Effect of the thromboxane receptor antagonist SQ 29,548 on myocardial infarct size in dogs.

The effect of thromboxane A2/prostaglandin endoperoxide receptor blockade on infarct size following myocardial ischemia plus reperfusion was determined in dogs. In anesthetized dogs SQ 29,548 (0.2 mg/kg/h) caused a 1,000-fold shift in the dose flow-response curve of renal and mesenteric beds to U-46619, indicating potent receptor blockade. The vasoconstrictor response of the left circumflex coronary artery (LCX) to U-46619 was completely inhibited by SQ 29,548. Three additional groups of anesthetized dogs were subjected to LCX occlusion and 10 min later were given (a) SQ 29,548 (0.2 mg/kg loading dose + 0.2 mg/kg/h infusion intravenously, i.v., n = 7), a thromboxane A2/prostaglandin endoperoxide receptor antagonist; (b) vehicle (n = 7); and (c) SQ 28,585 (0.2 mg/kg loading dose + 0.2 mg/kg/h infusion i.v., n = 3), an inactive compound structurally related to SQ 29,548. After 90 min of occlusion, the LCX was reperfused for 5 h. The area at risk and infarct size were then determined. The cardiac area at risk was similar in size for all groups. Infarct size as a percentage of the total area at risk was large, 79 +/- 2% in vehicle controls, but this was markedly reduced to 45 +/- 8% with SQ 29,548 treatment. SQ 28,585 did not alter infarct size as compared with vehicle controls. Area at risk and infarct size were highly correlated (r = 0.95) in vehicle-treated animals. None of the drug treatments resulted in a significantly altered hemodynamic status. Thus, blockade of thromboxane A2/prostaglandin endoperoxide receptors during ischemia plus reperfusion resulted in a significant salvage of myocardial tissue and suggests a deleterious role for thromboxane A2 in ischemia.