Thromboxane synthetase inhibition with CGS 13080 improves coronary blood flow after streptokinase-induced thrombolysis

Abstract

The focus of this investigation was to examine the potential beneficial effects of the selective thromboxane synthetase inhibitor CGS 13080 (imidazo [1,5-a] pyridine-5-hexanoic acid) on coronary blood flow after streptokinase-induced thrombolysis. Thrombotic occlusion of the circumflex coronary artery was produced by electrolytic (100 μA anodal current) injury to the intimal surface of the circumflex coronary artery at the site of a noncircumferential stenosis in dogs anesthetized with pentobarbital to have open-chest surgery. Intracoronary streptokinase, 6000 IU/kg in 3 ml saline solution, was infused at 0.05 ml/min for 1 hour, beginning 30 minutes after the formation of an occlusive thrombus. The animals were assigned randomly to two groups. In group I (n = 10) the intravenous infusion of vehicle was begun simultaneously with the intracoronary administration of streptokinase and continued for 2 hours after thrombolysis had been achieved. The animals in group II (n = 10) received intravenous CGS 13080 (1 mg/kg/hr) along with intracoronary streptokinase. Infarct size was assessed by a dual perfusion technique with Evans blue and triphenyltetrazolium stains to demarcate the normally perfused myocardium from the area at risk and the infarct zone within the risk region. The two groups did not differ with respect to baseline coronary blood flow, time to the development of coronary artery thrombotic occlusion, or time to achieve thrombolysis. Oscillations in coronary blood flow were more frequent in group I than in group II (group I, 9 ± 2.2; group II, 4.4 ± 0.8 oscillation/min × 100, p < 0.05 [mean ± SEM]). Reocclusion was observed more frequently in group I than in group II (8 of 10 [80%] vs 2 of 10 [20%], p < 0.05). Infarct size expressed as a percent of the total left ventricular mass was similar ([IZLV] group I, 5% ± 2%; group II, 4% ± 1%), as was the percent of the left ventricle dependent on the blood flow distribution from the left circumflex coronary artery or the area at risk of infarction ([ARLV] 37% ± 2% vs 40% ± 3%, respectively). These results demonstrate that the thromboxane synthetase inhibitor CGS 13080, in combination with the thrombolytic agent streptokinase, is able to maintain patency of the injured coronary artery after thrombolysis and to decrease the frequency of oscillatory flow responses. The results suggest a possible role for thromboxane as a contributor to the process of thrombotic reocclusion after successful thrombolysis.