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 wh ich enhance force of contraction via increasing intracellular Na remai n effective in failing human myocardium. Methods Cumulative concentrat ion-response curves with (+/-)BDF 9148 (0.01-10 mu mol l(-1)), a Na+-c hannel activator, and ouabain (0.01-0.1 mu mol l(-1)), a Na+/K+-ATPase inhibitor, were performed on electrically driven left ventricular hum an papillary muscle strips (1 Hz, 37 degrees C; dilative cardiomyopath y, NYHA IV, heart transplantation, n=16; nonfailing, donor hearts, n=5 ). The beta-adrenoceptor agonist isoprenaline (0.001-1 mu mol l(-1)) a nd Ca2+ (1.8-15 mmol l(-1)) were studied for control. In addition, Ca2 + response curves were obtained on skinned fibre preparations from lef t 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 investig ate a possible direct or indirect interaction of(+/-)BDF 9148 with the myofilaments. Results While isoprenaline was significantly less effec tive in increasing force of contraction in failing human myocardium th an in nonfailing myocardium (P<0.01), in NYHA IV, (+/-)BDF 9148 and ou abain were as effective as in nonfailing human tissue. In failing and nonfailing myocardium, (+/-)BDF 9148 and ouabain exerted positive inot ropic effects similar to those of Ca However, the potency for (+/-)BDF 9148 to increase force of contraction was higher in NYHA IV than in n onfailing human myocardium (P<0.05). Neither (+/-)BDF 9148 (1 mu mol l (-1)) nor an increased concentration of Na+ (50 mmol l(-1)) altered th e Ca2+ sensitivity or maximal developed tension of the contractile app aratus in experiments on chemically skinned left ventricular fibres. C onclusions The enhanced sensitivity of the failing human myocardium to wards Na+-channel modulation is not due to a direct or indirect intera ction of (+/-)BDF 9148 with cardiac myofilaments but may be due to an altered Na+-homeostasis in human heart failure.