Abstract

In mammalian cardiac ventricular myocytes, Ca efflux via Na/Ca exchange (NCX) occurs predominantly at T tubules. Heart failure is associated with disrupted t-tubular structure, but its effect on t-tubular function is less clear. We therefore investigated t-tubular NCX activity in ventricular myocytes isolated from rat hearts ∼18 wk after coronary artery ligation (CAL) or corresponding sham operation (Sham). NCX current (INCX) and l-type Ca current (ICa) were recorded using the whole cell, voltage-clamp technique in intact and detubulated (DT) myocytes; intracellular free Ca concentration ([Ca]i) was monitored simultaneously using fluo-4. INCX was activated and measured during application of caffeine to release Ca from sarcoplasmic reticulum (SR). Whole cell INCX was not significantly different in Sham and CAL myocytes and occurred predominantly in the T tubules in Sham myocytes. CAL was associated with redistribution of INCX and ICa away from the T tubules to the cell surface and an increase in t-tubular INCX/ICa density from 0.12 in Sham to 0.30 in CAL myocytes. The decrease in t-tubular INCX in CAL myocytes was accompanied by an increase in the fraction of Ca sequestered by SR. However, SR Ca content was not significantly different in Sham, Sham DT, and CAL myocytes but was significantly increased by DT of CAL myocytes. In Sham myocytes, there was hysteresis between INCX and [Ca]i, which was absent in DT Sham but present in CAL and DT CAL myocytes. These data suggest altered distribution of NCX in CAL myocytes.

Highlights

  • Na/Ca exchange (NCX) is normally located predominantly in the T tubules of cardiac ventricular myocytes

  • CONTRACTION OF CARDIAC VENTRICULAR myocytes is initiated by Ca influx across the cell membrane via the L-type Ca current (ICa), which activates ryanodine receptors (RyRs) in adjacent sarcoplasmic reticulum (SR) membrane, triggering Ca-induced Ca release (CICR) from the SR

  • Representative caffeine-induced Ca transients and inward (depolarizing) NCX current (INCX) in DT sham operation (Sham) and CAL cells are shown in Fig. 1B: DT did not significantly alter peak [Ca]i in Sham cells (2.06 Ϯ 0.69 ␮M) but increased peak [Ca]i in CAL cells

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Summary

Introduction

Na/Ca exchange (NCX) is normally located predominantly in the T tubules of cardiac ventricular myocytes. ICa, CICR, and Ca efflux via NCX occur predominantly at invaginations of the surface membrane, called T tubules [5] Because of this colocation, Ca close to the site of CICR appears to be more effective than bulk cytoplasmic Ca at stimulating Ca efflux via NCX, and –since NCX carries three Na for each Ca–the associated inward (depolarizing) NCX current (INCX) [35]. This is important for normal Ca efflux and because under conditions of Ca overload, spontaneous SR Ca release occurs, activating inward INCX and causing delayed afterdepolarisations (DADs), which can trigger action potentials and arrhythmias [18]. In the present study we investigated the distribution of INCX between the t-tubular and surface membranes, and its functional consequences, in myocytes from normal and HF rats

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