The antianginal effect of
RS-5773 ((2S,3S)-3-acetoxy-8-benzyl-2,3-dihydro-5-[2-(dimethylamino)- ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepine-4-(5H)-one hydrochloride), a newly developed benzothiazepine derivative, was evaluated in an angina model rat. Close-coronary artery
injections of
methacholine in anesthetized rats evoked ischemic electrocardiographic (ECG) changes (S wave elevation of about 0.6 mV). The ECG changes produced by
methacholine were reproducible for as long
as 6 hr. Intravenous and intraduodenal administration of
RS-5773,
diltiazem or
clentiazem produced dose-dependent suppressions of the ischemic ECG changes.
RS-5773 exceeded the other two agents both in the maximum suppressive effect on S wave elevation and in the duration of action after
intravenous administration. The antianginal potency expressed as AUC (area under the curve), i.e., the percent suppression of S wave elevation integrated over time, revealed that
RS-5773 was 16 times and 7 times more potent than
diltiazem and
clentiazem, respectively. A similar order of potency difference 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 profile as an antianginal agent.