Abstract
BACKGROUND: Intracellular sodium concentration (Na$^+$(i)) modulates
cardiac contractile and electrical activity through Na/Ca exchange
(NCX). Upregulation of NCX in heart failure (HF) may magnify the
functional impact of altered Na$^+$(i). METHODS AND RESULTS:
We measured Na$^+$(i) by using sodium binding benzofuran isophthalate
in control and HF rabbit ventricular myocytes (HF induced by aortic
insufficiency and constriction). Resting Na$^+$(i) was 9.7+/-0.7
versus 6.6+/-0.5 mmol/L in HF versus control. In both cases, Na$^+$(i)
increased by approximately 2 mmol/L when myocytes were stimulated
(0.5 to 3 Hz). To identify the mechanisms responsible for Na$^+$(i)
elevation in HF, we measured the Na$^+$(i) dependence of Na/K
pump-mediated Na$^+$ extrusion. There was no difference in V(max)
(8.3+/-0.7 versus 8.0+/-0.8 mmol/L/min) or K(m) (9.2+/-1.0 versus
9.9+/-0.8 mmol/L in HF and control, respectively). Therefore, at
measured Na$^+$(i) levels, the Na/K pump rate is actually higher
in HF. However, resting Na$^+$ influx was twice as high in HF
versus control (2.3+/-0.3 versus 1.1+/-0.2 mmol/L/min), primarily
the result of a tetrodotoxin-sensitive pathway. CONCLUSIONS: Myocyte
Na$^+$(i) is elevated in HF as a result of higher diastolic
Na$^+$ influx (with unaltered Na/K-ATPase characteristics). In
HF, the combined increased Na$^+$(i), decreased Ca$^2+$
transient, and prolonged action potential all profoundly affect cellular
Ca$^2+$ regulation, promoting greater Ca$^2+$ influx through
NCX during action potentials. Notably, the elevated Na$^+$(i)
may be critical in limiting the contractile dysfunction observed
in HF.
- 12034663
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