Endothelin A receptor antagonism by PD 156707 does not reduce infarct size after coronary artery occlusion/reperfusion in pigs.
Episodes of myocardial ischemia are associated with increases in cardiac venous plasma endothelin (ET) concentrations, suggesting that ET may play a role in the development of myocardial infarction. The purpose of this study was to determine if selective blockade of ET(A) receptors by PD 156707 reduces infarct size caused by coronary artery occlusion and reperfusion in pentobarbital-anesthetized micropigs. A PD 156707 dose which selectively blocks the ET(A)-mediated vasopressor response, but not the ET(B)-mediated vasodepressor response to i.v. ET-1 challenges (0.3 nmol/kg), was established in dose ranging studies in anesthetized micropigs. In myocardial infarction studies, micropigs received either saline vehicle (n = 7) or PD 156707 (n = 8) at a loading dose of 10 mg/kg/1 hr, followed by a maintenance dose of 7 mg/kg/hr. Coinciding with the start of the maintenance dose, the left anterior descending coronary artery was occluded for 1 hr followed by 3 hr of reperfusion. PD 156707 caused a significant (29 mm Hg) decrease in arterial blood pressure before occlusion. PD 156707 had no effect on infarct size (61.1 +/- 5.6% of the region at risk in the PD 156707 treatment group vs. 70.1 +/- 3.9% in the control group). These results suggest that ET(A) receptor activation does not substantially contribute to coronary artery occlusion/reperfusion-induced myocardial infarction.
Mertz
T E
TE
Department of Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan, USA.
McClanahan
T B
TB
Flynn
M A
MA
Juneau
P
P
Reynolds
E E
EE
Hallak
H
H
Bradford
L
L
Gallagher
K P
KP
D000818:Animals; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects*; D004149:Dioxoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D005260:Female; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D015424:Reperfusion; D013552:Swine
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; C093321:PD 156707