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

• Published in: European journal of pharmacology 2000-11, Vol.408 (3), p.335-343
• Main Authors: Miller, Mark R, Roseberry, Marc J, Mazzei, Francesca A, Butler, Anthony R, Webb, David J, Megson, Ian L
• Format: Article
• Language: English
• Subjects: Animals; Blood vessel; Dose-Response Relationship, Drug; Drug Tolerance; Enzyme Inhibitors - pharmacology; Femoral Artery - drug effects; Femoral Artery - physiology; Glucosamine - analogs & derivatives; Glucosamine - pharmacology; Glutathione - analogs & derivatives; Glutathione - pharmacology; Guanylate Cyclase - antagonists & inhibitors; In Vitro Techniques; Male; Methemoglobin - pharmacology; Nitric oxide (NO); Nitric Oxide Donors - pharmacology; Nitroglycerin - pharmacology; Nitroso Compounds - chemistry; Nitroso Compounds - pharmacology; Organic nitrate; Oxadiazoles - pharmacology; Penicillamine - analogs & derivatives; Penicillamine - pharmacology; Phenylephrine - pharmacology; Quinoxalines - pharmacology; Rats; Rats, Wistar; S-Nitroso-N-Acetylpenicillamine; S-Nitrosoglutathione; S-Nitrosothiol; Tolerance; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(00)00777-9

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-β- 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 ω-nitro- l-arginine methyl ester ( l-NAME). Perfusion pressure was measured during 20 h treatment with supramaximal concentrations of NO donor (10 μM). 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.