Cyclooxygenase-dependent, endothelium-derived vasoconstrictor release modulates acetylcholine-induced peripheral vasodilation in patients with atherosclerosis. Improvement of endothelial dysfunction with aspirin may improve vasodilation, reduce thrombosis, and inhibit progression of atherosclerosis and provides a pathophysiological basis for the beneficial effects of aspirin in atherosclerosis.

Abstract-Our objectives were to (1) test the hypothesis that nitric oxide (NO) contributes to peak reactive hyperemia (RH) in the human peripheral vasculature, (2) examine the impact of atherosclerosis and its risk factors on RH, and (3) investigate whether L-arginine will improve RH in patients with endothelial dysfunction. The endothelium contributes to shear stress-mediated vasomotion by releasing a variety of dilating factors, including NO, but the contribution of NO to peak RH in patients with and without endothelial dysfunction is unknown. Endothelium-dependent and endothelium-independent function was assessed with intrafemoral arterial acetylcholine (ACh) and sodium nitroprusside. RH was produced by occlusion of blood flow to the leg for 3 minutes. The study was repeated after N G -monomethyl-L-arginine (L-NMMA) in 44 subjects and L-arginine in 9 patients with atherosclerosis. There were 15 normal control subjects without risk factors for atherosclerosis and 29 patients with risk factors or angiographic atherosclerosis. Microvascular vasodilation in response to ACh, but not to sodium nitroprusside, was lower in the patients with risk factors or atherosclerosis compared with normal control subjects, Pϭ0.048, and the inhibition of ACh-induced microvascular dilation by L-NMMA was also greater in normal control subjects (Pϭ0.045). Similarly, RH, including the peak response, was inhibited by L-NMMA in normal control subjects (Pϭ0.0011) but not in patients with risk factors or atherosclerosis, suggesting that the contribution of NO to both ACh-induced dilation and RH was diminished in patients with risk factors or atherosclerosis. L-Arginine did not affect vasodilation in response to ACh, sodium nitroprusside, or RH. We concluded that (1) NO contributes to all phases of RH in the normal human peripheral vasculature, (2) patients with atherosclerosis or its risks have abnormal NO bioactivity in response to pharmacological and physiological stimulation, and (3) L-arginine does not improve RH in atherosclerosis. Reduced physiological vasodilation in atherosclerosis may contribute to or exacerbate hypertension and ischemia. (Hypertension. 1998;32:9-15.) Key Words: hyperemia Ⅲ nitric oxide Ⅲ endothelium Ⅲ atherosclerosis M yogenic, neural, and local factors such as adenosine, prostaglandins, and ischemic metabolites are believed to play a critical role in the RH response that is stimulated by transient interruption of blood flow.1-11 The vascular endothelium, by releasing endothelium-derived relaxing factors [12][13][14] or by stimulation of ATP-sensitive potassium channels, also contributes to vascular smooth muscle relaxation, 10,15,16 but the role of these mediators in determining RH in humans remains controversial. The most important endotheliumderived relaxing factor, which plays a pivotal role in modulating smooth muscle tone in the human conductance and resistance vessels, is NO. 12,17,18 Endothelial NO release can be stimulated by physiological changes, including hypoxia and increases in shear stress, both...

These findings indicate that 1) there is a reduced basal activity of nitric oxide in the human atherosclerotic epicardial and microvascular coronary circulation; and 2) acetylcholine-induced coronary vascular dilation is at least partly due to stimulation of the activity of nitric oxide, and the reduced response to acetylcholine is due to attenuation in the stimulated activity of nitric oxide in patients with atherosclerosis.

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