© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Is there a transient rise in sub-sarcolemmal Na and activation of Na/K pump current following activation of INa in ventricular myocardium?
aCentre for Cardiovascular Biology and Medicine, The Rayne Institute, St. Thomas’ Hospital, King's College London, London SE1 7EH, UK
bDepartment of Physiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK
* Corresponding author. Tel.: +44-20-7928-9292x3376; fax: +44-20-7928-0658. michael.shattock{at}kcl.ac.uk
Objective: The primary aim of this study was to investigate whether activation of Na influx via voltage-gated Na channels can elevate sub-sarcolemmal (‘fuzzy-space’) [Na] and transiently activate Na/K pump current (Ip). Methods and results: Initially, Na/K pump activity was characterised in whole-cell voltage-clamped single guinea-pig ventricular myocytes. Ip was activated by intracellular Na with a Km of 15.5 mM and a Hill coefficient of 1.7. Extracellular K activated Ip with a Km of 1.6 mM. In these experiments, a finite ouabain-sensitive Ip was measured when the pipette [Na] was zero. This suggests that there is an accumulation of Na in a sub-sarcolemmal space that is not in equilibrium with the bulk cytosol (which is assumed to be efficiently dialysed by the low-resistance patch-pipettes used). Such a sub-sarcolemmal Na gradient was observed in separate experiments in intact rabbit papillary muscles using electron probe X-ray microanalysis. In these studies, a fuzzy-space of limited Na diffusion was observed 100–200 nm below the sarcolemmal membrane. This sub-sarcolemmal Na gradient was similar whether muscles were frozen at peak-systole or end-diastole suggesting that the fuzzy-space Na does not change over the course of the contractile cycle. This was further investigated in isolated guinea pig myocytes where evidence for a transient activation of Ip was sought immediately after the activation of voltage-gated Na channels. A single clamp step from –80 to 0 mV activated Na influx but, in the 10–2000 ms immediately following the initial Na influx no evidence for a transient activation of Ip was observed. Similarly, no activation of Ip could be detected immediately following a train of 20 rapid (5-Hz) pulses designed to maximise Na influx. Conclusions: These studies provide evidence for the existence of a maintained sub-sarcolemmal elevation of [Na] in ventricular myocardium; however, this fuzzy-space [Na] did not change immediately after the activation of Na influx via voltage-gated Na channels or throughout the contractile cycle.
KEYWORDS Electron microscopy; Intra/extracellular ions; Ion channels; Ion pumps; Myocytes; Na/K-pump
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