THE EFFECTS OF INHIBITORS OF CYCLOOXYGENASE, LIPOXYGENASE AND NITRIC-OXIDE SYNTHASE PATHWAYS ON THE TOXICITY OF HYDROXYUREA IN ADRENALECTOMIZED RATS

Our previous observations on the toxic effects of hydroxyurea (HU) in adrenalectomized (ADX) rats prompted us to suggest that these effects might be mediated by an increased synthesis of proinflammatory cytokin es, which display similar toxicological profiles (e.g. increased letha lity in adrenal-ablated animals). The present study was aimed at inves tigating whether some of the mediators of the biological effects of pr o-inflammatory cytokines (i.e. prostaglandins, leukotrienes and nitric oxide) are involved in the severe HU toxicity seen in ADX rats. The l atter were treated over a 5-day period with HU alone or HU plus specif ic inhibitors of prostaglandin, leukotriene and nitric oxide synthetic pathways. Mortality was recorded throughout the experiments. Results showed that, while corticosterone and dexamethasone afford significant protection against HU toxicity, the latter is not reduced and may eve n be aggravated by treatments with specific inhibitors of cyclo-oxygen ase, lipoxygenase or nitric oxide synthase.