Involvement of endothelin-1 in acute ischaemic arrhythmias in cats and rats

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 (1.5–6.0nmol/kg) was intracoronary injected just before LAD occlusion in cats, and preproET-1 mRNA antisense oligodeoxynucleotide (AS-ODN; 30–90nmol/kg) was intravenously injected 2h 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 6.0nmol/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 2h, and remained stable at 30min 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 90nmol/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.