the onset of reperfusion. PD 142893 was similarly cardioprotective as SNAP both in normoxia and reperfusion. These results suggest that in reperfusion, cardiac function is depressed, despite increased rather than decreased endogenous nitric oxide production, largely due to the prevalence of the deleterious effects of ET-1 which are overcome by antagonism of ET receptors or exogenous nitric oxide supplied by SNAP.

Topics: Acetylcholine; Animals; Cyclic AMP; Endothelin-1; Enzyme Inhibitors; Exudates and Transudates; Heart Rate; In Vitro Techniques; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oligopeptides; Penicillamine; Perfusion; Rats; Rats, Sprague-Dawley; S-Nitroso-N-Acetylpenicillamine

Reperfusion of ischemic rat hearts initiates the generation of inositol(1,4,5)trisphosphate [Ins(1,4,5)P3] and arrhythmias, provided that either norepinephrine or thrombin is present. In the current study, effects on endothelin-1 (ET-1) responses were investigated. Reperfusion of catecholamine-depleted, [3H]inositol-labeled hearts in the presence of ET-1 caused an increase in [3H]inositol phosphates (7,073 +/- 1,004 to 17,300 +/- 206 counts.min-1.g tissue-1, means +/- SE, n = 4, P < 0.01), which was quantitatively greater than the release observed under normoxic conditions, but there was no increase in [3H]Ins(1,4,5)P3. Gentamicin (150 microM) inhibited inositol phosphate responses in the presence of either norepinephrine or thrombin but did not inhibit the response to ET-1, providing additional evidence that the inositol phosphate response to ET-1 does not involve formation of Ins(1,4,5)P3, even under reperfusion conditions. In contrast to norepinephrine and thrombin, ET-1 did not initiate reperfusion arrhythmias (4.4% ventricular fibrillation compared with 0% ventricular fibrillation in catecholamine-depleted controls). The data provide strong evidence that the effect of ischemia-reperfusion on inositol phosphate responses is specific for particular receptor types and eliminates G proteins, phospholipase C enzymes, and substrate availability as the primary factors responsible for Ins(1,4,5)P3 generation under reperfusion conditions.

Topics: Animals; Arrhythmias, Cardiac; Endothelin-1; Endothelin-3; Heart Rate; In Vitro Techniques; Inositol; Inositol Phosphates; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley

Although the investigation of coronary microcirculation is of great importance, available methods have severe restrictions. They do not allow the study of vasodynamics of resistance vessels and microscopic conductance vessels simultaneously in the isolated beating rat heart. We now demonstrate that the combined measurement of perfusion which reflects the state of resistance vessels and cross-sections of microscopic conductance vessels is feasible in the model of the isolated constant flow perfused rat heart. Perfusion measurement was based on injection of coloured microspheres. Cross-sections of microscopic conductance vessels (diameter >140 micron) were determined by NMR-microscopy by flow weighted imaging. Both methods were established recently by our group. The combined measurement was applied to hearts which were subjected to ischaemia and reperfusion (group 1: n=5, 15 min ischaemia/group 2: n=7, 30 min ischaemia/measurements before ischaemia and 15/30 min after reperfusion), 200 pmol endothelin-1 bolus application (group 3: n=6/measurements before and 5 min after drug application), continuous infusion of the endothelin-1 antagonist BQ 610 (group 4: n=6/measurements before and 20 min after onset of infusion), and 200 pmol endothelin-1 application superimposed on 20 min of continuous BQ 610 infusion (group 5: n=7/combined measurement before BQ 610 infusion and 5 min after endothelin-1 application). In group 1, 15 min reperfusion restored the pre-ischaemic perfusion state, whereas conductance vessels were dilated (80.8+/-2.6%), after 30 min reperfusion pre-ischaemic conditions were also restored for conductance vessels. In group 2, a redistribution of perfusion from left ventricular endocardium to the right ventricular wall was observed. Post-ischaemic rhythm disturbances made NMR-imaging in this group impossible. In group 3, a shift of perfusion from the left ventricular myocardium to the right ventricular wall was observed. Similarly, the cross-section of left ventricular conductance vessels decreased (-32.6+/-2.1%), whereas size of right ventricular vessels increased. In group 4, BQ 610 had no effect on perfusion nor on vessel size and antagonized the effect of endothelin-1 on perfusion and vessel size in group 5.

