The effects of inhibitors of cyclo-oxygenase, lipoxygenase and nitric oxide synthase pathways on the toxicity of hydroxyurea in adrenalectomized rats

Abstract

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 cytokines, which display similar toxicological profiles (e.g. increased lethality in adrenal-ablated animals). The present study was aimed at investigating whether some of the mediators of the biological effects of pro-inflammatory cytokines (i.e. prostaglandins, leukotrienes and nitric oxide) are involved in the severe HU toxicity seen in ADX rats. The latter were treated over a 5-day period with HU alone or HU plus specific 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 even be aggravated by treatments with specific inhibitors of cyclo-oxygenase, lipoxygenase or nitric oxide synthase.