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

Abstract

Mutations in the endothelial nitric oxide synthase (eNOS) gene may be associated with abnormal nitric oxide (NO) production and cardiovascular diseases. In this study, we investigated the prevalence of two eNOS polymorphisms, the Glu298Asp variant on exon 7, and the 4a/b variable number of tandem repeats (VNTR) on intron 4, and their association with blood pressure (BP), NO production, salt sensitivity and cardiovascular risk factors in healthy Venezuelans. The prevalence of both polymorphisms in Venezuelans was comparable to that described for Caucasians, but significantly different from that known for African-Americans and Japanese. The 4a/b genotype was associated with reduced levels of NO metabolites (25% decrease), larger BP lowering in response to salt restriction (9.0 vs 4.8 mmHg, Po0.05), greater prevalence of salt sensitivity (39% in 4a/b and 27% in 4b/b; Po0.05) and with higher LDL-cholesterol levels. The Glu298T polymorphism did not affect NO production, nor it was associated with salt sensitivity. Glu298Asp polymorphism was positively associated with higher weight, triglycerides and LDL-cholesterol. Neither polymorphism was associated with changes in fasting or postload serum glucose, BP, obesity and albuminuria. In conclusion, the prevalence of eNOS polymorphisms is strongly determined by ethnic factors. The 4a/b gene polymorphism could be a genetic susceptibility factor for the BP response to salt intake and for the genetic control of NO production. The reduced NO production in subjects with the 4a/b genotype may be responsible for the increased sensitivity of their BP to salt.

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

“…35 NO has been shown to play a role in animal models of salt sensitivity. 14,18,19,32,34,36 NO is involved in the control of intrarenal hemodynamics and sodium homeostasis, and inhibits Cl-reabsorption at the ascending thick loop of Henle to induce natriuresis. 15,35 Treatment with an NO-synthesis inhibitor induces salt sensitivity, whereas administration of L-arginine and/or of an NO-donor corrects salt sensitivity.…”

“…[1][2][3][4][5] Although the pathogenesis of salt sensitivity is unknown, both genetic and environmental factors appear to interact to determine the exaggerated BP response to changes in salt intake. [6][7][8][9][10][11][12][13][14][15] Increased reactivity of BP to salt is commonly observed in subjects with obesity and associated cardiovascular risk factors. [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.…”

“…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.…”

Hypertension and genes: perspectives from this journal

“…The prevalence of eNOS polymorphism is strongly determined by ethnicity and that the 4a/b gene polymorphism within intron 4 (27-base-pair repeat polymorphism) of the eNOS gene could be a genetic determinant for the blood pressure (BP) response to salt intake. 9 Again, the prevalence of this genetic polymorphism depends on ethnicity.…”

Towards understanding the aetiology and pathophysiology of human hypertension: where are we now?

“…29 Other researchers have demonstrated many further genetic associations but consensus is lacking. [30][31][32][33][34][35][36][37][38][39] Clearly, the availability of data from diverse populations, including Chinese, 31 Hispanics 32,33 and African-Americans 34 cohorts, is encouraging, gene variants may influence target organ damage 35 in hypertension and blood pressure variation, 36 but again, more data from diverse populations are needed. Although in the current environment, the cynics would argue that the genetic basis for essential hypertension is tenuous and far from conclusive, the hope still remains to locate specific genes for hypertension that could provide for novel targeted therapy, which would improve our current management of this condition.…”