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From the Cardiology Branch, National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, Md.
Correspondence to Dr Julio A. Panza, Cardiology Branch, National Institutes of Health, Building 10, Room 7B-15, Bethesda, MD 20892-1650. E-mail panzaj{at}gwgate.nhlbi.nih.gov
Background—Patients with essential
hypertension have impaired endothelial NO activity, but
the mechanism underlying this abnormality is unknown.
Methods and Results—To investigate whether the
endothelial dysfunction of hypertensive patients is
related to a selective defect in NO synthesis, we studied the forearm
blood flow responses to intra-arterial infusion of
acetylcholine (7.5 to 30 µg/min), an endothelial
agonist linked to NO synthase through the Ca2+ signaling
pathway, and isoproterenol (50 to 200 ng/min), a ß-adrenoceptor
agonist that stimulates NO production by increasing
intracellular cAMP, in 12 normotensive subjects and 12 hypertensive
patients. The infusion of isoproterenol was repeated during the
concurrent blockade of NO synthesis by
NG-monomethyl-L-arginine
(L-NMMA; 4 µmol/min). The vasodilator response to acetylcholine
was significantly reduced in hypertensives compared with normotensives
(maximum blood flow: 10.4±4.6 versus 14.4±3.7 mL ·
min-1 · dL-1; P=.008).
However, the vasodilator effect of isoproterenol was similar in
normotensives and hypertensives (maximum blood flow: 14.4±5.4 versus
13.5±5 mL · min-1 · dL-1;
P=.56) and was significantly (both
P<.01) and equally blunted by L-NMMA in both groups
(maximum blood flow: 11±3 mL · min-1 ·
dL-1 in normotensives versus 10.8±3.9 mL ·
min-1 · dL-1 in hypertensives;
P=.77). The vasodilator response to sodium nitroprusside
(0.8 to 3.2 µg/min), an exogenous NO donor, was similar in both
groups and was not modified by L-NMMA.
Conclusions—Hypertensive patients have impaired
endothelium-dependent vasodilation in response to
acetylcholine but preserved NO activity in response to ß-adrenergic
stimulation. These findings suggest that the
endothelial dysfunction in essential hypertension is
due to a selective abnormality of NO synthesis, probably related to a
defect in the phosphatidylinositol/Ca2+ signaling pathway.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Selective Defect in Nitric Oxide Synthesis May Explain the Impaired Endothelium-Dependent Vasodilation in Patients With Essential Hypertension
Key Words: receptors, adrenergic, beta • signal transduction • acetylcholine • nitric oxide • hypertension
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