Effects of BDF 9198 on action potentials and ionic currents from guinea-pig isolated ventricular myocytes

1 BDF 9198 (a congener of DPI 201-106 and BDF 9148) was found to be a positive inotrope on guinea-pig isolated ventricular muscle strips. The effects of BDF 9198 on action potentials and ionic currents from guinea-pig isolated ventricular myocytes were studied using the whole cell patch damp method. 2 In normal external solution, at 37 degrees C, action potential duration at 50% repolarization (APD(50)) was 167.4 +/- 8.36 ms (n = 37). BDF 9198 produced a concentration-dependent increase in APD(50) (no significant increase at 1x10(-10) M; and APD(50) values of 273.03+/-35.8 ms at 1 x 10(-9) M; n=6, P<0.01 and 694.7+/-86.3 ms at 1 x 10(-7) M; P<0.001, n=7). At higher concentrations in the range tested, BDF 9198 also induced early and delayed and after-depolarizations. 3 Qualitative measurements of I-Na with physiological [Na](o) showed prolongation of the current by BDF 9198, and the appearance of transient oscillatory inward currents at high concentrations. 4 Quantitative recording conditions for I-Na were established using low external [Na] and by making measurements at room temperature. The current-voltage relation, activation parameters and timecourse of INa were similar before and after a partial blocking dose of Tetrodotoxin (TTX, 1 mu M), despite a 2 fold difference in current amplitude. This suggests that voltage-clamp during flow of I-Na was adequately maintained under our conditions. 5 Selective measurements of I-Na at room temperature showed that BDF 9198 induced a concentration-dependent, sustained component of I-Na (I-Late) and caused a slight left-ward shift in the current-voltage relation for peak current. The drug-induced I-Late showed a similar voltage dependence to peak current in the presence of BDF 9198. Both peak current acid I-Late were abolished by 30 mu M TTX and were sensitive to external [Na]. 6 Inactivation of control I-Na during a 200 ms test pulse to - 30 mV followed a bi-exponential timecourse. In addition to inducing a sustained current component, BDF 9198 left the magnitude of the fast inactivation time-constant unchanged, but increased the magnitude of the slow inactivation time-constant. Additional experiments with a longer pulse (1 s) raised the possibility that in the presence of BDF 9198, I-Na inactivation may be comprised of more than two phases. 7 No significant effects of 1x10(-6) M BDF 9198 were observed on the L-type calcium current, or delayed and inward rectifying potassium currents measured at 37 degrees C. 8 It is concluded that the prolongation of APD(50) by BDF 9198 resulted from selective modulation of I-Na. Reduced current inactivation induced a persistent I-Na, increasing the net depolarizing current during the action potential. This action of the drug indicates a potential for 'QT prolongation' of the EGG. The observation of after-depolarizations suggests a potential for proarrhythmia at some drug concentrations.