Increase in force of contraction by activation of the Na+/Ca2+-exchanger in human myocardium

Aims The aim of the present study was to investigate whether agents which enhance force of contraction via increasing intracellular Na remain effective in failing human myocardium. Methods Cumulative concentration-response curves with (+/-)BDF 9148 (0.01-10 mu mol l(-1)), a Na+-channel activator, and ouabain (0.01-0.1 mu mol l(-1)), a Na+/K+-ATPase inhibitor, were performed on electrically driven left ventricular human papillary muscle strips (1 Hz, 37 degrees C; dilative cardiomyopathy, NYHA IV, heart transplantation, n=16; nonfailing, donor hearts, n=5). The beta-adrenoceptor agonist isoprenaline (0.001-1 mu mol l(-1)) and Ca2+ (1.8-15 mmol l(-1)) were studied for control. In addition, Ca2+ response curves were obtained on skinned fibre preparations from left ventricular myocardium (NYHA IV, n=7) in the presence of BDF 9148 (1 mu mol l(-1)) or a high Na+ concentration (50 mmol l(-1)) to investigate a possible direct or indirect interaction of(+/-)BDF 9148 with the myofilaments. Results While isoprenaline was significantly less effective in increasing force of contraction in failing human myocardium than in nonfailing myocardium (P<0.01), in NYHA IV, (+/-)BDF 9148 and ouabain were as effective as in nonfailing human tissue. In failing and nonfailing myocardium, (+/-)BDF 9148 and ouabain exerted positive inotropic effects similar to those of Ca However, the potency for (+/-)BDF 9148 to increase force of contraction was higher in NYHA IV than in nonfailing human myocardium (P<0.05). Neither (+/-)BDF 9148 (1 mu mol l(-1)) nor an increased concentration of Na+ (50 mmol l(-1)) altered the Ca2+ sensitivity or maximal developed tension of the contractile apparatus in experiments on chemically skinned left ventricular fibres. Conclusions The enhanced sensitivity of the failing human myocardium towards Na+-channel modulation is not due to a direct or indirect interaction of (+/-)BDF 9148 with cardiac myofilaments but may be due to an altered Na+-homeostasis in human heart failure.