Abstract
In the presence of its substrates hypoxanthine and xanthine, xanthine oxidase generates oxygen free radicals that cause postischemic injury. Recently, it has been demonstrated that the burst of xanthine oxidase-mediated free radical generation in the reperfused heart is triggered by a large increase in substrate formation, which occurs secondary to the degradation of adenine nucleotides during ischemia. It is not known, however, whether blocking this substrate formation is sufficient to prevent radical generation and functional injury. Therefore, studies were performed in isolated rat hearts in which xanthine oxidase substrate formation was blocked with the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), and measurements of contractile function and free radical generation were performed. Chromatographic measurements of the intracellular adenine nucleotide pool showed that preischemic administration of EHNA blocked postischemic hypoxanthine, xanthine, and inosine formation. Electron paramagnetic resonance spin trapping measurements of free radical generation showed that inhibition of adenosine deaminase with EHNA blocked free radical generation and that it also increased the recovery of contractile function by more than 2-fold. Exogenous infusion of hypoxanthine and xanthine totally reversed the protective effects of EHNA. These results demonstrate that blockade of xanthine oxidase substrate formation by adenosine deaminase inhibition can prevent free radical generation and contractile dysfunction in the postischemic heart.
Highlights
In the presence of its substrates hypoxanthine and xanthine, xanthine oxidase generates oxygen free radicals that cause postischemic injury
It has been demonstrated that the burst of xanthine oxidasemediated free radical generation in the reperfused heart is triggered by a large increase in substrate formation, which occurs secondary to the degradation of adenine nucleotides during ischemia
It was demonstrated that the burst of xanthine oxidasemediated free radical generation in the reperfused heart is triggered and its time course controlled by a large increase in substrate formation, which occurs secondary to the degradation of ATP during ischemia
Summary
In the presence of its substrates hypoxanthine and xanthine, xanthine oxidase generates oxygen free radicals that cause postischemic injury. It has been demonstrated that the burst of xanthine oxidasemediated free radical generation in the reperfused heart is triggered by a large increase in substrate formation, which occurs secondary to the degradation of adenine nucleotides during ischemia It is not known, whether blocking this substrate formation is sufficient to prevent radical generation and functional injury. Exogenous infusion of hypoxanthine and xanthine totally reversed the protective effects of EHNA These results demonstrate that blockade of xanthine oxidase substrate formation by adenosine deaminase inhibition can prevent free radical generation and contractile dysfunction in the postischemic heart. Since the availability of xanthine oxidase substrates was shown to be the primary factor that triggers and controls the burst of oxygen free radical generation in the postischemic heart, blocking the formation of these enzyme substrates should inhibit radical generation and prevent radical-mediated myocardial dysfunction. These studies demonstrate that inhibition of xanthine oxidase substrate formation by blockade of adenosine deaminase can greatly decrease free radical generation and contractile dysfunction in the postischemic heart
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