Endothelin and ischaemic arrhythmias-antiarrhythmic or arrhythmogenic?

Objective: The aim of this study was to investigate the influence of endogenously released and exogenously applied endothelin-l (ET-I) on ischaemia-induced arrhythmias. Methods: Ischaemia was induced in pentobarbitone-anaesthetised rats by ligation of a coronary artery for 30 min. To determine the role of endogenous ET-I in ischaemic arrhythmias, either the ETA receptor antagonist BQ123 (50 mu g/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 (Q(1)-Q(3)) 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. Results: In control animals (n=20), the incidence of VF was 65% and the total VEE count was 2775 (1870-4041). Both BQ123 and the higher dose of PD161721 reduced the VEE 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-I. Conclusions: ET-1 released endogenously during ischaemia is arrhythmogenic whereas exogenous application of ET-1 may, under certain conditions, be antiarrhythmic. (C) 1998 Published by Elsevier Science BN. All rights reserved.