COMPARISON OF THE ACTION-POTENTIAL PROLONGING AND POSITIVE INOTROPIC ACTIVITY OF DPI-201-106 AND BDF-9148 IN HUMAN VENTRICULAR MYOCARDIUM

The aim of our study was to compare the effects on contractile function and action potential duration of the new Na+ channel modulator BDF 9148 with the parent compound DPI 201-106 in human ventricular myocardium. Right ventricular papillary muscles were obtained from explanted hearts of heart transplant recipients or from non-failing hearts not suitable for transplantation. BDF 9148 induced an increase in force of contraction that was accompanied by prolongation of action potential duration. The action potential duration prolonging effect of BDF 9148 was not significantly different to that of DPI 201-106. The effects of BDF 9148 were similar in muscles obtained from non-failing and failing hearts. Using Nai-sensitive electrodes, we have demonstrated that the positive inotropic effect of BDF 9148 is accompanied by an increase in intracellular Na+ activity. Our results indicate: (i) that BDF 9148 is as effective as DPI 201-106 in increasing force of contraction and prolonging action potential duration in human ventricular myocardium; (ii) that BDF 9148 is effective in enhancing force of contraction, in spite of heart failure; (iii) that the positive inotropic effect is related to an increased Na+ load; and (iv) due to action potential duration prolongation, changes in Q-T interval of the electrocardiogram could be possible during in vivo use of BDF 9148.