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Circulation, Vol 90, 35-41, Copyright © 1994 by American Heart Association
DM Gilligan, V Guetta, JA Panza, CE Garcia, AA Quyyumi and RO Cannon 3rd
BACKGROUND: Endothelial dysfunction is increasingly recognized as an early
and important feature of vascular disease. Endothelium-dependent
vasodilation is impaired in humans with hypercholesterolemia, although it
is unknown whether this defect is selective for some pathways of nitric
oxide production or indicates a more generalized abnormality of endothelial
function. The aim of this study was to further elucidate the nature of
endothelial dysfunction in human hypercholesterolemia by comparing vascular
responses of agonists that use different signal transduction pathways to
activate production of nitric oxide. METHODS AND RESULTS: Forearm flow was
measured in 12 hypercholesterolemic patients (total cholesterol, 286 +/- 35
mg/dL [mean +/- SD]) aged 50 +/- 11 years and in 12 healthy subjects (total
cholesterol, 173 +/- 27 mg/dL) aged 48 +/- 7 years using strain-gauge
plethysmography and brachial artery drug infusions. The
endothelium-dependent vasodilators used were acetylcholine (7.5, 15, and 30
micrograms/min), which uses a pertussis toxin-sensitive signal transduction
pathway, and bradykinin (100, 200, and 400 ng/min), which uses a pertussis
toxin-insensitive signal transduction pathway to activate nitric oxide
production. Sodium nitroprusside (0.8, 1.6, and 3.2 micrograms/min) was
used to test endothelium-independent vasodilation. The maximum flow in
response to acetylcholine was markedly impaired in patients compared with
healthy subjects (8.0 +/- 5.1 versus 17.5 +/- 7.7 mL.min-1. 100 mL-1, P =
.002). However, the maximum forearm flow in response to bradykinin was
similar in the two groups (13.0 +/- 4.5 versus 16.2 +/- 5.5 mL.min-1 x 100
mL-, P = .14), as was the maximum flow in response to sodium nitroprusside
(7.0 +/- 2.8 versus 8.4 +/- 2.2 mL.min-1 x 100 mL-1, P = .13).
NG-Monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, reduced
the maximum forearm vasodilation induced by bradykinin to the same extent
in patients and in healthy subjects (-29 +/- 8% versus -32 +/- 6% reduction
in peak flow, P = .80), with similar maximum flows in response to
bradykinin (9.2 +/- 4.0 versus 10.4 +/- 2.6 mL.min-1 x 100 mL-1, P = .35).
CONCLUSIONS: Hypercholesterolemic patients are capable of normal nitric
oxide bioavailability in response to bradykinin. Impairment of
microvascular endothelial vasodilator function in human
hypercholesterolemia is selective, and the defect occurs at the level of
the acetylcholine receptor or its signal transduction pathway.
ARTICLES
Selective loss of microvascular endothelial function in human hypercholesterolemia
Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md 20892.
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