Thromboxane A2 antagonist and diltiazem-induced enhancement of contractile function: the effect of timing of treatment

GJ Grover and IE Fulmor

Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey.

We determined the ability of the thromboxane A2 antagonist SQ 29,548 or diltiazem to enhance postischemic myocardial function and if the effects of these compounds were occurring during occlusion or reperfusion periods. Anesthetized open-chest dogs were pretreated with i.v. saline, SQ 29,548 (0.20 mg/kg + 0.20 mg/kg/hr) or diltiazem (0.18 mg/kg) 15 min before the left anterior descending coronary artery was occluded. In another group, animals were given saline, SQ 29,548 or diltiazem 1 min before reperfusion. The occlusion was maintained for 15 min and reperfusion instituted for 5 hr. Subendocardial segmental shortening was monitored throughout the experiment using sonomicrometry. Left anterior descending coronary artery occlusion resulted in marked systolic bulging to similar levels in all groups. Upon reperfusion, function returned immediately but, after several min, hypokinesia existed in saline-treated animals. At 5-hr postreperfusion, percentage of shortening returned to only 20% of base-line values in saline-treated animals. Both diltiazem and SQ 29,548 pretreatment resulted in significant (P less than .05) improvements in function such that at 5-hr postreperfusion, shortening returned to 60% of base-line values. When given immediately before reperfusion, SQ 29,548 still resulted in significant protection of function, although this occurred much later compared to pretreated animals. Diltiazem did not improve function when given immediately before reperfusion. SQ 29,548 improves reperfusion function and, thus by inference, thromboxane A2 may play a role in postischemic hypokinesia and some of its protective effects may occur during reperfusion. Diltiazem seems to protect reperfusion function only when present during ischemia per se.

Volume 247, Issue 2, pp. 445-452, 11/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics