INVESTIGATION OF DECREASED AVAILABILITY OF NITRIC-OXIDE PRECURSOR AS THE MECHANISM RESPONSIBLE FOR IMPAIRED ENDOTHELIUM-DEPENDENT VASODILATION IN HYPERCHOLESTEROLEMIC PATIENTS
Pr. Casino et al., INVESTIGATION OF DECREASED AVAILABILITY OF NITRIC-OXIDE PRECURSOR AS THE MECHANISM RESPONSIBLE FOR IMPAIRED ENDOTHELIUM-DEPENDENT VASODILATION IN HYPERCHOLESTEROLEMIC PATIENTS, Journal of the American College of Cardiology, 23(4), 1994, pp. 844-850
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.