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