Mechanism of Endothelin-Induced Malignant Ventricular Arrhythmias in Dogs

Abstract

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.

Angiotensin II induces afterdepolarizations via reactive oxygen species and calmodulin kinase II signaling

“…Thus, it is very likely that NADPH oxidase-ROS-CaMKII pathway could represent a common mechanism accounting for arrhythmias induced by the agonists of above receptors. Supporting this assumption, endothelin-1 has been reported to cause ventricular tachyarrhythmias via prolongation of APD and formation of EADs [34–36], promote mitochondrial ROS production triggered by NADPH oxidase [37], and activates I Ca,L by CaMKII [38]. Further studies are needed to provide direct link between these individual steps.…”

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].…”

Expressed monophasic action potential alternans before the onset of ventricular arrhythmias induced by intracoronary bolus administration of endothelin-1 in dogs

“…In our previous study, the appearance of significant ventricular arrhythmias, induced by 30-min intracoronary infusion of ET-1 (60 pmol\min), was observed without ischaemic MAP and ECG changes [5]. ET-1 infusion for 30 min did not lead to ischaemic MAP or ECG changes.…”

“…The intracoronary bolus administration of ET-1 has been shown to induce severe ventricular tachyarrhythmias, associated with myocardial ischaemia [1][2][3]. We have demonstrated previously a direct arrhythmogenic effect of low-dose intracoronary infusion of ET-1 [4][5][6]. The development of multifocal ventricular tachycardias was based on action potential prolongation and the occurrence of early after-depolarizations (EADs).…”