oxypurinol and Myocardial-Infarction

Allopurinol, an inhibitor of xanthine oxidase, was shown to improve the regional ventricular function after coronary artery occlusion and reperfusion in animal models. The effects of oral administration of allopurinol on a transient increase in free radical generation after primary percutaneous transluminal coronary angioplasty (PTCA) in patients with acute myocardial infarction (AMI) and on their clinical outcomes were examined. Thirty-eight AMI patients undergoing primary PTCA were randomly assigned to control (group 1, n = 20) and allopurinol treatment groups (group 2, n = 18). Allopurinol (400 mg) was administered orally just after the admission (approximately 60 min before reperfusion). Free radical production was assessed by successive measurement of urinary excretion of 8-epi-prostaglandin F(2alpha) (PGF(2alpha)) after PTCA. Urinary 8-epi-PGF(2alpha) excretion was increased by twofold at 60-90 min after PTCA compared with the baseline value in group 1. This increase was completely inhibited in group 2. Plasma allopurinol concentration was 1,146 +/- 55 ng/ml in group 2 when reperfusion was achieved. Slow flow in the recanalized coronary artery after PTCA occurred less frequently in group 2 than in group 1. Cardiac index determined just after reperfusion and left ventricular ejection fraction at 6 months after PTCA were both significantly greater in group 2 than in group 1 although pulmonary capillary wedge pressure was similar in the two groups. In conclusion, allopurinol pretreatment is effective in inhibiting generation of oxygen-derived radicals during reperfusion therapy and the recovery of left ventricular function in humans.

Topics: Administration, Oral; Aged; Allopurinol; Angioplasty, Balloon, Coronary; Dinoprost; Electrocardiography; F2-Isoprostanes; Female; Free Radical Scavengers; Free Radicals; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion Injury; Oxypurinol; Ventricular Function, Left

After myocardial infarction, ventricular geometry and function, as well as energy metabolism, change markedly. In nonischemic heart failure, inhibition of xanthine oxidase (XO) improves mechanoenergetic coupling by improving contractile performance relative to a reduced energetic demand. However, the metabolic and contractile effects of XO inhibitors (XOIs) have not been characterized in failing hearts after infarction. After undergoing permanent coronary ligation, mice received a XOI (allopurinol or oxypurinol) or matching placebo in the daily drinking water. Four weeks later, 1H MRI and 31P magnetic resonance spectroscopy (MRS) were used to quantify in vivo functional and metabolic changes in postinfarction remodeled mouse myocardium and the effects of XOIs on that process. End-systolic (ESV) and end-diastolic volumes (EDV) were increased by more than sixfold after infarction, left ventricle (LV) mass doubled (P < 0.005), and the LV ejection fraction (EF) decreased (14 +/- 9%) compared with control hearts (59 +/- 8%, P < 0.005) at 1 mo. The myocardial phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) was also significantly decreased in infarct remodeled hearts (1.4 +/- 0.6) compared with control animals (2.1 +/- 0.5, P < 0.02), in agreement with prior studies in larger animals. The XOIs allopurinol and oxypurinol did not change LV mass but limited the increase in ESV and EDV of infarct hearts by 50%, increased EF (23 +/- 9%, P = 0.01), and normalized cardiac PCr/ATP (2.0 +/- 0.5, P < 0.04). We conclude that XOIs improve ventricular function after infarction and normalize high-energy phosphate ratio in heart failure. Thus XOI therapy offers a new and potentially complementary approach to limit the adverse contractile and metabolic consequences after infarction.

Topics: Adenosine Triphosphate; Allopurinol; Animals; Cardiac Output, Low; Energy Metabolism; Enzyme Inhibitors; Heart; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mice; Myocardial Infarction; Myocardium; Oxypurinol; Phosphocreatine; Stroke Volume; Ventricular Function; Ventricular Remodeling; Xanthine Oxidase

