endothelin-1 and Arrhythmias--Cardiac

Fibrotic diseases are a significant global burden for which there are limited treatment options. The effector cells of fibrosis are activated fibroblasts called myofibroblasts, a highly contractile cell type characterized by the appearance of α-smooth muscle actin stress fibers. The underlying mechanism behind myofibroblast differentiation and persistence has been under much investigation and is known to involve a complex signaling network involving transforming growth factor-β, endothelin-1, angiotensin II, CCN2 (connective tissue growth factor), and platelet-derived growth factor. This review addresses the contribution of these signaling molecules to cardiac fibrosis.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Inflammatory Agents; Arrhythmias, Cardiac; Atrophy; Cicatrix; Connective Tissue Growth Factor; Endothelin Receptor Antagonists; Endothelin-1; Fibrosis; Humans; Hypoxia; Models, Cardiovascular; Molecular Targeted Therapy; Myocardium; Myofibroblasts; Platelet-Derived Growth Factor; Pyridones; Rats; Signal Transduction; Transforming Growth Factor beta

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 heartbeat is initiated and coordinated by a heterogeneous set of tissues, collectively referred to as the pacemaking and conduction system (PCS). While the structural and physiological properties of these specialized tissues has been studied for more than a century, distinct new insights have emerged in recent years. The tools of molecular biology and the lessons of modern embryology are beginning to uncover the mechanisms governing induction, patterning and developmental integration of the PCS. In particular, significant advances have been made in understanding the developmental biology of the fast conduction network in the ventricles--the His-Purkinje system. Although this progress has largely been made by using animal models such as the chick and mouse, the insights gained may help explain cardiac disease in humans, as well as lead to new treatment strategies.

Topics: Animals; Arrhythmias, Cardiac; Calcium Signaling; Chick Embryo; Endothelin-1; Endothelium; Fetal Proteins; Gestational Age; Heart; Heart Conduction System; Humans; Mice; Mice, Knockout; Morphogenesis; Myocardial Contraction; Myocardium; Purkinje Fibers; Rats

Endothelin-1 (ET-1), the member of a newly discovered family of vasoactive peptides is the most aggressive endogenous vasoconstrictor agent known to science. This paper summarizes the recent work of a Hungarian research group related to the regulatory role of ET-1 in the mammalian heart. The results highlighted the unique pathophysiological and clinical features of the ET-1 action in the coronary vascular bed suggesting the potential role of the peptide in precipitating coronary spasm as well as its outstanding capacity for inducing cardiac arrhythmias. Contrary to the classical tenets of homeostasis, such effects do not reduce but increase variability and inhomogeneity (both in myocardial blood flow distribution and generation of electrical impulses), indicating the involvement of new types of regulatory principles in the cardiovascular system.

Topics: Arrhythmias, Cardiac; Coronary Disease; Endothelin-1; Heart; Humans

Patients with congestive heart failure (CHF) have a high incidence of ventricular arrhythmias and sudden arrhythmic death. CHF entails profound and complex abnormalities in humoral responses that are thought to promote arrhythmic events. However, it is unknown which of the many endogenous mediators that accumulate as part of neurohormonal activation is important in arrhythmogenesis in the setting of CHF. The study included 83 patients admitted to the hospital for treatment of decompensated CHF. Neurohormonal and cytokine activation was assessed by measuring plasma renin activity, aldosterone, norepinephrine, endothelin-1, tumor necrosis factor-alpha, and interleukin-6 levels. Atrial and ventricular arrhythmic events were assessed by 24-hour Holter monitoring. In a univariate analysis, a highly significant, positive relationship was found between plasma endothelin-1 levels and the average hourly total premature ventricular beats (P = 0.003), the frequency of ventricular pairs (P = 0.0003), and the frequency of ventricular tachycardia episodes (P = 0.001). After inclusion of clinical variables, drug therapies, neurohormones, and cytokine levels in a multivariate analysis, the positive relationship between plasma endothelin-1 level and the average hourly total premature ventricular beats (P = 0.008), the frequency of ventricular pairs (P = 0.007), and ventricular tachycardia episodes (P = 0.009) remained independent. No association between other neurohormones or cytokines and arrhythmic events was demonstrated. The results of the present study suggest that increased endothelin-1 concentrations may be involved in promoting the occurrence of ventricular ectopy in patients with decompensated CHF. Proarrhythmic effects may account, in part, for the poor outcome associated with increased endothelin-1 levels in patients with decompensated CHF.

Topics: Arrhythmias, Cardiac; Cardiotonic Agents; Cytokines; Dobutamine; Electrocardiography, Ambulatory; Endothelin-1; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Agents; Natriuretic Peptide, Brain; Neurotransmitter Agents; Ventricular Premature Complexes

Atrial arrhythmias are considered prominent phenomena in pulmonary arterial hypertension (PAH) resulting from atrial electrical and structural remodeling. Endothelin (ET)-1 levels correlate with PAH severity and are associated with atrial remodeling and arrhythmia. In this study, hemodynamic measurement, western blot analysis, and histopathology were performed in the control and monocrotaline (MCT, 60 mg/kg)-induced PAH rabbits. Conventional microelectrodes were used to simultaneously record the electrical activity in the isolated sinoatrial node (SAN) and right atrium (RA) tissue preparations before and after ET-1 (10 nM) or BQ-485 (an ET-A receptor antagonist, 100 nM) perfusion. MCT-treated rabbits showed an increased relative wall thickness in the pulmonary arterioles, mean cell width, cross-sectional area of RV myocytes, and higher right ventricular systolic pressure, which were deemed to have PAH. Compared to the control, the spontaneous beating rate of SAN-RA preparations was faster in the MCT-induced PAH group, which can be slowed down by ET-1. MCT-induced PAH rabbits had a higher incidence of sinoatrial conduction blocks, and ET-1 can induce atrial premature beats or short runs of intra-atrial reentrant tachycardia. BQ 485 administration can mitigate ET-1-induced RA arrhythmogenesis in MCT-induced PAH. The RA specimens from MCT-induced PAH rabbits had a smaller connexin 43 and larger ROCK1 and phosphorylated Akt than the control, and similar PKG and Akt to the control. In conclusion, ET-1 acts as a trigger factor to interact with the arrhythmogenic substrate to initiate and maintain atrial arrhythmias in PAH. ET-1/ET-A receptor/ROCK signaling may be a target for therapeutic interventions to treat PAH-induced atrial arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Connexin 43; Disease Models, Animal; Endothelin-1; Familial Primary Pulmonary Hypertension; Monocrotaline; Proto-Oncogene Proteins c-akt; Pulmonary Arterial Hypertension; Pulmonary Artery; Rabbits

