Xanthine oxidase inhibition does not limit canine infarct size.

Abstract

BACKGROUND 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. METHODS AND RESULTS 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. CONCLUSIONS 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.

Coronary vasoregulation in health and disease

“…Animal studies (27)(28)(29)(30) have shown both antinecrosis and antiarrhythmic effects with a host of pharmacological agents that modulate different intraand extracellular mechanisms. Indeed, Kingma et al (27,28), Denniss et al (29) and Werns et al (30) have documented significant reductions of infarct size in animal preparations of chronic coronary artery occlusion in the absence of restoration of blood flow.…”

“…Animal studies (27)(28)(29)(30) have shown both antinecrosis and antiarrhythmic effects with a host of pharmacological agents that modulate different intraand extracellular mechanisms. Indeed, Kingma et al (27,28), Denniss et al (29) and Werns et al (30) have documented significant reductions of infarct size in animal preparations of chronic coronary artery occlusion in the absence of restoration of blood flow. Acute myocardial infarction significantly lowers vasoregulatory capacity, which probably contributes to reducing contractile dysfunction; however, postischemic deficits in cardiac contractile function (ie, myocardial stunning/hibernation) are dependent on the duration or severity of the ischemic insult and on the adequacy of return of blood flow to reversibly injured myocardium (31,32).…”

Impaired glutathione biosynthesis in the ischemic‐reperfused rabbit myocardium

“…Hence, considering a substantial (approx. 70%) inhibition of G-GCS by BSO treatment in vivo [3] and the decrement of about 27% of G-GCS activity observed in our severe ischemia-reperfusion model, it may be calculated that such a decrement could have conditioned a 15% decline in heart GSH content. A similar G-GCSrelated decline, although relatively small, might not be insignificant for the myocardium subjected to ischemia-reperfusion and oxidative stress [1].…”

“…Thus, the impaired GSH enzymatic biosynthesis of the reperfused myocardium, which represents a previously unrecognized finding, may contribute to tissue GSH depression after severe ischemia. In this context, studies performed with the G-GCS inhibitor buthionine sulfoximine (BSO) have shown that GSH concentrations are 40% lower in the perfused hearts of BSO-treated animals than in those of controls after ischemia-reperfusion [3]. Hence, considering a substantial (approx.…”

Study of potential xanthine oxidase inhibitors: In silico and in vitro biological activity

“…The assay was done in triplicate and IC50 values were calculated from the percentage inhibition (Werns et al, 1991).…”