Effects of a novel cardioprotective drug, JTV-519, on membrane currents of guinea pig ventricular myocytes

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 (i(Na)) 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 IC50 of approximately 1.2 and 2 mu M 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 mu M JTV-519 shortened the time-course and increased the level of iNa block, indicating a frequency-dependent block. The time-course of i(Na) blocking by JTV-519 was slower than that of lidocaine and similar to that of quinidine. Ca2+ current (i(Ca)) and the inwardly rectifying K+ current (i(K1)) 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 i(Na) as well as inhibition of i(Ca) and i(K1).