Interest in the functions of intracellular chloride expanded about twenty years ago but mostly this referred to tissues other than smooth muscle. On the other hand, accumulation of chloride above equilibrium seems to have been recognised more readily in smooth muscle. Experimental data is used to show by calculation that the Donnan equilibrium cannot account for the chloride distribution in smooth muscle but it can in skeletal muscle. The evidence that chloride is normally above equilibrium 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 with 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 contributions to chloride accumulation vary and appear to be characteristic of individual smooth muscles. Thus, (Na+K+Cl) always drives chloride inwards, chloride/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 permeability are considered and the calculations underlying them are worked out fully. 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 influence on the membrane potential, a concept which, experience tells us, some people find confusing. The major topic is the role of chloride in the regulation of smooth muscle contractility. Whilst there is strong evidence that the opening of the calcium-dependent chloride channel leads to depolarisation, calcium entry and contraction in some smooth muscles, it appears that chloride serves a different function in others. Thus, although activation and inhibition of (Na+K+Cl) cotransport is associated with contraction and relaxation respectively, the converse association of inhibition and contraction has been seen. Nevertheless, inhibition of chloride/bicarbonate exchange and "pump III" and stimulation of (K+Cl) cotransport can all cause relaxation and this suggests that chloride is always involved in the contraction of smooth muscle. The evidence that (Na+K+Cl) cotransport more active in experimental hypertension 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 hypertensive rats confirms that (Na+K+Cl) cotransport is activated in hypertension but there are several other differences, of which the depolarisation of the membrane potential may be the most important.Finally, a simple calculation is made which indicates as much as 40% of the energy...

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SUMMARY1. In outdated human red blood cells, there was a Ko-dependent, ouabain-insensitive efflux of Na that was inhibited by frusemide and phloretin.2. It was reduced or absent (a) in media containing Ca or Mg, (b) in fresh cells.3. In media with Cl partly replaced by NO3, Na efflux, and its sensitivity to Ko and frusemide, were reduced. 4. The saturable component of ouabain-insensitive K influx was dependent on Cl and inhibited by frusemide and by phloretin.5. Bromide also supported a frusemide-sensitive, ouabain-insensitive K influx but acetate and SO4 (like NO3) did not.

1 Double-barrelled ion-selective microelectrodes were used to examine the e ects of exogenous noradrenaline upon the membrane potential (E m ) and intracellular chloride concentration ([Cl] i ) of arterial smooth muscle from the saphenous branch of the femoral artery of the rat. 2 After treatment with 0.6 mM 6-hydroxydopamine (to functionally denervate the tissue), exogenous noradrenaline (5 nM) caused repeatable depolarization of E m from 763.7+2.4 mV (s.d., n=18) to 753.8+3.4 mV (P50.0001) and increases in [Cl] i from 31.0+0.5 mM to 42.5+2.2 mM (P50.0001). 3 In the presence of 10 mM bumetanide (an inhibitor of (Na-K-Cl) cotransport), 5 nM noradrenaline caused a depolarization of E m of 3.0+3.2 mV, and a rise in [Cl] i of 4.5+2.5 mM. 4 In the presence of bumetanide and 1 mM acetazolamide (used as an inhibitor of a Na-independent inward Cl pump), noradrenaline had no e ect on E m or [Cl] i . 5 In the absence of extracellular chloride, the rise in apparent [Cl] i in response to 5 nM noradrenaline was abolished but there was a depolarization of 2.0+3.9 mV. 6 These results are consistent with the stimulation of (Na-K-Cl) cotransport and a Na-independent Cl pump by exogenous noradrenaline and with the consequent increase in [Cl] i and shift in E Cl potentiating the depolarization caused by noradrenaline. The possibility that modulation of [Cl] i may be a general mechanism of E m regulation is discussed.