Abstract
The Na,K-ATPase is of major importance for active ion transport across the sarcolemma and thus for electrical as well as contractile function of the myocardium. Furthermore, it is receptor for digitalis glycosides. In human studies of the regulatory aspects of myocardial Na,K-ATPase concentration a major problem has been to obtain tissue samples. Methodological accomplishments in quantification of myocardial Na,K-ATPase using vanadate facilitated 3H-ouabain binding to intact samples have, however, made it possible to obtain reliable measurements on human myocardial necropsies obtained at autopsy as well as on biopsies of a wet weight of only 1–2 mg obtained during heart catheterisation. However, access to the ultimately, normal, vital myocardial tissue has come from the heart transplantation programs, through which myocardial samples from cardiovascular healthy organ donors have become available. In the present paper we evaluate the various values reported for normal human myocardial Na,K-ATPase concentration, its regulation in heart disease and the association with digitalization. Normal myocardial Na,K-ATPase concentration level is found to be 700 pmol/g wet weight. No major variations were found between or within the walls of the heart ventricles. During the first few years of life a marked decrease in myocardial Na,K-ATPase concentration is followed by a stable level obtained in early adulthood and normally maintained throughout life. In patients with enlarged cardiac x-ray silhouette a significant positive, linear correlation between left ventricular ejection fraction (EF) and Na,K-ATPase concentration was established. A maximum reduction in Na,K-ATPase concentration of 89% was obtained when EF was reduced to 20%. Generally, heart failure associated with heart dilatation, myocardial hypertrophy as well as ischaemic heart disease is associated with reductions in myocardial Na,K-ATPase concentration of around 25%. During digoxin treatment of heart failure patients a further reduction in functional myocardial Na,K-ATPase concentration of 15% has been found. Thus, the total reduction in functional myocardial Na,K-ATPase concentration in digitalised heart failure patients may well be of the magnitude 40%. In conclusion, it has become possible to quantify human myocardial Na,K-ATPase in health and disease. Revealed reductions are in heart failure of importance for contractile function, generation of arrhythmia and for digoxin treatment.
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References
Smith TW: Digitalis: Mechanisms of action and clinical use. N Engl J Med 318: 358–365, 1988
Nørgaard A, Kjeldsen K, Hansen O, Clausen T, Larsen CG, Larsen FG: Quantification of the 3H-ouabain binding site concentration in human myocardium: A postmorten study. Cardiovasc Res 20: 428–435, 1986
Nørgaard A, Bagger JP, Bjerregaard P, Baandrup U, Kjeldsen K, Thomsen PE: Relation of left ventricular function and Na,K-pump concentration in suspected idiopathic dilated cardiomyopathy. Am J Cardiol 61: 1312–1315, 1988
Jones LR, Besch J.H.R.: Isolation of canine cardiac sarcolemmal vesicles. Meth Pharmacol 5: 1–12, 1984
Hansen O, Clausen T: Quantitative determination of Na+-K+-ATPase and other sarcolemmal components in muscle cells. Am J Physiol 254: 1–7, 1988
Schmidt TA, Kjeldsen K: Enhanced clearance of specifically bound digoxin from human myocardial and skeletal muscle samples by specific digoxin antibody fragments: Subsequent complete digitalis glycoside receptor (Na,K-ATPase) quantification. J. Cardiovasc Pharmacol 17: 670–677, 1991
Schmidt TA, Holm Nielsen P, Kjeldsen K: No upregulation of digitalis glycoside receptor (Na,K-ATPase) concentration in human heart left ventricle samples obtained at necropsy after long term digitalisation. Cardiovasc Res 25: 684–691, 1991
