Upregulation of NOS by simulated microgravity, potential cause of orthostatic intolerance

Prolonged exposure to microgravity during spaceflight or extended bed rest results in cardiovascular deconditioning, marked by orthostatic intolerance and hyporesponsiveness to vasopressors. Earlier studies primarily explored fluid and electrolyte balance and baroreceptor and vasopressor systems in search of a possible mechanism. Given the potent vasodilatory and natriuret ic actions of nitric oxide (NO), we hypothesized that cardiovascular adapta tion to microgravity may involve upregulation of the NO system. Male Wistar rats were randomly assigned to a central group or a group subjected to sim ulated microgravity by hindlimb unloading (HU) for 20 days. Tissues were ha -vested after death for determination of total nitrate and nitrite (NOx) as well as endothelial (e), inducible (i), and neuronal (n) NO synthase (NOS) proteins by Western blot. Separate subgroups were used to test blood press ure response to norepinephrine and the iNOS inhibitor aminoguanidine. Compa red with controls, the HU group showed a significant increase in tissue NOx content and an upregulation of iNOS protein abundance in thoracic aorta, h eart, and kidney and of nNOS protein expression in the brain and kidney but ; no discernible change in eNOS expression. This was associated with marked attenuation of hypertensive response to norepinephrine and a significant i ncrease in hypertensive response to aminoguanidine, suggesting enhanced iNO S-derived NO generation in the HU group. Upregulation of these NOS isotypes can contribute to cardiovascular adaptation to microgravity by promoting v asodilatory tone and natriuresis and depressing central sympathetic outflow . If true in humans, short-term administration of an iNOS inhibitor may ame liorate orthostatic intolerance in returning astronauts and patients after extended bed rest.