Pathways for the movements of ions during calcium-free perfusion and the induction of the 'calcium paradox'.

The intracellular sodium content of cardiac cells in fish and amphibia, measured with either an isotope technique or with sodium-sensitive micro-electrodes, rises steeply from around 15 mmol/l in calcium-containing solution to as much as 70 mmol/l, during exposure to a Ca2+-free solution. This increase is associated with the development of spontaneous and prolonged action potentials so that the membrane may stabilise around -20 mV. On reperfusion with calcium-containing medium the membrane repolarises before a strong contracture develops. Inhibition of the Na-pump increases both the sodium gain and the subsequent calcium re-admission tension. A number of agents e.g. divalent cations, anti-arrhythmic drugs, local anaesthetics and Ca-channel blockers are able to prevent the development of the contracture but only if they are present during the calcium-free perfusion. They also inhibit the development of spontaneous electrical activity and the rise in Nai. The calcium re-admission contracture can be blocked in amphibian preparations voltage clamped around the resting potential during low calcium perfusion. From the known pharmacological action of these agents and the voltage and time dependence of the calcium channel, it is concluded that during calcium depletion, the prolongation of the action potentials is associated with a sustained entry of Na+ via the Ca-channels which leads to the rise in Nai. Once Nai has risen, these agents with the exception of Mn2+, a known inhibitor of the Na/Ca exchange, are unable to prevent the development of the contracture. This suggests that the re-admission contracture follows calcium uptake by way of the Na/Ca exchange.