title: Investigation of decreased availability of nitric oxide precursor as the mechanism responsible for impaired endothelium-dependent vasodilation in hypercholesterolemic patients.
abstract: OBJECTIVE
  The purpose of this study was to determine whether the impaired endothelium-dependent vasodilation of hypercholesterolemic patients is due to decreased availability of L-arginine, the substrate for nitric oxide.
  
  
  BACKGROUND
  Patients with hypercholesterolemia have impaired endothelium-dependent vasodilation that is related to a defect in the endothelium-derived nitric oxide system. However, the precise location of this abnormality has not been determined.
  
  
  METHODS
  The study included 12 hypercholesterolemic patients (6 men, 6 women; 52 +/- 9 years old; serum cholesterol > 240 mg/dl) and 15 normal volunteers (8 men, 7 women; 50 +/- 6 years old; serum cholesterol < 210 mg/dl). The forearm vascular responses to intraarterial infusion of acetylcholine, an endothelium-dependent vasodilator (7.5, 15, 30 micrograms/min), and sodium nitroprusside, a direct smooth muscle dilator (0.8, 1.6, 3.2 micrograms/min) were studied before and during infusion of L- or D-arginine (a stereoisomer of arginine that is not a nitric oxide precursor).
  
  
  RESULTS
  The response to acetylcholine was lower in hypercholesterolemic patients than in control subjects. However, no significant difference was observed with sodium nitroprusside infusion. L-Arginine augmented the response to acetylcholine in normal subjects (maximal blood flow increased from 14.4 +/- 7 to 18.9 +/- 10 ml/min per 100 ml, p < 0.002). In contrast, in the hypercholesterolemic patients, only a mild but not significant improvement in the response to acetylcholine was observed with the infusion of L-arginine (maximal blood flow increased from 6.8 +/- 4 to 8.4 +/- 5 ml/min per 100 ml; p = 0.16); however, a similar mild 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 100 ml, p = 0.07). L-Arginine did not modify the response to sodium nitroprusside in either group.
  
  
  CONCLUSIONS
  The augmentation of endothelium-dependent vasodilation by L-arginine, the nitric oxide precursor, is defective in hypercholesterolemic patients. This supports the concept of an abnormal endothelium-derived nitric oxide system in hypercholesterolemia and indicates that decreased availability of nitric oxide substrate is not responsible for the impaired endothelial function in this condition.
authors.affiliation: Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: P R
authors.initials: PR
authors.lastname: Casino
authors.forename: C M
authors.initials: CM
authors.lastname: Kilcoyne
authors.forename: A A
authors.initials: AA
authors.lastname: Quyyumi
authors.forename: J M
authors.initials: JM
authors.lastname: Hoeg
authors.forename: J A
authors.initials: JA
authors.lastname: Panza
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001120:Arginine / Q000494:pharmacology*; D016022:Case-Control Studies; D004730:Endothelium, Vascular / Q000502:physiology / Q000503:physiopathology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D006937:Hypercholesterolemia / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D009599:Nitroprusside; D001120:Arginine; D000109:Acetylcholine