Abstract
The ability of various nitric oxide (NO) donors to induce long-lasting inhibition of contraction in isolated arteries was compared. All the studied compounds elicited a relaxant effect in rat aortic rings precontracted with norepinephrine (NE). Almost maximal relaxation was obtained with 1 μM of each compound. The S-nitrosating agents S-nitrosoglutathione (GSNO), S-nitroso-N-acetylpenicillamine, S-nitroso-N-acetylcysteine, and sodium nitroprusside (1 μM) produced a decrease of the maximal effect of NE that persisted after removal of the drug. This hyporesponsiveness to NE was associated with a relaxant effect of N-acetylcysteine, a low-molecular weight thiol that can displace NO from cysteine-NO bonds. Such modifications of contraction were not observed in aortic rings previously exposed to 1 μM S-nitrosocysteine, glyceryl trinitrate, 3-morpholinosydnonimine, or 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA-NO). The same differential effects of GSNO and DEA-NO on contraction were also observed in porcine coronary arteries. Rat aortic rings previously exposed to 100 μM GSNO, but not to 100 μM DEA-NO, displayed a persistent increase in NO content (determined by NO spin trapping) and cysteine-NO residues (determined by immunostaining with an anti-cysteine-NO antiserum). The GSNO-induced increase in cysteine-NO residues in aortic tissue was prevented by the thiolmodifying agent p-hydroxymercuribenzoic acid. This study shows that in isolated arteries, the effects of S-nitrosating agents differed from those of other NO-donating agents. S- Nitrosating agents induced a persistent inhibition of contraction, which was attributed to the formation of releasable NO stores by S-nitrosation of tissue thiols. These differential effects of NO donors may be important for orientating their therapeutic indications.
Footnotes
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This work was partially supported by a grant from Fondation de France. J.L.A. is recipient of a fellowship from CAPES-Brazil. I.L. is a visitor scientist from Institute of Chemical Physics, Russian Academy of Science (Moscow) and is recipient of fellowships from the Association pour la Recherche sur le Cancer (in Toulouse) and Collège Doctoral Européen (in Strasbourg). E.P.R. studies were supported by the Association pour la Recherche sur le Cancer (Grant 7547).
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DOI: 10.1124/jpet.103.052605.
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ABBREVIATIONS: NO, nitric oxide; SNP, sodium nitroprusside; LMW, low-molecular weight; RSNO, S-nitrosothiols; GSNO, S-nitrosoglutathione; NONOates, diazeniumdiolates; SNP, sodium nitroprusside; NAC, N-acetylcysteine; EPR, electron paramagnetic resonance; NE, norepinephrine; U46619, 9,11-dideoxy-11α, 9α-epoxymethanoprostaglandin F(2α); SIN-1, 3-morpholinosydnonimine; SOD, superoxide dismutase; p-HMBA, para-hydroxymercuribenzoic acid; S-NO-cys-g-BSA, S-nitroso-glutaraldehyde-conjugated bovine serum albumin; DETC, diethyldithiocarbamate; oxyHb, oxyhemoglobin; metHb, methemoglobin; DEA-NO, 2-(N,N-diethylamino)-diazenolate-2-oxide; SNAP, S-nitroso-N-acetylpenicillamine; CysNO, S-nitrosocysteine; SNAC, S-nitroso-N-acetylcysteine; MANOVA, mutianalysis of variance.
- Received April 3, 2003.
- Accepted June 17, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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