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.
D000200:Action Potentials / Q000187:drug effects; D000317:Adrenergic alpha-Antagonists; D000818:Animals; D001158:Arteries / Q000187:drug effects; D002118:Calcium / Q000037:antagonists & inhibitors; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D015237:Dinoprost; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000633:toxicity; D010210:Papillary Muscles / Q000187:drug effects; D010276:Parasympatholytics; D011188:Potassium / Q000494:pharmacology; D011460:Prostaglandins F / Q000037:antagonists & inhibitors; D012702:Serotonin Antagonists
D000317:Adrenergic alpha-Antagonists; D007546:Isoquinolines; D010276:Parasympatholytics; D011460:Prostaglandins F; D012702:Serotonin Antagonists; C052931:Ro 22-4839; D015237:Dinoprost; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine