oxypurinol and Vascular-Diseases

Radiation exposure is associated with the development of various cardiovascular diseases. Although irradiation is known to cause elevated oxidant stress and chronic inflammation, both of which are detrimental to vascular function, the molecular mechanisms remain incompletely understood. We previously demonstrated that radiation causes endothelial dysfunction and increased vascular stiffness by xanthine oxidase (XO) activation. In this study, we investigated whether dietary inhibition of XO protects against radiation-induced vascular injury. We exposed 4-mo-old rats to a single dose of 0 or 5 Gy gamma radiation. These rats received normal drinking water or water containing 1 mM oxypurinol, an XO inhibitor. We measured XO activity and superoxide production in rat aorta and demonstrated that both were significantly elevated 2 wk after radiation exposure. However, oxypurinol treatment in irradiated rats prevented aortic XO activation and superoxide elevation. We next investigated endothelial function through fluorescent measurement of nitric oxide (NO) and vascular tension dose responses. Radiation reduced endothelium-dependent NO production in rat aorta. Similarly, endothelium-dependent vasorelaxation in the aorta of irradiated rats was significantly attenuated compared with the control group. Dietary XO inhibition maintained NO production at control levels and prevented the development of endothelial dysfunction. Furthermore, pulse wave velocity, a measure of vascular stiffness, increased by 1 day postirradiation and remained elevated 2 wk after irradiation, despite unchanged blood pressures. In oxypurinol-treated rats, pulse wave velocities remained unchanged from baseline throughout the experiment, signifying preserved vascular health. These findings demonstrate that XO inhibition can offer protection from radiation-induced endothelial dysfunction and cardiovascular complications.

Topics: Animals; Aorta; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Elasticity; Endothelium, Vascular; Enzyme Inhibitors; Gamma Rays; Male; Nitric Oxide; Oxypurinol; Pulsatile Flow; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Superoxides; Time Factors; Ultrasonography, Doppler; Vascular Diseases; Vasodilation; Vasodilator Agents; Whole-Body Irradiation; Xanthine Oxidase

The prevalence of the endothelium-impaired function disorders, such as hypertension and diabetes mellitus, and the severity of their complications are considerably greater in blacks than whites. Evidence has accumulated that superoxide (O2-) production and its interaction with nitric oxide (NO), yielding the strong oxidant peroxynitrite (ONOO-), play central roles in vascular pathophysiology. We hypothesized that the differences in endothelial NO/O2-/ONOO- metabolism may highlight the potential predisposition to endothelial dysfunction and cardiovascular complications prevalent in blacks.. Highly sensitive tandem electrochemical NO/O2-/ONOO- nanosensors were positioned in single human umbilical vein endothelial cells (HUVECs) isolated from blacks and whites, and the kinetics of NO/O2-/ONOO- release were recorded in vitro. HUVECs were also analyzed by Western immunoblotting and enzyme activity assays for NAD(P)H-oxidase and endothelial NO synthase (eNOS). Compared with whites, HUVECs from blacks elicited reduced release of bioactive NO with an accompanying increase in the release of both O2- and ONOO-. The greater potency of NO production because of eNOS upregulation in HUVECs from blacks is associated with a decrease in the NO bioavailability. This is due to increased NO degradation by excess O2- produced primarily by 2 enzymatic sources: NAD(P)H-oxidase and uncoupled eNOS.. Compared with whites, the steady-state NO/O2-/ONOO- balance in endothelial cells from blacks is kept closer to the redox states characteristic for the endothelium-impaired function disorders. This may explain the differences in racial predisposition to the endothelium dysfunction during ongoing vascular disturbances with the hallmark of enhanced NO inactivation within the endothelium by oxidative stress.

Topics: Acetophenones; Adult; Benzopyrans; Black or African American; Cells, Cultured; Disease Susceptibility; Endothelial Cells; Endothelium, Vascular; Female; Humans; Meclofenamic Acid; NAD; NADP; NADPH Oxidases; Nanotechnology; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oxidation-Reduction; Oxidative Stress; Oxypurinol; Peroxynitrous Acid; Phosphoproteins; Rotenone; Superoxides; Umbilical Veins; Vascular Diseases; White People