Electrophysiological Effects of Intrapericardial Infusion of Endothelin‐1

Abstract

Recently, extremely high levels of endothelin-1 (ET-1) were detected in the pericardial fluid of patients undergoing open-heart surgery. ET-1 has been suggested to have direct arrhythmogenic effect on myocardium. The aim of the present study was to examine the putative arrhythmogenic effect of intrapericardial infusion of ET-1 in anesthetized dogs (n = 15). In preliminary experiments, ET-1 (0.125-1.0 nmol/min, n = 7) was infused into the closed pericardial sack for 40 min. ET-1 induced non-sustained and/or sustained ventricular tachyarrhythmias in all but the lowest dose. For detailed arrhythmia analysis in addition to standard ECG ventricular endocardial and epicardial monophasic action potentials (MAP) were recorded. ET-1 (0.250 nmol/min, n = 7) induced mono- and polymorphic ventricular tachycardias, which degenerated into ventricular fibrillation in two instances. Moderate if any ischemic signs could be detected before the onset of arrhythmias. The arrhythmias spontaneously disappeared in all instances with the exception when ventricular fibrillation terminated the experiment. QT interval (260 +/- 23 ms vs. 317 +/- 31 ms, P < 0.05), and endo- and epicardial MAPD90 (at 300 ms cycle length) prolonged significantly (in average 182 +/- 12 ms vs. 224 +/- 25 ms, P < 0.05). Using MAP recording afterdepolarizations were detected in three instances. In control animals (n = 3) arrhythmias were not observed and all electrophysiological parameters remained unchanged. The present results show that intrapericardial administration of ET-1 can induce ventricular arrhythmias in dogs. The arrhythmogenic effect of ET-1 may be based on prolongation of MAP duration and development of afterdepolarizations. However, the elucidation of the precise mechanism needs further investigation.

Impulse conduction and gap junctional remodelling by endothelin‐1 in cultured neonatal rat ventricular myocytes

“…Ventricular hypertrophy is associated with an increased incidence of spontaneous ventricular arrhythmias, cardiovascular events and arrhythmia‐related deaths [1, 2] as well as greater vulnerability to the arrhythmogenic effects of acute ischaemia [3, 4]. Endothelin‐1 (ET‐1) is an important mediator of hypertrophy [5, 6] and has an acute pro‐arrhythmic effect on its own and in the setting of ischaemia [7–10]. Several mechanisms have been proposed for the detrimental effects of ET‐1: ( i ) ET‐1 has direct toxic effects on cardiac myocytes [11, 12]; ( ii ) ET‐1 causes hypertrophy of cardiac myocytes [5, 6] and increases myocardial fibrosis [13, 14]; ( iii ) ET‐1 has a long‐term positive inotropic effect in rats with congestive heart failure (CHF), and thus may contribute to the progression of CHF by increasing myocardial energy utilization [15]; ( iv ) ET‐1 administration induces ventricular arrhythmias [16].…”

Endothelin-1 receptor antagonists reduce cardiac electrical instability induced by high glucose in rats

“…Finally, the results obtained with different ET receptor blockers indicate that the haemodynamic responses to high glucose were mediated mainly by the ET B receptor, whereas the electrical responses were mediated by the ET A receptor. That ET-1 lengthens the cardiac QT interval has been reported previously Geller et al 1998), however the link to high glucose levels is novel. Since a high glucose concentration induces QT prolongation by increasing cardiac oxidative stress (D'Amico et al 2001), and oxidative stress is one determinant of the increased ET-1 production (Kahler et al 2000;Chen et al 2000) we propose that high glucose causes the increase in cardiac ET-1 levels and this in turn contributes to QT prolongation, by stimulating its own pathway(s).…”

Myocardial drug distribution generated from local epicardial application: Potential impact of cardiac capillary perfusion in a swine model using epinephrine

“…Prior studies have demonstrated pharmacologic response following epicardial (EC) application of antiarrhythmic drugs [7–14], proarrhythmic agents [15, 16], vasodilators [17–21], and antiproliferative chemotherapeutics [22]. Other studies have demonstrated favorable pharmacokinetics, with elevated myocardial drug levels and minimal peripheral concentration, when drug is given to the pericardial sac [23–28].…”