Differential inhibition of vascular smooth muscle responses to alpha 1- and alpha 2-adrenoceptor agonists by diltiazem and verapamil.

This work was undertaken to investigate whether diltiazem and verapamil, two blockers of the voltage-activated calcium channel, interfered with vascular smooth muscle responses mediated by stimulation of alpha 1- or alpha 2-adrenoceptors. In pithed rats (and in isolated canine saphenous vein strips) cirazoline behaved as a preferential alpha 1-adrenoceptor agonist, since its pressor (and contractile) effects were blocked selectively by the alpha 1-adrenoceptor antagonist prazosin and were relatively unaffected by the alpha 2-adrenoceptor antagonist yohimbine. In the same preparations, M-7 (2,N,N-dimethylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene) exhibited preferential alpha 2-adrenoceptor agonist properties. The pressor response to M-7 developed much more slowly than that to cirazoline, M-7 requiring approximately twice as long as cirazoline to reach the same peak effect. Pithed rats received a 30-minute intravenous infusion of either diltiazem (12.5-25.0 micrograms/kg per min) or verapamil (6.2-12.5 micrograms/kg per min) that was continued while dose-response curves to M-7 and cirazoline were generated. These compounds depressed the maxima and the slopes of arterial pressure dose-response curves to M-7 but not cirazoline. In canine saphenous vein strips, diltiazem did not change the contractile response to cirazoline but inhibited those to M-7. Verapamil however did antagonize the responses to cirazoline although significantly less than those to M-7. These results indicate that diltiazem and verapamil preferentially inhibit alpha 2-adrenoceptor-mediated responses. The hypothesis is advanced that the pharmacomechanical coupling for alpha 2-adrenoceptors involves a receptor-operated calcium channel that is sensitive to diltiazem and verapamil and, thus, might become activated when the potential across the cellular membrane attains critical values.