Potent inhibitory action of chlorethylclonidine on the positive inotropic effect and phosphoinositide hydrolysis mediated via myocardial alpha 1-adrenoceptors in the rabbit ventricular myocardium.
The influence of the alpha 1b-adrenoceptor-selective antagonist chlorethylclonidine on the alpha 1-adrenergic positive inotropic effect and the phosphoinositide hydrolysis induced by phenylephrine was investigated in the rabbit ventricular myocardium. Pretreatment of membrane fractions derived from the rabbit ventricular muscle with 10(-5) mol/l chlorethylclonidine decreased the specific binding of [3H]prazosin (at a saturating concentration of 10(-9) mol/l) from the control value of 11.27 +/- 0.48 to 4.18 +/- 1.87 fmol/mg protein. The inhibition by adrenaline of the binding of [3H]prazosin (slope factor and affinity) was not affected by chlorethylclonidine. The positive inotropic effect of phenylephrine (in the presence of 3 x 10(-7) mol/l bupranolol) was inhibited by chlorethylclonidine in a concentration-dependent manner (10(-7)-10(-5) mol/l) and abolished by 10(-5) mol/l chlorethylclonidine. The concentration of chlorethylclonidine to inhibit the phenylephrine-induced maximum response to 50% was 2.4 x 10(-6) mol/l. The accumulation of [3H]inositol monophosphate and [3H]inositol trisphosphate induced by 10(-5) mol/l phenylephrine was inhibited by chlorethylclonidine in the same concentration range. These findings indicate that the myocardial alpha 1-adrenoceptors mediating a positive inotropic effect in the rabbit ventricular myocardium may belong to the chlorethylclonidine-sensitive alpha 1b-subtype, and that the subcellular mechanism of action involve phosphoinositide hydrolysis.
Department of Pharmacology, Yamagata University School of Medicine, Japan.
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Takanashi
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Norota
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Endoh
D000317:Adrenergic alpha-Antagonists; D000818:Animals; D002046:Bupranolol / Q000494:pharmacology; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D004837:Epinephrine / Q000032:analysis / Q000097:blood; D006352:Heart Ventricles / Q000187:drug effects; D007295:Inositol Phosphates / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010210:Papillary Muscles / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011224:Prazosin / Q000378:metabolism; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism / Q000502:physiology*
D000317:Adrenergic alpha-Antagonists; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine; C051731:chlorethylclonidine; D002046:Bupranolol; D003000:Clonidine; D011224:Prazosin; D004837:Epinephrine