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


RESULTS
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.


CONCLUSIONS
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.
Weber
Christopher R
CR
Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Ill 60153, USA.
Piacentino
Valentino
V
Houser
Steven R
SR
Bers
Donald M
DM
D000200:Action Potentials / Q000187:drug effects; D000494:Allosteric Regulation / Q000187:drug effects; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002469:Cell Separation; D004594:Electrophysiology; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism; D012964:Sodium / Q000378:metabolism* / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism*
D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium