Effects of ionophore-mediated transport on the cardiac resting potential

The monovalent carboxylic ionophores form lipid-soluble complexes with alkali cations which transport these ions across membranes. In a biological setting, they promote an electrically neutral exchange of intracellular potassium for extracellular sodium (Pressman, 1976). The ionophore monensin, which has a complexation preference for sodium (Pressman, 1968), has very little capability for complexing or transporting calcium or catecholamines (Pressman, Painter & Fahim, 1980). However, monensin produces a strong positive inotropic effect (Pressman, Harris, Jagger & Johnson, 1967; Sutko et al. 1977; Shlafer, Somani, Pressman & Palmer, 1978; Saini, Hester, Somani & Pressman, 1979) which is attenuated, but not abolished, by β-adrenergic blockade (Sutko et al. 1977; Shlafer et al. 1978; Saini et al. 1979). This indicates that the inotropic effect is partially mediated through an indirect release of catecholamines and, also, through a more direct mechanism, presumably by an alteration of transcellular cation gradients. Studies with cardiac Purkinje fibres show that monensin produces a shortening of the action potential, without an accompanying alteration in the resting potential (Sutko et al. 1977; Shlafer et al. 1978). Inasmuch as monensin should decrease the transcellular gradients of both sodium and potassium, one would expect that not only the action potential, dominated by the sodium diffusion potential, but also the resting potential, dominated by the potassium diffusion potential, should decrease. The present investigation was directed toward resolving the paradox of why monensin fails to alter the resting potential of cardiac muscle segments under the same conditions which alter the action potential. Our results show that depolarization of the resting potential, induced by monensin, is normally masked by the activity of the electrogenic sodium pump, and if the pump is inhibited by ouabain, then the expected depolarization is observed.