[Pharmacological study on functional significance of alpha 1-adrenoceptor subtypes in mammalian ventricular myocardium].
The present study was undertaken to determine alpha 1-adrenoceptor subtype involved in the inotropic, electrophysiological and phosphoinositide responses to myocardial alpha 1-adrenoceptor stimulation. Phenylephrine in the presence of the beta-adrenoceptor antagonist, propranolol, elicited a positive inotropic effect in a concentration-dependent manner in both rat and rabbit papillary muscles. In rat papillary muscle, the positive inotropic effect of phenylephrine was antagonized by the alpha 1A-selective antagonist, WB4101, but not affected by the alpha 1B-antagonist, chloroethylclonidine (CEC). On the other hand, the positive inotropic effect in rabbit papillary muscle was antagonized by both WB4101 and CEC. The inotropic response of rat papillary muscle to phenylephrine was composed of a negative inotropic phase and a positive inotropic phase, both of which were blocked only by WB4101. In both rat and rabbit papillary muscles, phenylephrine caused prolongation of action potential duration. WB4101, but not CEC, significantly suppressed the APD prolongation. Only in rat papillary muscle, phenylephrine exerted hyperpolarization of resting membrane potential, an effect which was also eliminated by WB4101. Furthermore, stimulation of phosphoinositide hydrolysis induced by phenylephrine (evaluated by [3H] inositol monophosphate accumulation) was inhibited by WB4101 in a concentration-dependent fashion, but the inhibitory effect on the response to phenylephrine was seen with CEC only at a higher concentration. From these results, it was concluded that both myocardial alpha 1A- and alpha 1B-adrenoceptor subtypes are able to mediate a positive inotropic effect, and that the alpha 1A-adrenoceptor-mediated positive inotropic effect is exclusively dependent on the prolongation of action potential duration, while the alpha 1B-adrenoceptor-mediated one appear to be due to a mechanism other than electrophysiological changes. In addition, based on the previous respects that the phosphatidyl-inositol hydrolytic products do not contribute to the alpha 1-adrenoceptor-mediated electrophysiological effects, the present data suggest that the coupling of alpha 1A-adrenoceptors to phosphatidylinositol hydrolysis may be independent of the positive inotropism.
Nagashima
M
M
Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
D000200:Action Potentials / Q000187:drug effects; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006352:Heart Ventricles; D006868:Hydrolysis / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000502:physiology*; D013268:Stimulation, Chemical
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D010716:Phosphatidylinositols; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; C051731:chlorethylclonidine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D003000:Clonidine