Role of nitric oxide and superoxide balance in hypoxia-reoxygenation proximal tubular injury.

Under normal physiological conditions activation of nitric oxide synthases produces both nitric oxide and superoxide in equimolar concentrations (Figure 1). We propose a hypothesis that in hypoxia-reoxygenation injury this balanced co-production of nitric oxide and superoxide is disturbed and results in pathological effects. Specifically, under hypoxic conditions nitric oxide synthase is activated, resulting in a relative excess of free nitric oxide as compared to superoxide. This imbalance with excess nitric oxide results in cytotoxicity. This excess of nitric oxide can be neutralized by an exogenous source of superoxide generating system, with resultant cytoprotection. The reverse occurs during reoxygenation, when increased superoxide is generated secondary to the action of xanthine oxidase. This excess of superoxide is accompanied by reduced free nitric oxide levels due to deactivation of nitric oxide synthase and the scavenging effect of molecular oxygen. During reoxygenation exogenous nitric oxide therefore restores balance by neutralizing superoxide and thus attenuating its cytotoxicity. In this review arguments are presented in support of this provocative hypothesis. Nitric oxide (NO) is a recently recognized messenger