Journal
HYPERTENSION
Volume 40, Issue 5, Pages 755-762Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.HYP.0000037063.90643.0B
Keywords
apocynin; NAD(P)H oxidase; nitric oxide; superoxide; humans; blood vessels
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The NO/superoxide (O-2(-)) balance is a key regulator of endothelial function. O-2 levels are elevated in many forms of cardiovascular disease; therefore, decreasing O-2(-) should improve endothelial function. To explore this hypothesis, internal mammary arteries and saphenous veins, obtained from patients undergoing coronary artery revascularization, and aortic and carotid arteries from Wistar-Kyoto and spontaneously hypertensive stroke-prone. rats were incubated with O-2(-) dismutase or NAD(P)H oxidase inhibitors. O-2(-) levels were measured using lucigenin chemiluminescence; NO bioavailability was assessed in organ chambers; and mRNA expression of NAD(P)H oxidase components was quantified by use of a Light Cycler. In rat arteries, phenylarsine oxide, 4-(2-aminoethyl)benzenesulfanyl fluoride, and apocynin all decreased NADH-stimulated O-2(-) production, but only apocynin increased NO bioavailability. In human internal mammary arteries and saphenous veins, apocynin decreased NAD(P)H-stimulated O-2(-) generation and caused vasorelaxation that was endothelium dependent and reversed on addition of the NO synthase inhibitor N-G-nitro-L-arginine methyl ester. In addition, it increased NO production from cultured human endothelial saphenous vein cells. Polyethylene-glycolated O-2(-) dismutase also increased NO bioavailability in rat carotid arteries and human blood vessels, but the effects were smaller than those observed with apocynin. NADH-generated O-2(-) and mRNA expression of p22(phox), gp91(phox), and nox-1 were comparable between the 2 strains of rat. This is the first study to demonstrate pharmacological effects of apocynin in human blood vessels. The increases in NO bioavailability shown here suggest that the NAD(P)H oxidase pathway may be a novel target for drug intervention in cardiovascular disease.
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