Xiaoying Qiao, Ikuo Norota and Masao Endoh*
Department of Pharmacology, Yamagata University School of Medicine, 2-2-2 lida-nishi, Yamagata 990-9585, Japan
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 (1ÊHz at 37¡C). JTH-601 (0.1-10ÊmM) shifted the concentration-response curve (CRC) for PIE of phenylephrine mediated by a1-adrenoceptor (with timolol at 1ÊmM) to the right and downward. In the presence of 100ÊnM WBÊ4101, an a1A antagonist, the shift to the right disappeared and JTH-601 (1-3ÊmM) shifted CRC for phenylephrine downward. The antagonistic action of JTH-601 was unchanged by 100ÊnM (+)-niguldipine, another a1A antagonist. Following pretreatment with 10ÊmM chloroethylclonidine, an a1B antagonist, the shift of CRC for phenylephrine to the right disappeared and JTH-601 (3-10ÊmM) shifted CRC downward. Antagonistic action of JTH-601 (3ÊmM) was unaltered by 100ÊnM BMYÊ7378, an a1D antagonist. JTH-601 (10ÊmM) 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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