endothelin-1 and Ventricular-Fibrillation

The predominant isoform of the endothelin peptide family. endothelin-1 (ET-1) exerts various biological effects. These include effects on arterial smooth muscle cells causing intense vasoconstriction and stimulation of cardiac cells. ET-1 promotes changes in cardiomyocytes that are consistent with electrical remodelling such as changes in ionic current density and inhomogeneous prolongation of action potential duration resulting in increased dispersion. As for the underlying mechanisms, ET-1 was shown to suppress several cAMP-dependent ionic currents, such as ICa, IK and ICl in various mammalian cardiac preparations including human myocytes; however, the degree of suppression of these currents is different and highly dependent on experimental conditions. The proposed arrhythmogenic effects of ET-1 may also involve enhancement of Ca2+ release from intracellular stores, generation of IP3, and acidosis due to stimulation of the Na+/H+ exchange. Furthermore, ET-1 acts as the natural counterpart to endothelium-derived nitric oxide, which exerts vasodilator, antithrombotic and antiproliferative effects, and inhibits leukocyte adhesion to the vascular wall. Effects of ET-1 are mediated through interaction with two major types of cell surface receptors. ETA receptors have been associated with electrical remodelling, vasoconstriction and cell growth, while ETB receptors are involved in the clearance of ET-1, inhibition of endothelial apoptosis, release of NO and prostacyclins, and inhibition of the expression of ET-1 converting enzyme. The derangement of endothelial function in various cardiovascular diseases, such as cardiomyopathies, hypertension or arteriosclerosis, is a crucial element of the pathomechanism, thus ET receptors are considered as important therapeutic targets. Indeed, ET receptor antagonists may be able to preserve or restore endothelial integrity and may have antiarrhythmic properties; therefore, they are promising tools in cardiovascular medicine.

Topics: Animals; Calcium; Electric Stimulation; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Muscle, Smooth, Vascular; Myocardial Contraction; Myocytes, Cardiac; Protein Isoforms; Signal Transduction; Vasoconstriction; Ventricular Fibrillation

To determine the prognostic role of big endothelin-1 (ET-1) in left ventricular non-compaction cardiomyopathy (LVNC).. We prospectively enrolled patients whose LVNC was diagnosed by cardiac MRI and who had big ET-1 data available. Primary end point was a composite of all-cause mortality, heart transplantation, sustained ventricular tachycardia/fibrillation and implanted cardioverter defibrillator discharge. Secondary end point was cardiac death or heart transplantation.. Altogether, 203 patients (median age 44 years; 70.9% male) were divided into high-level (≥0.42 pmol/L) and low-level (<0.42 pmol/L) big ET-1 groups according to the median value of plasma big ET-1 levels. Ln big ET-1 was positively associated with Ln N-terminal pro-brain natriuretic peptide, left ventricular diameter, but negatively related to age and Ln left ventricular ejection fraction. Median follow-up was 1.9 years (IQR 0.9-3.1 years). Kaplan-Meier analysis showed that, compared with patients with low levels of big ET-1, those with high levels were at greater risk for meeting both primary (p<0.001) and secondary (p<0.001) end points. The C-statistic estimation of Ln big ET-1 for predicting the primary outcome was 0.755 (95% CI 0.685 to 0.824, p<0.001). After adjusting for confounding factors, Ln big ET-1 was identified as an independent predictor of the composite primary outcome (HR 1.83, 95% CI 1.27 to 2.62, p=0.001) and secondary outcome (HR 1.93, 95% CI 1.32 to 2.83, p=0.001).. Plasma big ET-1 may be a valuable index to predict the clinical adverse outcomes in patients with LVNC.

