Xanthine Oxidase–Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia

Abstract

We hypothesized that in hyperhomocysteinemia (HHcy), flow-induced arteriolar constriction is due to an enhanced generation of reactive oxygen and/or nitrogen species, causing an impairment of nitric oxide (NO) and prostaglandin mediation of the response. Changes in diameter of isolated, pressurized (at 80 mm Hg) gracilis muscle arterioles (diameter ≈170 μm) from control and methionine diet–induced HHcy rats were measured by videomicroscopy. Increases in intraluminal flow (from 0 to 25 μL/min) resulted in NO- and prostaglandin-mediated dilations of control arterioles (maximum, control, 30±4 μm) but elicited significant constrictions of HHcy arterioles (maximum, HHcy, −32±3 μm), which were abolished by the thromboxane A 2 receptor blocker SQ 29,548. Intraluminal administration of superoxide dismutase plus catalase did not affect flow-mediated dilations of control arterioles, but in HHcy arterioles, it reversed the flow-induced constrictions to dilations (maximum 18±4 μm), which were abolished by an NO synthase inhibitor. Flow-induced constrictions of HHcy arterioles were prevented by the presence of the xanthine oxidase inhibitor oxypurinol [but not by the NAD(P)H-oxidase inhibitor diphenyleneiodonium] and by urate, a known peroxynitrite scavenger. Also, authentic peroxynitrite elicited arteriolar constrictions (−31±8 μm) that were eliminated by urate and SQ 29,548. Thus, we suggest that in HHcy, xanthine oxidase–derived superoxide scavenges NO released to flow, forming peroxynitrite, which promotes release of thromboxane A 2 , resulting in arteriolar constriction.