allopurinol and Aortic-Aneurysm

Increasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy.. In aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1. Allopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients.

Topics: Allopurinol; Animals; Aorta; Aortic Aneurysm; Disease Models, Animal; Hydrogen Peroxide; Marfan Syndrome; Mice; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species

Reactive oxygen species (ROS) generated from xanthine oxidase (XO) play an important role in ischemia-induced injury. We hypothesize that XO and xanthine dehydrogenase (XDH) are released into the circulation with ischemia reperfusion to the human liver and intestine. Blood was drawn from a patient, before and at intervals after an aortic cross-clamp procedure. Plasma was incubated in the presence of xanthine, with NAD+ (for XD +XO) and without NAD+ (for XO). The amount of urate formed was quantified using a high-performance liquid chromatograph (HPLC). The calculated XDH+XO and XO activity increased from 1.88 and 1.66 microU/mg protein, respectively, before the cross clamp to 3.77 and 3.11 microU/mg, respectively, 7 minutes after reperfusion to the superior mesenteric, celiac, and right renal artery beds. The release of a significant biological source of ROS may explain the damage to lung or heart observed after ischemia to the human liver and intestine.

Topics: Aged; Anastomosis, Surgical; Aorta; Aortic Aneurysm; Chromatography, High Pressure Liquid; Constriction; Humans; Intestines; Ischemia; Liver; Male; Reactive Oxygen Species; Reperfusion Injury; Xanthine Dehydrogenase; Xanthine Oxidase

The efficacy of pharmacologic agents for prevention and control of oxygen-derived free radical damage in ischemia-reperfusion injury of the spinal cord was assessed in a swine model of thoracic and thoracoabdominal aortic crossclamping. Animals were exposed to 30 minutes of ischemia that induced lethal, irreversible injury and paraplegia. The experimental groups were as follows: group A (n = 7), control group, receiving no pharmacologic intervention; group B (n = 7), deferoxamine 50 mg/kg/day administered intravenously over 3 to 4 hours before ischemia; group C (n = 7), allopurinol pretreatment 50 mg/kg/day for 3 days; and group D (n = 7), superoxide dismutase 60,000 units administered with 50,000 units before removal of the aortic crossclamp and 10,000 units over 10 minutes of reperfusion. Proximal hypertension was controlled with sodium nitroprusside and volume depletion. The methods of assessment were neurologic by a modified Tarlov criteria and blood flow by radiolabeled microspheres. Results of blood flow assessment confirmed a true ischemic episode of 30 minutes for all animals in all groups. The blood flow fell significantly during ischemia (p less than 0.01) and a hyperemic response was evident in the early reperfusion period. All animals in control group A were paraplegic. The group B (deferoxamine) results were superior; 85% had grade III function on a modified Tarlov scale, with animals in the group standing and even walking with difficulty. Only one animal in this group had good movements of hind limbs but was unable to stand or walk. Neurologic recovery was limited in the allopurinol group (group C), with 85% showing slight neurologic recovery with limited movement of the hind limbs. The animals in the superoxide dismutase group (group D) all had good recovery, with strong motor response of hind limbs, but were not able to stand. In summary, the results of this experimental protocol confirmed the possible role of oxygen-derived free radicals in the pathophysiology of spinal cord injury, induced by aortic crossclamping. Moreover, it proved that ischemia-reperfusion injury could be altered by pharmacologic interventions.

Topics: Allopurinol; Animals; Aorta; Aortic Aneurysm; Constriction; Deferoxamine; Free Radicals; Paraplegia; Postoperative Complications; Reperfusion Injury; Spinal Cord; Superoxide Dismutase; Swine