There is now a considerable amount of evidence, both direct and indirect, that most excitable cells are permeable to chloride ions. The relative permeability to chloride varies from cell to cell and consequently its physiological significance varies. Where the relative permeability to chloride is low, as for example in giant squid axons, chloride ions play a minor role in the electrical events associated with activity. Where the relative permeability is high, as in skeletal muscle and to a lesser extent in cardiac muscle, chloride ions play a significant role in the electrical events during activity. In the latter situation, the contribution of currents caused by chloride is less important when the sodium and potassium currents are high during certain phases of activity.
In the absence of active transport, the actual concentration of chloride inside the cell is a function of the membrane permeability to chloride, the chloride concentration outside the cell, and the behavior of the membrane potential as a function of time. In cells which are either periodically or continually active, the instantaneous internal chloride concentration is related to the past history of the cell rather than to the momentary or even short-term average membrane potential. For cells in a steady state of constant activity the internal chloride concentration is a function of the steady state. The actual concentration depends on precise temporal behavior of the membrane potential and the chloride permeability of the membrane. The chloride equilibrium potential is somewhere between the limits set by the maximum and minimum values of the membrane potential during activity. In quiescent cells where the membrane potential remains constant, and in the absence of active transport, the chloride equilibrium potential should assume a value equal to the membrane potential. To a first approximation this seems to be the case in skeletal striated muscle. On the other hand, this appears not to be the case in squid giant axon where an inwardly directed pump for chloride ions appears to be present. The influence of foreign anions in the lyotropic series on the electrical events in excitable cells is largely ascribable to either 1) the fact that their permeance is different from that of chloride and consequently they contribute a different amount of anion current, or 2) the fact that they alter the passage of chloride through the membrane, or both of these mechanisms. The effects that foreign anions have on the sodium conductance seem to produce minor consequences.
In the case of contractile tissues, the evidence indicates that there is a change in the ability of the membrane potential to control the contractile process when other anions replace chloride in the external medium. To the extent that one can generalize to other processes controlled by the membrane potential, it is tempting to suppose that neurosecretion and other processes may be altered by changes in the external anion composition. To recognize such analogies and to pursue them experimentally might prove fruitful in furthering our understanding of the role that chloride ions play in the functioning of excitable cells.