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.