Na+-channel activators increase intracellular Na+ and thereby enhance the transport rate of sarcolem-mal Na+, K + -ATPase. We investigated the interaction of the new Na+-channel activator BDF 9148 (BDF) with the cardiac glycoside ouabain (OUA) in human myocardium. The influence of OUA (0.01–0.1μ,M) and of OUA after prestimulation with BDF (0.1 μM, 1 μM; BDF + OUA) on isometric force of contraction (FOC, force of contraction; + T/-T, peak rate of tension increase/decay) of electrically driven (1 Hz, 37°C) papillary muscle strips from terminally failing [New York Heart Association classification IV (NYHA IV) heart transplants, n = 19] human myocardium was studied. We also examined the effects of BDF and OUA on nonfailing human myocardium (brain death resulting from traumatic injury, n = 5). 0.01 μOUA enhanced FOC only after prestimulation with BDF (NYHA IV + 2.9± 0.4 mN; p < 0.01). The time until maximal (T1/2max: BDF + OUA 117 min, OUA 166 min), half-maximal (TI/2max: BDF + OUA 47 min, OUA 85 min) inotropic effects and time until toxic signs (contracture, extrasystoles) occurred were significantly shorter with BDF + OUA as compared with OUA alone. BDF influenced Tmax, T,1/2max, and time until toxic side effects occurred (Ttox) of the OUA-mediated inotropism in a concentration-dependent manner. Both OUA and BDF enhanced +T and -T. The effectiveness of OUA and BDF in increasing FOC was similar to that of Ca2+ (1.8–15 mAf) but significantly (p < 0.01) higher as compared with the p-adrenoceptor-agonist isoprenaline in NYHA IV. In myocardial membranes, [3H]ouabain binding (Bmax, Ka) was not affected by BDF. These results suggest that BDF enhances the potency of OUA to increase FOC in human myocardium but also enhances toxicity of OUA. The influence of BDF on the effects of OUA is probably indirect and may be related to cellular Na+ load. Because BDF 9148 can decrease the inotropic and toxic concentration for cardiac glycosides, great caution appears to be necessary when these compounds are used simultaneously to treat human heart failure.