Topics: Adult; Biomarkers; Death, Sudden, Cardiac; Defibrillators, Implantable; Endothelin-1; Female; Heart Transplantation; Heart Ventricles; Humans; Isolated Noncompaction of the Ventricular Myocardium; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Prospective Studies; Stroke Volume; Tachycardia, Ventricular; Ventricular Fibrillation

In ST segment elevation acute myocardial infarction (STEMI), the endothelin (ET) system imbalance, reflected by the circulating ET-1:ET-3 ratio has not been investigated. This study's primary objective was to measure the circulating ET-1:ET-3 ratio and correlate it with the risk stratification for 1 year mortality of STEMI based on TIMI score. On admission, the TIMI risk score and at discharge, the dynamic TIMI risk score were calculated in 68 consecutive subjects with STEMI. Subjects with high TIMI risk score were associated with higher mean ET-1 level and ET-1:ET-3 ratio. The ET-1:ET-3 ratio more accurately predicted the high on admission TIMI risk score than the ET-1 level. Subjects with high dynamic TIMI risk score were associated with higher mean ET-1 level and ET-1:ET-3 ratio. The ET-1:ET-3 ratio more accurately predicted the high at discharge dynamic TIMI risk score than ET-1 level. From multivariable analysis, the ET-1:ET-3 ratio was not independently associated with high on admission TIMI risk score but independently predicted high at discharge dynamic TIMI risk score (odds ratio = 9.186,

Topics: Adult; Aged; Cardiotonic Agents; Electric Countershock; Electrocardiography; Endothelin-1; Endothelin-3; Female; Heart Failure; Hospital Mortality; Humans; Male; Middle Aged; Patient Admission; Patient Discharge; Percutaneous Coronary Intervention; Prognosis; Prospective Studies; Recurrence; Risk Assessment; Risk Factors; Shock, Cardiogenic; ST Elevation Myocardial Infarction; Treatment Outcome; Ventricular Fibrillation

Chronically elevated levels of endothelin-1 (ET-1) have been detected in several cardiovascular diseases. In this study, we investigated the chronic effects of ET-1 on the electrophysiological characteristics expected to influence the genesis and maintenance of ventricular arrhythmia (VA). Rabbits were randomized to ET-1 (ET-1 group) or 0.9% saline (control group) for 2 weeks. The S1-S2 protocol and S1-S1 dynamic pacing were performed to assess the action potential duration restitution (APDR) and to induce APD alternans or VA in 4 sites of Langendorff-perfused rabbit hearts. The beat-to-beat variability of repolarization was quantified as short-term variability and long-term variability. Compared with the control group, chronic ET-1 administration significantly prolonged QT intervals, APD at 90% repolarization (APD₉₀), and effective refractory period (ERP), steepened the maximum slopes of the APDR curve, decreased the ERP/APD₉₀ ratio, and increased the spatial dispersions of APD₉₀, ERP, and maximum slopes (P < 0.05 for all). Moreover, chronic ET-1 administration markedly increased the short-term variability and long-term variability (P < 0.01 for all). APD alternans occurred in both groups, but the threshold of APD alternans was decreased at all sites in the ET-1 group (P < 0.01 for all). We also observed that chronic ET-1 stimulation significantly increased the incidence and duration of the VA episodes. These results suggest that chronic stimulation with ET-1 facilitated VA by steepening the APDR curve and increasing the spatial dispersion of APDR and beat-to-beat variability of repolarization.

Topics: Action Potentials; Animals; Cardiotoxins; Disease Models, Animal; Electrophysiologic Techniques, Cardiac; Endothelin-1; Heart Rate; Heart Ventricles; Infusion Pumps; Infusions, Intravenous; Male; Perfusion; Rabbits; Random Allocation; Refractory Period, Electrophysiological; Ventricular Fibrillation

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

Lysophosphatidylcholine (LPC), which accumulates in the ischemic myocardium, is responsible for mechanical and metabolic derangements of hearts, and also contributes to the development of ventricular arrhythmias. We examined the effects of pravastatin on the LPC-induced cardiac dysfunction in isolated rat hearts. Rat hearts were randomly divided into four groups. The groups comprised a control group (n=10), a group treated with LPC (5 microM) (n=20), a group treated with pravastatin (400 ng/ml) (n=10) and a group treated with both LPC and pravastatin (n=20). Our data suggest that, pravastatin possesses some protective profiles against LPC, as manifested by better recovery of cardiac function (improvement in heart rate, left ventricular developed pressure, maximal and minimal first derivatives of left ventricular developed pressure, coronary flow and coronary resistance, less release of biomarkers of cardiac injury (lactate dehydrogenase, creatine kinase-MB and endothelin-1), and attenuation of ventricular arrhythmias (ventricular tachyarrhythmia and ventricular fibrillation).