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

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

Ventricular arrhythmia (VA) is a major component of sudden cardiac death (SCD). To investigate the expression of brain natriuretic peptide (BNP), endothelin-1 (ET-1), and transforming growth factor-beta 1 (TGF-β1) during VA, we established a rat model of VA induced by BaCl

Topics: Animals; Arrhythmias, Cardiac; Benzamides; Death, Sudden, Cardiac; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression; Male; Myocardium; Natriuretic Peptide, Brain; Oligopeptides; Rats, Sprague-Dawley; Receptors, Endothelin; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta1

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

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

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

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

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

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

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

Inositol 1,4,5-trisphosphate (IP(3)) is a second messenger that regulates intracellular Ca(2+) release through IP(3) receptors located in the sarco(endo)plasmic reticulum of cardiac myocytes. Many prohypertrophic G protein-coupled receptor (GPCR) signaling events lead to IP(3) liberation, although its importance in transducing the hypertrophic response has not been established in vivo.. Here, we generated conditional, heart-specific transgenic mice with both gain- and loss-of-function for IP(3) receptor signaling to examine its hypertrophic growth effects following pathological and physiological stimulation.. Overexpression of the mouse type-2 IP(3) receptor (IP(3)R2) in the heart generated mild baseline cardiac hypertrophy at 3 months of age. Isolated myocytes from overexpressing lines showed increased Ca(2+) transients and arrhythmias in response to endothelin-1 stimulation. Although low levels of IP(3)R2 overexpression failed to augment/synergize cardiac hypertrophy following 2 weeks of pressure-overload stimulation, such levels did enhance hypertrophy following 2 weeks of isoproterenol infusion, in response to Galphaq overexpression, and/or in response to exercise stimulation. To inhibit IP(3) signaling in vivo, we generated transgenic mice expressing an IP(3) chelating protein (IP(3)-sponge). IP(3)-sponge transgenic mice abrogated cardiac hypertrophy in response to isoproterenol and angiotensin II infusion but not pressure-overload stimulation. Mechanistically, IP(3)R2-enhanced cardiac hypertrophy following isoproterenol infusion was significantly reduced in the calcineurin-Abeta-null background.. These results indicate that IP(3)-mediated Ca(2+) release plays a central role in regulating cardiac hypertrophy downstream of GPCR signaling, in part, through a calcineurin-dependent mechanism.

Topics: Age Factors; Angiotensin II; Animals; Arrhythmias, Cardiac; Calcineurin; Calcium Signaling; Cardiomegaly; Disease Models, Animal; Endothelin-1; GTP-Binding Protein alpha Subunits, Gq-G11; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Isoproterenol; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myocytes, Cardiac; Phenotype; Physical Exertion

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

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

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

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

Endothelin-1 has important cardiovascular effects and is activated during atrial fibrillation. Pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. The aim of this study was to evaluate whether endothelin-1 affects PV arrhythmogenic activity.. Conventional microelectrodes were used to record the action potentials (APs) and contractility in isolated rabbit PV tissue specimens before and after the administration of endothelin-1 (0.1, 1, 10 nM). The ionic currents of isolated PV cardiomyocytes were investigated before and after the administration of endothelin-1 (10 nM) through whole-cell patch clamps.. In the tissue preparation, endothelin-1 (1, 10 nM) concentration dependently shortened the AP duration and decreased the PV firing rates. Endothelin-1 (10 nM) decreased the resting membrane potential. Endothelin-1 (0.1, 1, 10 nM) decreased the contractility and increased the resting diastolic tension. In single PV cardiomyocytes, endothelin-1 (10 nM) decreased the PV firing rates from 2.7 +/- 1.0 Hz to 0.8 +/- 0.5 Hz (n = 16). BQ-485 (100 microM, endothelin-1 type A receptor blocker) reversed and prevented the chrono-inhibitory effects of endothelin-1 (10 nM). Endothelin-1 (10 nM) reduced the L-type calcium currents, transient outward currents, delayed rectifier currents, transient inward currents, and sodium-calcium exchanger currents in the PV cardiomyocytes with and without pacemaker activity. Endothelin-1 (10 nM) increased the inward rectifier potassium current, hyperpolarization-induced pacemaker current, and the sustained outward potassium current in PV cardiomyocytes with and without pacemaker activity.. Endothelin-1 may have an antiarrhythmic potential through its direct electrophysiological effects on the PV cardiomyocytes and its action on multiple ionic currents.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Biological Clocks; Dose-Response Relationship, Drug; Endothelin-1; Heart Conduction System; In Vitro Techniques; Pulmonary Veins; Rabbits

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

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

Endothelin-1 (ET-1) is elevated in patients with atrial fibrillation (AF) and heart failure. We investigated effects of ET-1 on human atrial cellular electrophysiological measurements expected to influence the genesis and maintenance of AF. Action potential characteristics and L-type Ca(2+) current (I(CaL)) were recorded by whole cell patch clamp, in atrial isolated myocytes obtained from patients in sinus rhythm. Isoproterenol (ISO) at 0.05 muM prolonged the action potential duration at 50% repolarisation (APD(50): 54 +/- 10 vs. 28 +/- 5 ms; P < 0.05, N = 15 cells, 10 patients), but neither late repolarisation nor cellular effective refractory period (ERP) were affected. ET-1 (10 nM) reversed the effect of ISO on APD(50), and had no basal effect (in the absence of ISO) on repolarisation or ERP. During repetitive stimulation, ISO (0.05 microM) produced arrhythmic depolarisations (P < 0.05). Each was abolished by ET-1 at 10 nM (P < 0.05). ISO (0.05 microM) increased peak I(CaL) from -5.5 +/- 0.4 to -14.6 +/- 0.9 pA/pF (P < 0.05; N = 79 cells, 34 patients). ET-1 (10 nM) reversed this effect by 98 +/- 10% (P < 0.05), with no effect on basal I(CaL). Chronic treatment of patients with a beta-blocker did not significantly alter basal APD(50) or I(CaL), the increase in APD(50) or I(CaL) by 0.05 microM ISO, nor the subsequent reversal of this effect on APD(50) by 10 nM ET-1. The marked anti-adrenergic effects of ET-1 on human atrial cellular action potential plateau, arrhythmic depolarisations and I(CaL), without affecting ERP and independently of beta-blocker treatment, may be expected to contribute a potentially anti-arrhythmic influence in the atria of patients with AF and heart failure.

