Effects of calcium, inorganic phosphate, and pH on isometric force in single skinned cardiomyocytes from donor and failing human hearts

• Published in: Circulation (New York, N.Y.) Vol. 104; no. 10; pp. 1140 - 1146
• Main Authors: VAN DER VELDEN, J, KLEIN, L. J, STIENEN, G. J. M, ZAREMBA, R, BOONTJE, N. M, HUYBREGTS, M. A. J. M, STOOKER, W, EIJSMAN, L, DE JONG, J. W, VISSER, C. A, VISSER, F. C
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 04.09.2001; American Heart Association, Inc
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Calcium - pharmacology; Cardiology. Vascular system; Dose-Response Relationship, Drug; Electrophoresis, Gel, Two-Dimensional; Female; Heart; Heart Failure - pathology; Heart Failure - physiopathology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Heart Ventricles - cytology; Heart Ventricles - drug effects; Humans; Hydrogen-Ion Concentration; Male; Medical sciences; Middle Aged; Myocardial Contraction - drug effects; Myosin Light Chains - drug effects; Myosin Light Chains - metabolism; Phosphates - pharmacology; Phosphorylation - drug effects; Ventricular Function; Heart; Human; Heart failure; Prognosis; Calcium; Pathogenesis; Contractility; Cardiovascular disease; Coronary heart disease; Myocardial disease; Vascular disease; Organ donation; Ischemia; Heart disease; Myocardium; pH
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/hc3501.095485

During ischemia, the intracellular calcium and inorganic phosphate (P(i)) concentrations rise and pH falls. We investigated the effects of these changes on force development in donor and failing human hearts to determine if altered contractile protein composition during heart failure changes the myocardial response to Ca(2+), P(i), and pH. Isometric force was studied in mechanically isolated Triton-skinned single myocytes from left ventricular myocardium. Force declined with added P(i) to 0.33+/-0.02 of the control force (pH 7.1, 0 mmol/L P(i)) at 30 mmol/L P(i) and increased with pH from 0.64+/-0.03 at pH 6.2 to 1.27+/-0.02 at pH 7.4. Force dependency on P(i) and pH did not differ between donor and failing hearts. Incubation of myocytes in a P(i)-containing activating solution caused a potentiation of force, which was larger at submaximal than at maximal [Ca(2+)]. Ca(2+) sensitivity of force was similar in donor hearts and hearts with moderate cardiac disease, but in end-stage failing myocardium it was significantly increased. The degree of myosin light chain 2 phosphorylation was significantly decreased in end-stage failing compared with donor myocardium, resulting in an inverse correlation between Ca(2+) responsiveness of force and myosin light chain 2 phosphorylation. Our results indicate that contractile protein alterations in human end-stage heart failure alter Ca(2+) responsiveness of force but do not affect the force-generating capacity of the cross-bridges or its P(i) and pH dependence. In end-stage failing myocardium, the reduction in force by changes in pH and [P(i)] at submaximal [Ca(2+)] may even be less than in donor hearts because of the increased Ca(2+) responsiveness.