SB 209670 inhibits the arrhythmogenic actions of endothelin-1 in the anesthetized dog.
SB 209670 reduced basal mean arterial pressure (16%) without affecting left-circumflex coronary artery (LCX) flow, cardiac output, heart rate, or global/regional myocardial contractility. In vehicle-treated animals, i.e. endothelin (ET)-1 produced an initial hyperemic response in the LCX, followed by a secondary reduction in flow. This response was accomplished by decreases in LCX regional wall fractional shortening, +dP/dt and -dP/dt, but an increase in left anterior wall fractional shortening. ET-1 also produced dose-related, fatal ventricular fibrillation. Whereas SB 209670 administration did not inhibit the initial increase in coronary flow produced by ET-1, the secondary constrictor responses were markedly antagonized. SB 209670 also attenuated the reduction in LCX regional wall fractional shortening and converted the increase in left anterior wall contractility to a reduction in contractility. Although SB 209670 produced only a modest inhibition of the ET-1-mediated reductions in dP/dt, the induction of fatal ventricular arrhythmias was completely abolished. Therefore, the data are consistent with the hypothesis that the coronary ischemic and proarrythmic actions of ET-1 are distinct. Therefore, ET receptor antagonists may be useful in treatment of disturbances in cardiac rhythm.
Douglas
S A
SA
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Nichols
A J
AJ
Feuerstein
G Z
GZ
Elliott
J D
JD
Ohlstein
E H
EH
D000768:Anesthesia, General; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000517:prevention & control*; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006439:Hemodynamics / Q000187:drug effects; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007189:Indans; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-