Evidence for functional relevance of an enhanced expression of the Na+-Ca2+ exchanger in failing human myocardium

The present study aimed at investigating the expression of the Na(+)-Ca2+ exchanger and its functional role in human failing myocardium. 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)...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 1996-09, Vol.94 (5), p.992-1002
Main Authors: FLESCH, M, SCHWINGER, R. H. G, SCHIFFER, F, FRANK, K, SÜDKAMP, M, KUHN-REGNIER, F, ARNOLD, G, BÖHM, M
Format: Article
Language:English
Subjects:
Adult
Atrial Natriuretic Factor - genetics
Azetidines - pharmacology
Biological and medical sciences
Calcium - metabolism
Cardiology. Vascular system
Carrier Proteins - analysis
Carrier Proteins - genetics
Female
Heart
Heart Failure - metabolism
Heart failure, cardiogenic pulmonary edema, cardiac enlargement
Humans
Immunohistochemistry
Isoproterenol - pharmacology
Male
Medical sciences
Middle Aged
RNA, Messenger - analysis
Sodium - metabolism
Sodium-Calcium Exchanger
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Summary:The present study aimed at investigating the expression of the Na(+)-Ca2+ exchanger and its functional role in human failing myocardium. 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 degrees 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] mumol/L; NF, 1.65 [1.3 to 3.0] mumol/L). In NYHA class IV, BDF 9148 (0.1 mumol/L) restored the positive force-frequency relationship and reduced the frequency-dependent increase in diastolic tension in relation to force of contraction. 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.
ISSN:0009-7322
1524-4539
DOI:10.1161/01.cir.94.5.992