Inhibition of membrane phosphotyrosyl-protein phosphatase activity by vanadate.

Functional comparisons between isoforms of the sarcoplasmic or endoplasmic reticulum family of calcium pumps.

Cyclin activation of p34cdc2

The aetiology of essential hypertension, a disease prevalent in cultured societies, is unknown. However, much evidence suggests that abnormal sodium metabolism has a critical role—this has led to the hypothesis that an increase in the circulating concentration of an inhibitor of (Na+ + K+) ATPase is responsible for the increased peripheral vascular resistance in essential hypertension1. Evidence for relatively high levels of a Na+ pump inhibitor in essential hypertension has come from bioassay and cytochemical assays of plasma and urine from normotensive and hypertensive individuals2,3. There is also evidence for increased plasma levels of a Na+ pump inhibitor in some animal models (for example, renal and deoxycorticosterone acetate (DOCA) models) of hypertension4. Nevertheless, direct biochemical determination of (Na+ + K+) ATPase inhibition by this substance has not yet been reported. We demonstrate here, with a kinetic (Na+ + K+) ATPase assay, a highly significant correlation between levels of a plasma inhibitor of (Na+ + K+)ATPase activity and mean arterial blood pressure (MAP) in normotensive and hypertensive individuals. These data provide evidence for the involvement of a circulating Na+ pump inhibitor in the genesis of essential hypertension. Moreover, our assay methods may be useful for the isolation and characterization of this inhibitor.

A circulating inhibitor of (Na+ + K+) ATPase associated with essential hypertension

The mechanism of insulin action is still unknown1. One approach to this problem is to apply substances which mimic the action of the hormone to target cells. Ouabain and deprivation of extracellular K+ (refs 2,3), which inhibit the active transport of Na+ and K+ ions, are both known to activate glucose transport and oxidation in isolated adipocytes. Vanadate (V) ions have recently been shown to act as very efficient inhibitors of the sodium pump or (Na+ + K+)ATPase in in vitro preparations4. They have a natriuretic and diuretic effect in rats5 and a positive inotropic effect on cat heart muscle6. Many tissues contain vanadium at a concentration of about 0.1–1.0 μM (ref. 7) and so endogenous vanadate could be a physiological regulator of the sodium pump. But this is still open to debate, because the bulk of the vanadium is probably in the vanadyl (IV) form8,9 and VO2+ ions bind tightly to proteins8,10. VO2+ is a relatively ineffective inhibitor of (Na+ + K+) ATPase in vitro8,11. We report here that externally applied vanadate ions at low concentrations mimic fully the effect of insulin on glucose oxidation in rat adipocytes. However, this simulation seems to be due mainly to the effects of vandyl (IV) ions, probably produced within the cells, and not primarily to inhibition of the sodium pump. Also, externally applied vanadyl (IV) ions stimulate glucose oxidation substantially. Vanadyl ions are known to be powerful inhibitors of alkaline phosphatase12 and we therefore consider the possibility that they inhibit a cellular phosphatase activity. An early event in insulin action may involve alteration of the degree of phosphorylation of protein(s) involved in regulation of sugar transport.

M Yanagisawa

Papers

Vanadate is a potent (Na,K)-ATPase inhibitor found in ATP derived from muscle.