Evidence supporting the role of xanthine oxidase in myocardial reperfusion injury is based on studies with pharmacological interventions used to inhibit enzyme function. Controversy exists, however, regarding the true role of xanthine oxidase in reperfusion injury. This study was performed to determine whether xanthine oxidase inhibition limits myocardial injury due to coronary artery occlusion and reperfusion.. Anesthetized dogs underwent coronary artery occlusion (90 minutes) and reperfusion (6 hours). Oxypurinol (28 mg/kg) or amflutizole (30 mg/kg), chemically unrelated inhibitors of xanthine oxidase, or vehicle was infused intravenously 15 minutes before and 3 hours after reperfusion. Regional myocardial blood flow was determined with radiolabeled microspheres. Infarct size was determined with the tetrazolium method. Myocardial infarct size (percent of risk region) was less in oxypurinol-treated dogs, 32 +/- 16%, compared with that of the control group, 46 +/- 15%. Infarct size for the amflutizole-treated dogs, 40 +/- 21%, was not significantly different from that of the control group. There were no differences in rate-pressure product or collateral blood flow to account for differences in infarct size. Uric acid concentration in the coronary venous plasma increased after reperfusion in the dogs treated with vehicle but not in the drug-treated dogs. Xanthine oxidase inhibition was demonstrated in each of the drug treatment groups, but only oxypurinol limited the extent of myocardial injury.. Previously reported cardioprotective effects of allopurinol, noted to occur only when the drug was administered chronically, may be related to a property of oxypurinol, a major metabolite of allopurinol. The beneficial effect of oxypurinol is unrelated to inhibition of superoxide formation during xanthine oxidase-catalyzed oxidation of xanthine and hypoxanthine.

Topics: Animals; Dogs; Free Radicals; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Oxypurinol; Thiazoles; Time Factors; Xanthine Oxidase

The authors tested whether allopurinol or oxypurinol could limit infarct size when treatment was started just prior to reperfusion and continued until sacrifice. In closed chest, anesthetized dogs, a branch of the left coronary artery was reversibly occluded for 90 mins followed by 24 h of reperfusion. Fifteen minutes prior to reperfusion, dogs received a bolus of either allopurinol (10 dogs), or oxypurinol (nine dogs), 10 mg/kg intravenously, followed by a 24 h infusion, 55 mg/kg/day. Eleven control dogs received equal volumes of saline. Investigators were blinded to the identity of the agent. Hearts were removed 24 h after reperfusion. Arrhythmias for 30 mins after reperfusion were quantitated. Oxypurinol caused 28% less of the risk zone to infarct for any level of collateral flow than that seen in the controls. This difference was significant. Allopurinol-treated hearts averaged only 18% less infarction and did not achieve significance. Ventricular arrhythmias and mortality did not differ among the three groups. Therefore, unlike allopurinol, oxypurinol with continued administration can limit tetrazolium-indicated necrosis in the dog heart in the absence of pretreatment.

Topics: Allopurinol; Animals; Collateral Circulation; Coronary Circulation; Dogs; Electrocardiography; Female; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Oxypurinol; Pyrimidines; Risk Factors

In the rabbit myocardium, ischemia (produced by ligation of the left circumflex coronary artery) is associated with a reduction in antioxidant capacity. This is reflected by an increased glutathione depletion and production of thiobarbituric acid reactive substances following in vitro oxidative challenge with t-butylhydroperoxide. This effect is greatly intensified by reperfusion following periods of ischemia longer than 20 mins, thereby paralleling the onset of irreversible injury. Chronic allopurinol pretreatment (1 mg/mL in drinking water or approximately 75 mg/kg/day for seven days prior to ligation) provides significant protection of the ischemic/reperfused myocardium to t-butylhydroperoxide induced glutathione depletion and production of thiobarbituric acid reactive substances. This protection was not associated with any significant alterations in levels of tissue ATP or in the activities of the myocardial antioxidant enzymes catalase, copper,zinc-superoxide dismutase or glutathione peroxidase, suggesting that allopurinol may exert its effects by direct radical scavenging or by some other mechanism unrelated to xanthine oxidase inhibition.

Topics: Adenosine Triphosphate; Allopurinol; Animals; Catalase; Energy Metabolism; Glutathione; Glutathione Peroxidase; Lipid Peroxidation; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Oxypurinol; Rabbits; Superoxide Dismutase