Topics: Animals; Creatine Kinase, MB Form; Endothelin-1; Heart; Heart Ventricles; Hemodynamics; L-Lactate Dehydrogenase; Lysophosphatidylcholines; Male; Pravastatin; Rats; Rats, Sprague-Dawley; Tachycardia; Ventricular Fibrillation

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

The aim of this study was to verify whether exaggerated arrhythmogenesis is attributed to inflammatory factors actively involving an excess of reactive oxygen species (ROS), transforming growth factor (TGF)-beta and endothelin (ET). We hypothesized that CPU86017, derived from berberine, which possesses multi-channel blocking activity, could suppress inflammatory factors, resulting in inhibition of over-expression of ether-a-go-go (ERG) and an augmented incidence of ventricular fibrillation (VF) in ischaemia/reperfusion (I/R). Rats with cardiomyopathy (CMP) induced by thyroxine (0.2 mg(-1)kg(-1) s.c. daily for 10 days) were treated with propranolol (10 mgkg(-1) p.o.) or CPU86017 (80 mgkg(-1) p.o.) on days 6-10. On the 11th day, arrhythmogenesis of the CMP was evaluated by I/R. In the CMP control group, an increase in VF incidence was found with the I/R episode, accompanied by increased ROS, which manifested as an increased level of malondialdehyde and decreased activities of SOD, glutathione peroxidase and catalase in the myocardium. Levels of inducible nitric oxide synthase and TGF-beta mRNA were increased in association with upregulation of preproET-1 and ET-converting enzyme. We found increased levels of ERG, which correlated well with arrhythmogenesis. Treatment with CPU86017 or propranolol reversed these changes. These experiments verified our hypothesis that the inflammatory factors ROS, iNOS, TGF-beta and ET-1 are actively involved in upregulation of ERG and arrhythmogenesis. CPU86017 and propranolol reduced VF by suppressing these inflammatory factors in the myocardium.

Topics: Animals; Anti-Arrhythmia Agents; Antioxidants; Aspartic Acid Endopeptidases; Berberine; Cardiomegaly; Cardiomyopathies; Disease Models, Animal; Endothelin-1; Endothelin-Converting Enzymes; Ether-A-Go-Go Potassium Channels; Inflammation Mediators; Male; Metalloendopeptidases; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Propranolol; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroxine; Transforming Growth Factor beta; Up-Regulation; Ventricular Fibrillation

Dissociation of FKBP12.6 from RyR2 is considered as an important molecular event resulting in calcium leak and an increased risk in arrhythmogenesis. We hypothesized that augmented ventricular fibrillation (VF) on reperfusion of rat cardiomyopathy induced by l-thyroxin may result from elevated diastolic Ca(2+) levels due to dissociation (downregulation) of FKBP12.6 and upregulation of endothelin (ET-1) signaling pathway.. Rats were treated with l-thyroxin (0.4 mg/kg, s.c.) for 10 days. Dajisentan (CPU0213), a dual endothelin receptor antagonist (100 mg/kg p.o.), or propranolol was administered on day 6 to 10. Susceptibility to VF was evaluated on ischemia/reperfusion episode. mRNA expression of FKBP12.6, and ET-1 levels were determined. Calcium transients and FKBP12.6 immunohistochemistry were measured by confocal microscopy in isolated cardiomyocytes from cardiomyopathy.. Cardiomyopathy induced by l-thyroxin resulted in an increased susceptibility to VF on ischemia/reperfusion. Upregulated mRNA expression of RyR2 and PKA in association with downregulated FKBP12.6 expression was found in l-thyroxin-treated rats compared to controls. Calcium transients evoked by field electrical stimulation showed an increase in Ca(2+) by +75% during diastole. An increase in ET-1 (ng/mg protein) (+36.6%) and mRNA abundance of preproET-1 were found in the left ventricle. A decreased mRNA ratio of FKBP12.6 to RyR2 likely reflected dissociation of FKBP12.6 in cardiomyopathy. These changes were normalized by Dajisentan, comparable to propranolol.. Increased susceptibility to VF in l-thyroxin-induced cardiomyopathy is related to increase in diastolic Ca(2+) levels, resulting from downregulated FKBP12.6 and upregulated ET system. ET antagonism might be useful in settings of FKBP12.6 dissociation.

