Effects of endothelin-1 and the ETA-receptor antagonist, BQ123, on ischemic arrhythmias in anesthetized rats.
The effects of intravenous (i.v.) infusions of exogenous endothelin-1 (ET-1, 0.05 and 0.1 nmol/kg/min) on incidence and severity of ventricular arrhythmias during 30-min period of acute myocardial ischemia were assessed in anesthetized rats. We examined the role of ETA-receptors in the proarrhythmic effects of both exogenous and endogenous ET using the ETA-receptor antagonist, BQ123. Exogenous ET-1 increased the severity and incidence of ischemic arrhythmias dose dependently. Both doses increased the total incidence of ventricular fibrillation (VF: from 30% in controls to 100 and 88% in rats given 0.05 and 0.1 nmol/kg/min ET-1, respectively); the higher dose also increased total arrhythmia count and duration of ventricular tachycardia (VT). BQ123 (10 micrograms/kg/min) completely abolished this proarrhythmic effect of exogenous ET-1. To assess the role of endogenous ET-1 in the genesis of ischemic arrhythmias, we studied the effects of a range of doses of BQ123 (5-100 micrograms/kg/min) on ischemic arrhythmias. Only one dose of BQ123 (10 micrograms/kg/min) attenuated arrhythmias by reducing total ventricular ectopic count (from 1,423 +/- 112 in controls to 677 +/- 159). The highest dose of BQ123 tested (100 micrograms/kg/min) increased arrhythmias by significantly increasing the incidence of irreversible VF (from 25 to 75%). These results suggest that exogenous ET-1 can aggravate ischemia-induced arrhythmias, an effect that is sensitive to ETA-receptor blockade. However, although endogenous ET-1 may make some contribution to the genesis of arrhythmias resulting from coronary occlusion through an action at ETA receptors, the observed proarrhythmic effect of BQ123 at high doses suggests that this may unmask an effect of ET-1 at other receptors.
Garjani
A
A
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland.
Wainwright
C L
CL
Zeitlin
I J
IJ
Wilson
C
C
Slee
S J
SJ
D000758:Anesthesia; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004562:Electrocardiography / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000008:administration & dosage / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)