During heart failure, alterations occur in contractile protein expression and phosphorylation, which may influence the effects of Ca2+- sensitizers. To quantify the magnitude of these effects, isometric force was studied in mechanically isolated Triton-skinned myocytes from end-stage failing and non-failing donor hearts under control conditions (pH 7.2; no added inorganic phosphate (Pi)) and under mimicked ischemic conditions (pH 6.5; 10 mM Pi). Two different Ca2+-sensitizers were used: EMD 53998 (10 μM), which exerts its influence through the actin-myosin interaction, and OR-1896 (10 μM) (the active metabolite of levosimendan), which affects the Ca2+-sensory function of the thin filaments. The maximal force (Po) measured at saturating Ca2+ concentration and the resting force (Prest) determined in the virtual absence of Ca2+ (pCa 9) did not differ between the failing and non-failing myocytes, but the Ca2+ concentration required to induce the half-maximal force under control conditions was significantly lower in the failing than in the non-failing myocytes (ΔpCa50=0.15). This difference in Ca2+-sensitivity, however, was abolished during mimicked ischemia. EMD 53998 increased Po and Prest by approximately 15% of Po and greatly enhanced the Ca 2+-sensitivity (ΔpCa50 > 0.25) of force production. OR-1896 did not affect Po and Prest, and provoked a small, but significant Ca2+-sensitization (ΔpCa 50 ≈ 0.1). All of these effects were comparable in the donor and failing myocytes, but, in contrast with OR-1896, EMD 53998 considerably diminished the difference in the Ca2+-sensitivities between the failing and non-failing myocytes. The action of Ca2+-sensitizers under mimicked ischemic conditions was impaired to a similar degree in the donor and the failing myocytes. Our results indicate that the Ca2+- activation of the myofibrillar system is altered in end-stage human heart failure. This modulates the effects of Ca2+-sensitizers both under control and under mimicked ischemic conditions.
|Number of pages||6|
|Journal||Journal of Muscle Research and Cell Motility|
|Publication status||Published - 1 Dec 2004|