title: Differential inhibition of vascular smooth muscle responses to alpha 1- and alpha 2-adrenoceptor agonists by diltiazem and verapamil.
abstract: 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.
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009284:Naphthols / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D000316:Adrenergic alpha-Agonists; D001552:Benzazepines; D002121:Calcium Channel Blockers; D007093:Imidazoles; D009284:Naphthols; D011942:Receptors, Adrenergic, alpha; C009957:5,6-dihydroxy-2-dimethylaminotetralin; D014700:Verapamil; D004110:Diltiazem; C014282:cirazoline