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.
Soler
Marta
M
Laboratory of Inflammation Mediators, Institute of Research, Hospital Santa Creu i Sant Pau, Barcelona, Spain.
Camacho
Mercedes
M
Vila
Luís
L
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D011464:Epoprostenol / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014652:Vascular Diseases / Q000517:prevention & control*
D003497:Cyclic N-Oxides; D007093:Imidazoles; D007375:Interleukin-1; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D010656:Phenylephrine; D011464:Epoprostenol