Topics: Animals; Color; Coronary Circulation; Endothelin-1; In Vitro Techniques; Magnetic Resonance Spectroscopy; Male; Microcirculation; Microscopy; Microspheres; Myocardial Ischemia; Myocardial Reperfusion Injury; Oligopeptides; Perfusion; Rats; Rats, Wistar; Vasomotor System

Topics: Animals; Cold Temperature; Endothelin-1; Male; Myocardial Ischemia; Rabbits

1. The effects of the calcium channel blockers, verapamil and nifedipine on myocardial ischaemia and oedema evoked by endothelin-1 (ET-1) or IRL 1620, an ETB receptor-selective agonist were studied in anaesthetized and conscious rats. 2. Bolus injection of ET-1 (1 nmol kg-1, i.v.) or IRL 1620 (1 nmol kg-1, i.v.) to conscious chronically catheterized rats evoked a transient depressor response followed by a prolonged pressor effect. Corresponding to changes in blood pressure, a transient tachycardia and a sustained bradycardia were observed. Pretreatment of the animals with verapamil (1 mg kg-1, i.v.) or nifedipine (200 micrograms kg-1, i.v.) produced on average 5 mmHg decrease in mean arterial blood pressure. Both verapamil and nifedipine inhibited by 63 and 44% the pressor actions of ET-1 or IRL 1620 (1 nmol kg-1), respectively, and the accompanying bradycardia. Both verapamil and nifedipine potentiated the magnitude of the depressor action of ET-1 and IRL 1620 without affecting the accompanying tachycardia. Decreasing mean arterial blood pressure with hydralazine (0.2 - 0.3 micromol kg-1, i.v.) to levels comparable to those observed after verapamil or nifedipine had no significant effects on the haemodynamic responses to ET-1 or IRL-1620. 3. Intravenous bolus injection of ET-1 or IRL 1620 (0.1-2 nmol kg-1) into anaesthetized rats produced dose-dependent ST segment elevation of the electrocardiogram without causing arrhythmias. ST segment elevation developed within 30-50s and persisted for at least 10-20 min following injection of the peptides. 4. Pretreatment of the animals with verapamil (1 mg kg-1, i.v.) or nifedipine (200 micrograms kg-1, i.v.) inhibited on average by 79 and 76% the ST segment elevation elicited by ET-1 (1 nmol kg-1), respectively. Verapamil and nifedipine also attenuated IRL 1620 (1 nmol kg-1)-induced ST segment elevation on average by 71 and 74%, respectively. In contrast, no significant inhibition was observed with hydralazine (0.2-0.3 mumol kg-1). 5. Both ET-1 and, to a lesser extent, IRL 1620 (0.1-2 nmol kg-1) evoked albumin accumulation in cardiac tissues in a dose-dependent fashion as measured by the local extravascular accumulation of Evans blue dye in conscious rats. ET-1 and IRL 1620 (1 nmol kg-1) enhanced albumin extravasation by 109 and 82%, and 34 and 44% in the left ventricle and right atrium, respectively. ET-1 or IRL 1620-induced albumin extravasation was completely prevented by verapamil (1 mg kg-1) or nifedipine (200

Topics: Albumins; Animals; Blood Pressure; Calcium Channel Blockers; Dose-Response Relationship, Drug; Edema; Electrocardiography; Endothelin-1; Endothelins; Heart Rate; Hydralazine; Male; Myocardial Ischemia; Nifedipine; Peptide Fragments; Rats; Rats, Wistar; Receptors, Endothelin; Vasodilator Agents; Verapamil

The effects of a new endothelin receptor antagonist, TAK-044, (cyclo[D-alpha-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]L-alan yl-L-alpha aspartyl-D-2-(2-thienyl)glycyl-L-leucyl-D-tryptophyl]disodium salt, on ischemic and post-ischemic myocardial dysfunction (stunned myocardium) were studied in anesthetized open-chest dogs. A short (15 min) occlusion of the left anterior descending coronary artery followed by 5-h reperfusion significantly reduced myocardial segment shortening during and after the ischemic period in the ischemic region. Regional myocardial blood flow was also decreased significantly 10 min after the occlusion, whereas it returned almost completely to its pre-ischemic value 5 h after reperfusion TAK-044 (3 mg/kg,i.v.) administered 10 min before occlusion significantly improved the reduced myocardial segment shortening in the ischemic region during and after occlusion. Cardiovascular hemodynamics and regional myocardial blood flow in a TAK-044-treated group were identical to those in the control group. These results indicate that endogenous endothelin contributes to the cause of ischemic and post-ischemic myocardial dysfunction without changing either hemodynamics or regional myocardial blood flow.

