| Abstract: | Aims The aim of the present study was to investigate whether agents which enhance force of contraction via increasing intracellular Na+, i.e. cAMP-independently, remain effective in failing human myocardium.Methods Cumulative concentration-response curves with (±)BDF 9148 (0.01–10 μmol l?1?), a Na+-channel activator, and ouabain (0.01–0.1 μmol l?1?), a Na+/K+-ATPase inhibitor, were performed on electrically driven left ventricular human papillary muscle strips (1 Hz, 37° C; dilative cardiomyopathy, NYHA IV, heart transplantation, n=16; nonfailing, donor hearts, n=5). The β-adrenoceptor agonist isoprenaline (0.001–1 μmol 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 μmol 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 Ca2+. 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 μmol 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. |
