oxypurinol and Disease-Models--Animal

Ventricular tachycardia or fibrillation (VT/VF) of focal origin due to triggered activity (TA) from delayed afterdepolarizations (DADs) is reproducibly inducible after anterior coronary artery occlusion. Both VT/VF and TA can be blocked by reducing reactive oxygen species (ROS). We tested the hypothesis that inhibition of NADPH oxidase and xanthine oxidase would block VT/VF.. 69 dogs received apocynin (APO), 4 mg/kg intraveneously (IV), oxypurinol (OXY), 4 mg/kg IV, or both APO and OXY (BOTH) agents, or saline 3 h after coronary occlusion. Endocardium from ischemic sites (3-D mapping) was sampled for Rac1 (GTP-binding protein in membrane NADPH oxidase) activation or standard microelectrode techniques. Results (mean±SE, * p<0.05): VT/VF originating from ischemic zones was blocked by APO in 6/10 *, OXY in 4/9 *, BOTH in 5/8 * or saline in 1/27; 11/16 VT/VFs blocked were focal. In isolated myocardium, TA was blocked by APO (10(-6) M) or OXY (10(-8) M). Rac1 levels in ischemic endocardium were decreased by APO or OXY.. APO and OXY suppressed focal VT/VF due to DADs, but the combination of the drugs was not more effective than either alone. Both drugs inhibited ischemic Rac1 with inhibition by OXY suggesting ROS-induced ROS. The inability to totally prevent VT/VF suggests that other mechanisms also contribute to ischemic VT.

Topics: Acetophenones; Action Potentials; Animals; Blotting, Western; Disease Models, Animal; Dogs; Female; Male; Myocardial Ischemia; NADPH Oxidases; Oxypurinol; rac1 GTP-Binding Protein; Tachycardia, Ventricular; Ultrasonography; Ventricular Fibrillation; Xanthine Oxidase

Acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality. Oxygen-free radicals (OFRs) produced during ischemia and reperfusion (IR) have been implicated as the final common pathway in the pathogenesis of this syndrome. Spin traps have been shown to decrease IR injury in several animal lung models. The hydroxylamine, OXANOH (2-ethyl-2,5,5-trimethyl-3-oxazolidine) has been proposed as an ideal spin trap that would trap extra- and intracellular OFRs producing the stable radical, OXANO• (2-ethyl-2,5,5-trimethyl-3-oxazolidinoxyl). Electron microscopy was used to investigate whether OXANOH would protect against IR injury in the rabbit lung.. OXANOH was obtained by hydrogenation of its stable radical, OXANO• using a safe laboratory technique. Several doses of OXANOH were tested to identify a nontoxic dose. Two quantitative methods were used based on the average surface area of the alveoli and average number of alveoli per unit surface area using scanning electron microscopy (SEM). A total of 20 animals were subjected to 2 hours of ischemia followed by 4 hours of reperfusion. On reperfusion, the 4 groups (N = 5) received no treatment, OXANOH, superoxide dismutase (SOD)/catalase, or oxypurinol.. A therapeutic dose of 250 μmol/L of OXANO• was suggested in this in vitro model. All the 3 treatments showed significantly less injury compared to the control group and that SOD/catalase was significantly different from OXANOH and oxypurinol (P < .008).. OXANOH ameliorated IR injury in the isolated rabbit lung, almost as effectively as SOD/catalase and oxypurinol.

Topics: Animals; Antioxidants; Catalase; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Lung; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Oxazoles; Oxypurinol; Rabbits; Reactive Oxygen Species; Reperfusion Injury; Spin Labels; Superoxide Dismutase; Time Factors

