The selective inhibition of serotonin-induced contractions of rabbit cerebral vascular smooth muscle by calcium-antagonistic dihydropyridines. An investigation of the mechanism of action of nimodipine.
I studied the role of calcium in the activation of isolated rings of saphenous and basilar arteries of the rabbit by comparing the effect of calcium withdrawal with the effect of the calcium antagonist nimodipine [isopropyl(2-methoxyethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate]. Serotonin-induced contractions of both vessels were inhibited quickly by incubation in calcium-free solution, showing the contractions of both vessels to be dependent on extracellular calcium. Potassium-induced contractions of both vessels were inhibited markedly by nimodipine (basilar: ID50 = 1.7 X 10(-10) mol/liter; saphenous: ID50 = 2.6 X 10(-10) mol/liter), showing depolarization-induced calcium influx (probably through "potential sensitive channels", PSCs) to be sensitive to nimodipine. In the basilar artery the sustained, tonic phase of serotonin-induced contractions (probably through "receptor operated channels," ROCs) was potently inhibited (ID50 = 7.3 X 10(-10) mol/liter) by nimodipine. However, the initial short-lived phase of this contraction of the basilar artery was relatively unaffected (ID50 = 2 X 10(-6) mol/liter), indicating that the inhibitory action of nimodipine on tonic contractions of the basilar artery was not due to antagonism at the serotonin receptor level. In contrast, in the saphenous artery the serotonin-induced contractions were unaffected by nimodipine in doses up to 2.4 X 10(-5) mol/liter. It is postulated that the selective inhibition of the sustained tonic contraction of the basilar artery is due to a selective inhibition by nimodipine of calcium movement through ROCs in this vessel. Agonist-induced activation of ROCs in peripheral blood vessels does not seem to be affected by calcium antagonists.
D000818:Animals; D001921:Brain / Q000187:drug effects*; D002118:Calcium / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009539:Nicotinic Acids / Q000494:pharmacology; D009553:Nimodipine; D009578:Nitrobenzenes / Q000494:pharmacology; D011188:Potassium; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology*
D009539:Nicotinic Acids; D009578:Nitrobenzenes; D011743:Pyrimidines; D012701:Serotonin; D009553:Nimodipine; D011188:Potassium; D002118:Calcium