In vivo inhibition of platelet aggregation and occlusive coronary thrombus formation by a new calcium antagonist...

Reports have shown that all three major classes of calcium antagonists can inhibit platelet aggregation in vitro. In this study, we compared the platelet antiaggregatory effects of R023-6152, a thiazepinone-type calcium antagonist, with diltiazem in an in vivo canine model of spontaneous coronary thrombosis. Plasma serotonin (5-HT) levels measured in the coronary sinus were used as an index of in vivo platelet aggregation and coronary flow measured by a Doppler flow probe. Untreated controls developed total coronary occlusion in 62 +/- 18 min after the current used to initiate thrombus formation was discontinued. Control 5-HT levels peaked at 213 +/- 63 ng/ml just before occlusion. Dogs receiving intravenous (i.v.) R023-6152 (200 micrograms/kg) or diltiazem (50 micrograms/kg) immediately after the current was discontinued exhibited no significant elevations in 5-HT values (12.3 +/- 1.4 and 1.84 +/- 0.42 ng/ml for R023-6152 and diltiazem, respectively) or development of coronary occlusions in the next 3 h. Small, transient decreases in arterial pressure (8-10 mm Hg) and changes in contractility occurred during infusion of both drugs. Gravimetric determinations of thrombus weights showed significantly smaller thrombi in the drug-treated animals as compared with controls. The results indicate that both R023-6152 and diltiazem are effective in suppressing in vivo platelet aggregation associated with occlusive coronary thrombus formation.