Increase in force of contraction by activation of the Na^+‘ox/Ca²⁺‘ox‐exchangerin human myocardium

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.

DOI: 10.1046/j.1365-2125.1997.00581.x

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