Altered Na/Ca exchange distribution in ventricular myocytes from failing hearts

Abstract

Na/Ca exchange (NCX) is normally located predominantly in the T tubules of cardiac ventricular myocytes. However, redistribution of NCX occurs in myocytes from failing hearts, resulting in more uniform distribution between T tubule and surface sarcolemma; this alters access of NCX to Ca released from sarcoplasmic reticulum and thus cellular Ca handling.

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 ( I _NCX) and l-type Ca current ( I _Ca) 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. I _NCX was activated and measured during application of caffeine to release Ca from sarcoplasmic reticulum (SR). Whole cell I _NCX 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 I _NCX and I _Ca away from the T tubules to the cell surface and an increase in t-tubular I _NCX/ I _Ca density from 0.12 in Sham to 0.30 in CAL myocytes. The decrease in t-tubular I _NCX 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 I _NCX 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.