Post-treatment of transient focal cerebral ischemia in rats with the novel cerebrovascular-selective Ca2+ channel antagonist (+/-)-(E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]-oxepine-11-yl)-4-(3-pheny l-2-propenyl)-piperazine dimaleate.

Article

Author: Fujitani, B ; Hosoki, K ; Minato, H ; Masuda, Y ; Kikuta, C

The efficacy of post-ischemic treatment with AJ-3941 ((+/-)-(E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]-oxepine-11-yl )-4-(3-phenyl-2- propenyl)-piperazine dimaleate, CAS 143110-70-7), a cerebrovascular selective Ca2+ channel antagonist, on brain infarction induced by focal ischemia-reperfusion in rats was evaluated. Focal ischemia was induced by transient occlusion of middle cerebral artery (MCA) with a 3-0 nylon monofilament for 90 min. One day after MCA occlusion (MCAo), brain infarct size was determined by measuring 2,3,5-triphenyltetrazonium chloride-negative stained area of the serial brain sections. The development of cerebral infarction was observed in both regions of cortex and subcortex, such as striatum, caudatum, putamen, hippocampus and corpus callosum. Post-ischemic treatment with AJ-3941 (1 or 3 mg/kg p.o., 10 min and 3 h after the occlusion) significantly reduced the infarct size and volume in the ipsilateral hemisphere in a dose-dependent manner, compared to the solvent control. The reducing effect was observed mainly in the cortical region, and a significant reduction of the subcortical infarct volume was found at the higher dose (3 mg/kg). Post-ischemic treatment with the thromboxane A2 synthetase inhibitor, sodium ozagrel (150 micrograms/kg/min i.v. infusion, between 1 h and 24 h after the MCAo) did not reduce the infarct volume in the hemisphere after ischemia-reperfusion. AJ-3941 had only minimum effect on the elevation of body temperature during ischemia-reperfusion. These results indicate that post-ischemic treatment with AJ-3941 may ameliorate the brain injury after the transient focal cerebral ischemia, and they suggest that AJ-3941 has beneficial effects for treatment of ischemic cerebral damage, such as stroke.

01 Apr 1997·Arzneimittel-Forschung

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.

Article

Author: Fujitani, B ; Hosoki, K ; Minato, H ; Masuda, Y ; Hashizume, M

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.

01 Nov 1996·European Journal of PharmacologyQ3 · MEDICINE

Prevention by the new Ca2+ channel antagonist, AJ-3941, of loss of endothelium-dependent relaxation after subarachnoid hemorrhage in rats

Q3 · MEDICINE

Article

Author: Hosoki, Kanoo ; Masuda, Yoshinobu ; Fujitani, Buichi ; Minato, Hisao ; Honda, Yayoi

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Stroke	Discovery	JP	Dainippon Pharmaceutical Co., Ltd.	-

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