Free radicals such as superoxide (.O2-) produced by xanthine oxidase might cause cell death during reperfusion after myocardial ischemia. The effect of the xanthine oxidase inhibitor allopurinol on infarct size in ischemia-reperfusion models has been variable, possibly because of differences in treatment duration. Adequate inhibition of xanthine oxidase may require a sufficient pretreatment period to permit conversion of allopurinol to oxypurinol, the actual inhibitor of superoxide production. To test more definitively whether xanthine oxidase-derived free radicals cause cell death during reperfusion, the effect of oxypurinol on infarct size was evaluated in an ischemia-reperfusion model. Open chest dogs underwent 40 min of circumflex coronary artery occlusion followed by reperfusion for 4 days. Twelve dogs were treated with oxypurinol (10 mg/kg body weight intravenously 10 min before occlusion and 10 mg/kg intravenously 10 min before reperfusion) and 11 control dogs received drug vehicle alone (pH 10 normal saline solution). Nine control dogs from a concurrent study also were included. Infarct size was measured histologically and analyzed with respect to its major baseline predictors, including anatomic area at risk and collateral blood flow (measured with radioactive microspheres). Infarct size as a percent of the area at risk averaged 23.8 +/- 2.7% (mean +/- SEM) in the oxypurinol group (n = 10) and 23.1 +/- 4.2% in the control group (n = 17) (p = NS). Collateral blood flow to the inner two thirds of the ischemic wall averaged 0.08 +/- 0.01 ml/min per g in the oxypurinol group and 0.09 +/- 0.02 ml/min per g in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Coronary Circulation; Coronary Vessels; Dogs; Hemodynamics; Myocardial Infarction; Oxypurinol; Perfusion; Pyrimidines; Time Factors

It has been postulated that oxygen-centered free radicals are produced in significant quantities upon reperfusion of ischemic myocardium and could cause the death of myocytes that are still reversibly injured at the end of ischemia ("reperfusion injury"). However, we have shown previously that anti-free radical therapies including superoxide dismutase (SOD) and inhibitors of xanthine oxidase did not limit infarct size after 40 minutes of ischemia and 4 days of reperfusion in dogs. To test whether 40 minutes of ischemia is too brief a period to produce the prerequisite conditions for free radical-mediated necrosis upon reperfusion, we studied infarcts produced by 90 minutes of ischemia followed by reperfusion. Dogs in an SOD-catalase group received a 60-minute infusion of SOD (15,000 units/kg) and catalase (55,000 units/kg) beginning 25 minutes before and ending 35 minutes after reperfusion. A second group of dogs received a single injection of the xanthine oxidase inhibitor oxypurinol (20 mg/kg) 25 minutes before reperfusion. Infarct size was assessed histologically relative to the size of the area at risk and to collateral blood flow to the ischemic region. Infarct size as a percentage of the area at risk was similar in the control group (40.7 +/- 5.5%, n = 11), the SOD-catalase group (38.0 +/- 6.4%; n = 8), and the oxypurinol-treated group (41.4 +/- 6.1%; n = 7) [p = not significant (NS) by analysis of variance]. In controls, there was an inverse relation between infarct size and collateral blood flow; neither of the treatments altered this relation (p = NS by analysis of covariance).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Catalase; Coronary Circulation; Coronary Disease; Dogs; Female; Free Radicals; Hemodynamics; Male; Myocardial Infarction; Oxygen; Oxypurinol; Superoxide Dismutase; Time Factors

To explore the role of oxygen free radicals produced by the xanthine oxidase pathway on infarct size and left ventricular function, the effect of oxypurinol, an active metabolite of allopurinol and a potent noncompetitive inhibitor of xanthine oxidase, was assessed in a 90 min, closed-chest, canine preparation of occlusion-reperfusion. Animals were randomized to receive 25 mg/kg iv oxypurinol (n = 13) or saline (n = 13) 60 min after occlusion. Regional myocardial blood flow was measured with radioactive microspheres and regional ventricular function with contrast ventriculography. Hemodynamic variables, regional myocardial blood flow, and size of the occluded bed were similar in the two groups. Oxypurinol failed to reduce infarct size 24 hr after reperfusion when expressed as a percentage of the area at risk (36.3 +/- 4.9% vs 36.0 +/- 5.6%; p = NS). Both groups exhibited comparative radial shortening at baseline and similar degrees of dyskinesia 1 hr into occlusion (-6.6 +/- 1.2% vs -4.9 +/- 1.0%). However, oxypurinol-treated animals demonstrated an improved regional ventricular function at 3 hr after reperfusion (0.7 +/- 2.6% vs -2.8 +/- 2.0%) and a significant improvement at 24 hr (5.4 +/- 2.5% vs -3.2 +/- 1.7%; p less than .05). A reduced neutrophil infiltrate was observed in the border zone in treated animals. These findings suggest that oxygen free radicals derived from the xanthine oxidase pathway contribute to stunning of reversibly damaged myocardium but do not determine the final extent of myocardial necrosis in a canine preparation of reperfusion.

Topics: Animals; Collateral Circulation; Coronary Circulation; Dogs; Female; Free Radicals; Heart; Hemodynamics; Male; Myocardial Infarction; Myocardium; Oxypurinol; Perfusion; Pyrimidines; 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