Preservation of myocardium in transient ischemia by the thromboxane synthetase inhibitor UK 38.485

Abstract

This study was performed to examine potential protective effects of UK 38.485, an inhibitor of thromboxane synthetase, in canine myocardium stressed by transient ischemia. On anesthetized open-chest mongrel-dogs (n = 9) repeated ischemia (3 min) was produced by proximal, intermittent occlusion of the left anterior descending artery. A total of 18 occlusions after 3 mg UK 38.485/kg body wt. and 12 occlusions after 5 mg UK 38.485/kg body wt. were compared to a total of 24 occlusions under control conditions. In each experiment, 2-3 control occlusions and 3-4 therapy occlusions were performed. The drug was applied i.v. in a dose of 3 or 5 mg/body wt. 30 min before the first therapy occlusion. In both groups, hemodynamics and energetics did not significantly change as compared to control. The efficiency of the drug in protecting ischemically stressed myocardium was examined by (a) quantification of oxygen debt and oxygen repayment in the occlusion and reperfusion periods and (b) the amounts of inorganic phosphate, lactate, and potassium released in the first minute of reperfusion. Compared to control occlusions, premedication with either 3 or 5 mg UK 38.485 led to a significantly reduced oxygen debt combined with a significant decrease of the release of inorganic phosphate, lactate, and potassium. The protective effect is suggested to be mainly due to enhanced flow to ischemic areas. Data obtained in this study suggest protective effects of the compound in the preservation of myocardium in transient ischemia and attest to the concept that thromboxane A2 may aggravate the metabolic and energetic situation of myocardium in circumstances with reduced oxygen supply.

Ifetroban Sodium: An Effective TxA2/PGH2 Receptor Antagonist

“…A deleterious effect of TxA 2 on ischemic myocardium was hypothesized either to be due to vascular effects, platelet effects or direct effects on the myocardium. In diverse animal models and species, inhibition of TxA 2 synthase was shown to exert cardioprotective effects, as was antagonism of TP receptors (2,13,22,31,53). The beneficial effect of TP receptor antagonism (SQ29,548 and BMS-30741) was clearly shown in infarcting myocardium in several species (13,23).…”

The effect of the thromboxane A2 receptor antagonist SQ 29,548 on the severity of pacing-induced ischemia

“…TXA2-receptor blockade may be of potential therapeutic benefit in some forms of angina pectoris. Experimental and clinical studies have shown mixed results for TXA2 synthetase or receptor antagonists in angina (6,12,13,22), but the present study indicates further investigations in this area are warranted.…”

“…Previous studies from our laboratory have shown that diltiazem also only works in the later pacing episodes in this model of ischemia (8). A study be Hoeft et al (12) also indicated efficacy of a TXA2 synthetase inhibitor in a model of transient ischemia. With the use of a selective TXA2 receptor antagonist in the present study, the role of TXA2 in angina is further and more specifically implicated.…”

“…Early clinical trials with TXA2 synthetase inhibitors and receptor antagonists have given mixed results (6,13). A study by Hoeft et al (12) has indicated that inhibition of TXA2 synthesis appears to reduce severity of ischemia in a model of transient ischemia, though again, possible alterations in production of other arachidonic acid metabolites may cloud interpretation of the results. Thus, the purpose of this study was to determine if the TXAa-receptor antagonist SO 29,548 (17) can reduce the severity of ischemia in a model of pacing-inducing ischemia simulating effort-induced angina pectoris.…”