Jpn. J. Pharmacol. 84 (3), 301-309 (2000)

Pharmacological Characteristics of Inhibitory Action of the Selective a1-Antagonist JTH-601 on the Positive Inotropic Effect Mediated by a1-Adrenoceptors in Isolated Rabbit Papillary Muscle

Xiaoying Qiao, Ikuo Norota and Masao Endoh*

Department of Pharmacology, Yamagata University School of Medicine, 2-2-2 lida-nishi, Yamagata 990-9585, Japan
*Corresponding author.FAX:+81-23-628-5235

Abstract: 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 a1-adrenoceptor antagonist, on a1-mediated positive inotropic effect (PIE) was studied in isolated rabbit papillary muscle (1Hz at 37C). JTH-601 (0.1-10mM) shifted the concentration-response curve (CRC) for PIE of phenylephrine mediated by a1-adrenoceptor (with timolol at 1mM) to the right and downward. In the presence of 100nM WB4101, an a1A antagonist, the shift to the right disappeared and JTH-601 (1-3mM) shifted CRC for phenylephrine downward. The antagonistic action of JTH-601 was unchanged by 100nM (+)-niguldipine, another a1A antagonist. Following pretreatment with 10mM chloroethylclonidine, an a1B antagonist, the shift of CRC for phenylephrine to the right disappeared and JTH-601 (3-10mM) shifted CRC downward. Antagonistic action of JTH-601 (3mM) was unaltered by 100nM BMY7378, an a1D antagonist. JTH-601 (10mM) had no effect on b-mediated PIE of isoproterenol. These results indicate that JTH-601 exerts an inhibitory action on a1-mediated PIE through antagonism of a1A- and/or a1B-adrenoceptors in rabbit ventricular myocardium. As an a1 antagonist, JTH-601 is much less potent in rabbit ventricular muscle than in smooth muscle.

Keywords: a1-Adrenoceptor, Positive inotropic effect, Selective of a1-adrenoceptor antagonist, JTH-601,
Rabbit ventricular myocardium

Copyright The Japanese Pharmacological Society 2000

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