Topics: Action Potentials; Adrenergic beta-Antagonists; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Calcium Channels; Endothelin-1; Endothelins; Female; Heart Atria; Humans; Isoproterenol; Male; Middle Aged

Endothelin (ET)-1(1-21) is known to play an important role in the pathogenesis of acute ischemic arrhythmia. In the present study, we attempted to determine whether administration of ET-1(1-31) would result in arrhythmia in perfused isolated rat hearts. Forty-eight Sprague-Dawley rats weighing approximately 250-350 g were randomized into 6 groups. Heart was isolated and perfused in a Langendorff mode. The effects of ET-1(1-31) on arrhythmia, heart rate, coronary flow, and heart function were analyzed. Perfusion with 1 nM ET-1(1-31) resulted in frequent ventricular ectopic beats (VEBs) and ventricular tachycardia (VT). Overall VEB was 128.0 (approximately 66.0-1015.0), and the arrhythmia score (AS) was 2.18 +/- 0.87; both were significantly higher than those of the control group (P < 0.01). Pretreatment with perfusion of 10 nM of the ETA-receptor antagonist BQ(123) markedly attenuated the occurrence of VEB and VT induced by ET-1(1-31). AS in 10 nM BQ123 group was significantly lower than that in 1 nM ET-1(1-31) group (P < 0.01). The arrhythmia induced by 1 nM ET-1(1-31) was partially but significantly reduced by phosphoramidon (1 microM), a neutral endopeptidase/ET-converting enzyme inhibitor. ET-1(1-31) per se caused arrhythmia in perfused isolated rat hearts. This arrhythmogenic action is in part mediated by ET(A) receptor and may be attributed mainly to the conversion of ET-1(1-31) to ET-1(1-21.).

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Endothelin-1; Glycopeptides; In Vitro Techniques; Male; Peptides, Cyclic; Perfusion; Protease Inhibitors; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Endothelin

Although ventricular cardiomyocytes express inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptors, it is unclear how these Ca2+ channels contribute to the effects of Gq-coupled agonists. Endothelin-1 augmented the amplitude of pacing-evoked Ca2+ signals (positive inotropy), and caused an increasing frequency of spontaneous diastolic Ca2+-release transients. Both effects of endothelin-1 were blocked by an antagonist of phospholipase C, suggesting that Ins(1,4,5)P3 and/or diacylglycerol production was necessary. The endothelin-1-mediated spontaneous Ca2+ transients were abolished by application of 2-aminoethoxydiphenyl borate (2-APB), an antagonist of Ins(1,4,5)P3 receptors. Incubation of electrically-paced ventricular myocytes with a membrane-permeant Ins(1,4,5)P3 ester provoked the occurrence of spontaneous diastolic Ca2+ transients with the same characteristics and sensitivity to 2-APB as the events stimulated by endothelin-1. In addition to evoking spontaneous Ca2+ transients, stimulation of ventricular myocytes with the Ins(1,4,5)P3 ester caused a positive inotropic effect. The effects of endothelin-1 were compared with two other stimuli, isoproterenol and digoxin, which are known to induce inotropy and spontaneous Ca2+ transients by overloading intracellular Ca2+ stores. The events evoked by isoproterenol and digoxin were dissimilar from those triggered by endothelin-1 in several ways. We propose that Ins(1,4,5)P3 receptors support the development of both inotropy and spontaneous pro-arrhythmic Ca2+ signals in ventricular myocytes stimulated with a Gq-coupled agonist.

Topics: Animals; Arrhythmias, Cardiac; Boron Compounds; Calcium; Calcium Channels; Calcium Signaling; Digoxin; Endothelin-1; Heart Ventricles; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Isoproterenol; Myocytes, Cardiac; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Type C Phospholipases

Recent studies have suggested that inositol-1,4,5-trisphosphate-receptor (IP3R)-mediated Ca2+ release plays an important role in the modulation of excitation-contraction coupling (ECC) in atrial tissue and the generation of arrhythmias, specifically chronic atrial fibrillation (AF). IP3R type-2 (IP3R2) is the predominant IP3R isoform expressed in atrial myocytes. To determine the role of IP3R2 in atrial arrhythmogenesis and ECC, we generated IP3R2-deficient mice. Our results revealed that endothelin-1 (ET-1) stimulation of wild-type (WT) atrial myocytes caused an increase in basal [Ca2+]i, an enhancement of action potential (AP)-induced [Ca2+]i transients, an improvement of the efficacy of ECC (increased fractional SR Ca2+ release), and the occurrence of spontaneous arrhythmogenic Ca2+ release events as the result of activation of IP3R-dependent Ca2+ release. In contrast, ET-1 did not alter diastolic [Ca2+]i or cause spontaneous Ca2+ release events in IP3R2-deficient atrial myocytes. Under basal conditions the spatio-temporal properties (amplitude, rise-time, decay kinetics, and spatial spread) of [Ca2+]i transients and fractional SR Ca2+ release were not different in WT and IP3R2-deficient atrial myocytes. WT and IP3R2-deficient atrial myocytes also showed a significant and very similar increase in the amplitude of AP-dependent [Ca2+]i transients and Ca2+ spark frequency in response to isoproterenol stimulation, suggesting that both cell types maintained a strong inotropic reserve. No compensatory changes in Ca2+ regulatory protein expression (IP3R1, IP3R3, RyR2, NCX, SERCA2) or morphology of the atria could be detected between WT and IP3R2-deficient mice. These results show that lack of IP3R2 abolishes the positive inotropic effect of neurohumoral stimulation with ET-1 and protects from its arrhythmogenic effects.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium Channels; Calcium Signaling; Endothelin-1; Heart Atria; Inositol 1,4,5-Trisphosphate Receptors; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Contraction; Myocytes, Cardiac; Receptors, Cytoplasmic and Nuclear; Sarcoplasmic Reticulum

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

Plasma levels of endothelin-1 (ET-1) increase after coronary angioplasty (PTCA) due to endothelial injury during the procedure. ET-1 has been found in human endocardial and myocardial cells. It is not known whether ET-1 increases after thermal injury induced by radiofrequency catheter ablation (RFA).. We determined plasma ET-1 levels at baseline, immediately after, and at 2 and 6 h post-procedure in 31 patients undergoing PTCA and 16 patients undergoing RFA. Patients subjected to diagnostic coronary angiography (n=15) or electrophysiology study (n=13) served as controls.. Compared to baseline, ET-1 levels increased significantly immediately post-PTCA (55.1+/-20.1 vs. 42.7+/-14.9 pg/ml, p<0.01) and at 2 h post-RFA (98.0+/-11.7 vs. 53.0+/-17.4 pg/ml, p<0.01) and returned to baseline measurements at 2 h post-PTCA and 6 h post-RFA. There was no change of ET-1 levels in the control groups. ET-1 kinetics curve was significantly higher post-RFA compared to post-PTCA (p<0.001). ET-1 immediately post-PTCA correlated with total pressure-time product applied for balloon inflation during the procedure (r=0.56, p<0.01). There was no correlation between ET-1 levels and the number of RFA applications. No patient developed ischemia post-PTCA. There were no complications or arrhythmia recurrences post-RFA.. Endocardial thermal injury incurred during RFA is another mechanism of endothelin increase apart from mechanical injury of the coronary endothelium during PTCA and represents further evidence for the existence of the peptide in human endocardial endothelial and myocardial cells. ET-1 increase is delayed and more pronounced post-RFA compared to post-PTCA. Despite that, it does not seem to have any clinical impact in the immediate post-RFA period.