Topics: Animals; Calcium; Cardiomyopathy, Hypertrophic; Diastole; Disease Models, Animal; Down-Regulation; Endothelin-1; Male; Rats; Rats, Sprague-Dawley; Risk Factors; RNA, Messenger; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Tacrolimus Binding Proteins; Thyroxine; Up-Regulation; Ventricular Fibrillation

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

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

Topics: Animals; Arrhythmias, Cardiac; Endothelin-1; Guinea Pigs; In Vitro Techniques; Male; Myocardial Reperfusion; Norepinephrine; Ventricular Fibrillation

We evaluated the protective effects of retrograde coronary sinus perfusion to offset potential systolic and diastolic dysfunction (myocardial stunning) after temporary regional ischemia needed for off-pump coronary artery bypass grafting.. Twenty Yorkshire-Duroc pigs (31.8 +/- 3.9 kg) underwent 15 minutes of mid-left anterior descending coronary artery ischemia in the beating heart. In 8 pigs, no protective measures were used. In 12 pigs, an aorta-coronary sinus shunt (with conventional cannulas) allowed retrograde perfusion during temporary ischemia; in 6 of these pigs, no leakage to the right atrium was ensured. Regional endocardial contraction was measured with sonomicrometer crystals. Systolic dysfunction (impaired regional shortening), diastolic dysfunction (contraction extending into early diastole), and coronary sinus nitric oxide and endothelin-1 levels were recorded.. Before ischemia, contraction did not extend into the diastolic interval. During ischemia, paradoxic bulging occurred in all hearts except in the occlusive coronary sinus shunt group (16% +/- 6% of baseline, P <.01). Sixty minutes after ischemia, systolic segment shortening recovered 36% +/- 24% without retrograde perfusion versus 56% +/- 20% and 61% +/- 14% with coronary sinus shunting (P <.05). Diastolic dysfunction (as percentage of diastolic time in contraction) was 38% +/- 16% in the nontreated group versus 22% +/- 22% and 9% +/- 9% (P <.05) after shunting and occlusive shunting, respectively. This correlated with a left ventricular end-diastolic pressure increase of 4 mm Hg in the ischemic group versus no change in the retrograde perfusion groups. Nitric oxide decreased 15% without shunting and increased 8% after occlusive coronary sinus shunting (P <.05).. Retrograde coronary sinus perfusion during simulated off-pump coronary revascularization diminishes systolic and diastolic dysfunction. An aortic-coronary sinus shunt is a rapid, recognized approach that can improve myocardial muscle and endothelial safety during off-pump coronary artery bypass grafting.

Topics: Animals; Biomarkers; Blood Pressure; Coronary Artery Bypass; Coronary Artery Disease; Coronary Circulation; Creatine Kinase; Creatine Kinase, MB Form; Disease Models, Animal; Endothelin-1; Female; Infusion Pumps, Implantable; Isoenzymes; Male; Models, Cardiovascular; Myocardial Contraction; Myocardial Reperfusion; Nitric Oxide; Postoperative Complications; Stroke Volume; Swine; Ventricular Fibrillation

