Cerebrovascular selectivity and vasospasmolytic action of the novel calcium antagonist (+/-)-(E)-1-(3-fluoro-6, 11-dihydrodibenz[b,e]oxepin-11-yl)-4-(3-phenyl-2-propenyl)-piperazine dimaleate in isolated cerebral arteries of the rabbit and dog.
The cerebrovascular selectivity and vasospasmolytic action of AJ-3941 ((+/-)-(E)-1-(3-fluoro-6, 11-dihydrodibenz[b,e]oxepin-11-yl)-4-(3-phenyl-2-propenyl)-p iperazine dimaleate. CAS 143110-70-7), a new calcium antagonist, were studied in isolated rabbit and dog arterial preparations. In rabbit arterial ring preparations, AJ-3941 dose-dependently inhibited the contractions of various arteries caused by high K(+)-depolarization (high K+) and prostaglandin F2 alpha (PG). The inhibitory potency of AJ-3941 varied in different arteries, in descending order as follows: high K+: basilar > coronary > femoral > renal > mesenteric artery, PG: basilar > coronary > > femoral and renal artery. The median inhibitory concentration (IC50) in the basilar artery was over 40 times lower than that in the mesenteric or femoral artery for which the weakest inhibition in the examined arteries was observed. This selective action of AJ-3941 for cerebral artery was also observed in the frontal and middle cerebral arteries of dogs. The selectivity for the rabbit basilar artery was higher than those of flunarizine and nicardipine. Additionally, the contractile response of the rabbit basilar artery induced by phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC), was greater than those of the arteries examined such as the coronary, femoral and mesenteric arteries. The response in the basilar artery was greatly reduced in Ca(2+)-free medium, while this was not the case in other arteries. AJ-3941 as well as H-7, an inhibitor of PKC, potently inhibited PDBu-induced contractile response in the basilar artery in the presence, but not in the absence of Ca2+ in the medium, whereas the existing calcium antagonists, diltiazem and nicardipine, did not inhibit the contractile response in both conditions. These results suggest that the PKC-dependent system which is mediated by influx of extracellular Ca2+ profoundly contributes to the contraction of the cerebral artery and that the cerebroselective-vasodilating effect of AJ-3941 may depend, at least partly, on the inhibition of the PKC-mediated contractile response. In rabbit basilar arteries, AJ-3941 caused a dose-dependent inhibition of the contraction induced by various vasospasmogens, such as endothelin-1 (ET), arachidonic acid, 15-hydroperoxy-eicosatetraenoic acid and the thromboxane A2-mimetic U-46619. Furthermore, when isolated basilar arteries of the dog were perfused intraluminally with AJ-3941 at the concentration that inhibits high K(+)- or PG-induced contraction in the rabbit basilar artery, AJ-3941 effectively antagonized the vasospasm induced by extraluminal application of PG or ET. However, when flunarizine, nicardipine, diltiazem or verapamil was used for intraluminal perfusion of the same preparations, none of these drugs exerted spasmolytic effect. These results indicate that AJ-3941 has cerebrovascular selective-vasospasmolytic action, and consequently is thought to be effective in cerebrovascular disorder such as vasospasm following subarachnoid hemorrhage.
Minato
H
H
Department of Pharmacology I, Discovery Research Laboratories I, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Hashizume
M
M
Masuda
Y
Y
Fujitani
B
B
Hosoki
K
K
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003990:Dibenzoxepins / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D003990:Dibenzoxepins; D010879:Piperazines; D011453:Prostaglandins; D014665:Vasodilator Agents; C077479:AJ 3941; D015240:Phorbol 12,13-Dibutyrate; D011188:Potassium