Ca2+ antagonists and inhibitory effects of dopamine on isolated rabbit ear artery.
Rabbit ear arteries were isolated and perfused with Krebs-bicarbonate buffer. Brief periods of supramaximal nerve stimulation caused reproducible constriction of the arteries, which was inhibited by dopamine (EC50 approximately equal to 0.1 microM). Verapamil or flunarizine (at 1 or 5 microM) antagonized this inhibitory effect of dopamine. The maximal effect of verapamil, 5 microM was reached after 8 min and that of flunarizine, 5 microM after 40 min of perfusion with the drug. The antagonism of dopamine by verapamil, even at 5 microM, was incomplete (approximately equal to 80%), whereas flunarizine, 5 microM completely antagonized the effect of dopamine. Nitrendipine, nimodipine, or nisoldipine, at either 1 or 5 microM, or solvent (ethanol, 0.03%) had no significant effect on dopamine-induced inhibition of vasoconstriction even after perfusion for 40 min. Antagonism of dopamine at central synapses may conceivably explain reported Parkinsonian side effects of flunarizine. Our results suggest a mechanism for the tendency of flunarizine to cause Parkinsonism and an explanation why 1,4-dihydropyridines are not likely to have this side effect.
Scriabine
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Miles Institute for Preclinical Pharmacology, West Haven, Connecticut.
Pan
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D000818:Animals; D001158:Arteries / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D004558:Electric Stimulation; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D005444:Flunarizine / Q000494:pharmacology; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010477:Perfusion; D011817:Rabbits; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D000431:Ethanol; D014700:Verapamil; D005444:Flunarizine; D004298:Dopamine