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

Respiratory muscle weakness resulting from both diaphragmatic contractile dysfunction and atrophy has been hypothesized to contribute to the weaning difficulties associated with prolonged mechanical ventilation (MV). While it is clear that oxidative injury contributes to MV-induced diaphragmatic weakness, the source(s) of oxidants in the diaphragm during MV remain unknown. These experiments tested the hypothesis that xanthine oxidase (XO) contributes to MV-induced oxidant production in the rat diaphragm and that oxypurinol, a XO inhibitor, would attenuate MV-induced diaphragmatic oxidative stress, contractile dysfunction, and atrophy. Adult female Sprague-Dawley rats were randomly assigned to one of six experimental groups: 1) control, 2) control with oxypurinol, 3) 12 h of MV, 4) 12 h of MV with oxypurinol, 5) 18 h of MV, or 6) 18 h of MV with oxypurinol. XO activity was significantly elevated in the diaphragm after MV, and oxypurinol administration inhibited this activity and provided protection against MV-induced oxidative stress and contractile dysfunction. Specifically, oxypurinol treatment partially attenuated both protein oxidation and lipid peroxidation in the diaphragm during MV. Further, XO inhibition retarded MV-induced diaphragmatic contractile dysfunction at stimulation frequencies >60 Hz. Collectively, these results suggest that oxidant production by XO contributes to MV-induced oxidative injury and contractile dysfunction in the diaphragm. Nonetheless, the failure of XO inhibition to completely prevent MV-induced diaphragmatic oxidative damage suggests that other sources of oxidant production are active in the diaphragm during prolonged MV.

Topics: Animals; Diaphragm; Disease Models, Animal; Electric Stimulation; Enzyme Inhibitors; Female; Hypoxanthine; Lipid Peroxidation; Muscle Contraction; Muscle Weakness; Muscular Atrophy; Oxidative Stress; Oxypurinol; Protein Carbonylation; Rats; Rats, Sprague-Dawley; Time Factors; Uric Acid; Ventilator-Induced Lung Injury; Xanthine; Xanthine Dehydrogenase; Xanthine Oxidase

Recent studies show that pulmonary vasodilator responses to nitrite are enhanced by hypoxia. However, the mechanism by which nitrite is converted to vasoactive nitric oxide (NO) is uncertain. In the present study, intravenous injections of sodium nitrite decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressure were enhanced when tone in the pulmonary vascular bed was increased with U-46619. Under elevated tone conditions, decreases in pulmonary and systemic arterial pressures in response to nitrite were attenuated by allopurinol in a dose that did not alter responses to the NO donors, sodium nitroprusside and diethylamine/NO, suggesting that xanthine oxidoreductase is the major enzyme-reducing nitrite to NO. Ventilation with a 10% O(2) gas mixture increased pulmonary arterial pressure, and the response to hypoxia was enhanced by N(G)-nitro-l-arginine methyl ester and not altered by allopurinol. This suggests that NO formed by the endothelium and not from the reduction of plasma nitrite modulates the hypoxic pulmonary vasoconstrictor response. Although intravenous injections of sodium nitrite reversed pulmonary hypertensive responses to U-46619, hypoxia, and N(G)-nitro-l-arginine methyl ester, the pulmonary vasodilator response to nitrite was not altered by ventilation with 10% O(2) when baseline pulmonary arterial pressure was increased to similar values in animals breathing room air or the hypoxic gas. These data provide evidence that xanthine oxidoreductase is the major enzyme-reducing nitrite to vasoactive NO, and that this mechanism is not modified by hypoxia.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Allopurinol; Animals; Blood Pressure; Cardiac Output; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hydrazines; Hypoxia; Injections, Intravenous; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroprusside; Oxypurinol; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Time Factors; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Xanthine Oxidase

An R120G mutation in alphaB-crystallin (CryAB(R120G)) causes desmin-related myopathy (DRM). In mice with cardiomyocyte-specific expression of the mutation, CryAB(R120G)-mediated DRM is characterized by CryAB and desmin accumulations within cardiac muscle, mitochondrial deficiencies, activation of apoptosis, and heart failure (HF). Excessive production of reactive oxygen species (ROS) is often a hallmark of HF and treatment with antioxidants can sometimes prevent the progression of HF in terms of contractile dysfunction and cardiomyocyte survival. It is unknown whether blockade of ROS is beneficial for protein misfolding diseases such as DRM. We addressed this question by blocking the activity of xanthine oxidase (XO), a superoxide-generating enzyme that is upregulated in our model of DRM. The XO inhibitor oxypurinol was administered to CryAB(R120G) mice for a period of 1 or 3 months. Mitochondrial function was dramatically improved in treated animals in terms of complex I activity and conservation of mitochondrial membrane potential. Oxypurinol also largely restored normal mitochondrial morphology. Surprisingly, however, cardiac contractile function and cardiac compliance were unimproved, indicating that the contractile deficit might be independent of mitochondrial dysfunction and the initiation of apoptosis. Using magnetic bead microrheology at the single cardiomyocyte level, we demonstrated that sarcomeric disarray and accumulation of the physical aggregates resulted in significant changes in the cytoskeletal mechanical properties in the CryAB(R120G) cardiomyocytes. Our findings indicate that oxypurinol treatment largely prevented mitochondrial deficiency in DRM but that contractility was not improved because of mechanical deficits in passive cytoskeletal stiffness.

