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

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 (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 i_Na in a concentration-dependent manner with an IC₅₀ of approximately 1.2 and 2 fiM 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 μM JTV-519 shortened the time-course and increased the level of i_Na 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 ica and i_K1.