Imidazolineoxyl N-oxide prevents the impairment of vascular contraction caused by interleukin-1beta through several mechanisms.

Overnight exposure to interleukin (IL)-1beta caused a dramatic hyporesponsiveness to phenylephrine, increased nitric oxide (NO) and prostacyclin production, and induced cycloxygenase-2 expression in rat aortic rings. Using different inhibitors, we found that this hyporeactivity was mediated by NO, prostacyclin, and activation of charybdotoxin-sensitive K(+) channels. The latter was independent of the presence of endothelium and NO and prostanoid synthesis during the challenge with phenylephrine. Activation of charybdotoxin-sensitive K(+) channels was probably due to NO stores formed during the exposition to IL-1beta; 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO), either when added with IL-1beta or in the organ bath, partially restored the contractility of IL-1beta-treated vessels. The cPTIO effect was mimicked by combinations of cyclooxygenase and NO-synthase inhibitors and by charybdotoxin. cPTIO significantly inhibited prostacyclin formation and prostacyclin-synthase activity during incubation with the cytokine. cPTIO antagonized the effect of IL-1beta by scavenging NO, reducing prostacyclin-synthase activity, and avoiding the contribution activation of K(+) channels.