Topics: alpha-Crystallin B Chain; Animals; Apoptosis; Cardiomyopathies; Compliance; Desmin; Disease Models, Animal; Enzyme Inhibitors; Free Radical Scavengers; Hemorheology; Membrane Potential, Mitochondrial; Mice; Mice, Transgenic; Mitochondria, Heart; Mutation; Myocardial Contraction; Myocytes, Cardiac; Oxidative Stress; Oxypurinol; Protein Folding; Reactive Oxygen Species; Sarcomeres; Ventricular Function, Left; Xanthine Oxidase

Ischemia-reperfusion (IR) injury is a major insult to postcapillary venules. We hypothesized that IR increases postcapillary venular hydraulic conductivity and that IR-mediated changes in hydraulic conductivity result from temporally and mechanistically separate processes. A microcannulation technique was used to determine hydraulic conductivity (Lp) in rat mesenteric postcapillary venules serially throughout ischemia (45 min) and reperfusion (5 h) induced by superior mesenteric artery occlusion and release. Mesenteric IR resulted in a biphasic increase in Lp. White blood cell (WBC) adhesion slowly increased with maximal adhesion corresponding to the second peak (P < 0.005). After IR, tissue was harvested for RT-PCR analysis of ICAM-1, E-selectin, and P-selectin mRNA. Intercellular adhesion molecule-1 (ICAM-1) mRNA in the gut showed the most significant upregulation. Quantitative real-time PCR revealed that ICAM-1 mRNA was upregulated 60-fold in the gut. An ICAM-1 antibody was therefore used to determine the effect of WBC adhesion on Lp during IR. ICAM-1 inhibition attenuated Lp during the first peak and completely blocked the second peak (P < 0.005). When rats were fed a tungsten diet to inhibit xanthine oxidase and then underwent IR, Lp was dramatically attenuated during the first peak and mildly decreased the second peak (P < 0.005). Inhibition of xanthine oxidase by oxypurinol decreased Lp during IR by over 60% (P < 0.002). Tempol, a superoxide dismutase mimetic, decreased Lp during IR by over 30% (P < 0.01). We conclude that IR induces a biphasic increase in postcapillary hydraulic conductivity. Reactive oxygen species impact both the first transient peak and the sustained second peak. However, the second peak is also dependent on WBC-endothelial cell adhesion. These serial measurements of postcapillary hydraulic conductivity may lead the way for optimal timing of pharmaceutical therapies in IR injury.

Topics: Animals; Antibodies; Cell Adhesion; Cricetinae; Cyclic N-Oxides; Disease Models, Animal; E-Selectin; Endothelium, Vascular; Enzyme Inhibitors; Female; Intercellular Adhesion Molecule-1; Leukocytes; Male; Mesentery; Mesocricetus; Oxypurinol; P-Selectin; Permeability; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; RNA, Messenger; Spin Labels; Time Factors; Tungsten Compounds; Venules; Xanthine Oxidase

At present no standard pharmacological intervention strategy is available to reduce these adverse effects of birth asphyxia. In the present study we aimed to evaluate placental transfer of allopurinol, an inhibitor of XOR. For this purpose, fetal catheterization of the jugular vein was conducted in five late pregnant sows (one fetus per sow). At 24-48 h after surgery, sows received allopurinol (15 mg/kg body weight; i.v.) and pharmacokinetics of allopurinol and its active metabolite oxypurinol were measured in both late pregnant sows and fetuses. Maternal and fetal blood samples were collected during and after allopurinol administration. Maternal C(max) values averaged 41.90 microg/mL (allopurinol) and 3.68 microg/mL (oxypurinol). Allopurinol crossed the placental barrier as shown by the average fetal C(max) values of 5.05 microg/mL at 1.47 h after allopurinol administration to the sow. In only one fetus low plasma oxypurinol concentrations were found. Incubations of subcellular hepatic fractions of sows and 24-h-old piglets confirmed that allopurinol could be metabolized into oxypurinol. In conclusion, we demonstrated that allopurinol can cross the placental barrier, a prerequisite for further studies evaluating the use of allopurinol as a neuroprotective agent to reduce the adverse effects following birth asphyxia in neonatal piglets.

