In isolated guinea-pig ventricular myocytes, BDF 9148 prolonged action potential duration and slowed sodium channel inactivation similarly to DPI 201-106, while inhibiting calcium currents.
BDF 9148 acts as a positive inotropic agent by modifying cardiac sodium channels and slowing their inactivation in guinea-pig myocytes.
The cardiotonic agent BDF 9148 (4-3'-(1''-benzhydryl-azetidine-3''-oxy)-2'-hydroxypropoxy-1H-indole- 2-carbonitrile) is structurally related to DPI 201-106 (4-3'-(4''-benzhydryl-1''-piperazinyl) -2'-hydroxypropoxy-1H-indole-2-carbonitrile) which is known to modify cardiac sodium channels. In guinea-pig papillary muscles, both compounds increase force of contraction with similar concentration-response curves. Like DPI 201-106, BDF 9148 prolongs the action potential duration in a tetrodotoxin-sensitive manner. With high concentrations (greater than 3 microM), however, the action potential duration shortens again. In order to elucidate the underlying changes in membrane currents, we have investigated the effects of BDF 9148 in isolated ventricular myocytes of the guinea-pig heart. 2. In isolated cells, a concentration of 1 microM BDF 9148 prolonged the action potential duration and markedly enhanced unloaded cell shortening, indicating that the procedure of cell isolation does not abolish the effect of the drug. 3. Membrane currents were studied with the single electrode voltage clamp technique. With clamp steps from -80 mV to -40 mV, BDF 9148 (1 microM) induced a slowly decaying inward current which was suppressed by tetrodotoxin. Therefore, like DPI 201-106, BDF 9148 slows the inactivation of the sodium channels. 4. In order to quantify the effects of BDF 9148 and DPI 201-106 on sodium current inactivation, we have measured the inward current amplitude still present at 100 ms after a depolarizing clamp step from -80 mV to -30 mV. Both drugs increased this current component in a concentration-dependent manner; however, BDF 9148 had a larger effect in the low concentration range.5. The calcium current was inhibited by BDF 9148 and DPI 201-106 in a concentration-dependent manner; the pD2 values were 5.70 and 5.95, respectively.6. The two compounds are thought to produce similar positive inotropic effects by imposing a sodium load on the muscle cells via modification of the sodium channels. The differences in action potential duration could be due to different contributions of ionic currents other than sodium or calcium currents and of pump and exchange currents. At present, there is not sufficient data to identify clearly distinct current components responsible for the differences in action potential prolongation.
Ravens et al. (Sun,) conducted a other in Isolated guinea-pig heart cells. BDF 9148 vs. DPI 201-106 was evaluated on Membrane currents and action potential duration. In isolated guinea-pig ventricular myocytes, BDF 9148 prolonged action potential duration and slowed sodium channel inactivation similarly to DPI 201-106, while inhibiting calcium currents.