Novel S-nitrosothiols do not engender vascular tolerance and remain effective in glyceryltrinitrate-tolerant rat femoral arteries

M R Miller, M J Roseberry, F A Mazzei, A R Butler, D J Webb, I L Megson

Research output: Contribution to journalArticlepeer-review

Abstract

Organic nitrates, such as glyceryltrinitrate, are nitric oxide (NO) donor drugs that engender tolerance with long-term use. Here, we tested the hypothesis that our novel S-nitrosothiols, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6, tetra-O-acetyl-beta-D-glucopyranose (RIG200) and S-nitroso-N-valeryl-D-penicillamine (D-SNVP), do not induce vascular tolerance ex vivo. Femoral arteries from adult male Wistar rats were preconstricted with phenylephrine and perfused with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Perfusion pressure was measured during 20 h treatment with supramaximal concentrations of NO donor (10 microM). Perfusion with glyceryltrinitrate caused a vasodilatation, which recovered over 2-20 h. In contrast, the S-nitrosothiols caused vasodilatations that were maintained throughout the 20 h perfusion period. Responses to S-nitrosothiols were partially reversed by the NO scavenger ferrohaemoglobin and fully reversed by the soluble guanylate cyclase inhibitor [1H-[1,2,4] oxadiazole [4,3-a]quinoxaline-1-one (ODQ). Glyceryltrinitrate-tolerant vessels were fully responsive to bolus injections of S-nitrosothiols. Resistance to tolerance is an attractive property of our novel compounds, particularly in view of their sustained activity in arteries with damaged endothelium.

Original languageEnglish
Pages (from-to)335-43
Number of pages9
JournalEuropean Journal of Pharmacology
Volume408
Issue number3
DOIs
Publication statusPublished - 24 Nov 2000

Keywords

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Enzyme Inhibitors
  • Femoral Artery
  • Glucosamine
  • Glutathione
  • Guanylate Cyclase
  • In Vitro Techniques
  • Male
  • Methemoglobin
  • Nitric Oxide Donors
  • Nitroglycerin
  • Nitroso Compounds
  • Oxadiazoles
  • Penicillamine
  • Phenylephrine
  • Quinoxalines
  • Rats
  • Rats, Wistar
  • S-Nitroso-N-Acetylpenicillamine
  • S-Nitrosoglutathione
  • Vasoconstrictor Agents
  • Vasodilation

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