Topics: Animals; Blood Pressure; Coronary Vessels; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Heart Rate; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Stunning; Peptides, Cyclic; Regional Blood Flow

To investigate if the response of the contralateral artery during coronary angioplasty (PTCA) is different in hypertensive than in normotensive patients and whether this response is related to plasma levels of endothelin-1 (ET-1). We examined the change in ET-1 plasma levels and the reactivity of the left circumflex artery (LCx) during PTCA of the left anterior descending branch in 10 hypertensive and 23 normotensive patients. Peripheral vein blood samples were drawn for ET-1 estimation at baseline, after the end of the first balloon inflation, at the end of PTCA, and 4 h later. Angiograms of the LCx were obtained at baseline and during the 1st balloon inflation. The ET-1 level in hypertensives increased from 6.81 +/- 3.76 at baseline to 7.54 +/- 4.76 pmol/l (P = n.s.) at the end of PTCA, while in normotensives it increased from 8.21 +/- 3.73 to 11.56 +/- 5.04 pmol/l (F = 7.48, P = 0.0002) respectively. The LCx distal segment diameter increased from 1.29 to 1.50 mm during balloon inflation in hypertensive, and from 1.44 to 1.53 mm (F = 5.03, P = 0.03) in normotensives. The diameter increase was related to the baseline ET-1 level (r = -0.67, P = 0.005) in the normotensives, but not in the hypertensives. Thus ET-1 has a weaker vasomotion effect on the coronary vasculature in hypertensives than in normotensives during PTCA.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Blood Pressure; Coronary Vessels; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged; Muscle, Smooth, Vascular; Myocardial Ischemia; Radioimmunoassay; Vasoconstriction

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

The effects of two endothelin (ET) receptor antagonists, PD 155080 (ET(A) selective) and BQ-788 (ET(B) selective), on cardiac function and ET-1 release were studied in isolated rat hearts. In normoxic hearts, infusion of PD 155080 (50 nM-5 microM) reduced coronary resistance, but had no effect on ET-1 release. Low concentrations of BQ-788 (2 and 20 nM) had no effect on coronary resistance; high concentrations (0.2 and 2 microM) increased it approximately 2-fold; all concentrations increased ET-1 release (up to 24-fold). Similar results were obtained in reperfused hearts. Although concentrations of ET-1 were higher in interstitial fluid than coronary effluent, levels never exceeded the low pg/ml range. These results indicate that (1) ET(A) receptors mediate coronary constriction, whereas ET(B) receptors bind and sequester ET-1, and (2) ET-1 displaced by ET(B) antagonist accesses ET(A) receptors resulting in coronary constriction.

Topics: Animals; Coronary Vessels; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Heart Rate; In Vitro Techniques; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Oligopeptides; Piperidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Vascular Resistance; Ventricular Function, Left

The purpose of this study was to determine the antagonistic effect of tetramethyl pyrazine (TMP), a sort of chinese herbal medicine, on coronary vasoconstriction induced by endothelin-1 (ET-1) in closed chest dogs. ET-1 at doses of 50, 75 and 100 pmol was selectively administered into left main coronary artery and coronary angiogram was performed in 1, 3 and 10 minutes after intracoronary administration of ET-1. After a 60 minute interval ET-1 administration and coronary angiogram were repeated in two groups in group A with 5 dogs intravenous infusion of saline solution was administered while in group B with 4 dogs TMP was infused at a dose of 80 mg/kg. Blood pressure of intra-femoral artery, heart rate and ECG were monitored during the experiment. The study demonstrated that coronary vessel diameter significantly decreased by 17% (P < 0.02) in group A and 20% (P < 0.02) in group B, associated with ischemia in ECG (4/5 in group A and 3/4 in group B) after intracoronary administration of ET-1. Endothelin-1 induced coronary vasoconstriction and ischemic changes in ECG were significantly inhibited by intravenous TMP. The coronary diameter increased by 20% (P < 0.03) after administration of TMP, comparing with the control group. Heart rate had an increased response to TMP. In conclusion this study demonstrated that intracoronary administration of ET-1 caused significant myocardial ischemia through coronary vasoconstriction, which was inhibited by TMP. TMP significantly dilated coronary artery.