Topics: Allopurinol; Animals; Area Under Curve; Asphyxia Neonatorum; Blood Gas Analysis; Disease Models, Animal; Enzyme Inhibitors; Female; Half-Life; Humans; Infant, Newborn; Male; Maternal-Fetal Exchange; Metabolic Clearance Rate; Oxypurinol; Pregnancy; Swine; Xanthine Dehydrogenase

Tissue injury following reperfusion represents an essential problem of reconstructive vascular surgery. Pathogenetically toxic oxygen radicals are considered to play a pivotal role. Pharmacotherapeutical approaches are based particularly on antioxidants and vasodilators. However, a standardized regimen is not yet clinically introduced. In 48 adult Lewis-rats lower limb ischemia was induced by aortal cross-clamping. Following 3.5 hours of ischemia intravascular flushing perfusion via the distal aorta with a heparinized electrolyte solution (group B). Group C received additionally oxypurinol, group D alprostadil and group E sodium selenite into the flushing solution. At 4 hours recirculation was established. After 10 min, 30 min and 24 hours of reperfusion we determined lactate, creatine kinase, lactate dehydrogenase, urea, malondialdehyde and the laser Doppler flux. At the end of the experiments biopsies were taken from M. tibialis anterior. In comparison to control animals (group A) we observed an attenuation of reperfusion injury in the groups treated with flushing perfusion. Free oxygen radical reactions measured by malondialdehyde release were significantly reduced (30 min: A-209.1 +/- 45.4, B-127.3 +/- 36.9, C-113.2 +/- 14.1, D-99.6 +/- 24.5, E-123.6 +/- 11.2 mmol/l, p < 0.05). The laser Doppler flux measurements corresponded with the biochemical analyses (30 min: A-52.4 +/- 11.1, B-48.0 +/- 11.0, C-72.6 +/- 12.0, D-74.4 +/- 13.3, E-62.6 +/- 10.8% of baseline). Histologically, treatment with alprostadil (PGE1) and oxypurinol revealed superior results. Standardized intraarterial flushing perfusion with antioxidants and vasodilators reduces reperfusion injury. Clinical trials are urgently required to confirm the experimental findings and to optimize the therapy of extremity ischemia/reperfusion injury in humans.

Topics: Animals; Disease Models, Animal; Extremities; Muscle, Skeletal; Oxypurinol; Prostaglandins E; Rats; Reperfusion; Reperfusion Injury; Sodium Selenite; Vascular Surgical Procedures

In addition to the inhibition of xanthine oxidase, allopurinol is known to act, dependent on the dose, as a free radical scavenger, an antioxidant, and a "scavenger" of hypochlorous acid. This activity was investigated using a model of lens-induced uveitis.. Lipid peroxides (LPO) were determined in aqueous humor and in retinal tissue. Reduced and oxidized glutathione (GSH and GSSG) of the aqueous humor and myeloperoxidase (MPO) activity in the iris-ciliary body complex were analyzed. Allopurinol and oxypurinol concentrations were determined by high-performance liquid chromatography in aqueous humor and retinal tissue of both control eyes and eyes with uveitis. These measurements were performed 6 hours after intravenous application of allopurinol.. In lens-induced uveitis, LPO are significantly elevated, GSH is reduced, and GSSG and MPO are increased. A xanthine oxidase inhibition dose (< 10 mg/kg body weight) of allopurinol showed no effects on oxidative tissue damage in the model used in this study. Higher doses, however, were able to reduce the oxidative damage. Allopurinol (20 mg/kg body weight) had slight effects on GSH and GSSG. All parameters improved using a dose of 50 mg/kg body weight; a dose of 100 mg/kg body weight only showed additional improvement in GSH and GSSG. There was no further change in the other parameters. Allopurinol and oxypurinol concentrations in aqueous humor and retinal tissue showed a dose dependency reaching scavenger concentrations after application of 50 mg/kg body weight of allopurinol.. These results suggest that the xanthine oxidase mechanism plays a minor role in the oxidative tissue damage due to lens-induced uveitis. Free radicals and oxidants are generated by activated leukocytes; therefore, the effect of higher doses of allopurinol is due to its free radical scavenging and antioxidative activity.

