Positive inotropic effects of the novel Na+-channel modulator BDF 9198 in human nonfailing and failing myocardium

The aim of this study was to investigate the inotropic properties of the novel Na+-channel modulator BDF: 9198 in human nonfailing and failing myocardium, For comparison the Na+-channel modulator BDF 9148, the beta-adrenoceptor-agonist isoprenaline, and calcium were studied. Concentration-response curves for BDF 9198 (0.01-30 mu M), BDF 9148 (0.01-30 mu M), isoprenaline (0.001-1 mu M), and calcium (1.8-15 mM) were obtained in electrically driven left ventricular human papillary muscle strips (1 Hz, 37 degrees C; dilated cardiomyopathy, NYHA IV, heart transplantation; nonfailing, donor hearts). Whereas isoprenaline was significantly less effective and less patent in increasing the farce of contraction in failing human myocardium than in nonfailing myocardium (p < 0.01), BDF 9198 and BDF 9148 were tin NYHA IV) as effective as in nonfailing:: human tissue. In both tissues, BDF 9198 and BDF 9148 exerted similar positive inotropic effects as calcium, with the novel Na+-channel modulator BDF9198 being more potent in increasing force of contraction than was the preceding agent BDF 9148. The potencies of both Na+-channel modulators, BDF 9198 and BDF 9148, were enhanced in human failing myocardium when compared with nonfailing myocardium. In summary, the novel Na+-channel modulator BDF 9198 increases force of contraction to the same extent as calcium and with a higher potency than BDF 9148. The sensitivity of failing human myocardium to Na+-channel modulators is increased when compared with nonfailing myocardium, which might be the result of an altered Na+ homeostasis in human heart failure.