Endogenous nitric oxide synthesis determines sensitivity to the pressor effect of salt

Abstract

Endogenous nitric oxide plays an important role in modulation of renal hemodynamics and sodium handling, with increased nitric oxide production inducing renal vasodilation and natriuresis. In the normal rat, nitric oxide activity increases as an adaptive response to increased dietary salt intake, perhaps facilitating natriuresis and thus blood pressure homeostasis. We hypothesized that impaired nitric oxide synthetic ability would result in sensitivity to the pressor effects of high dietary salt intake. Four groups of normal Sprague-Dawley rats were observed for eight weeks: Control, 0.4% NaCl chow and tap water; Salt, 4% NaCl chow and tap water; NAME, 0.4% NaCl chow and water containing the nitric oxide synthase inhibitor, L-nitro-arginine-methylester; Salt+NAME, 4% NaCl chow and water containing L-nitro-arginine-methylester. Compared to Controls, Salt rats demonstrated a significant increase in urinary excretion rate of the stable nitric oxide metabolites, NO2 and NO3, and had no increase in blood pressure. Furthermore, Salt rats had no functional or structural evidence of renal injury. In contrast, Salt+NAME rats demonstrated a significantly higher blood pressure than NAME rats, and urinary NO2 and NO3 excretion rate did not increase despite high salt intake. After eight weeks, Salt+NAME rats had significantly impaired renal function and proteinuria. We conclude that adaptive changes in endogenous NO production play a critical role in sodium and blood pressure homeostasis. Furthermore, impaired nitric oxide synthase activity may be a pathogenetic factor in the development of salt-sensitive hypertension.

Effects of lifestyle changes and metformin on salt sensitivity and nitric oxide metabolism in obese salt-sensitive Hispanics

“…Endothelial dysfunction, insulin resistance, hyperinsulinemia, decreased sympathetic activation, decreased NO production, hyperaldosteronism, increased endothelin levels, among others, could either alone or in combination, induce a state of salt sensitivity and thus increase subject's BP. 2,6,[16][17][18][19][20]23,[30][31][32][33][34] Correction of one or several of these factors may be responsible for the correction of salt sensitivity induced by the lifestylemetformin treatment. Experiments in dogs suggest that increase in sympathetic activity rather than insulin resistance is responsible for the increase in BP associated with obesity.…”

“…Intermediate values classified subjects as of intermediate salt sensitivity. 1,4,18,22 Urinary sodium excretion values were obtained for assessing levels of salt intake and compliance with sodium diets.…”

“…[6][7][8][9][10] Insulin resistance, hypertension, increased sympathetic activity, endothelial dysfunction and abnormal nitric oxide (NO) bioactivity are among the list of factors that have been proposed to directly or indirectly lead to salt sensitivity related to obesity. 2,4,6,[16][17][18] NO is involved in renal sodium homeostasis and inhibition of NO synthesis is associated with impaired natriuresis and salt sensitivity. 19 Impairment in NO production has been observed in salt-sensitive subjects when exposed to a high sodium diet.…”

“…19 Impairment in NO production has been observed in salt-sensitive subjects when exposed to a high sodium diet. 14,18 Lifestyle changes and metformin have been shown to reduce adiposity, improve insulin sensitivity, lower BP, reduce sympathetic activity and improve endothelial function. 17,20 To determine the role of acquired factors in the pathogenesis of salt sensitivity, we investigated whether treatment of obesity and associated metabolic abnormalities by means of a combined lifestyle-metformin program corrects salt sensitivity.…”

Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics

“…1,[38][39][40] Experimental evidence indicates that NO plays a key role in endothelial health and salt sensitivity. 41 In genetic models of salt sensitivity and in human subjects, salt sensitivity appears linked to impaired NO production, [2][3][4][5][6] an effect reversed by administration of the NO precursor, L-arginine. 42,43 Despite numerous evidences supporting the role for NO in salt sensitivity, prior to this work no studies had been conducted on the relationships between eNOS polymorphisms and salt sensitivity.…”