Endothelin-1 secretion and sympathetic activation may play important role in cardiovascular pathophysiology. In vivo interactions between these systems are not defined. We aimed to study the electrophysiological and haemodynamic effects of simultaneous intracoronary endothelin-1 and intravenous isoproterenol infusions. 18 anaesthetised open chest dogs were studied after AV-ablation. Mean arterial blood pressure, coronary blood flow, left ventricular contractility, standard electrocardiograms, right and left ventricular epi- and endocardial monophasic action potential (MAP) signals were recorded. Intracoronary endothelin-1 (30 pmol/min) was given to Group ET (n=6), intravenous isoproterenol (0.2 microg/kg/min) to Group ISO (n=6), both endothelin-1 and isoproterenol to Group ET+ISO (n=6) for 30 min. MAP duration increased in all studied regions of Group ET, decreased in all studied regions of Group ISO and ET+ISO (control vs. maximal changes of left ventricular epicardial MAP 90% duration, Group ET: 296+/-22 vs 369+/-20 ms, p<0.05, Group ISO: 298+/-18 vs 230+/-27 ms, p<0.01, Group ET+ISO: 302+/-18 vs 231+/-10 ms, p<0.01). In Group ET, early after depolarisations (3/6), polymorphic non-sustained ventricular tachycardias (6/6), and ventricular fibrillation (3/6) could be observed. In Group ISO, monomorphic non-sustained ventricular tachycardias (5/6) and atrial fibrillation (3/6) appeared. In Group ET+ISO, mono- and polymorphic non-sustained ventricular tachycardias occurred (5/6), neither ventricular fibrillation nor atrial fibrillation developed. An additive effect of endothelin-1 and isoproterenol on left ventricular contractility was observed. Isoproterenol treatment showed antagonistic effect against endothelin-1 induced MAP duration prolongation, early after depolarisation and ventricular fibrillation formation, while endothelin-1 showed protective effect against the development of isoproterenol induced atrial fibrillation.

Topics: Action Potentials; Adrenergic beta-Agonists; Animals; Atrial Fibrillation; Blood Pressure; Coronary Circulation; Coronary Vessels; Dogs; Drug Antagonism; Drug Therapy, Combination; Electrocardiography; Endothelin-1; Heart Ventricles; Hemodynamics; Infusions, Intra-Arterial; Infusions, Intravenous; Isoproterenol; Ventricular Fibrillation; Ventricular Function, Left

In this study, we evaluated whether median fibrillation frequency (MF) and mean fibrillation amplitude (AMP) reflect coronary perfusion pressure (CoPP) and predict successful defibrillation. MF, AMP, and CoPP were measured during prolonged ventricular fibrillation (VF) cardiac arrest and resuscitation in pigs. After 5 min of VF, cardiopulmonary resuscitation was started. At 10 min, the pigs received randomly a single dose of endothelin-1 50 mug (n = 7), 100 mug (n = 7), or 200 mug (n = 5), or repeated doses of epinephrine 0.04 mg/kg (n = 6), or saline (n = 6) every 3 min. At 25 min, the pigs were defibrillated to achieve restoration of spontaneous circulation (ROSC). In a nonparametric spectral analysis of the individual MF versus CoPP and AMP versus CoPP curves, we found no link between the different curves in different animals or therapies. No difference was found in MF in pigs with ROSC (n = 8) compared with animals not achieving ROSC (n = 23) immediately before defibrillation (P = 0.85). Our data suggest that, in prolonged VF cardiac arrest, MF and AMP might not be useful tools to reflect myocardial perfusion.

Topics: Adrenergic alpha-Agonists; Animals; Cardiopulmonary Resuscitation; Coronary Circulation; Electric Countershock; Electrocardiography; Endothelin-1; Epinephrine; Female; Heart Arrest; Male; Monitoring, Physiologic; Respiration, Artificial; Swine; Ventricular Fibrillation

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

Endothelin-1 (ET-1) is known to have a direct arrhythmogenic effect in the mammalian heart. Diabetes mellitus is accompanied by a series of endothelial and cardiac disfunctions; however, little is known about ET-1-induced direct arrhythmias in diabetes mellitus. Therefore, we infused ET-1 (33 pmol/min) into the left anterior descending coronary artery of 28 mongrel dogs, and measured basic hemodynamic parameters, coronary flow and an electrocardiogram. Diabetes mellitus was induced by alloxan (Group 4) and experiments were carried out 8 weeks later. Metabolically healthy dogs served as controls (Group 2). In a further control group, local hyperglycemia was induced by intracoronary glucose infusion (Group 3). ET-1 infusion induced prolongation of the QT-time and frequency-adjusted QT-time in all groups. Other electrophysiological parameters were comparable between the groups. This was followed by the occurence of ventricular premature beats, coupled extra-beats and later sustained ventricular tachycardia. Most of the experiments were terminated by ventricular fibrillation. The onset of arrhythmias was shorter in diabetic dogs as compared with control and locally hyperglycemic animals (18 +/- 8 minutes versus 24 +/- 8 minutes and 30 +/- 28 minutes, P < 0.05). However, there was no difference in the number of ventricular fibrillations, and the total elapsed time until the termination of the experiments. Therefore, the diabetic heart seems to be more prone to ET-1-induced arrhythmias and this is probably not a result of locally high glucose concentrations.

