INVESTIGATION OF DECREASED AVAILABILITY OF NITRIC-OXIDE PRECURSOR AS THE MECHANISM RESPONSIBLE FOR IMPAIRED ENDOTHELIUM-DEPENDENT VASODILATION IN HYPERCHOLESTEROLEMIC PATIENTS

Objectives. The purpose of this study was to determine whether the imp aired endothelium dependent vasodilation of hypercholesterolemic patie nts is due to decreased availability of L arginine, the substrate for nitric oxide. Background. Patients with hypercholesterolemia have impa ired endothelium dependent vasodilation that is related to a defect in the endothelium derived nitric oxide system. However, the precise loc ation of this abnormality has not been determined. Methods. The study included 12 hypercholesterolemic patients (6 men, 6 women; 52 +/- 9 ye ars old; serum cholesterol >240 mg/dl) and 15 normal volunteers (8 men , 7 women; 50 +/- 6 years old; serum cholesterol <210 mg/dl). The fore arm vascular responses to intraarterial infusion of acetylcholine, an endothelium-dependent vasodilator (7.5, 15, 30 mu g/min), and sodium n itroprusside, a direct smooth muscle dilator (0.8, 1.6, 3.2 mu g/min) were studied before and during infusion of L- or D-arginine (a stereoi somer of arginine that is not a nitric oxide precursor). Results. The response to acetylcholine was lower in hypercholesterolemic patients t han in control subjects. However, no significant difference was observ ed with sodium nitroprusside infusion. L-Arginine augmented the respon se to acetylcholine in normal subjects (maximal blood flow increased f rom 14.4 +/- 7 to 18.9 +/- 10 ml/min per 100 ml, p < 0.002). In contra st, in the hypercholesterolemic lesterolemic patients, only a mild but not significant improvement in the response to acetylcholine was obse rved with the infusion of L-arginine (maximal blood flow increased fro m 6.8 +/- 4 to 8.4 +/- 5 ml/min per 100 mi; p = 0.16); however, a simi lar mad but not significant change was also observed with D-arginine ( maximal blood flow increased from 6.8 +/- 4 to 8.3 +/- 4 ml/min per 10 0 ml,, p = 0.07). L-Arginine did not modify the response to sodium nit roprusside in either group. Conclusions. The augmentation of endotheli um-dependent vasodilation by L arginine, the nitric oxide precursor, i s defective in hypercholesterolemic patients. This supports the concep t of an abnormal endothelium derived nitric oxide system in hyperchole sterolemia and indicates that decreased availability of nitric oxide s ubstrate is not responsible for the impaired endothelial function in t his condition.