Topics: Arrhythmias, Cardiac; Biomarkers; Catheter Ablation; Coronary Angiography; Coronary Disease; Electrocardiography; Endocardium; Endothelin-1; Female; Follow-Up Studies; Humans; Male; Middle Aged; Postoperative Period; Severity of Illness Index; Treatment Outcome

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

Inositol-1,4,5-trisphosphate (IP(3))-dependent Ca(2+) release represents the major Ca(2+) mobilizing pathway responsible for diverse functions in non-excitable cells. In the heart, however, its role is largely unknown or controversial. In intact cat atrial myocytes, endothelin (ET-1) increased basal [Ca(2+)](i) levels, enhanced action potential-evoked [Ca(2+)](i) transients, caused [Ca(2+)](i) transients with alternating amplitudes (Ca(2+) alternans), and facilitated spontaneous Ca(2+) release from the sarcoplasmic reticulum (SR) in the form of Ca(2+) sparks and arrhythmogenic Ca(2+) waves. These effects were prevented by the IP(3) receptor (IP(3)R) blocker aminoethoxydiphenyl borate (2-APB), suggesting the involvement of IP(3)-dependent SR Ca(2+) release. In saponin-permeabilized myocytes IP(3) and the more potent IP(3)R agonist adenophostin increased basal [Ca(2+)](i) and the frequency of spontaneous Ca(2+) sparks. In the presence of tetracaine to eliminate Ca(2+) release from ryanodine receptor (RyR) SR Ca(2+) release channels, IP(3) and adenophostin triggered unique elementary, non-propagating IP(3)R-dependent Ca(2+) release events with amplitudes and kinetics that were distinctly different from classical RyR-dependent Ca(2+) sparks. The effects of IP(3) and adenophostin were prevented by heparin and 2-APB. The data suggest that IP(3)-dependent Ca(2+) release increases [Ca(2+)](i) in the vicinity of RyRs and thus facilitates Ca(2+)-induced Ca(2+) release during excitation-contraction coupling. It is concluded that in the adult mammalian atrium IP(3)-dependent Ca(2+) release enhances atrial Ca(2+) signalling and exerts a positive inotropic effect. In addition, by facilitating Ca(2+) release, IP(3) may also be an important component in the development of Ca(2+)-mediated atrial arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Atrial Function; Calcium; Calcium Channels; Calcium Signaling; Cats; Endothelin-1; Female; Heart Atria; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Intracellular Membranes; Male; Myocardium; Myocytes, Cardiac; Osmolar Concentration; Receptors, Cytoplasmic and Nuclear; Signal Transduction

Topics: Adult; Arrhythmias, Cardiac; Cardiovascular Diseases; Child; Comorbidity; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Epidemiologic Studies; Genetic Predisposition to Disease; Heart Failure; Humans; Hypertension; Male; Obesity; Risk Factors; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Thrombophilia

We studied the effects of blockade of nicotinic receptors in sympathetic and parasympathetic ganglia (hexamethonium), muscarinic receptors (atropine), and beta1-adrenoceptors (atenolol) on arrhythmogenic activity of endothelin-1 during inhibition of nitric oxide synthesis with Nomega-nitro-L-arginine in NMRI mice. Atropine reduced, while hexamethonium completely abolished the arrhythmogenic effect of endothelin-1 during nitric oxide synthase inhibition. Atenolol potentiated arrhythmogenic activity of Nomega-nitro-L-arginine, but endothelin-1 had no effect on the incidence of arrhythmias under these conditions.

Topics: Adrenergic Antagonists; Animals; Arrhythmias, Cardiac; Atenolol; Atropine; Cholinergic Antagonists; Endothelin-1; Hexamethonium; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide

The endothelins are peptides with vasoconstricting and growth-promoting properties. Endothelin-1 (ET-1) is known with its direct positive inotropic and chronotropic effects on isolated heart and with growth effects. The aim of this pilot study was to investigate the frequency distribution of the common polymorphism of the ET-1 gene and its possible relation with hemodynamic consequences of malignant ventricular arrhythmias in patients with structural heart disease. We studied 26 consecutive patients with malignant ventricular arrhythmias and implantable cardioverterdefibrillators with a mean age of 62.7 +/- 12.2 years and a mean left ventricular ejection fraction of 0.37 +/- 11.0. Taq polymorphism of ET-1 was detected using our original polymerase chain reaction method. The polymerase chain reaction product with a length of 358 basepairs (bp) (primers 5'-CAA ACC GAT GTC CTC TGT A-3' and 5'-ACC AAA CAC ATT TCC CTA TT-3') in its non-mutated form contains a target sequence for TaqI restrictive enzyme, while a mutated product loses this cleavage site. Of 26 patients, nine (34%) had recurrent palpitations and eight (30.8%) had syncopes during their malignant arrhythmias. Nineteen patients were given amiodarone after implantable cardioverter-defibrillator insertion and seven were not treated with amiodarone. Fifteen patients had (++), 11 (+-) and 0 (- -) ET-1 genotype. The risk for syncopes was associated with the (++) genotype of the ET-1 gene (P = 0.01). Patients receiving amiodarone had significantly higher frequency of the (++) genotype (P = 0.011). All our results indicate that the presence of the ET-1 genotype (++) in patients with structural heart disease, severe left ventricular dysfunction and malignant ventricular arrhythmias increases the risk for these patients of hemodynamic collapse during these arrhythmias.

