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Circulation, Vol 78, 450-461, Copyright © 1988 by American Heart Association

ARTICLES

Lack of involvement of thromboxane A2 in postischemic recovery of stunned canine myocardium

NE Farber, GM Pieper and GJ Gross
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226.

Modification of the thromboxane: prostacyclin ratio alters the severity of reperfusion arrhythmias and postischemic damage in long-term, irreversibly injured myocardium. In this study, the effects of the thromboxane synthetase inhibitor dazmegrel and the thromboxane receptor antagonist BM 13.505 on myocardial postischemic functional recovery and preservation of tissue adenine nucleotides was examined after a 15- minute episode of ischemia followed by 3 hours of reperfusion (myocardial stunning). Dazmegrel (3 or 8 mg/kg) or BM 13.505 (10 mg/kg) was given 15 minutes before coronary occlusion and compared with a control group in barbital-anesthetized dogs. Regional segment shortening (percent segment shortening, sonomicrometry), regional myocardial blood flow (microspheres), and coronary venous eicosanoid and high-energy phosphate levels (biopsies after 3 hours of reperfusion) were measured. Areas at risk, regional myocardial blood flow, and regional segment shortening during coronary occlusion were similar in all groups. Dazmegrel (3 mg/kg) attenuated the decrease in endocardial and midmyocardial adenosine 5'-triphosphate, and both doses significantly improved regional segment shortening during reperfusion. Coronary venous thromboxane levels were significantly decreased throughout the experiment in both dazmegrel-treated groups, and thromboxane levels were significantly elevated in the control group 3 hours after reperfusion. Prostacyclin, measured in the form of its main metabolite, 6-keto-prostaglandin F1 alpha, did not change significantly in the control group throughout the experiment, but it was markedly increased in dazmegrel groups throughout reperfusion, particularly in the dazmegrel group receiving 3 mg/kg. BM 13.505 exerted no beneficial effects on postischemic function or metabolism. In conclusion, after a reversible ischemic insult, postischemic recovery of function and metabolic status was not enhanced by preocclusion treatment with a thromboxane receptor blocker, and thus, the beneficial effects of thromboxane synthesis inhibition on postischemic abnormalities was not due to a reduction in thromboxane but was the result of endoperoxide shunting and a subsequent increase in prostacyclin. Therefore, thromboxane does not appear to be an important mediator of reversible ischemia-reperfusion damage.

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