Topics: Animals; Blood Pressure; Coronary Circulation; Diabetes Mellitus, Experimental; Dogs; Electrocardiography; Endothelin-1; Glucose; Heart Rate; Hemodynamics; Infusions, Parenteral; Risk Factors; Tachycardia, Ventricular; Time Factors; Ventricular Fibrillation; Ventricular Premature Complexes

Endothelin-1 (ET-1) is a potent endogenous arrhythmogenic substance. The aim of our study was to investigate the changes of serum ET-1 and big-endothelin levels in patients suffering from spontaneous, incessant ventricular tachyarrhythmias. The 11 consecutive patients' (mean age, 59 +/- 11 years) underlying diseases were ischemic heart disease, valvular heart disease, dilated cardiomyopathy, primary electrical disease, and arrhythmogenic right ventricular dysplasia in five cases, three cases, one case, one case, and one case, respectively. The mean ejection fraction was 39 +/- 14%, New York Heart Association functional status was I, II, and III in two cases, four cases, and five cases, respectively. Ventricular tachycardias (VT) were detected in five patients, ventricular fibrillation (VF) in three patients, and VT + VF in three patients. VTs terminated spontaneously in two cases. Six patients required multiple external cardioversion/defibrillation shocks, while implantable cardioverter defibrillators terminated all sustained arrhythmias successfully in four cases. Blood samples were collected during arrhythmias and 24 hours (control) following the last VT/VF episode. Serum ET-1 and big-endothelin levels were measured with western blot analysis after immunoprecipitation. Serum ET-1 and big-endothelin levels were significantly higher during the last VT/VF compared with the control period (ET-1, 65.8 +/- 26.8 fmol/mL versus 53.9 +/- 22.3 fmol/mL, P < 0.05; big-endothelin, 115.2 +/- 39.3 fmol/mL versus 89.2 +/- 25.1 fmol/mL, P < 0.05). There was a negative correlation between the age and big-endothelin level measured at both times (during VT/VF, r = 0.94, P < 0.05; control, r = 0.91, P < 0.05). In conclusion, serum big-endothelin and ET-1 levels were significantly higher during incessant VT/VF, which can be a cause of multiple arrhythmia recurrence.

Topics: Adult; Aged; Defibrillators, Implantable; Electric Countershock; Endothelin-1; Female; Humans; Male; Middle Aged; Protein Precursors; Recurrence; Severity of Illness Index; Stroke Volume; Tachycardia, Ventricular; Treatment Outcome; Up-Regulation; Ventricular Fibrillation

Topics: Animals; Brain; Cardiopulmonary Resuscitation; Cerebrovascular Circulation; Combined Modality Therapy; Disease Models, Animal; Endothelin-1; Epinephrine; Heart Arrest; Infusions, Intravenous; Reference Values; Sensitivity and Specificity; Swine; Ventricular Fibrillation

