Mechanisms of the regulation of myofibrillar function in vascular smooth muscle.

inhibition convincingly to increased vascular smoothmuscle tone. Furthermore, any hypothesis which attempts to relate such a substance to the pathogenesis of essential hypertension must take into account, in addition to the problems outlined above, the fact that while there is consistent evidence of inhibition of Na+ ,K+-ATPase in the leucocytes of patients with essential hypertension, the body of evidence suggests that Na+,K+-ATPase activity is increased in their erythrocytes (see Swales, 1982). A suitable hypothesis is that the proposed endogenous inhibitor of Na' ,K+ -ATPase could cause hypertension by increasing vascular smooth-muscle tone, but by mechanisms unrelated to Na+ ,K+-ATPase inhibition. One would have to assume, however, that such a substance does possess some properties of digitalis other than inhibition of Na+ ,K+-ATPase. While digitalis inhibits Na+,K+-ATPase in the sorts of concentrations usually found in the tissues during its therapeutic use, in lower concentrations it has been found to have at least two other effects (Hart et al., 1983). (1) Stimulation of Na+ ,K+-ATPase, associated with a negative inotropic effect in sheep Purkinje fibres. (2) A direct, as yet uncharacterized, effect on calcium, associated with a positive inotropic effect. In rat ventricles two separate positive inotropic effects are clearly distinguishable (Grupp et al., 1984). An endogenous substance which, on testing in vitro, appears to be an inhibitor of Na+ ,K+-ATPase might in viuo have those actions associated with very low concentrations of digitalis, and might, therefore, cause increased vascular smoothmuscle tone by a direct effect on calcium. In erythrocytes, which lack the very high-affinity binding site for digitalis suggested to be associated with the effect on calcium, the substance would produce apparent stimulation of Na+ ,K+ -ATPase. In leucocytes, however, inhibition might occur, perhaps because of the much higher density of digitalis-binding sites on leucocyte membranes (see Boon et al., 1984).