Jpn. J. Pharmacol. 79 (3), 275-281 (1999)

Effects of a Novel Cardioprotective Drug, JTV-519, on Membrane Currents of Guinea Pig Ventricular Myocytes

Junko Kimura, Masanori Kawahara, Eiichi Sakai, Junichi Yatabe and Hironori Nakanishi

Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan

Abstract: We investigated effects of a novel cardioprotective drug, JTV-519 (4-[3-(4-benzylpiperidin-1-yl)

propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine monohydrochloride) on membrane currents of guinea pig ventricular myocytes by whole-cell voltage and current clamp methods. The fast Na+ current (iNa) was activated by ramp pulses from various holding potentials of -90, -80 or -60 mV to 10 mV with various intervals. At 0.2 Hz, JTV-519 inhibited iNa in a concentration-dependent manner with an IC50of approximately 1.2 and 2 microM at the holding potential of -60 and -90 mM, respectively, implicating a voltage-dependent block. Increasing the pulse frequency from 1 to 2 or 3.3 Hz in the presence of 1 microM JTV-519 shortened the time-course and increased the level of iNa block, indicating a frequency-dependent block. The time-course of iNa blocking by JTV-519 was slower than that of lidocaine and similar to that of quinidine. Ca2+ current (iCa) and the inwardly rectifying K+ current (iKl) were also inhibited by JTV-519. JTV-519 decreased the duration and the height of the plateau of the action potential. We conclude that JTV-519 has frequency- and voltage-dependent blocking effects on iNa as well as inhibition of ica and iKl.

Keywords: JTV-519, Na+ channel, Na+ channel inhibitor, Cardiac myocyte, Antiarrhythmic drug

Copyrightę The Japanese Pharmacological Society 1999

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