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Abstract-The NO/superoxide (O 2Ϫ ) balance is a key regulator of endothelial function. O 2 Ϫ levels are elevated in many forms of cardiovascular disease; therefore, decreasing O 2 Ϫ 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 Ϫ dismutase or NAD(P)H oxidase inhibitors. O 2 Ϫ 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 Ϫ production, but only apocynin increased NO bioavailability. In human internal mammary arteries and saphenous veins, apocynin decreased NAD(P)H-stimulated O 2 Ϫ 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 Ϫ 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 Ϫ 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.

The systemic inflammatory response after coronary artery bypass grafting using cardiopulmonary bypass (CPB) contributes substantially to postoperative organ dysfunction and coagulation disorders. Important features of this inflammatory reaction include the activation of complement and leukocytes, the release of proinflammatory cytokines, alterations in the metabolism of nitric oxide, and an increase in the production of oxygen-free radicals, which in some cases may lead to oxidant stress injury. Several strategies including the use of steroids, use of aprotinin, heparin-coated CPB circuits, and hemofiltration have been reported to reduce the inflammatory reaction induced by CPB and its consequences. A more radical and effective way of counteracting the effects of the inflammatory reaction and oxidative stress may be the omission of CPB itself. The development and application of off-pump coronary artery bypass (OPCAB) technology has largely been driven by this theme of avoiding systemic inflammatory reaction to decrease the incidence and/or severity of adverse outcomes. This review article discusses the influence of cardiopulmonary bypass on systemic inflammation and attempts to evaluate the current best available evidence on the impact of OPCAB on systemic inflammation.

Internal mammary arteries (IMAs) and saphenous veins (SVs) were collected at the time of cardiac surgery. Vessels were incubated in Krebs buffer at 37 degrees C.O(2)(-) was measured by lucigenin chemiluminescence. Basal. O(2)(-) concentrations were greater in IMAs than SVs. Inhibitors of NAD(P)H oxidase (10 micromol/L to 200 micromol/L diphenyleneiodonium) and xanthine oxidase (1 mmol/L allopurinol) caused reductions in.O(2)(-) concentrations in both IMAs and SVs. Western blotting of superoxide dismutase proteins demonstrated similar expression in IMAs and SVs. Vessels were also incubated in the presence or absence of Ang II (1 pmol/L to 1 micromol/L). Ang II increased.O(2)(-) production in IMAs at 4 hours of incubation (control, 978+/-117 pmol. min(-1). mg(-1); 1 micromol/L of Ang II, 1690+/-213 pmol. min(-1). mg(-1); n=27, P=0.0001, 95% CI 336, 925) but not in SVs. This effect was completely inhibited by coincubation of IMAs with DPI (100 micromol/L), a nonspecific Ang II antagonist ([sar(1), thre(8)]-Ang II, 1 micromol/L) and a specific Ang II type 1 (AT(1)) receptor antagonist (losartan, 1 micromol/L). Conclusions-. O(2)(-) production is greater in human IMAs than in SVs. NAD(P)H oxidase and xanthine oxidase are sources of.O(2)(-) production in these vessels. The vasoactive peptide Ang II increases.O(2)(-) production in human arteries by an AT(1) receptor-dependent mechanism.

Endothelial dysfunction is associated with raised levels of superoxide and biomarkers of oxidative stress in saphenous veins from CAD patients. LDL cholesterol is a major determinant of endothelial dysfunction and oxidative stress in these patients. These results support intensive LDL cholesterol-lowering therapy as suggested by recent clinical trials.