Casey, David B., Pankey, Edward A., Badejo, Adeleke M., Bueno, Franklin R., Bhartiya, Manish, Murthy, Subramanyam N., Uppu, Rao M., Nossaman, Bobby D., and Kadowitz, Philip J.
Peroxynitrite (PN) worsens pathological conditions associated with oxidative stress. However, beneficial effects have also been reported. PN has been shown to demonstrate vasodilator as well as vasoconstrictor properties that are dependent upon the experimental conditions and the vascular bed studied. PN-induced vascular smooth muscle relaxation may involve the formation of nitric oxide (NO) donors. The present results show that PN has significant vasodilator activity in the pulmonary and systemic vascular beds, and that responses to PN were not attenuated by L-penicillamine (L-PEN), a PN scavenger, whereas responses to sodium nitroprusside (SNP) were decreased. PN had a small inhibitory effect on decreases in arterial pressure in response to the NO donors diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA/NO) and S-nitrosoglutathione (GSNO). PN partially reversed hypoxic pulmonary vasoconstriction. PN responses were attenuated by the soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and responses to PN and the PN precursor, 3-morpholinosydnonimine (SIN-1), were different. These data show that PN has potent pulmonary vasodilator activity in the rat, and provide evidence that a PN interaction with S-nitrosothiols is not the major mechanism mediating the response. These data suggest that responses to PN are mediated by the activation of sGC, and that PN has a small inhibitory effect on NO responses. Key words: pulmonary vasodilator responses, systemic circulation, oxidant stress, hypoxia, peroxynitrite, L- penicillamine, sodium nitroprusside, glyceryl trinitrate, S-nitrosoglutathione, DEA/NO, SIN-1, ODQ. Le peroxynitrite (PN) aggrave les conditions pathologiques associees au stress oxydant. Cependant, des effets benefiques ont aussi ete rapportes. Le PN possede des activites de vasodilatatrices ou vasoconstrictrices qui dependent des conditions experimentales et du lit vasculaire etudie. Le relachement du muscle lisse vasculaire induit par le PN peut impliquer la formation de donneurs d'oxyde nitrique (NO). Les resultats presents montrent que le PN possede une activite vasodilatatrice significative dans les lits vasculaires pulmonaire et systemique et que les reponses au PN ne sont pas attenuees par la L-penicillamine (L-PEN), un piegeur de PN, alors que les reponses au nitroprussiate de sodium etaient diminuees. Le PN presentait un leger effet inhibiteur sur les diminutions de tension arterielle en reponse au diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA/NO) et au S-nitrosogluthathion (GSNO), des donneurs de NO. Le PN renversait partiellement la vasoconstriction pulmonaire hypoxique. Les reponses au PN etaient attenuees par le 1H- [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), un inhibiteur de la guanylate cyclase soluble et les reponses au PN et au 3-morpholinosydnonimine (SIN-1), un precurseur de PN, etaient differentes. Ces donnees montrent que le PN possede une activite vasodilatatrice pulmonaire puissante chez le rat et fournissent la preuve qu'une interaction entre le PN et les S-nitrosothiols n'est pas un mecanisme majeur implique dans cette reponse. Ces donnees suggerent que les reponses au PN sont dues a l'activation de la sGC et que le PN possede un leger effet inhibiteur sur les reponses au NO. Mots-cles : reponses vasodilatatrices pulmonaires, circulation systemique, stress oxydant, hypoxie, peroxynitrite, L-penicillamine, nitroprussiate de sodium, glyceryle trinitrate, S-nitrosogluthation, DEA-NO, SIN-1, ODQ. [Traduit par la Redaction], Introduction Peroxynitrite (PN; [ONOO.sup.-]) is a reactive oxygen species that is generated in the body by the rapid reaction of nitric oxide ([NO.sup.*]) and superoxide anion ([O.sup.*-.sub.2]) (Beckman et al. [...]