Combined thromboxane A2 synthase inhibition and prostaglandin endoperoxide receptor antagonism limits myocardial infarct size after mechanical coronary occlusion and reperfusion at doses enhancing coronary thrombolysis by streptokinase
G Vandeplassche,
C Hermans,
Y Somers,
F Van de Werf,
and
F de Clerck
Department of Cardiovascular Pharmacology, Janssen Research Foundation, Beerse, Belgium.
OBJECTIVES. We sought to examine to what extent a combination of strong thromboxane A2 synthase inhibition and moderate endoperoxide receptor blockade enhances streptokinase-induced coronary thrombolysis and provides anti-ischemic activity independent from its thrombolytic activity. METHODS. Coronary thrombi, induced by crush injury and stenosis of the coronary artery, were lysed with streptokinase, 10,000 IU/kg body weight over 90 min, in anesthetized dogs receiving solvent (n = 11), ridogrel, 0.31 mg/kg intravenously, for thromboxane A2 synthase inhibition (n = 7) or ridogrel, 5 mg/kg, for additional prostaglandin endoperoxide receptor antagonism in addition to thromboxane A2 synthase inhibition (n = 7) 10 min before the administration of streptokinase. RESULTS. Thrombolytic efficacy was greatest in animals receiving both dual-acting ridogrel, 5 mg/kg intravenously, and streptokinase as evidenced by the highest incidence of high grade coronary reperfusion (solvent 3 of 11; ridogrel, 0.31 mg/kg, 5 of 7; ridogrel, 5 mg/kg, 7 of 7; p < 0.05 vs. solvent) within the shortest delay (solvent 210 min; ridogrel, 0.31 mg/kg, 85 min; ridogrel, 5 mg/kg, 37 min; p < 0.05 vs. solvent and ridogrel, 0.31 mg/kg) and the lowest incidence of reocclusion (solvent 5 of 7; ridogrel, 0.31 mg/kg, 2 of 7; ridogrel, 5 mg/kg, 1 of 7; p < 0.05 versus solvent). Myocardial infarct size after coronary artery ligation (90 min) and subsequent reperfusion (150 min) in anesthetized dogs was 49.3 +/- 4.3% versus 29 +/- 3.9% (p < 0.05 vs. solvent) of the area of the left ventricle at risk in dogs receiving solvent (n = 9) or ridogrel, 5 mg/kg intravenously (n = 10), respectively, despite similar hemodynamic characteristics, collateral blood flow and area at risk in both groups. CONCLUSIONS. Combined thromboxane A2 synthase inhibition and endoperoxide receptor antagonism 1) upgrades thrombolysis with streptokinase in canine coronary arteries, 2) limits myocardial infarct size after nonthrombotic coronary occlusion and reperfusion, and 3) may preserve ventricular function compromised by coronary occlusion through dual manipulation of the arachidonic acid cascade in blood and myocardial tissue, respectively.
