Spasmolytic action of the cerebral circulation improver 6,7-dimethoxy-1- (3,4-dimethoxybenzyl)-4-[( 4-(2-methoxyphenyl)-1-piperazinyl]methyl) isoquinoline in isolated canine vessels.

Vasodilating action of a new calmodulin antagonist, 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-[( 4-(2- methoxyphenyl)-1-piperazinyl] methyl) isoquinoline (Ro 22-4849) was examined in various isolated canine vessels. Ro 22-4839 was found to dilate basilar and middle cerebral arteries and to non-selectively antagonize submaximal contraction of these arteries under the treatment of various constrictors (K+, Ca2+, PGF2 alpha (dinoprost), serotonin and incubated blood) with IC50 values ranging from 0.043 to 1.69 mumol/l. Vasospasmolytic action of the compound in these cerebral arteries was 9 and 20 times greater than those in coronary and femoral arteries, respectively. The arterial relaxation by Ro 22-4839 was hardly overcome by addition of extra calcium and Ro 22-4839 did not alter calcium channels in the guinea-pig papillary muscle, although the compound inhibited the tension development, confirming its calmodulin antagonistic properties. Ro 22-4839 inhibited norepinephrine (NE)-induced contraction of femoral arterial strips concentration-dependently, and prevented NE-induced lethal extravasation in mice with an ED50 value of 1.96 mg/kg p.o. In in vitro [3H]-dihydroergocryptine binding assay and ex vivo [3H]-WB-4101 (2-[(2',6'-dimethoxy)phenoxyethylamino] methylbenzodioxan) binding assay, the compound showed a potent inhibitory action on alpha 1-adrenoceptor. These findings indicate that Ro 22-4839 exerts the spasmolytic effects on cerebral vessels through calmodulin antagonistic properties combined with alpha 1-adrenoceptor blocking action.