Effects of phenothiazine on contractions induced by prostaglandin F2 alpha and 5-hydroxytryptamine in normal and spastic canine cerebral artery.
We have investigated the effect of phenothiazine, a compound known to inhibit calmodulin, on the responses of normal and spastic cerebral arteries, using the canine "two hemorrhage" model of cerebrovascular spasm. Ring preparations from control vessels or vessels removed three or seven days after injection of blood, were contracted with either 5-hydroxytryptamine (5-HT) or prostaglandin F2 alpha (PGF2 alpha) and then exposed to increasing concentrations of phenothiazine. In normal arteries, low concentrations of phenothiazine enhanced the response to PGF2 alpha, while higher concentrations caused relaxation. Responses to 5-HT were inhibited by all concentrations of phenothiazine tested. When normal arteries were compared with arteries from animals injected with blood, in the case of 5-HT, phenothiazine was a less effective antagonist at low doses, but equieffective at higher doses. Similar experiments conducted with PGF2 alpha showed that phenothiazine was a more effective antagonist in spastic vessels. We conclude that 5-HT and PGF2 alpha have significant differences in the mechanism by which they produce contraction of cerebral vessels, that phenothiazine has secondary effects on contraction independent of inhibition of calmodulin, and, finally that the effects of phenothiazine in clinical vasospasm may be insufficient to reverse the condition, despite the observation that vessels in spasm may be more sensitive to this agent.
Doi
M
M
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Saito
K
K
Konno
H
H
Ohta
H
H
Nishizawa
Y
Y
Cook
D
D
D000818:Animals; D002147:Calmodulin / Q000378:metabolism; D002536:Cerebral Arteries; D015237:Dinoprost / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D007537:Isometric Contraction / Q000187:drug effects*; D008297:Male; D009128:Muscle Spasticity / Q000188:drug therapy; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010640:Phenothiazines / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology
D002147:Calmodulin; D010640:Phenothiazines; D012701:Serotonin; D015237:Dinoprost; C031637:phenothiazine