Comparison of the effects of a thromboxane synthase inhibitor or prostacyclin in combination with a phosphodiesterase inhibitor for prevention of experimental thrombosis and sudden death in rabbits

EF Smith and JW Egan

This study was designed to determine the in vivo effects of a phosphodiesterase inhibitor (HL 725) in combination with a thromboxane synthase inhibitor (CGS 13080) or prostacyclin (PGI2) as inhibitors of thrombin-induced changes in platelet function and prevention of sudden death. In anesthetized rabbits, the i.v. administration of thrombin reduced the circulating number of platelets from 256,000 +/- 32,000/microliter to 8 +/- 2% of the initial value, and produced a right ventricular thrombus of 285 +/- 52 mg. All animals died within 5 min. PGI2 (0.3 microgram/kg/min) or HL 725 (2 micrograms/kg/min) did not prevent the thrombin-induced fall in the number of circulating platelets, the formation of a right ventricular thrombus or death. Administration of 2 mg/kg of CGS 13080 reduced significantly the mass of the right ventricular thrombus, but did not prevent completely the reduction in the circulating platelet count or death. After the administration of the combination of CGS 13080 with HL 725, the thrombocytopenia was transient, the right ventricular thrombus was reduced (P less than .05), and survival increased to 75% (P less than .05). The combination of PGI2 with HL 725 was similar in benefit to the combination of CGS 13080 and HL 725. Survival for the group of the combination of CGS 13080 with 725 was significantly greater than survival in the CGS 13080 or HL 725 groups, indicating a synergistic effect for the combination. The decrease in blood pressure response to HL 725 was greater with PGI2, but not with CGS 13080.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 241, Issue 3, pp. 855-860, 06/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics