Effect of increased availability of endothelium-derived nitric oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension.

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Abstract
BACKGROUND Patients with essential hypertension have a deficit in the endothelium-derived nitric oxide system that results in impaired endothelium-dependent vascular relaxation. The objective of this study was to determine whether this abnormality is caused by a deficiency of substrate for nitric oxide synthesis. METHODS AND RESULTS The vascular responses to acetylcholine (an endothelium-dependent vasodilator infused at 7.5, 15, and 30 micrograms/min) and sodium nitroprusside (a direct smooth muscle dilator infused at 0.8, 1.6, and 3.2 micrograms/min) were studied during combined administration of dextrose 5% or L-arginine (substrate for nitric oxide synthesis infused at 40 mumol/min) in 12 normal control subjects (seven men and five women; age, 49.3 +/- 7 years) and 14 hypertensive patients (nine men and five women; age, 48.4 +/- 7 years). In addition, the effect of D-arginine (stereoisomer of arginine that is not a precursor of nitric oxide) on the vascular responses to acetylcholine was studied in eight normal control subjects and seven hypertensive patients. Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by strain gauge plethysmography. The vasodilator response to acetylcholine was significantly blunted in hypertensive patients compared with normal control subjects (maximum flow, 8.9 +/- 5 versus 15.7 +/- 6 mL.min-1.100 mL-1, respectively; p < 0.007); however, no difference was observed in the response to sodium nitroprusside (11.4 +/- 6 and 11.7 +/- mL.min-1.100 mL-1, respectively). L-Arginine did not significantly change basal blood flow or vascular resistance in either group. In normal control subjects, the infusion of L-arginine significantly augmented the vasodilator response to acetylcholine (maximum flow, 15.7 +/- 6 versus 21.4 +/- 8 mL.min-1.100 mL-1 before and after L-arginine, respectively; p < 0.001). In contrast, in hypertensive patients, the infusion of L-arginine did not alter the response to acetylcholine (maximum flow, 8.9 +/- 5 and 8.4 +/- 4 mL.min-1.100 mL-1 before and after L-arginine, respectively). The administration of L-arginine did not modify the response to sodium nitroprusside in either group. Similarly, the infusion of D-arginine did not alter the response to acetylcholine in either group. CONCLUSIONS In normal humans, availability of substrate for production of nitric oxide is a rate-limiting step for endothelium-dependent vascular relaxation. In contrast, increased availability of nitric oxide precursor does not modify endothelium-mediated vasodilation in hypertensive patients. These findings provide further evidence of a defect in the endothelium-derived nitric oxide system in hypertension and indicate that this abnormality is not related to decreased availability of substrate for nitric oxide production.