Role of alpha 1A adrenoceptor subtype in production of the positive inotropic effect mediated via myocardial alpha 1 adrenoceptors in the rabbit papillary muscle: influence of selective alpha 1A subtype antagonists WB 4101 and 5-methylurapidil.
In order to elucidate the contribution of alpha 1A subtype to the positive inotropic effect mediated by myocardial alpha 1 adrenoceptors, the influence of the alpha 1A selective antagonists WB 4101 and 5-methylurapidil on the alpha 1-mediated positive inotropic effect (induced by phenylephrine in the presence of a beta adrenoceptor blocking agent bupranolol) was assessed in the isolated rabbit papillary muscle. WB 4101 (10(-9)-10(-7) mol/l) shifted the concentration-response curve of the alpha 1-mediated positive inotropic effect to the right in parallel, but the slope of Schild plot did not meet the competitive antagonism: WB 4101 shifted the curve by log one unit at 10(-9) mol/l, whereas it did not cause further shift at higher concentrations of 10(-8) and 10(-7) mol/l. WB 4101 did not affect the beta adrenoceptor-mediated positive inotropic effect. 5-Methylurapidil (10(-9) to 10(-7) mol/l) shifted the curve of alpha 1-mediated positive inotropic effect to the right and downwards in a concentration-dependent manner; the slope of Schild plot calculated at the level of 20% of the maximum response to phenylephrine was close to unity. 5-Methylurapidil at 3 x 10(-7) mol/l abolished the alpha 1-mediated positive inotropic effect. In addition, 5-methylurapidil inhibited the beta adrenoceptor-mediated positive inotropic effect in the same concentration range as it antagonized the alpha 1-mediated positive inotropic effect, indicating that 5-methylurapidil is not selective for myocardial alpha 1 adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, Yamagata University School of Medicine, Japan.
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Endoh
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Takanashi
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Norota
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D004146:Dioxanes / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects*; D010656:Phenylephrine / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D013268:Stimulation, Chemical
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; C057446:5-methylurapidil; D010656:Phenylephrine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane