Antianginal effect of RS-5773, a diltiazem congener, in the methacholine-induced anginal model in rats.
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.
Shiga
H
H
Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Miyake
S
S
Fukuda
N
N
Yorikane
R
R
Koike
H
H
D000788:Angina Pectoris, Variant / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013841:Thiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D002121:Calcium Channel Blockers; D013841:Thiazepines; D014665:Vasodilator Agents; D016210:Methacholine Chloride; C076757:RS 5773; D004110:Diltiazem