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-1 (ET-1) 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-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.


RESULTS
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.


CONCLUSIONS
ET-1 released endogenously during ischaemia is arrhythmogenic whereas exogenous application of ET-1 may, under certain conditions, be antiarrhythmic.
Sharif
I
I
Department of Physiology and Pharmacology, University of Stratchlyde, Glasgow, Scotland, UK.
Kane
K A
KA
Wainwright
C L
CL
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004147:Dioxins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000502:physiology*; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013997:Time Factors; D018879:Ventricular Premature Complexes / Q000188:drug therapy
D004147:Dioxins; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; C116576:PD 161721; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C072247:cyclo(Trp-Asp-Pro-Val-Leu)