(+/-)-tamsulosin, an alpha 1A-adrenoceptor antagonist, inhibits the positive inotropic effect but not the accumulation of inositol phosphates in rabbit heart.
The influence of (+/-)-tamsulosin, a selective alpha 1A-adrenoceptor antagonist, on the positive inotropic effect and the accumulation of inositol phosphates that are induced via alpha 1-adrenoceptors was studied in comparison with that of another alpha 1A-adrenoceptor ligand oxymetazoline in the rabbit ventricular myocardium. Phenylephrine elicited a concentration-dependent positive inotropic effect via alpha 1-adrenoceptors in the presence of either (+/-)-bupranolol or S(-)-timolol. The mode of antagonism induced by (+/-)-tamsulosin on the effect of phenylephrine was dependent or the concentration applied: (+/-)-tamsulosin at 1 and 3 nM acted in a competitive manner, the slope of the regression line of the Schild plot being unity and the pA2 value being 9.12; at 10 nM, it shifted further the concentration-response curve to the right without affecting the maximal response but the slope became less than unity. At 100 nM and higher, it suppressed the maximal response to phenylephrine. (+/-)-Tamsulosin effectively antagonized the positive inotropic effect of phenylephrine even after inactivation of alpha 1B-adrenoceptors by treatment with chlorethylclonidine, which is an indication that the (+/-)-tamsulosin-sensitive subtype belongs to a class resistant to chlorethylclonidine. (+/-)-Tamsulosin, over the range of concentrations at which it antagonized the positive inotropic effect mediated by alpha 1-adrenoceptors, did not affect the accumulation of [3H]inositol phosphates that was induced by 10 microM phenylephrine. Oxymetazoline antagonized the positive inotropic effect of phenylephrine in a competitive manner without affecting the accumulation of inositol monophosphate induced by phenylephrine. These results indicate that the positive inotropic effect, mediated via (+/-)-tamsulosin- and oxymetazoline-sensitive subtype of alpha 1-adrenoceptors, is exerted by a subcellular mechanism that is independent of the accumulation of inositol phosphates.
Department of Pharmacology, Yamagata University School of Medicine, Japan.
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D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010109:Oxymetazoline / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D000077409:Tamsulosin; D014316:Tritium
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D007295:Inositol Phosphates; D013449:Sulfonamides; D014316:Tritium; C051731:chlorethylclonidine; D010109:Oxymetazoline; D000077409:Tamsulosin; D003000:Clonidine