aj-3941 and Ischemic-Attack--Transient

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.

Topics: Animals; Body Temperature; Brain; Calcium Channel Blockers; Cerebral Cortex; Cerebral Infarction; Dibenzoxepins; Enzyme Inhibitors; Ischemic Attack, Transient; Male; Methacrylates; Piperazines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thromboxane-A Synthase

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

Topics: Animals; Calcium Channel Blockers; Cerebral Arteries; Cerebrovascular Circulation; Dibenzoxepins; Dogs; Female; In Vitro Techniques; Ischemic Attack, Transient; Male; Muscle Contraction; Muscle, Smooth, Vascular; Phorbol 12,13-Dibutyrate; Piperazines; Potassium; Prostaglandins; Rabbits; Vasodilator Agents

A subarachnoid hemorrhage (SAH) model in rats was produced by the injection of homologous blood into the cisterna magna. Effects of AJ-3941 ((+/-)-(E)-1-(3-fluoro-6,11 -dihydrodibenz[b,e]-oxepine-11-yl)-4-(3-phenyl-2-propenyl)-p iperazine dimaleate, CAS 143110-70-7) on the development of cerebral vasospasm and the change of regional cerebral blood flow (rCBF) following SAH was investigated in this model. Cerebral vasospasm following SAH showed a biphasic pattern with an early phrase at 10 min and a late phrase on 1 day after blood injection. The physiological parameters (blood pressure, heart rate and blood gas contents) remained stable within the physiological range throughout the course of the experiment. AJ-3941 (0.01 mg/kg i.v. or 0.3 mg/kg p.o.) significantly prevented the development of late phase cerebral vasospasm. Cisternal injection of homologous blood significantly reduced rCBF immediately after the injection and the reduction lasted during the observation period (30 min). Reduction in rCBF after the injection of homologous blood was prevented by AJ-3941 (0.01 mg/kg i.v.). rCBF in AJ-3941-treated rats completely returned to the basal values after 30 min. The present suggest that AJ-3941 may be useful in the prevention of late spasm and in the improvement of cerebral circulation impaired with SAH.

Topics: Animals; Cerebrovascular Circulation; Dibenzoxepins; Disease Models, Animal; Ischemic Attack, Transient; Male; Piperazines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Subarachnoid Hemorrhage; Vasodilator Agents