Circulating Inhibitors of the Na Pump, Exchange, and Hypertension.

Excessive dietary Na, and a tendency to Na retention and blood volume expansion invariably lead to hypertension. The missing link between Na and hypertension may be a new adrenocortical hormone that is a ouabain isomer. Chronic parenteral administration of exogenous (plant) ouabain induces hypertension in rats. Low levels of ouabain influence cell metabolism mainly by raising cytosolic Na+ slightly. This also tends to raise cytosolic Ca2+, via exchange, but most of the entering Ca is sequestered in the sarcoplasmic reticulum (SR) of vascular smooth muscle (VSM) cells and the endoplasmic reticulum (ER) of other cell types. Because the concentrates Ca, it acts as an amplifier: very small changes in cytosolic Ca2+ are associated with large changes in stored Ca. This may be a consequence of the co-localization of the Na pump and exchanger molecules in plasmalemmal microdomains that overlie subplasmalemmal . The is a major source of “activator” Ca in most cells, including VSM. Thus, cell responsiveness is directly influenced by the relative Ca content. These mechanisms provide a logical link between dietary salt and hypertension: ↑ Na retention → ↑ endogenous ouabain → ↑ cytosolic Na+ → ↑ cytoslic Ca2+ (via exchange) → ↑ ↑ Ca → ↑ ↑ cell responsiveness. In VSM cells and sympathetic neurons, this leads to increased vascular tone and peripheral vascular resistance, and thereby elevates blood pressure.