1999 Volume 79 Issue 3 Pages 275-281
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 IC50 of approximately 1.2 and 2 μM 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 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 (iK1) 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 iK1.