Topics: Allopurinol; Animals; Anterior Eye Segment; Antioxidants; Chromatography, High Pressure Liquid; Crystallins; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers; Glutathione; Lens, Crystalline; Lipid Peroxides; Male; Oxypurinol; Peroxidase; Rats; Rats, Wistar; Retina; Uveitis

We have previously shown that generation of superoxide anion occurs in cerebral cortex during asphyxia/reventilation in newborn pigs and that a high dose of indomethacin (5 mg/kg i.v.) abolishes superoxide anion production. The purposes of this study were 1) to determine whether the generation of superoxide anion occurs primarily during asphyxia or whether reventilation must take place, 2) to investigate the effects of indomethacin pretreatment at a therapeutic dose of 0.2 mg/kg i.v. on superoxide anion generation, and 3) to investigate the effects of oxypurinol, an oxygen free radical scavenger, on superoxide anion production during asphyxia/reventilation. Superoxide anion production on cerebral cortex was determined by superoxide dismutase-inhibitable nitroblue tetrazolium (NBT) reduction using closed cranial windows. Superoxide anion generation during asphyxia without reventilation was 4 +/- 2 pmol NBT/mm2 per 20 min, which was significantly lower than during asphyxia/reventilation (16 +/- 4 pmol NBT/mm2 per 20 min) but comparable to the control group (3 +/- 1 pmol NBT/mm2 per 20 min). Indomethacin given at therapeutic dosage before asphyxia/reventilation decreased superoxide anion production to 3 +/- 1 pmol NBT/mm2 per 20 min, values not significantly different from the control group and from piglets pretreated with oxypurinol at a dose of 50 mg/kg i.v. (4 +/- 2 pmol NBT/mm2 per 20 min). We conclude that in newborn pigs 1) superoxide anions are generated largely during reventilation rather than during asphyxia; 2) the therapeutic dose of indomethacin (0.2 mg/kg) is effective in inhibiting the superoxide anion generation during asphyxia/reventilation; and 3) oxypurinol reduces the superoxide anion accumulation on cerebral cortex during asphyxia/reventilation.

Topics: Animals; Animals, Newborn; Asphyxia Neonatorum; Blood Pressure; Cerebral Cortex; Disease Models, Animal; Humans; Indomethacin; Infant, Newborn; Oxygen; Oxypurinol; Reactive Oxygen Species; Respiration, Artificial; Superoxides; Swine

Chronic inflammation of the colon and the rectum was induced by intracolonic administration of 25 mg trinitrobenzoic sulfonic acid (TNB) in 0.25 ml 30% ethanol. Three weeks after TNB administration the colon and the rectum showed transmural, granulomatous inflammation which had many similarities to Crohn's disease and furthermore to the morphological and functional changes which occur in early phases of postischemic intestinal damage. In the colon of TNB-treated animals the ATP and GTP levels were markedly decreased. The accumulation of thiobarbituric acid-reactive substances (TBA-RS) demonstrated a free radical-mediated component of the tissue damage. Treatment with oxypurinol radical scavenger and xanthine oxidoreductase inhibitor diminished the morphological changes, the loss of energy-rich nucleotides and the TBA-RS accumulation.

