Dynamic regulation of sodium/calcium exchange function in human heart failure

Sarcolemmal Na/Ca exchange (NCX) regulates cardiac Ca and contractility. NCX function during the cardiac cycle is determined by intracellular [Ca] and [Na] ([Ca]i, and [Na]i) and membrane potential (Em), which all change in human heart failure (HF). Therefore, changes in NCX function may contribute...

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Published in:Circulation (New York, N.Y.) N.Y.), 2003-11, Vol.108 (18), p.2224-2229
Main Authors: WEBER, Christopher R, PIACENTINO, Valentino III, HOUSER, Steven R, BERS, Donald M
Format: Article
Language:English
Subjects:
Action Potentials - drug effects
Allosteric Regulation - drug effects
Biological and medical sciences
Blood and lymphatic vessels
Calcium - metabolism
Calcium - pharmacology
Cardiology. Vascular system
Cell Separation
Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous
Electrophysiology
Heart Failure - metabolism
Humans
Ion Transport - drug effects
Medical sciences
Myocardial Contraction
Myocytes, Cardiac - metabolism
Sodium - metabolism
Sodium - pharmacology
Sodium-Calcium Exchanger - drug effects
Sodium-Calcium Exchanger - metabolism
Space life sciences
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Summary:Sarcolemmal Na/Ca exchange (NCX) regulates cardiac Ca and contractility. NCX function during the cardiac cycle is determined by intracellular [Ca] and [Na] ([Ca]i, and [Na]i) and membrane potential (Em), which all change in human heart failure (HF). Therefore, changes in NCX function may contribute to abnormal Ca regulation in human HF. We assessed the cellular bases of differences in NCX function in ventricular myocytes from failing (F) and nonfailing (NF) human hearts. Allosteric activation of NCX by [Ca]i was comparable in F and NF myocytes (K1/2=150+/-31 nmol/L, n=7). The steady-state relation between [Ca]i and NCX current (INCX) was used to infer the local submembrane [Ca]i ([Ca]sm) that is sensed by NCX dynamically during the action potential (AP) and Ca transient (37 degrees C). This involved "tail" INCX measurement during abrupt repolarization of APs and Ca transients, where peak inward INCX indicates [Ca]sm. This allows inference of the direction of Ca transport by the NCX during the AP. In NF myocytes, NCX extrudes Ca for most of the AP. Three factors shift the direction of NCX-mediated Ca transport (to favor more Ca influx) in F versus NF myocytes, as follows: (1) reduced [Ca]sm, (2) prolonged AP duration, and (3) elevated [Na]i. These results show that Ca entry through NCX may limit systolic dysfunction due to reduced sarcoplasmic reticulum Ca stores in HF but could contribute to slow decay of the [Ca]i transient and to diastolic dysfunction.
ISSN:0009-7322
1524-4539
DOI:10.1161/01.cir.0000095274.72486.94