Pharmacological Characteristics of Inhibitory Action of the Selective α_1-Antagonist JTH-601 on the Positive Inotropic Effect Mediated by α_1-Adrenoceptors in Isolated Rabbit Papillary Muscle

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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 α1-adrenoceptor antagonist, on α1-mediated positive inotropic effect (PIE) was studied in isolated rabbit papillary muscle (1 Hz at 37°C). JTH-601 (0.1-10 μM) shifted the concentration-response curve (CRC) for PIE of phenylephrine mediated by α1-adrenoceptor (with timolol at 1 μM) to the right and downward. In the presence of 100 nM WB 4101, an α1A antagonist, the shift to the right disappeared and JTH-601 (1-3 μM) shifted CRC for phenylephrine downward. The antagonistic action of JTH-601 was unchanged by 100 nM (+)-niguldipine, another α1A antagonist. Following pretreatment with 10 μM chloroethylclonidine, an α1B antagonist, the shift of CRC for phenylephrine to the right disappeared and JTH-601 (3-10 μM) shifted CRC downward. Antagonistic action of JTH-601 (3 μM) was unaltered by 100 nM BMY 7378, an α1D antagonist. JTH-601 (10 μM) had no effect on β-mediated PIE of isoproterenol. These results indicate that JTH-601 exerts an inhibitory action on α1-mediated PIE through antagonism of α1A- and/or α1B-adrenoceptors in rabbit ventricular myocardium. As an α1 antagonist, JTH-601 is much less potent in rabbit ventricular muscle than in smooth muscle.
社団法人日本薬理学会の論文
2000-11-01