© 1993 by European Society of Cardiology
Copyright © 1993, European Society of Cardiology
A role for sodium/calcium exchange in the action potential shortening caused by strophanthidin in guinea pig ventricular myocytes
Department of Physiology, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, United Kingdom: Dr A Levi.
Objective: The aim was to investigate the nature of the membrane currents which underlie the shortening of the action potential in guinea pig cardiac myocytes upon exposure to the digitalis analogue strophanthidin. Methods: Ventricular myocytes were isolated enzymatically from the guinea pig heart and impaled with conventional microelectrodes to measure action potentials. Cells were voltage clamped and the change in membrane current upon strophanthidin exposure was recorded. Contractile activity was assessed optically as cell shortening. Results: Strophanthidin caused an initial lengthening followed by a progressive shortening of the action potential. The initial lengthening was due to an inhibition of outward Na/K pump current caused by strophanthidin. The subsequent action potential shortening was associated with the progressive activation of a membrane current that reversed at –54.5(SD 7.5) mV, n=8. Since this current was outward over the potential range of the action potential plateau, it participated in causing the action potential shortening with strophanthidin. This component of membrane current was not sensitive to potassium channel blockers, but it was blocked by removing external Ca and applying 5 mM nickel externally. Removal of external Ca inhibits outward current generated by the Ca entry/Na extrusion mode of the Na/Ca exchange, whereas nickel is known to block the Na/Ca exchange. Conclusions: The voltage dependence of the membrane current associated with progressive action potential shortening, and its sensitivity to external Ca and nickel, suggest that it is carried on the Na/Ca exchange. It is proposed that the Na/Ca exchange generates this membrane current in response to the combined rise of intracellular sodium and calcium that occurs with strophanthidin. Theoretical calculations simulating the effect of a combined rise of intracellular sodium and calcium on Na/Ca exchange predict closely the reversal potential and characteristics of the experimentally measured current. The results of this study suggest that a membrane current generated by the Na/Ca exchange makes an important contribution to the action potential shortening that occurs with digitalis compounds.
Cardiovascular Research 1993;27:471-481
KEYWORDS cardiac muscle; cardiac glycoside; myocyte; voltage clamp; sodium-potassium pump; sodium-calcium exchange; action potential
I owe a huge debt to Professor Roger Thomas for his friendship, constant encouragement, stimulating discussion and constructive criticism. I am grateful to Sarah Price, Paul Brooksby, Jackie Addison, Jules Hancox, David Gadsby, Jon Lederer, and Richard Vaughan-Jones for helpful discussions and comments. I also wish to thank John Dempster for supplying his excellent analysis programs (and for modifying them so rapidly) and Margaret Clements for much needed secretarial assistance. This work was supported by the Wellcome Trust, the British Heart Foundation and the Royal Society.
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