Topics: Aged; Amino Acid Sequence; Amiodarone; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Defibrillators, Implantable; Endothelin-1; Female; Gene Frequency; Genetic Predisposition to Disease; Hemodynamics; Humans; Male; Middle Aged; Molecular Sequence Data; Phenotype; Pilot Projects; Polymorphism, Genetic; Recurrence; Risk Factors; Stroke Volume; Syncope; Time Factors; Treatment Outcome; Ventricular Function, Left

Arrythmogenic effects of endothelin-1 were studied in NMRI mice under conditions of NO-synthase blockade with N omega-nitro-L-arginine methyl ester. Intravenous injection of endothelin-1 increased heart rate variability in awake mice. NO-synthase blockade potentiated the arrythmogenic effects of endothelin-1. In narcotized animals the arrythmogenic effect of endothelin-1 was not observed and was considerably weakened under conditions of NO-synthase blockade. Arrhythmia was paralleled by atrioventricular block and lengthening of the ST segment.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Electrocardiography; Endothelin-1; Enzyme Inhibitors; Heart; Heart Rate; Male; Mice; Mice, Inbred Strains; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase

Topics: Animals; Arrhythmias, Cardiac; Cats; Endothelin-1; gamma-Aminobutyric Acid; Medulla Oblongata; Metoprolol

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

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

The endothelins are peptides with vasoconstricting and growth-promoting properties. Endothelin-1 (ET-1) is known for its direct positive inotropic and chronotropic effects on isolated heart, and for growth effects. The aim of this pilot study was to investigate the frequency distribution of a common polymorphism of the endothelin (ET-1) gene and its possible relation to the hemodynamic consequences of malignant ventricular arrhythmia in patients with structural heart disease.. We studied 26 consecutive patients with malignant ventricular arrhythmia and implantable cardioverter defibrillators (ICD), mean age 62.7 +/- 12.2 years, mean LVEF 0.37 +/- 11. The Taq polymorphism of ET-1 was detected using our original PCR method. The PCR product with a length of 358 bp in its non-mutated form contains a target sequence for the TaqI restrictive enzyme, while the mutated product loses this cleavage site.. Out of the 26 patients, 9 (34%) had recurrent palpitations and 8 (30.8%) had syncopes during their malignant arrhythmic episodes. 19 of the patients were receiving amiodarone after ICD implantation, 7 were not. 15 patients had the (++) and 11 had the (+ -) ET-1 genotype; none had the (- -) genotype. The risk of syncopes was associated with the (++) genotype (p=0.01). Patients with amiodarone had a significantly higher frequency of the (++) genotype (p=0.011).. All our results suggested that the presence of the (++)ET-1 genotype in patients with structural heart disease, severe left ventricular dysfunction, and malignant ventricular arrhythmia put these patients at a higher risk of hemodynamic collapse during arrhythmic episodes.

Topics: Aged; Arrhythmias, Cardiac; Endothelin-1; Female; Genotype; Hemodynamics; Heterozygote; Homozygote; Humans; Male; Middle Aged; Pilot Projects; Polymerase Chain Reaction; Polymorphism, Genetic

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

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

Various cardio-active stimuli, including endothelin-1 (ET-1), exhibit potent arrhythmogenicity, but the underlying cellular mechanisms of their actions are largely unclear. We used isolated rat atrial myocytes and related changes in their subcellular Ca(2+) signalling to the ability of various stimuli to induce diastolic, premature extra Ca(2+) transients (ECTs). For this, we recorded global and spatially resolved Ca(2+) signals in indo-1- and fluo-4-loaded atrial myocytes during electrical pacing. ET-1 exhibited a higher arrhythmogenicity (arrhythmogenic index; ratio of number of ECTs over fold-increase in Ca(2+) response, 8.60; n = 8 cells) when compared with concentrations of cardiac glycosides (arrhythmogenic index, 4.10; n = 8 cells) or the beta-adrenergic agonist isoproterenol (arrhythmogenic index, 0.11; n = 6 cells) that gave similar increases in the global Ca(2+) responses. Seventy-five percent of the ET-1-induced arrhythmogenic Ca(2+) transients were accompanied by premature action potentials, while for digoxin this proportion was 25 %. The beta-adrenergic agonist failed to elicit a significant number of ECTs. Direct activation of inositol 1,4,5-trisphosphate (InsP(3)) receptors with a membrane-permeable InsP(3) ester (InsP(3) BM) mimicked the effect of ET-1 (arrhythmogenic index, 14.70; n = 6 cells). Inhibition of InsP(3) receptors using 2 microM 2-aminoethoxydiphenyl borate, which did not display any effects on Ca(2+) signalling under control conditions, specifically suppressed the arrhythmogenic action of ET-1 and InsP(3) BM. Immunocytochemistry indicated a co-localisation of peripheral, junctional ryanodine receptors with InsP(3)Rs. Thus, the pronounced arrhythmogenic potency of ET-1 is due to the spatially specific recruitment of Ca(2+) sparks by subsarcolemmal InsP(3)Rs. Summation of such sparks efficiently generates delayed after depolarisations that trigger premature action potentials. We conclude that the particular spatial profile of cellular Ca(2+) signals is a major, previously unrecognised, determinant for arrhythmogenic potency and that the InsP(3) signalling cassette might therefore be a promising new target for understanding and managing atrial arrhythmia.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Calcium Channels; Calcium Signaling; Cardiotonic Agents; Digoxin; Electric Stimulation; Electrophysiology; Endothelin-1; Heart Atria; Immunohistochemistry; In Vitro Techniques; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Male; Membrane Potentials; Microscopy, Fluorescence; Patch-Clamp Techniques; Rats; Receptors, Cytoplasmic and Nuclear; Subcellular Fractions

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

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

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

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

Besides being a strong vasoconstrictor, endothelin-1 (ET-1) also causes severe ventricular arrhythmias. The aim of our study was to differentiate between the vasoconstrictor and arrhythmogenic actions of ET-1 by using the selective endothelin-A-(ETA) receptor antagonist LU 135.252 (LU). A bolus injection of 5 mg/kg LU was administered to 10 anesthetized mongrel dogs in group A. The 30 min intracoronary ET-1 infusion was started 20 min after the LU bolus at a rate of 60 pmol/min. In the control group (group B, n = 8) only ET-1 was administered (60 pmol/min). The left anterior descending coronary artery blood flow (CBF), cardiac output, electrocardiograph (ECG) and arterial blood pressure were monitored. Two monophasic action potential duration (MAPD) catheters were placed onto the left ventricular epicardium (LVEP) and into the right ventricular endocardium (RVEND) to follow electrophysiologic changes. No significant changes were observed in blood pressure (0 min vs 30 min: group A, 99.0 +/- 4.5 vs 90.0 +/- 5.2 mmHg, p = NS; group B, 103 +/- 6 vs 104 +/- 3 mmHg, p = NS), cardiac output (0 min vs 30 min: group A, 3.5 +/- 0.7 vs 3.2 +/- 0.8 l/min, p = NS; group B, 3.6 +/- 0.4 vs 3.3 +/- 0.3 l/min, p = NS), and MAPD90 (0 min vs 30 min: group A, LVEP, 241 +/- 11 vs 260 +/- 14 ms; RVEND, 233 +/- 5 vs 239 +/- 8 ms, p = NS), whereas a significant decrease was observed in CBF (deltaCBF 30 min: group A, -28 +/- 2%, p < 0.05; group B, -32 +/- 3%, p < 0.05). In group A ventricular fibrillation (VF) occurred once. Ventricular premature contractions (VPCs) and short, nonsustained ventricular tachycardias (nsVTs) were observed in seven cases. Early after depolarizations and a MAPD90 increase were observed in the control group B (0 min vs 30 min: LVEP, 244 +/- 10 vs 292 +/- 12 ms; RVEND, 255 +/- 9 vs 290 +/- 8 ms) accompanied by VPCs, incessant nsVTs. Sustained VT and VF were evident in seven cases. Our results indicate, that the applied single bolus injection of LU effectively prevents ET-1-induced major ventricular arrhythmias, whereas it has no effect on coronary vasoconstriction. These data support the notion that ET-1 possesses a direct arrhythmogenic action.

