A role for sodium/calcium exchange in the action potential shortening caused by strophanthidin in guinea pig ventricular myocytes.
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.
Department of Physiology, School of Medical Sciences, University of Bristol, United Kingdom.
A J
AJ
Levi
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006168:Guinea Pigs; D006352:Heart Ventricles; D017136:Ion Transport; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009532:Nickel / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects; D013327:Strophanthidin / Q000494:pharmacology*; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D013757:Tetraethylammonium Compounds; D013327:Strophanthidin; D019789:Tetraethylammonium; D009532:Nickel; D012964:Sodium; D015761:4-Aminopyridine; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium