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Cardiovascular Research 2003 57(4):986-995; doi:10.1016/S0008-6363(02)00848-9
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

[Na+]i and the driving force of the Na+/Ca2+-exchanger in heart failure

A Baartscheer*, C.A Schumacher, C.N.W Belterman, R Coronel and J.W.T Fiolet

Experimental and Molecular Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

a.baartscheer{at}amc.uva.nl

* Corresponding author. Laboratory of Experimental Cardiology, Room M-0-052, Academic Medical Center, University of Amsterdam, P.O. Box 22700, Meibergdreef 9, 1100 DE Amsterdam, The Netherlands. Tel.: +31-20-566-3265; fax: +31-20-697-5458.

* For this manuscript Professor A. Fabiato acted as guest editor.

Objective: Diastolic calcium is increased in myocytes from failing hearts despite up-regulation of the principal calcium extruding mechanism the Na+/Ca2+-exchanger (NCX). We hypothesize that increased diastolic calcium ([Ca2+]i) is secondary to increased cytosolic sodium ([Na+]i) and decreased driving force of NCX ({Delta}Gexch). Methods: The stimulation rate dependence of simultaneously measured cytosolic sodium ([Na+]i), calcium transients ([Ca2+]i) and action potentials were determined with SBFI, indo-1 and the perforated patch technique in midmural left ventricular myocytes isolated from rabbits with pressure and volume overload induced heart failure (HF) and in age matched controls. Dynamic changes of {Delta}Gexch were calculated. Results: With increasing stimulation frequency, 0.2–3 Hz (all data HF versus control): [Na+]i increased (6.4 to 10.8 versus 3.8 to 6.4 mmol/l), diastolic [Ca2+]i increased (142 to 219 versus 47 to 98 nmol/l), calcium transient amplitude decreased in HF (300 to 250 nmol/l) but increased in control (201 to 479 nmol/l), action potential duration (APD90) decreased (380 to 260 versus 325 to 205 ms) and time averaged {Delta}Gexch decreased (6.8 to 2.8 versus 8.7 to 6.4 kJ/mol. With increasing stimulation rate the forward mode time integral of {Delta}Gexch decreased in HF by about 30%, the reversed mode time integral increased about ninefold and the duration of reversed mode operation more than sixfold relative to control. Conclusions: [Na+]i is increased in HF and the driving force of NCX is decreased. NCX exerts thermodynamic control over diastolic calcium. Disturbed diastolic calcium handling in HF is due to decreased forward mode {Delta}Gexch secondary to increased [Na+]i and prolongation of the action potential. Enhanced reversed mode {Delta}Gexch may account for increased contribution of NCX to e–c coupling in HF.

KEYWORDS Calcium (cellular); Heart failure; Myocytes; Na/Ca-exchanger


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