Topics: Animals; Arrhythmias, Cardiac; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Phenylpropionates; Pyrimidines; Receptor, Endothelin A

Intrapericardial endothelin-1 (ET-1) infusion causes dose-dependent severe ventricular arrhythmias. We examined the effects of the endothelin-A- (ETA) receptor antagonist LU 135.252 (LU) on ET-1-induced arrhythmias on six open-chest mongrel dogs. Ten minutes after an intravenous bolus of LU (5 mg/kg), ET- 1 (33 pmol/kg/min) was given into the pericardial space for 30 min (LU group). Six dogs received ET-1 infusion without LU treatment (control group). Mean arterial blood pressure (MAP), cardiac output, electrocardiograph (ECG), right ventricular endocardial and epicardial (RVEND, RVEP), and left ventricular endocardial and epicardial (LVEND, LVEP) monophasic action potential durations (MAPDs) were recorded. No significant changes were observed in MAP and cardiac output. MAPD90s did not change significantly in the LU group (basic vs ET 20min: RVEP, 186 +/-7 vs 190 +/- 7; LVEP, 189 +/- 8 vs 201 +/- 11; RVEND, 191 +/- 10 vs 192 +/- 9; LVEND, 199 +/- 11 vs 203 +/- 11 ms), while significant MAPD90 prolongation was found in all investigated regions of the control group (ET start vs ET 20 min: LVEP, 174 +/- 3 vs 208 +/- 10*; RVEND, 206 +/- 9 vs 241 +/- 12* ms, *p < 0.05). No early after depolarization (EAD) was observed in the LU group, while EADs occurred in three controls. In the LU group, we have not found any significant arrhythmias except nonsustained ventricular tachycardias (nsVTs) in one animal. In the control group incessant nsVTs were observed in six, sustained VTs (sVTs) in four and ventricular fibrillation (VF) in two instances. Significant ST-elevation was observed in all animals in the LU and control groups (LU: 6.7 +/- 2.1 mV; control: 10.1 +/- 2.0 mV, p = NS). In conclusion, the arrhythmogenic action and the main electrophysiological effects of pericardial ET-1 infusion, MAPD prolongation and EAD formation, are inhibited by LU. However, LU could not prevent the ischemic changes resulting from ET-1 infusion.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Phenylpropionates; Pyrimidines; Receptor, Endothelin A

In earlier studies severe ventricular arrhythmias developed during intrapericardial (i.p.) endothelin-1 (ET-1) infusion. Monophasic action potential duration (MAPD90) increase and significant ST segment elevation preceded the onset of arrhythmias. The aim of this study was to test the antiarrhythmic and anti-ischemic efficacy of the mixed endothelin-A- and -B- (ETA/B) receptor antagonist bosentan (BOS) on ET-1-induced arrhythmias on six mongrel dogs. Ten minutes after an intravenous bolus dose of BOS (10 mg/kg), ET-1 (33 pmol/kg/min) was given into the pericardial space for 30min (BOS group). Six control dogs received only ET-1 infusion (control group). Mean arterial blood pressure (MAP), cardiac output, electrocardiograph (ECG), right and left ventricular endo- and epicardial (RVEND, RVEP, LVEND, LVEP) MAPD90s were recorded. MAP and cardiac output did not change significantly in the BOS group. Significant MAPD90 prolongation was found in all investigated regions of the control group (ET start vs ET 20 min: LVEP, 174 +/- 3 vs 208 +/- 10*; RVEND, 206 +/- 9 vs 241 +/- 12* ms, *p < 0.05), while significant MAPD90 alterations were not observed in the BOS group (basic vs ET 20 min: RVEP, 189 +/- 5 vs 196 +/- 5; LVEP, 199 +/- 5 vs 199 +/- 4; RVEND, 194 +/- 5 vs 195 +/- 6; LVEND, 209 +/- 3 vs 213 +/- 5 ms). Early after depolarizations (EADs) were observed in three control dogs. Severe ventricular arrhythmias [incessant nonsustained ventricular tachycardias (nsVTs) in all cases, sustained VTs (sVTs) in four, ventricular fibrillation (VF) in two instances] were present in the control group, whereas nsVTs were observed only in two dogs in the BOS group. ST segment elevation was more pronounced in the control group than in the BOS group (1.01 +/- 0.2 vs 0.41 +/- 0.07 mV, p < 0.05). In summary, bosentan effectively inhibits intrapericardial ET- 1-induced ventricular arrhythmias, moreover it may have a protective effect against epimyocardial ischemia.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Blood Pressure; Bosentan; Cardiac Output; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides

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

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

SB 209670 reduced basal mean arterial pressure (16%) without affecting left-circumflex coronary artery (LCX) flow, cardiac output, heart rate, or global/regional myocardial contractility. In vehicle-treated animals, i.e. endothelin (ET)-1 produced an initial hyperemic response in the LCX, followed by a secondary reduction in flow. This response was accomplished by decreases in LCX regional wall fractional shortening, +dP/dt and -dP/dt, but an increase in left anterior wall fractional shortening. ET-1 also produced dose-related, fatal ventricular fibrillation. Whereas SB 209670 administration did not inhibit the initial increase in coronary flow produced by ET-1, the secondary constrictor responses were markedly antagonized. SB 209670 also attenuated the reduction in LCX regional wall fractional shortening and converted the increase in left anterior wall contractility to a reduction in contractility. Although SB 209670 produced only a modest inhibition of the ET-1-mediated reductions in dP/dt, the induction of fatal ventricular arrhythmias was completely abolished. Therefore, the data are consistent with the hypothesis that the coronary ischemic and proarrythmic actions of ET-1 are distinct. Therefore, ET receptor antagonists may be useful in treatment of disturbances in cardiac rhythm.

