Abstract
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 language | English |
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Pages (from-to) | 111-9 |
Number of pages | 9 |
Journal | European Journal of Pharmacology |
Volume | 403 |
Issue number | 1-2 |
Publication status | Published - 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