Nitric oxide synthase inhibitors and hypertension in children and adolescents

Objective To establish the role played by the circulating nitric oxide synthase inhibitors N-G-monomethyl-L-arginine (L-NMMA), asymmetrical dimethyl arginine (ADMA) and symmetric dimethyl arginine (SDMA) and its association with hypertension of children and adolescents. Design We measured plasma concentrations of L-NMMA, ADMA and SDMA in 38 hypertensives (median age 7.7 years) and in nine healthy normotensive controls (median age 8.2 years) using high-performance liquid chromatography. In addition, their plasma renin activity was determined. The subjects' glomerular filtration rates were calculated from plasma creatinine and height measurements. To determine the vasoactive potency of the arginine analogues, concentration-response curves were plotted for the responses in isolated endothelium-intact and endothelium-denuded mouse aortic rings that had been pre-contracted by administration of a threshold concentration of phenylephrine. Results Plasma ADMA and SDMA concentrations in members of the hypertensive group [0.23 +/- 0.03 and 1.37 +/- 0.06 mu mol/l, respectively (means +/- SEM)] were significantly higher than those in members of the control group (ADMA 0.10 +/- 0.01 mu mol/l and SDMA 1.18 +/- 0.06 mu mol/l). Plasma concentrations of L-NMMA were similar in members of the hypertensive (0.21 +/- 0.01 mu mol/l) and control (0.18 +/- 0.02 mu mol/l) groups. The glomerular filtration rate of the hypertensive group was below normal [70.4 +/- 5.4 ml/min per 1.73 m(2) (mean +/- SEM)] and was significantly associated with elevated plasma concentrations of ADMA (r = -0.77, P < 0.001), SDMA (r = -0.38, P = 0.02) and L-NMMA (r = 0.35, P = 0.03). Higher plasma ADMA concentrations were associated with a lower plasma renin activity (r = -0.36, P = 0.04). The vasoactive potencies of ADMA (concentration for half-maximal effect with the endothelium intact 25.4 +/- 7.1 mu mol/l) and L-NMMA (concentration for half-maximal effect with the endothelium intact 8.2 +/- 2.9 mu mol/l) was significantly (P < 0.05) greater than that of SDMA. Both ADMA and L-NMMA (at 3 mu mol/l concentrations) initiated a significant vasocontractile response from baseline (P = 0.03 and P < 0.001, respectively). These effects were absent after the endothelium had been removed. SDMA had no effect. Conclusions Plasma ADMA and SDMA levels are increased in hypertensive children. By inference from in-vitro data, ADMA appears to attain sufficient concentrations to produce a significant change in vascular tone and hence might play a role in the pathophysiology of childhood hypertension.