Intracellular Na+ concentration is elevated in heart failure but Na/K pump function is unchanged

Sanda Despa, Mohammed A. Islam, Christopher R. Weber, Steven M. Pogwizd, Donald M Bers

Research output: Contribution to journalArticle

223 Citations (Scopus)

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 ≈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 Vmax(8.3±0.7 versus 8.0±0.8 mmol/L/min) or Km (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 Ca2+ transient, and prolonged action potential all profoundly affect cellular Ca2+ regulation, promoting greater Ca2+ influx through NCX during action potentials. Notably, the elevated [Na+]i may be critical in limiting the contractile dysfunction observed in HF.

Original languageEnglish (US)
Pages (from-to)2543-2548
Number of pages6
JournalCirculation
Volume105
Issue number21
DOIs
StatePublished - May 28 2002
Externally publishedYes

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Heart Failure
Muscle Cells
Action Potentials
Tetrodotoxin
Constriction
Up-Regulation
Sodium
Rabbits

Keywords

  • Calcium
  • Heart failure
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Intracellular Na+ concentration is elevated in heart failure but Na/K pump function is unchanged. / Despa, Sanda; Islam, Mohammed A.; Weber, Christopher R.; Pogwizd, Steven M.; Bers, Donald M.

In: Circulation, Vol. 105, No. 21, 28.05.2002, p. 2543-2548.

Research output: Contribution to journalArticle

Despa, Sanda ; Islam, Mohammed A. ; Weber, Christopher R. ; Pogwizd, Steven M. ; Bers, Donald M. / Intracellular Na+ concentration is elevated in heart failure but Na/K pump function is unchanged. In: Circulation. 2002 ; Vol. 105, No. 21. pp. 2543-2548.
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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 ≈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 Vmax(8.3±0.7 versus 8.0±0.8 mmol/L/min) or Km (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 Ca2+ transient, and prolonged action potential all profoundly affect cellular Ca2+ regulation, promoting greater Ca2+ influx through NCX during action potentials. Notably, the elevated [Na+]i may be critical in limiting the contractile dysfunction observed in HF.",
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AU - Despa, Sanda

AU - Islam, Mohammed A.

AU - Weber, Christopher R.

AU - Pogwizd, Steven M.

AU - Bers, Donald M

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N2 - 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 ≈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 Vmax(8.3±0.7 versus 8.0±0.8 mmol/L/min) or Km (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 Ca2+ transient, and prolonged action potential all profoundly affect cellular Ca2+ regulation, promoting greater Ca2+ influx through NCX during action potentials. Notably, the elevated [Na+]i may be critical in limiting the contractile dysfunction observed in HF.

AB - 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 ≈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 Vmax(8.3±0.7 versus 8.0±0.8 mmol/L/min) or Km (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 Ca2+ transient, and prolonged action potential all profoundly affect cellular Ca2+ regulation, promoting greater Ca2+ influx through NCX during action potentials. Notably, the elevated [Na+]i may be critical in limiting the contractile dysfunction observed in HF.

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