Topics: Animals; Coronary Angiography; Coronary Vessels; Dogs; Endothelin-1; Heart Rate; Male; Myocardial Ischemia; Pyrazines; Vasoconstriction; Vasodilator Agents

Following reperfusion of ischaemic human hearts subjected to cold (4 degrees C) cardioplegia during coronary bypass surgery, there was an increase in cardiac outflow of endothelin-1 but not the pro-peptide big endothelin-1. Furthermore, specific endothelin-1 binding in human lung membrane preparations was displaced by incubation in buffer medium at 4 degrees C. The present results thus indicate that cold-induced displacement of endothelin-1 binding, rather than increased synthesis, may explain the cardiac release of endothelium-1 following ischaemia during heart surgery in which cold cardioplegia has been used.

Topics: Aged; Cold Temperature; Coronary Artery Bypass; Endothelin-1; Endothelins; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardial Reperfusion; Protein Precursors; Receptors, Endothelin

The effects of diltiazem and phosphoramidon on sudden death induced by endothelin (ET)-1 and by big ET-1 were compared in rodents. Diltiazem (2 mg/kg, i.v.) remarkably diminished the lethal toxicity of ET-1 with a reduction in the extent of the rise in plasma immunoreactive ET-1-like activity (IR-ET-1), tissue IR-ET-1 accumulation in the heart and the rise in plasma potassium concentration. In big ET-1-induced lethality, diltiazem only slightly prolonged the latency and did not reduce the mortality. Although diltiazem moderately inhibited the rise in plasma IR-ET-1 and potassium concentration in these mice, it did not affect the accumulation of IR-ET-1 in the heart, lung or kidney. Phosphoramidon (2 mg/kg, i.v.) decreased the lethality of big ET-1 with the decrement in elevation of IR-ET-1 in the heart, lung and plasma as well as with the decrease in plasma potassium concentration, but it failed to improve any parameters in ET-1-induced lethality. In anesthetized rats, ET-1 (5 nmol/kg, i.v.) elevated ST-segment of electromyocardiograms, and diltiazem (2 mg/kg, i.v.) significantly reversed this change. Big ET-1 (25 nmol/kg, i.v.) also induced the ST-segment elevation, which was significantly inhibited by phosphoramidon but not by diltiazem. These findings suggest that accumulation of ET-1 in the heart, which may lead to lethal cardiac ischemia, is an important factor in the lethality of ET-1, while additional factors (such as hemoconcentration and bronchoconstriction) may be involved in big ET-1-induced lethality.

Topics: Anesthesia; Animals; Death, Sudden, Cardiac; Diltiazem; Electrocardiography; Endothelin-1; Endothelins; Glycopeptides; Kidney; Lung; Male; Mice; Mice, Inbred ICR; Myocardial Ischemia; Myocardium; Potassium; Protease Inhibitors; Protein Precursors

The effect of endothelin-1 (ET-1) and big ET-1 on coronary flow and contractile function was determined in isolated nonischemic and ischemic rat hearts. Both ET-1 (IC50 = 12 pMol) and big ET-1 (IC50 = 2 nMol) reduced coronary flow in a concentration-dependent manner, although ET-1 was > 100-fold more potent. Both compounds decreased contractility, an effect which was lost when coronary flow was held constant, indicating that ET-1 and big ET-1 decrease contractility secondary to reducing coronary flow. Mechanical reduction in coronary flow to levels equivalent to those seen for ET-1 or big ET-1 caused similar reductions in contractility. Both 30 pMol ET-1 and 10 nMol big ET-1 pretreatment significantly reduced the time to contracture in globally ischemic rat hearts, suggesting a proischemic effect. Phosphoramidon (100 microM, endothelin-converting enzyme inhibitor) and BQ-123 (0.3 microM, ETA receptor antagonist) abolished the preischemic increase in coronary perfusion pressure induced by big ET-1 as well as its proischemic effect, whereas only BQ-123 abolished the cardiac effect of ET-1. Neither phosphoramidon nor BQ-123 had an effect on severity of ischemia when given alone. Phosphoramidon was also given i.v. to rats subjected to coronary occlusion and reperfusion and was found to significantly reduce infarct size 24 hr postischemia. Thus, in isolated rat hearts, big ET-1 appears to be converted to ET-1 and is a potent coronary constrictor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Coronary Circulation; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Glycopeptides; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Peptides, Cyclic; Protein Precursors; Rats; Rats, Sprague-Dawley