Effects of Ca2+ -sensitizers in permeabilized cardiac myocytes from donor and end-stage failing human hearts.
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 microM), which exerts its influence through the actin-myosin interaction, and OR-1896 (10 microM) (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 (DeltapCa50=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 Ca2+ -sensitivity (DeltapCa50 > 0.25) of force production. OR-1896 did not affect Po and Prest, and provoked a small, but significant Ca2+ -sensitization (DeltapCa50 approximately 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.
UDMHSC, Division of Clinical Physiology, Institute of Cardiology, Debrecen, Hungary.
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Papp
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Van Der Velden
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Borbély
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Edes
G J M
GJ
Stienen
D000081:Acetamides / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D013829:Thiadiazines / Q000494:pharmacology*; D014019:Tissue Donors
D000081:Acetamides; C414222:N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; D011724:Pyridazines; D011804:Quinolines; D013829:Thiadiazines; C070609:EMD 53998; D002118:Calcium