Schmidt TA, Allen PD, Colucci WS, Marsh JD, Kjeldsen K: No adaptation to digitalization as evaluated by digitalis receptor (Na,K-ATPase) quantification in explanted hearts from donors without heart disease and from digitalized recipients with end-stage heart failure. Am J Cardiol 71: 110–114, 1993
Ellingsen Ø, Holthe R, Svindland A, Aksnes G, Sejersted OM, Ilebekk A: Na,K-pump concentration in hypertrophied human hearts. Eur Heart J 15: 1184–1190, 1994
Kjelsen K, Bjerregaard P, Richter EA, Thomsen PE, Nørgaard A: Na+,K+-ATPase concentration in rodent and human heart and skeletal muscle: Apparent relation to muscle performance. Cardiovasc Res 22: 95–100, 1988
Nørgaard A, Kjeldsen K: Human myocardial Na,K-pumps in relation to heart disease. J Appl Cardiol 4: 239–245, 1989
Nørgaard A, Bjerregaard P, Baandrup U, Kjeldsen K, Reske Nielsen E, Thomsen PE: The concentration of the Na,K-pump in skeletal and heart muscle in congestive heart failure. Int J Cardiol 26: 185–190, 1990
Shamraj OI, Grupp IL, Grupp G, Melvin D, Gradoux N, Kremers W, Lingrel JB, De Pover A: Characterisation of Na/K-ATPase, its isoforms, and the inotropic response to ouabain in isolated failing human hearts. Cardiovasc Res 27: 2229–2237, 1993
Kjeldsen K, Grøn P: Age-dependent change in myocardial cardiac glycoside receptor (Na,K-pump) concentration in children. J Cardiovasc Pharmacol 15: 332–337, 1990
Wettrell G, Andersson KE: Clinical pharmacokinetics of digoxin in infants. Clin Pharmacokinet 2: 17–31, 1977
Schwinger RHG, Böhm M, Erdmann E: Effectiveness of cardiac glycosides in human myocardium with and without ‘downregulated’ β-adrenoceptors. J Cardiovasc Pharmacol 15: 692–697, 1990
Morgan JP: Abnormal intracellular modulation of calcium as a major cause of cardiac contractile dysfunction. N Engl J Med 325: 625–632, 1991
Schmidt TA, Bundgaard H, Larsen JS, Arendrup H, Kjeldsen K: Reduced left ventricular Na,K-ATPase concentration in symptomatic patients with chronic aortic valvular disease. J Mol Cell Cardiol 27: a239, 1995
O'Gorman DJ, Sheridan DJ: Abnormalities of the coronary circulation associated with left ventricular hypertrophy. Clin Sci 81: 703–713, 1991
Beller GA, Conroy J, Smith TW: Ischaemia-induced alterations in myocardial (Na+ + K+)-ATPase and cardiac glycoside binding. J Clin Invest 57: 341–350, 1976
Schwartz A, Wood JM, Allen JC, Bornet EP, Entman ML, Goldstein MA: Biochemical and morphologic correlates of cardiac ischaemia. I. Membrane systems. Am J Cardiol 32: 46–61, 1973
Schmidt TA, Svendsen JH, Haunsø S, Kjeldsen K: Quantification of the total Na,K-ATPase concentration in atria and ventricles from mammalian species by measuring 3H-ouabain binding to intact myocardial samples. Stability to short term ischemia reperfusion. Basic Res Cardiol 85: 411–427, 1990
Rasmussen HH, Okita GT, Hartz RS, Ten Eick RE: Inhibition of electrogenic Na+-pumping in isolated atrial tissue from patients treated with digoxin. J Pharmacol Exp Ther 252: 60–64, 1990
Dørup I, Skajaa K, Thybo NK: Oral magnesium supplementation restores the concentrations of magnesium, potassium and sodium-potassium pumps in skeletal muscle of patients receiving diuretic treatment. J Int Med 233: 117–123, 1993
Schmidt TA, Holm Nielsen P, Kjeldsen K: Human skeletal muscle digitalis glycoside receptors (Na,K-ATPase) — importance during digitalization. Cardiovasc Drugs Ther 7: 175–181, 1993
Schmidt TA, Bundgaard H, Olsesen HL, Secher NH, Kjeldsen K: Digoxin affects potassium homeostasis during exercise in patients with heart failure. Cardiovasc Res 29: 506–511, 1995
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Bundgaard, H., Kjeldsen, K. Human myocardial Na,K-ATPase concentration in heart failure. Mol Cell Biochem 163, 277–283 (1996). https://doi.org/10.1007/BF00408668
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DOI: https://doi.org/10.1007/BF00408668