ANTIANGINAL EFFECT OF RS-5773, A DILTIAZEM CONGENER, IN THE METHACHOLINE-INDUCED ANGINAL MODEL IN RATS

The antianginal effect of RS-5773 acetoxy-8-benzyl-2,3-dihydro-5-[2-(d imethylamino)- 2-(4-methoxyphenyl)-1,5-benzothiazepine-4-(5H)-one hydr ochloride), a newly developed benzothiazepine derivative, was evaluate d in an angina model rat. Close-coronary artery injections of methacho line in anesthetized rats evoked ischemic electrocardiographic (EGG) c hanges (S wave elevation of about 0.6 mV). The ECG changes produced by methacholine were reproducible for as long as 6 hr. Intravenous and i ntraduodenal administration of RS-5773, diltiazem or clentiazem produc ed dose-dependent suppressions of the ischemic ECG changes. RS-5773 ex ceeded the other two agents both in the maximum suppressive effect on S wave elevation and in the duration of action after intravenous admin istration. The antianginal potency expressed as AUC (area under the cu rve), i.e., the percent suppression of S wave elevation integrated ove r time, revealed that RS-5773 was 16 times and 7 times more potent tha n diltiazem and clentiazem, respectively. A similar order of potency d ifference was observed after intraduodenal administration, and RS-5773 sustained its effect for about 6 hr at 3 mg/kg. In addition, RS-5773 did not cause excessive hypotension or depression of atrioventricular conduction. These results suggest that RS-5773 has a preferable profil e as an antianginal agent.