AJ-3941. a new calcium antagonist, attenuates phorbol 12,13-dibutyrate-induced vasoconstriction of cerebral arteries in rabbit

• Published in: Japanese Journal of Pharmacology 1995, Vol.67 (suppl.1), p.185-185
• Main Authors: Hashizume, Masahide, Minato, Hisao, Fujitani, Buichi, Masuda, Yoshinobu, Hosoki, Kanoo
• Format: Article
• Language: English
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1016/S0021-5198(19)46704-8

We previously reported that AJ-3941, a new calcium antagonist, had vasospasmolytic action which was selective for cerebral artery (J. Cereb. Blood Flow Metab., 13, S654, 1993) and preventive effect on subarachnoid hemorrhage (SAH) model (Jap. J. Pharmacol.,64, Suppl 1, 239, 1994). In the late phase of spasm affer SAH, it was reported that Ca^2+ /phospholipid-dependent protein kinase (protein kinase C：PKC) was activated in canine basilar artery. In the present study, we have investigated whether cerebrovascular-selective action of AJ-3941 is mediated by the inhibitory effects on activation of PKC-dependent mechanism. PKC-mediated contractile response was dose-dependently induced by phorbol 12,13-dibutyrate (PDBu)(0.01-1 μM), an activator of PKC, in various isolated arteries of rabbits. The contractile response of basilar artery induced by PDBu was considerably more sensitive than those of coronary, renal, femoral and mesenteric arteries. In basilar artery, pre-treatment with AJ-3941 (10 μM) as well as H-7 (10 μM), a PKC inhibitor, prevented the contractile responses induced by PDBu, but with diltiazem (10 μM) and nicardipine (10nM) did not. However, AJ-3941 did not inhibit the PKC activity assayed by enzymatic determination. These results suggest that the contractile response of cerebral artery is more largely dependent on PKC-mediated mechanism than those of other arteries in rabbit. AJ-3941 in addition to blocking calcium channel(s), may exert its cerebral-vasospasmolytic action by inhibiting the PKC-mediated, but as yet undefined mechanism.