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

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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Organic nitrates, such as glyceryl trinitrate, 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)111-9
Number of pages9
JournalEuropean Journal of Pharmacology
Issue number1-2
Publication statusPublished - 1 Sept 2000

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Enzyme Inhibitors
  • Femoral Artery
  • Glucosamine
  • Glutathione
  • Hemoglobins
  • In Vitro Techniques
  • NG-Nitroarginine Methyl Ester
  • Nitric Oxide Donors
  • Nitroglycerin
  • Nitroso Compounds
  • Oxadiazoles
  • Penicillamine
  • Perfusion
  • Phenylephrine
  • Quinoxalines
  • Rats
  • Rats, Wistar
  • S-Nitrosoglutathione
  • Vasoconstriction
  • Vasoconstrictor Agents
  • Vasodilator Agents


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