Enantioselective inotropic actions of the Na+-channel activators BDF 9148, BDF 9196 and BDF 9167 in human failing and nonfailing myocardium.

Our study investigated the inotropic effect of the novel Na+-channel activator BDF 9148 and its enantiomeres [S(-)BDF 9169, R(+)BDF 9167] in human failing [New York Heart Association Class (NYHA IV) heart transplants, n = 15] and nonfailing myocardium (NF, donor hearts, n = 5). We studied the effect of BDF 9148 (BDF, 0.03-10 micromol/liter) and of its enantiomeres [S(-) BDF 9196; R(+)BDF 9167] on isometric force of contraction (1 Hz) as well as on the force-frequency-relationship (0.5-3 Hz) in electrically driven (37 degrees C) left ventricular papillary muscle strips, BDF and S-BDF, but not R-BDF, increased force of contraction in a dose-dependent manner in NYHA IV and NF. The effectiveness of BDF, S-BDF and Ca2+ (15 mmol/liter) to increase force of contraction was similar in human nonfailing and failing myocardium. The potency of BDF and S-BDF to increase force of contraction was significantly higher in NYHA IV compared to NF. Carbachol (1 mmol/liter) did not affect the positive inotropic response of the studied compounds. In the presence of 3 micromol/liter BDF or S-BDF force of contraction increased after an increase in stimulation frequency only from 0.5 to 1 Hz in NYHA IV and human nonfailing myocardium. At frequencies above 1 Hz the force-frequency-relationship was negative in human nonfailing myocardium and NYHA IV in the presence of high concentrations of BDF or S-BDF. These results suggest that the racemic Na+-channel activator BDF 9148 and the S(-) BDF-enantiomere, but not the R(+) BDF-enantiomere, are effective to increase force development maximally in NYHA IV and in nonfailing myocardium. Human failing myocardium exerts an enhanced sensitivity toward the Na+-channel activator BDF 9148 and its S(-) enantiomere to increase force of contraction when compared to nonfailing tissue. As Na+-channel activators increase force in a frequency-dependent mode of action the force-frequency-relationship may depend on the intracellular Ca2+- and Na+- homeostasis.