Reduction in the incidence of thrombosis by the thromboxane synthetase inhibitor CGS 13080 in a canine model of coronary artery injury
Simpson, P.J.; Smith, C.B.; Rosenthal, G.; Lucchesi, B.R.
Journal of Pharmacology and Experimental Therapeutics 238(2): 497-501
1986
ISSN/ISBN: 0022-3565 PMID: 3735129 Document Number: 286155
The antithrombotic potential of the thromboxane (TX) synthetase inhibitor CGS 13080 (CGS) was studied in an anesthetized open-chest canine model of coronary artery intimal wall injury induced by the local application of a low amperage electrical current (100 microA for 6 hr). CGS was administered by i.v. infusion (1 mg/kg/min) beginning 30 min before applying the direct current to the intimal wall of the vessel. CGS did not alter basal values for heart rate, blood pressure or coronary blood flow. After 6 hr of current application to the vessel, 1 of 10 CGS-treated dogs exhibited complete thrombotic occlusion of the circumflex coronary artery compared to 8 of 10 nontreated control dogs (P less than .01). Thrombus masses within the injured left circumflex coronary artery were: Control, 25.9 +/- 4.5 mg (n = 10) and CGS, 11.0 +/- 2.8 mg (n = 10); P less than .01. The concentration of TXB2 determined ex vivo in serum from thrombin-activated whole blood was decreased by CGS administration: Control, 43.15 +/- 16.08 ng/ml (n = 9) vs. CGS, 1.72 +/- .69 ng/ml (n = 10); P less than .001. Ex vivo platelet aggregometry demonstrated that arachidonic acid (0.65 mM)-induced aggregation was reduced from a control value of 82.3 +/- 7.8% (n = 10) to 45.0 +/- 11.3% (n = 10) (P less than .05), whereas aggregation in response to ADP (5 micrograms/ml) or collagen (156 and 312 micrograms/ml) was unaffected. CGS was compared with two other TX synthetase inhibitors, U63557A and OKY1581, for the ability to divert cyclic endoperoxide metabolism to the synthesis of prostaglandin (PG) E2 and prostacyclin in response to stimulation of whole blood in vitro with collagen (25 micrograms/ml). CGS, U63557A and OKY 1581 were found to be equally effective with respect to PGE2 and 6-keto PGF1 alpha production in vitro. The data demonstrate that CGS is an effective antithrombotic agent in vivo and that it selectively inhibits arachidonic acid-induced platelet aggregation ex vivo and the formation of TXA2 in thrombin-activated whole blood.