Prevention by the new Ca2+ channel antagonist, AJ-3941, of loss of endothelium-dependent relaxation after subarachnoid hemorrhage in rats.
AJ-3941 ((+/-)-(E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]-oxepine-11-yl ) -4-(3-phenyl-2-propenyl)-piperazine dimaleate; CAS No. 143110-70-7), a cerebrovascular-selective Ca2+ channel antagonist having anti-lipid peroxidative action, was reported to prevent cerebral vasospasm following subarachnoid hemorrhage in rats. The present study was undertaken to determine whether AJ-3941 protects the impairment of cerebroarterial endothelium-dependent relaxation which is concomitantly induced with cerebral vasospasm. Subarachnoid hemorrhage biphasically suppressed the response to acetylcholine in rat basilar artery, at 0.5 h (n = 4; P < 0.06) and 1 day (n = 5; P < 0.05) after subarachnoid hemorrhage. The reduction of the responses was correlated significantly to the degree of vasospasm determined angiographically. This reduction was accompanied by a 49% increase of arterial lipid peroxide contents. Endothelium-independent relaxation in subarachnoid hemorrhage rats was preserved in response to 3-morpholinosydnonimine, sodium nitroprusside and papaverine. AJ-3941 prevented (n = 6-8, P < 0.05) the suppression of the acetylcholine-induced response and the increase in lipid peroxide content in subarachnoid hemorrhage rats. These results suggest that AJ-3941 could exert its vasospasmolytic effect by preserving endothelial function through its anti-lipid peroxidative action, in addition to its inhibition of vasospasmogen-induced vasoconstriction related to intracellular Ca2+ mobilization.
Minato
H
H
Department of Pharmacology I, Discovery Research Laboratories I, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Honda
Y
Y
Masuda
Y
Y
Fujitani
B
B
Hosoki
K
K
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003990:Dibenzoxepins / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy*
D002121:Calcium Channel Blockers; D003990:Dibenzoxepins; D010879:Piperazines; C077479:AJ 3941; D000109:Acetylcholine