title: The preferential inhibition of alpha 1- over beta-adrenoceptor-mediated positive inotropic effect by organic calcium antagonists in the rabbit papillary muscle.
abstract: Experiments were carried out to elucidate the mechanism that the positive inotropic effect mediated by alpha 1-adrenoceptors is more susceptible to organic calcium antagonists than the beta-adrenoceptor-mediated effect. Verapamil and diltiazem displaced the specific binding of [3H]prazosin to the membrane fraction derived from the rabbit ventricular myocardium, verapamil being about 70 times more potent than diltiazem. Nifedipine did not displace the binding. While these compounds suppressed the positive inotropic effect mediated via alpha 1-adrenoceptors in a concentration-dependent manner, there was no correlation between the potency of the compounds to displace the [3H]prazosin binding and to inhibit the alpha-mediated positive inotropic effect. The relative potency of three calcium antagonists to decrease the basal force of contraction and the alpha 1-mediated effect (of the same extent as compared to basal force of contraction) was consistent to each other. The positive inotropic effect mediated by beta-adrenoceptors was inhibited much less, and was enhanced by low concentrations of organic calcium antagonists. The differential action of calcium antagonists on the alpha- and beta-mediated positive inotropic effect was mimicked by lowering the extracellular calcium concentration to 1/2, 1/4 and 1/8 of that in normal Krebs-Henseleit solution (2.5 mmol/l). These results indicate that the alpha 1-adrenoceptor blocking activity does not play an essential role for the preferential inhibition of alpha-mediated positive inotropic effect by organic calcium antagonists. Difference in the subcellular mechanism involved in mobilization of intracellular Ca2+ subsequent to alpha 1- and beta-adrenoceptor activation may be responsible for the differential inhibitory action of calcium antagonists in the rabbit heart.
authors.affiliation: Department of Pharmacology, Yamagata University School of Medicine, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kushida
authors.forename: T
authors.initials: T
authors.lastname: Hiramoto
authors.forename: M
authors.initials: M
authors.lastname: Endoh
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D011224:Prazosin / Q000378:metabolism; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D014700:Verapamil; D004110:Diltiazem; D009543:Nifedipine; D002118:Calcium; D011224:Prazosin