S-Nitrosating Nitric Oxide Donors Induce Long-Lasting Inhibition of Contraction in Isolated Arteries

  1. Jacicarlos L. Alencar,
  2. Irina Lobysheva,
  3. Karel Chalupsky,
  4. Michel Geffard,
  5. Françoise Nepveu,
  6. Jean-Claude Stoclet and
  7. Bernard Muller
  1. Université Louis Pasteur, Faculté de Pharmacie, Pharmacologie and Physico-Chimie, Unité Mixte Recherche Centre National de la Recherche Scientifique, Illkirch, France (J.L.A., K.C., J.-C.S., B.M.); Universidade Federal da Paraíba, Laboratório de Tecnologia Farmacêutica, Departamento de Ciências Básicas da Saúde, Campina Grande, Brazil (J.L.A.); Université Paul Sabatier, Faculté des Sciences Pharmaceutiques, Unité Mixte de Recherche, Institut de Recherche pour le Developpement, Toulouse, France (I.L., F.N.); Ecole Pratique des Hautes Etudes, Physique des Interactions Ondes-Matières, Pessac, France (M.G.); and Université Victor Segalen, Laboratoire de Pharmacologie, Unité de Formation et de Recherche Sciences Pharmaceutiques and Equipe Mixte Institut National de la Santé et de la Recherche Médicale, Bordeaux, France (B.M.)
  1. Address correspondence to:
    Prof. Bernard Muller, Laboratoire de Pharmacologie, UFR Sciences Pharmaceutiques/INSERM EMI 0356, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France. E-mail: bernard.muller{at}phcodyn.ubordeaux2.fr

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

  • 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).

  • DOI: 10.1124/jpet.103.052605.

  • 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.
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  1. Published online before print September 3, 2003, doi: 10.1124/jpet.103.052605 JPET October 2003 vol. 307 no. 1 152-159
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