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.