Effects of endothelin-receptor antagonism with PD156707 on myocardial stunning in swine.
Endothelin (ET) has been proposed to play a role in pathogenesis of myocardial ischemia/reperfusion injury. The potential role of ET in myocardial stunning has not been examined. Therefore we tested the hypothesis that selective blockade of ETA receptors with PD156707 {sodium 2-benzo[1,3]dioxol-5-yl-4-(4-methoxy-phenyl) -4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoate} could improve postischemic contractile dysfunction in open-chest pigs. Myocardial stunning was achieved by a sequence of three 10-min left anterior descending (LAD) occlusions interspersed with 15 min of reperfusion. All pigs received either an intravenous saline vehicle (n =6) or PD156707 (n = 6) at a loading dose infusion of 10 mg/kg/h for 1 h before the first occlusion followed by a maintenance dose of 7 mg/kg/h for 4 h. Systolic wall thickening (percentage of baseline) was measured with sonomicrometers. There was no significant difference in systolic thickening between groups at baseline, at the end of the final stunning occlusion, or at any of the time points during reperfusion. PD156707 significantly reduced arterial blood pressure before myocardial ischemia and throughout reperfusion. There was no significant difference in size of the region at risk between groups. In conclusion, selective blockade of ETA receptors with PD156707 did not significantly alter postischemic contractile function in open-chest pigs. These results suggest that activation of ETA receptors by endogenous ET does not play a significant role in the pathogenesis of myocardial stunning.
McClanahan
T B
TB
Cardiovascular Therapeutics Section, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA.
Mertz
T E
TE
Ignasiak
D P
DP
Juneau
P L
PL
Gallagher
K P
KP
D000818:Animals; D004149:Dioxoles / Q000627:therapeutic use*; D065128:Endothelin Receptor Antagonists; D005260:Female; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D017682:Myocardial Stunning / Q000188:drug therapy* / Q000503:physiopathology; D013552:Swine; D013556:Swine, Miniature
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; C093321:PD 156707