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Characterization of the effects of the new inotropic agent BDF 9148 in isolated papillary muscles and myocytes of the guinea‐pig heart

1 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 (> 3 μm), 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 μm 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 μm) 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.;