Effects of acute euglycemic hyperinsulinemia on urinary nitrite/nitrate excretion and plasma endothelin-1 levels in men with essential hypertension and normotensive controls.

Insulin stimulates the production of endothelin-1 (ET-1) and nitric oxide (NO) by isolated endothelial cells. Additionally, insulin-dependent glucose transport and insulin-mediated NO production partially share common elements in signal transduction. There are discordant data on plasma ET-1 levels during acute euglycemic systemic hyperinsulinemia in normotensive men and men with essential hypertension (EH) (known to be insulin-resistant), as well as on the relations between insulin sensitivity and vascular function. Our aim was to assess the response of approximate measures of whole-body generation of NO and ET-1 to acute euglycemic hyperinsulinemia in EH patients and controls. We studied 17 newly diagnosed untreated men with uncomplicated EH and 10 normotensive controls. Plasma ET-1 and urinary excretion of nitrite plus nitrate, stable NO metabolites (Uno(x)), were measured before and during a 3-hour hyperinsulinemic-euglycemic clamp. Both in hypertensives and normotensives, plasma ET-1 levels were reduced after 2 hours of the clamp (EH: baseline, 3.1+/-1.9 pg/mL; 2 hours, 1.9+/-1.2 pg/mL, P = .04 v baseline; controls: baseline, 4.2+/-2.6 pg/mL; 2 hours, 2.8+/-1.4 pg/mL, P = .04 v baseline). No significant changes in Uno(x) during the clamp were observed. Changes in Uno(x) during the clamp (deltaUno(x)) and differences in plasma ET-1 measured before the end and before the beginning of the clamp (deltaET-1) were correlated in the controls (r = .75, P = .01) but not in EH (r = -.01, P = .97). No parameter of glucose metabolism correlated with basal Uno(x), basal plasma ET-1, deltaUno(x), and deltaET-1, whether absolute or percent values, in either group. Thus, acute euglycemic hyperinsulinemia produces a decrease in plasma ET-1 in both EH patients and controls. The lack of correlation between deltaUno(x) and deltaET-1 under these conditions in EH may suggest an impairment of systems governing interactions between the NO-dependent pathway and ET-1. In addition, insulin actions on glucose metabolism and on the endothelial mediators appear dissociated.

Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension.

Our aim was to investigate systemic nitric oxide (NO) production and its potential determinants such as insulin resistance, dyslipidemia, and circulating methylated analogs of L-arginine in uncomplicated essential hypertension (EH). Nineteen newly diagnosed, untreated male subjects with mild pure uncomplicated EH and 11 normotensive controls were studied at rest after an overnight fast. The groups had comparable age, body mass index, creatinine clearance, cholesterol, fasting glucose, and insulin. In hypertensives, the urinary excretion rate of nitrite plus nitrate (Unox), an index of endogenous NO production, was depressed (56+/-17 vs. 77+/-23 micromol/mmol creatinine; p < 0.05), whereas plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis, were increased (2.4+/-1.1 vs. 1.1+/-0.7 microM; p < 0.005). Circulating concentrations of symmetric dimethylarginine were similar in both groups (1.4+/-1.3 vs. 1.5+/-1.1 microM; p = NS). The L-arginine-to-ADMA ratio was reduced in hypertension (3.3+/-0.5 vs. 4.5+/-0.8; p < 0.001 for In-transformed data). There was no correlation between Unox and either the magnitude of insulin resistance or dyslipidemia in EH. Thus in male subjects with EH, endogenous systemic NO formation appears depressed, which is unrelated to accompanying insulin resistance or dyslipidemia. Circulating ADMA levels are increased in uncomplicated EH, which may be of potential relevance.