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


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 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.


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.
Flesch
M
M
Klinik III für Innere Medizin Universität zu Köln, FRG.
Schwinger
R H
RH
Schiffer
F
F
Frank
K
K
Südkamp
M
M
Kuhn-Regnier
F
F
Arnold
G
G
Böhm
M
M
D000328:Adult; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001384:Azetidines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis* / Q000235:genetics; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger
D001384:Azetidines; D002352:Carrier Proteins; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; C071117:BDF 9148; D009320:Atrial Natriuretic Factor; D012964:Sodium; D007545:Isoproterenol; D002118:Calcium