Jpn. J. Pharmacol. 72, 365-374 (1996)
Antianginal Effect of RS-5773, a Diltiazem Congener, in the Methacholine-Induced
Anginal Model in Rats
Hiroshi Shiga, Shigeki Miyake, Norio Fukuda, Ryosuke Yorikane and Hiroyuki
Koike (*)
Research Laboratories, Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku
Tokyo 140, Japan
(*) To whom correspondence should be addressed.
Abstract: 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.
Keywords: Methacholine, Antianginal effect, Benzothiazepine derivative,
RS-5773
Copyright© The Japanese Pharmacological Society 1996
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