Pharmacological characteristics of inhibitory action of the selective alpha1-antagonist JTH-601 on the positive inotropic effect mediated by alpha1-adrenoceptors in isolated rabbit papillary muscle.
Influence of JTH-601 [N-(3-hydroxy-6-methoxy-2,4,5-trimethylbenzyl)-N-methyl-2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethylamine hemifumarate], a selective alpha1-adrenoceptor antagonist, on alpha1-mediated positive inotropic effect (PIE) was studied in isolated rabbit papillary muscle (1 Hz at 37 degrees C). JTH-601 (0.1-10 microM) shifted the concentration-response curve (CRC) for PIE of phenylephrine mediated by alpha1-adrenoceptor (with timolol at 1 microM) to the right and downward. In the presence of 100 nM WB 4101, an alpha1A antagonist, the shift to the right disappeared and JTH-601 (1-3 microM) shifted CRC for phenylephrine downward. The antagonistic action of JTH-601 was unchanged by 100 nM (+)-niguldipine, another alpha1A antagonist. Following pretreatment with 10 microM chloroethylclonidine, an alpha1B antagonist, the shift of CRC for phenylephrine to the right disappeared and JTH-601 (3-10 microM) shifted CRC downward. Antagonistic action of JTH-601 (3 microM) was unaltered by 100 nM BMY 7378, an alpha1D antagonist. JTH-601 (10 microM) had no effect on beta-mediated PIE of isoproterenol. These results indicate that JTH-601 exerts an inhibitory action on alpha1-mediated PIE through antagonism of alpha1A- and/or alpha1B-adrenoceptors in rabbit ventricular myocardium. As an alpha1 antagonist, JTH-601 is much less potent in rabbit ventricular muscle than in smooth muscle.
Qiao
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Department of Pharmacology, Yamagata University School of Medicine, Japan.
Norota
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Endoh
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D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D003408:Cresols / Q000494:pharmacology*; D003864:Depression, Chemical; D004095:Dihydropyridines / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D011817:Rabbits; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000502:physiology
D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D003408:Cresols; D004095:Dihydropyridines; D004146:Dioxanes; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; C101291:JTH 601; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; C053428:BMY 7378; D007545:Isoproterenol; C054074:niguldipine