In vivo inhibition of platelet aggregation and occlusive coronary thrombus formation by a new calcium antagonist (R023-6152)

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.