CEREBROVASCULAR SELECTIVITY AND VASOSPASMOLYTIC ACTION OF THE NOVEL CALCIUM-ANTAGONIST (+ 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]oxepin-11-yl)-4-(3-phenyl-2-propenyl)-piperazine dimaleate, CAS 1431 10-70-7), a new calcium antagonist, were studied in isolated rabbit an d dog arterial preparations. In rabbit arterial ring preparations, AJ- 3941 dose-dependently inhibited the contractions of various arteries c aused by high K+-depolarization (high K+) and prostaglandin F-2 alpha (PG). The inhibitory potency of AJ-3941 varied in different arteries, in descending order as follows; high K+: basilar>coronary>femoral>rena l>mesenteric artery, PG: basilar>coronary much greater than femoral an d renal artery. The median inhibitory concentration (IC50) in the basi lar artery was over 40 times lower than that in the mesenteric or femo ral artery for which the weakest inhibition in the examined arteries w as 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 fl unarizine and nicardipine. Additionally, the contractile response of t he rabbit basilar artery induced by phorbol 12,13-dibutyrate (PDBu), a n activator of protein kinase C (PKC), was greater than those of the a rteries examined such as the coronary, femoral and mesenteric arteries . The response in the basilar artery was greatly reduced in Ca2+-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 contract ile response in the basilar artery in the presence, but not in the abs ence 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 contribut es to the contraction of the cerebral artery and that the cerebroselev tive-vasodilating effect of AJ-3941 may depend, at least partly, on th e inhibition of the PKC-mediated contractile response. In rabbit basil ar arteries, AJ-3941 caused a dose-dependent inhibition of the contrac tion induced by various vasospasmogens, such as endothelin-1 (ET), ara chidonic acid, 15-hydroperoxy-eicosatetraenoic acid and the thromboxan e A(2)-mimetic U-46619. Furthermore, when isolated basilar arteries of the dog were perfused intraluminally with AJ-3941 at the concentratio n that inhibits high K+- or PG-induced contraction in the rabbit basil ar artery, AJ-3941 effectively antagonized the vasospasm induced by ex traluminal application of PG or ET. However, when flunarizine, nicardi pine, diltiazem or verapamil was used for intraluminal perfusion of th e same preparations, none of these drugs exerted spasmolytic effect. T hese results indicate that AJ-3941 has cerebrovascular selective-vasos pasmolytic action, and consequently is thought to be effective in cere brovascular disorder such as vasospasm following subarachnoid hemorrha ge.