Chloride in smooth muscle

Interest in the functions of intracellular chloride expanded about twenty y ears ago but mostly this referred to tissues other than smooth muscle. On t he other hand, accumulation of chloride above equilibrium seems to have bee n recognised more readily in smooth muscle. Experimental data is used to show by calculation that the Donnan equilibriu m cannot account for the chloride distribution in smooth muscle but it can in skeletal muscle. The evidence that chloride is normally above equilibriu m in smooth muscle is discussed and comparisons are made with skeletal and cardiac muscle. The accent is on vascular smooth muscle and the mechanisms of accumulation and dissipation. The three mechanisms by which chloride can be accumulated are described wit h some emphasis on calculating the driving forces, where this is possible. The mechanisms are chloride/bicarbonate exchange, (Na + K + Cl) cotransport and a novel entity, "pump III", known only from own work. Their contributi ons to chloride accumulation vary and appear to be characteristic of indivi dual smooth muscles. Thus, (Na + K + Cl) always drives chloride inwards, ch loride/bicarbonate exchange is always present but does not always do it and "pump III" is not universal. Three quite different biophysical approaches to assessing chloride permeabi lity are considered and the calculations underlying them are worked out ful ly. Comparisons with other tissues are made to illustrate that low chloride permeability is a feature of smooth muscle. Some of the functions of the high intracellular chloride concentrations are considered. This includes calculations to illustrate its depolarising infl uence on the membrane potential, a concept which, experience tells us, some people find confusing. The major topic is the role of chloride in the regu lation of smooth muscle contractility. Whilst there is strong evidence that the opening of the calcium-dependent chloride channel leads to depolarisat ion, calcium entry and contraction in some smooth muscles, it appears that chloride serves a different function in others. Thus, although activation a nd inhibition of (Na + K + Cl) cotransport is associated with contraction a nd relaxation respectively, the converse association of inhibition and cont raction has been seen. Nevertheless, inhibition of chloride/bicarbonate exc hange and "pump III" and stimulation of (K + Cl) cotransport can all cause relaxation and this suggests that chloride is always involved in the contra ction of smooth muscle. The evidence that (Na + K + Cl) cotransport more active in experimental hyp ertension is discussed. This is a common but not universal observation. The information comes almost exclusively from work on cultured cells, usually from rat aorta. Nevertheless, work on smooth muscle freshly isolated from h ypertensive rats confirms that (Na + K + Cl) cotransport is activated in hy pertension but there are several other differences, of which the depolarisa tion of the membrane potential may be the most important. Finally, a simple calculation is made which indicates as much as 40% of the energy put into the smooth muscle cell membrane by the sodium pump is nece ssary to drive (Na + K + Cl) cotransport. Notwithstanding the approximation s in this calculation, this suggests that chloride accumulation is energeti cally expensive. Presumably, this is related to the apparently universal ro le of chloride in contraction. (C) 2001 Elsevier Science Ltd. All rights re served.