Topics: Anesthesia, General; Animals; Arrhythmias, Cardiac; Coronary Circulation; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Indans; Injections, Intravenous; Vasoconstriction; Vasodilation

In a previous study we established that endothelin-1 (ET-1) can induce characteristic ventricular tachycardias (VT) with significant prolongation of QT and QTc time. In this investigation we studied the role of CA2+ channels in the pro-arrhythmic effects of ET-1. In 24 anesthetized, open-chest mongrel dogs, ET-1 was administered into the left anterior descending coronary artery at a comparatively low dose (60 pmol/min) for 30 min. Twelve dogs received the Ca(2+)-channel blocker verapamil (0.4 mg/kg) before ET-1 application. The following parameters were recorded continuously over the infusion period: systemic arterial blood pressure, coronary blood flow, surface ECG leads, epicardial atrial and ventricular electrograms, and right and left ventricular endocardial monophasic action potentials (MAP). Electrophysiologic studies were performed by programmed electrical stimulation of the heart. Blockade of myocardial Ca2+ channels attenuated the arrhythmogenic action of ET-1. After verapamil administration to ET-1-treated dogs, sustained VT did not appear and ventricular fibrillation (VF) developed only in two dogs. In the control group serious and sustained VT and VF developed in nine animals. It is noteworthy that verapamil did not prevent ET-1-induced prolongation of QT time. The results appear to prove that myocardial Ca2+ channels are involved in the proarrhythmic effect of ET-1.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Electrocardiography; Endothelin-1; Hemodynamics; Verapamil

Recently, extremely high levels of endothelin-1 (ET-1) were detected in the pericardial fluid of patients undergoing cardiac surgery. This study was designed to assess the pathophysiologic importance of this finding by infusing ET-1 into the closed pericardial sac of anesthetized dogs. Systemic arterial blood pressure, heart rate, and standard ECG were recorded. Intrapericardial infusion of ET-1 (11 and 33 pmol/kg/min; n = 4/4) for 40 min induced ventricular arrhythmias in all instances. The lower dose of ET-1 induced a substantial number of ventricular extrasystoles, couplets, and triplets. In one instance, ventricular extrasystoles accelerated into nonsustained ventricular tachycardia (VT). In animals receiving the higher dose, nonsustained VTs occurred regularly, whereas sustained VTs were detected in two of four animals. Before the onset of arrhythmias, QT time was significantly prolonged [ET-1 (11 pmol/kg/min) 180 +/- 12 to 198 +/- 10 ms, p < 0.05; ET-1 (33 pmol/kg/min) 192 +/- 15 to 233 +/- 13 ms, p < 0.01]. Hemodynamic variables did not change significantly before the onset of ventricular arrhythmias. Our results show that administration of exogenous ET-1 into the pericardial space induces ventricular arrhythmias associated with prolongation of QT time.

Topics: Anesthesia; Animals; Arrhythmias, Cardiac; Body Fluids; Dogs; Electrocardiography; Endothelin-1; Female; Injections; Male; Pericardium

The effect of permanent bradycardia on the proarrhythmic action of endothelin-1 (ET) was investigated in 24 open-chest anesthetized mongrel dogs. In 12 dogs, permanent bradycardia was induced by radiofrequency ablation of the AV node and the hearts were paced at 70 beats/min. ET (60 pmol/min) was infused into the left anterior descending coronary artery. Blood pressure, coronary blood flow (CBF), and atrial and ventricular epicardial surface ECG were recorded continuously. Polymorphous ventricular tachycardia developed in every dog with permanent bradycardia, and ventricular fibrillation terminated the experiments in 11 cases. Bradycardia prolonged the basal QT but there was no difference in the frequency corrected QTc time between the two groups. ET prolonged the QT time in a similar fashion in both groups. In the control group, six dogs developed sustained ventricular tachycardias and ventricular fibrillation occurred in nine cases. EADP was found in six cases of eight registered. Signs of myocardial ischemia did not accompany the development of arrhythmias. We conclude that permanent bradycardia augments the direct proarrhythmic effect of ET in dogs.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Bradycardia; Coronary Vessels; Dogs; Electric Stimulation; Electrocardiography; Electrophysiology; Endothelin-1; Female; Infusions, Intravenous; Male

The aim of this study was to investigate the changes in monophasic action potentials (MAP) from different sites in the heart and to determine MAP dispersion during endothelin-1 (ET-1) infusion. Standard ECG, left ventricular anterior, right ventricular lateral, right ventricular septal, and right ventricular apical MAPs and intra-arterial blood pressure were monitored in seven anesthetized open-chest mongrel dogs. After radiofrequency atrioventricular node ablation, ventricular pacing (70/min) was performed and intracoronary ET-1 (60 pmol/min) was administered into the left anterior descending coronary artery. Both MAPd90 and MAPd90 dispersion increased significant during ET-1 infusion. The onset of spontaneous monomorphic and polymorphic sustained ventricular tachycardias (sVT) was observed in five dogs (around 40 min), and nonsustained VTs (nsVT) developed in another two dogs. The increases in MAP and MAP dispersion lasted until the appearance of polymorphic nsVTs and sVTs, but at the time of these VTs this difference decreased. At the termination of the experiments, ventricular fibrillation occurred in six cases. In four cases third-phase early afterdepolarizations were recorded. Our results suggest that increased MAP dispersion and development of EAD contribute to the arrhythmogenic action of ET-1, and these phenomena might explain the pathogenesis of a wide variety of ventricular arrhythmias with different morphology observed in this study.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Vessels; Dogs; Endothelin-1; Female; Heart Rate; Heart Ventricles; Infusions, Intravenous; Male; Time Factors

The development of ventricular tachyarrhythmias caused by low-dose intracoronary infusion of endothelin-1 (ET-1) has recently been observed in dogs. The aim of the present study was to investigate the pathomechanism of ET-1-induced ventricular arrhythmias in 32 anesthetized, open-chest mongrel dogs in group A (n = 14) without, in group B (n = 14), and in group C (n = 4 control) with atrioventricular node ablation. The coronary blood flow (CBF) was measured in the left anterior descending (LAD) coronary artery by an electromagnetic flowmeter. Standard ECG, atrial and ventricular electrograms, and in groups B and C endocardial and epicardial monophasic action potentials (MAPs) were recorded. ET-1 was administered into the LAD at a low dose (30-60 pmol/min). At the time of the appearance of premature beats, CBF was only slightly decreased. The effective ventricular refractory period did not change significantly. Onset of spontaneous polymorphic and monomorphic sustained ventricular tachycardia (sVT) was observed in five dogs without bradycardia and in nine dogs with bradycardia. VTs in dogs with complete AV block were longer and slower. In most of the cases, ventricular fibrillation occurred. ET-1 treatment resulted in a significant increase in MAP 90% duration (255 +/- 9 vs. 290 +/- 8 ms endocardial, 244 +/- 10 vs. 292 +/- 12 epicardial; p < 0.05) at 70 beats/min ventricular pacing. In eight cases (group B), third-phase early afterdepolarization could be recorded. According to our results, the mechanism of ET-1-induced arrhythmias appears to be based on prolongation of MAP duration and development of afterdepolarizations.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Circulation; Coronary Vessels; Dogs; Electric Stimulation; Electrocardiography; Endothelin-1; Female; Heart Block; Heart Ventricles; Infusions, Intravenous; Male