Topics: Animals; Colon; Disease Models, Animal; Free Radical Scavengers; Free Radicals; Inflammatory Bowel Diseases; Kinetics; Nucleotides; Oxypurinol; Rats; Thiobarbiturates; Trinitrobenzenesulfonic Acid; Xanthine Oxidase

Four pharmacological mechanisms for antagonizing free radical generation or reactions were compared in terms of their efficacy in attenuating hemorrhagic shock in rats. These included opposing superoxide generation by xanthine oxidase (e.g., oxypurinol), inhibiting arachidonic acid oxidation by cyclooxygenase (e.g., ibuprofen), chelating iron (e.g., desferal), and inhibiting lipid peroxidation (e.g., tirilazad mesylate [U-74006F] and U-78517G). Animals were hemorrhaged to a mean arterial pressure (MAP) of 43-45 mmHg where they were held for 2 hr. Five minutes prior to the end of the hemorrhage period, either vehicle, U-74006F (10 mg/kg), U-78517G (10 mg/kg), oxypurinol (10 or 25 mg/kg), desferal (10 or 25 mg/kg), or ibuprofen (10 mg/kg) was administered i.v., followed by the reinfusion of shed blood. In vehicle-treated animals, MAP declined progressively over the 2 hr post-reinfusion. Ibuprofen, desferal, and oxypurinol treatments each failed to attenuate this decline. In contrast, both U-74006F and U-78517G resulted in a significantly improved maintenance of MAP. Evidence of shock-induced lipid peroxidation was observed in terms of a 73.8% depletion in liver vitamin E content at 2 hr post-reinfusion in vehicle-treated rats. This decrease was prevented by both U-74006F and U-78517G. Inhibition of free radical-induced lipid peroxidation appears more effective for attenuating free radical pathophysiology in hemorrhagic shock that attempting to inhibit specific pathways of oxygen radical generation.

Topics: Animals; Antioxidants; Chromans; Deferoxamine; Disease Models, Animal; Ibuprofen; Lipid Peroxidation; Male; Oxypurinol; Piperazines; Pregnatrienes; Rats; Rats, Inbred Strains; Shock, Hemorrhagic; Vitamin E; Xanthine Oxidase

An in vitro canine tibia model was used to assess the effects of 48 h of hypothermic (4 degrees C) ischemia on bone vascular resistance and on responsiveness of intraosseous blood vessels to circulating norepinephrine. Three groups of bones were studied: Group I (n = 11), 48 h hypothermic ischemia; Group II (n = 11), 48 h hypothermic ischemia with pretreatment with allopurinol and oxypurinol; and Group III (n = 10), no ischemia. Resting vascular resistance in both ischemic groups (79 and 74 mmHg/ml/min) was significantly higher (p less than 0.0001) than in the nonischemic group (22 mmHg/ml/min). Effects of norepinephrine on vascular resistance were significantly greater in both ischemic groups (p less than 0.004). In all three groups, acetylcholine infusion attenuated the increases in perfusion pressure caused by norepinephrine. This demonstrates secretion of endothelial-mediated relaxing factors (EDRF) and prostaglandin for up to 48 h of hypothermic ischemia. As no significant differences were detected between the two ischemic groups, this study failed to demonstrate any protective effect of xanthine oxidase inhibitors.

Topics: Acetylcholine; Allopurinol; Animals; Cold Temperature; Disease Models, Animal; Dogs; Drug Hypersensitivity; Ischemia; Nitric Oxide; Norepinephrine; Oxypurinol; Regional Blood Flow; Reperfusion Injury; Tibia; Vascular Resistance; Xanthine Oxidase

The present study was designed to evaluate the ability of allopurinol to limit infarct size following permanent coronary occlusion in the greyhound. Coronary occlusion was produced by injecting 2.5 mm plastic beads into the coronary artery of the closed chest dog. Non-perfused myocardium, the area at risk, was visualised by autoradiography of 141Cerium labelled microspheres which were infused immediately following coronary embolization. The treated dogs (n = 12) received 400 mg of allopurinol orally one day before surgery. A 25 mg . kg-1 bolus was administered (iv) immediately before occlusion, and repeated every 8 h. 11 dogs served as controls. After 24 h, the dogs were killed and the hearts were sliced into 5.0 mm transverse sections. The infarcted myocardium was visualised by triphenyl tetrazolium chloride staining. The percentage of the risk zone which evolved to infarct was calculated. This percentage was 18.1 +/- 3.95% in the allopurinol group vs 58.4 +/- 2.81% in the control group (p less than 0.001). We conclude that allopurinol is a potent drug for the limitation of infarct size in the dog with permanent coronary occlusion.

Topics: Allopurinol; Animals; Coronary Vessels; Disease Models, Animal; Dogs; Embolism; Female; Male; Myocardial Infarction; Myocardium; Oxypurinol; Xanthine Oxidase