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(Circulation. 1996;94:992-1002.)
© 1996 American Heart Association, Inc.
Articles |
Evidence for Functional Relevance of an Enhanced Expression of the Na+-Ca2+ Exchanger in Failing Human Myocardium
Klinik III fur Innere Medizin (M.F., R.H.G.S., F.S., K.F., M.B.), Klinik fur Herz und Gefaßchirurgie (M.S., F.K.-R.), and Institut fur Pathologie der Universitat zu Koln (G.A.), Koln, Germany.
Correspondence to Prof Dr med M. Bohm, Klinik III fur Innere Medizin der Universitat zu Koln, Joseph Stelzmann Str 9, 50924 Koln, FRG.
Background The present study aimed at investigating the expression of the Na+-Ca2+ exchanger and its functional role in human failing myocardium.
Methods and Results Na+-Ca2+ exchanger mRNA and protein levels were examined in nonfailing (NF, n=8) and failing human myocardium (New York Heart Association functional class IV) with idiopathic dilated cardiomyopathy (DCM, n=8) or ischemic heart disease (ICM, n=6). The inotropic effect of the Na+ channel activator BDF 9148 was determined in electrically driven left ventricular papillary muscle strip preparations (1 Hz, 37°C) from nonfailing (n=8) and failing (n=8) human hearts. Na+-Ca2+ exchanger mRNA levels were significantly increased, by 79% (P<.001) in DCM and by 58% (P<.01) in ICM compared with NF; protein levels increased by 36% (P<.001) and by 20% (P<.05), respectively. BDF 9148 increased the force of contraction concentration dependently, with a similar maximal effect in NYHA class IV and NF, but was more potent in NYHA class IV as demonstrated by a significantly smaller (P<.01) EC50 value (NYHA class IV, 0.18 [0.16 to 0.22] µmol/L; NF, 1.65 [1.3 to 3.0] µmol/L). In NYHA class IV, BDF 9148 (0.1 µmol/L) restored the positive force-frequency relationship and reduced the frequency-dependent increase in diastolic tension in relation to force of contraction.
Conclusions The increased expression of the Na+-Ca2+ exchanger is a possible explanation for the increased inotropic potency of the Na+ channel activator BDF 9148 in failing human myocardium. The increase in exchanger molecules could be of functional relevance for the modulation of cardiac contractility by agents that increase the intracellular Na+ concentration. Enhancement of Na+-Ca2+ exchanger activity might be a powerful mechanism for increasing cardiac contractility in chronic heart failure.
Key Words: heart failure • calcium channels • inotropic agents • sodium • excitation
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A. R.W. Money-Kyrle, C. H. Davies, H. K. Ranu, P. O'Gara, N. Singh Kent, P. A. Poole-Wilson, and S. E. Harding The role of cAMP in the frequency-dependent changes in contraction of guinea-pig cardiomyocytes Cardiovasc Res, February 1, 1998; 37(2): 532 - 540. [Abstract] [Full Text] [PDF]
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S. B. Nicholas, W. Yang, S.-L. Lee, H. Zhu, K. D. Philipson, and J. Lytton Alternative promoters and cardiac muscle cell-specific expression of the Na+/Ca2+ exchanger gene Am J Physiol Heart Circ Physiol, January 1, 1998; 274(1): H217 - H232. [Abstract] [Full Text] [PDF]
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K. R. Sipido, M. Maes, and F. Van de Werf Low Efficiency of Ca2+ Entry Through the Na+-Ca2+ Exchanger as Trigger for Ca2+ Release From the Sarcoplasmic Reticulum : A Comparison Between L-Type Ca2+ Current and Reverse-Mode Na+-Ca2+ Exchange Circ. Res., December 19, 1997; 81(6): 1034 - 1044. [Abstract] [Full Text]
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S. E. Litwin and J. H. B. Bridge Enhanced Na+-Ca2+ Exchange in the Infarcted Heart : Implications for Excitation-Contraction Coupling Circ. Res., December 19, 1997; 81(6): 1083 - 1093. [Abstract] [Full Text]
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R. H. G. Schwinger, K. Brixius, U. Bavendiek, S. Hoischen, J. Müller-Ehmsen, B. Bölck, and E. Erdmann Effect of Cyclopiazonic Acid on the Force-Frequency Relationship in Human Nonfailing Myocardium J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 286 - 292. [Abstract] [Full Text]
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C. E. Zaugg, S. T. Wu, R. J. Lee, J. Wikman-Coffelt, and W. W. Parmley Intracellular Ca2+ Handling and Vulnerability to Ventricular Fibrillation in Spontaneously Hypertensive Rats Hypertension, September 1, 1997; 30(3): 461 - 467. [Abstract] [Full Text]
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Z. Wang, B. Nolan, W. Kutschke, and J. A. Hill Na+-Ca2+ Exchanger Remodeling in Pressure Overload Cardiac Hypertrophy J. Biol. Chem., May 18, 2001; 276(21): 17706 - 17711. [Abstract] [Full Text] [PDF]
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S.-H. Woo and M. Morad Bimodal regulation of Na+-Ca2+ exchanger by beta -adrenergic signaling pathway in shark ventricular myocytes PNAS, February 13, 2001; 98(4): 2023 - 2028. [Abstract] [Full Text] [PDF]
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