Since adrenaline (epinephrine) also has negative effects during and after cardiopulmonary resuscitation (CPR) a non-adrenergic vasoconstrictor like endothelin might be an alternative to increase vital organ blood flow. We studied the effect of different doses of endothelin-1 compared with adrenaline on the ability to resuscitate, cerebral and myocardial blood flow (MBF) in a closed chest cardiac arrest pig model. After 5 min of ventricular fibrillation, CPR with a ventilator and a mechanical compression device was started. At 10 min, 31 pigs were randomized to receive a single dose of endothelin-1 50, 100 or 200 microg or repeated doses of adrenaline 0.04 mg kg(-1) or saline every 3 min. After 25 min, the pigs were defibrillated to achieve restoration of spontaneous circulation. Blood flow was measured with the fluorescent microsphere method. In animals receiving endothelin-1 50, 100 and 200 microg the cerebral blood flow (CBF) increased from median 28 (25th; 75th quartile: 16; 40), 32 (15; 48) and 17 (4; 65) to 36 (31; 54), 47 (39; 57) and 63 (35; 83) ml min(-1) per 100 g, respectively, 6 min after drug administration (P<0.05 endothelin-1 50 microg vs. Control, P<0.01 endothelin-1 100 and 200 microg vs. Control). At the same time CBF decreased in the control and adrenaline group from 36 (21; 41) and 39 (15; 50) to 12 (2; 25) and 24 (15; 26) ml min(-1) per 100 g, respectively, (P<0.05 adrenaline vs. endothelin-1 200 microg). There was no difference in MBF between the treatment groups despite a higher coronary perfusion pressure (CoPP) in the endothelin-1 groups. Restoration of spontaneous circulation could be only achieved in the endothelin-1 50 microg (3 of 7; 43%) and 100 microg (5 of 7; 71%) group. This study suggests that endothelin-1 enhances CBF during CPR better than adrenaline and increases resuscitation success.

Topics: Animals; Blood Pressure; Brain; Cardiopulmonary Resuscitation; Coronary Circulation; Double Bind Interaction; Endothelin-1; Epinephrine; Heart Arrest; Prospective Studies; Random Allocation; Regional Blood Flow; Swine; Vasoconstrictor Agents; Ventricular Fibrillation

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

Vasoconstriction during cardiopulmonary resuscitation (CPR) improves coronary perfusion pressure (CPP) and thereby outcome. The combination of endothelin-1 (ET-1) plus epinephrine improved CPP during CPR compared with epinephrine alone in a canine cardiac arrest model. The effect of the combination on outcome variables, such as successful resuscitation and survival, has not been investigated.. Twenty-seven swine were randomly provided with 1 mg epinephrine (Epi group) or 1 mg epinephrine plus 0.1 mg ET-1 (ET-1 group) during a prolonged ventricular fibrillatory cardiac arrest. ET-1 resulted in substantially superior aortic relaxation pressure and CPP during CPR. These hemodynamic improvements tended to increase initial rates of restoration of spontaneous circulation (8 of 10 versus 8 of 17, P=0.12). However, continued intense vasoconstriction from ET-1 led to higher aortic diastolic pressure and very narrow pulse pressure after resuscitation. The mean pulse pressure 1 hour after resuscitation was 7+/-8 mm Hg with ET-1 versus 24+/-1 mm Hg with Epi, P<0.01. Most importantly, the postresuscitation mortality was dramatically higher in the ET-1 group (6 of 8 versus 0 of 8 in the Epi group, P<0.01).. These data establish that administration of ET-1 during CPR can result in worse postresuscitation outcome. The intense vasoconstriction from ET-1 improved CPP during CPR but had detrimental effects in the postresuscitation period.

Topics: Animals; Cardiopulmonary Resuscitation; Endothelin-1; Epinephrine; Heart Arrest; Hemodynamics; Swine; Treatment Failure; Vasoconstrictor Agents; Ventricular Fibrillation

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

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

Premature ventricular contraction (PVC), ventricular tachycardia (VT) and ventricular fibrillation (VF) were developed by endothelin-1 (ET-1) injected into the coronary ostia at the dose of 900 pmol/kg in anesthetized rats. No arrhythmia was elicited but blood pressure fell temporarily by calcitonin gene related peptide (CGRP), the injection into the coronary ostia. After pretreatment with CGRP incidence and severity of arrhythmia decreased at the same ET-1 dose. Arrhythmia score in CGRP 1200 pmol/kg + ET-1 group was lower than that in ET-1 group (P < 0.01). The results revealed that antiarrhythmic effect of CGRP may be partially brought about by its antagonistic effect against ET-1 induced arrhythmia.

Topics: Animals; Anti-Arrhythmia Agents; Calcitonin Gene-Related Peptide; Cardiac Complexes, Premature; Endothelin-1; Male; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Ventricular Fibrillation