Recently, extremely high levels of endothelin-1 (ET-1) were detected in the pericardial fluid of patients with heart disease; however, the pathophysiological importance of this finding is not known. The present study was designed to characterize ET-1 levels in canine pericardial fluid and to investigate the effects of local high concentrations of exogenous ET-1 in vivo.. In anesthetized, open-chest dogs ET-1 (Groups 1 and 2: 11 and 33 pmol.kg-1.min-1; n = 6 and 6, respectively) or physiological saline (Group 3, n = 5) were infused into the closed pericardial sac for 40 min. In serial pericardial fluid and aortic blood plasma samples, ET-1 levels were measured by radioimmunoassay, and analysed by high-performance liquid chromatography (HPLC). Systemic arterial blood pressure, heart rate, cardiac output (CO), standard ECG and right ventricular endocardial monophasic action potentials (MAPs) were recorded.. Basal pericardial fluid ET-1 levels were significantly higher than respective plasma levels (342 +/- 210 vs. 8.0 +/- 5.2 pmol.l-1, n = 14, P < 0.001. In HPLC analysis pericardial fluid ET-1 was indistinguishable from ET-1(1-21). Infusion of exogenous ET-1 into the pericardial space induced ventricular arrhythmias in all instances, which were associated with 9.7-fold increase in pericardial fluid ET-1 levels. Ventricular tachycardias developed in 9 of 12 animals. The arrhythmogenic effect of ET-1 was more apparent in dogs with the larger dose. Before the onset of arrhythmias, intrapericardial infusion of ET-1 increased QT time (Group 1: 207 +/- 18 to 230 +/- 23 ms, P < 0.01; Group 2: 220 +/- 12 to 277 +/- 17 ms, P < 0.01) and MAP duration at 90% repolarization (at 300 ms cycle length) (Group 1: 192 +/- 9 to 216 +/- 9 ms, P < 0.01; Group 2: 205 +/- 9 to 255 +/- 9 ms, P < 0.001). Hemodynamic variables did not change significantly prior to the onset of ventricular tachyarrhythmias. In Group 3, arrhythmias were not observed and all electrophysiological and hemodynamic parameters remained unchanged.. Administration of exogenous ET-1 into the pericardial space induces ventricular arrhythmias associated with prolongation of QT time and MAP duration. Whether pericardial fluid ET-1 under pathophysiological conditions can ever reach sufficiently high levels to induce ventricular arrhythmias remains to be elucidated.

Topics: Action Potentials; Analysis of Variance; Animals; Arrhythmias, Cardiac; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Endothelin-1; Female; Male; Pericardium; Statistics, Nonparametric

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

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

To determine the possible adverse effects of human cross-linked hemoglobin in endotoxemia.. Prospective, controlled, laboratory trial.. Animal research laboratory.. New Zealand white rabbits.. Conscious rabbits received intravenous infusions of either lipopolysaccharide (LPS) alone (10 micrograms/kg, Escherichia coli 0111:B4), human hemoglobin cross-linked between the alpha chains (alpha alpha Hb, 0.7 g/kg), or both LPS and alpha alpha Hb. The cardiovascular effects of alpha alpha Hb and LPS as single agents or administered together were then studied in anesthetized rabbits.. Mortality in conscious animals that received alpha alpha Hb followed by LPS 4 hrs later (n = 5), or LPS and alpha alpha Hb at the same time (n = 6) was 60% and 67%, respectively. In anesthetized animals, infusion of both LPS and alpha alpha Hb (n = 6) resulted in hypoxia, lactic acidosis, ventricular arrhythmias, and decreased myocardial contractility and left ventricular pressure. In contrast, anesthetized rabbits that received alpha alpha Hb (n = 5) or LPS (n = 5) alone did not develop hypoxia, acidosis, alteration in myocardial contractility, or arrhythmias. Furthermore, death did not occur in any of the conscious animals that received either LPS (n = 7) or alpha alpha Hb (n = 4) as single agents.. In an animal model of nonlethal endotoxemia, infusion of alpha alpha Hb significantly increases mortality. Our data suggest that mortality may be due to the acute increased cardiopulmonary toxicity of alpha alpha Hb in animals with underlying endotoxemia.

Topics: Acidosis, Lactic; Animals; Arrhythmias, Cardiac; Cross-Linking Reagents; Drug Administration Schedule; Endothelin-1; Endotoxemia; Escherichia coli; Hemodynamics; Hemoglobin A; Humans; Hypoxia; Leukopenia; Lipopolysaccharides; Male; Myocardial Contraction; Rabbits

The arrhythmogenic actions of endothelin peptides were studied in isolated perfused hearts from guinea pigs and rats. Digoxin-induced ectopic ventricular complexes were partially antagonized by phosphoramidon, an endothelin-converting enzyme inhibitor. On the contrary, these rhythm disturbances were potentiated by big endothelin-1 in isolated perfused whole hearts from guinea pigs. Endothelin-1, when infused through the coronary circulation at a concentration of 10(-10) mol/l, produced an increase in coronary perfusion pressure without altering the heart rate and contractility in the isolated perfused hearts of rats. However, ventricular ectopic complexes occurred when the rise in coronary perfusion pressure reached the peak value. BQ 485, an endothelin-A receptor antagonist, at a concentration of 10(-6) mol/l, completely blocked the vasoconstrictor and arrhythmogenic effects of endothelin-1. In BQ 485-pretreated rat hearts, endothelin-1 produced a fall in coronary perfusion pressure and a slight positive inotropic response which could be blocked by NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor. BQ 485 at the same concentration also caused a significant reduction in the duration but not the onset of ventricular ectopic complexes in the guinea pig isolated perfused heart induced by digoxin. These results were taken as evidence of the arrhythmogenic action of endothelin peptides and their possible participation in the ventricular dysrhythmia induced by digoxin.

Topics: Animals; Arrhythmias, Cardiac; Azepines; Cardiotonic Agents; Digoxin; Electrocardiography; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Enzyme Inhibitors; Female; Guinea Pigs; Heart; Hemodynamics; In Vitro Techniques; Male; Myocardial Contraction; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oligopeptides; Protein Precursors; Rats; Receptors, Endothelin