Block of Na+ channel by bepridil in isolated guinea-pig ventricular myocytes

The effects of bepridil, a potent antiarrhythmic agent, on the Na+ current (INa) of single guinea-pig ventricular myocytes were studied using the whole-cell patch-clamp technique. Bepridil inhibited INa in a dose-dependent manner without causing any change in the I-V. relationship for INa. Bepridil suppressed INa with Kd values of 342 and 40 microM when cells were clamped to holding potentials of -140 and -90 mV, respectively. 10 microM bepridil shifted the steady-state inactivation curve for INa toward more negative potentials by 7.7 mV (n = 6). Bepridil also produced marked use-dependent block with a rapid onset. Recovery of INa from inactivation was retarded (time constant 290 ms) at a holding potential of -140 mV in the presence of 10 microM bepridil. When the onset of INa block was studied in experiments using a double-pulse protocol, bepridil blocked INa by 11.5% after a 4-ms pre-pulse, but significantly blocked it after pre-pulses longer than 16 ms. These results suggest that: (1) bepridil has a higher affinity for the inactivated state than the resting state of Na+ channel; (2) the drug also produces an open channel block; and (3) the drug shows a lidocaine-like fast kinetic block of Na+ current.