Endothelial membrane potential regulates production of both nitric oxide and superoxide--a fundamental determinant of vascular health.

There is recent evidence that the membrane potential of vascular endothelium regulates not only nitric oxide (NO) synthesis, but also superoxide generation, such that hyperpolarization stimulates NO production while suppressing that of superoxide. Given that NO works in a variety of ways to inhibit atherothrombotic disease and hypertension, whereas superoxide not only vetoes the benefits of NO but also disrupts endothelial metabolism and promotes LDL oxidation through its oxidant activity, it is thus evident that endothelium membrane potential is a crucial determinant of cardiovascular risk. Membrane polarization can be enhanced by measures which increase the synthesis or availability of the Na+-K+-ATPase, moderately enhance serum K+ and increase the conductance of membrane K+ channels. Such measures may include high-K+/low-Na+ natural diets, insulin sensitizing modalities, 'euthyroid replacement therapy' and ACE inhibitors. Epidemiological correlations of insulin resistance with hypertension and cardiovascular risk may reflect the low membrane potential of insulin-resistant vascular endothelium. Adjunctive measures for suppressing the generation or half-life of endothelial superoxide are suggested.