title: Novel S-nitrosothiols do not engender vascular tolerance and remain effective in glyceryltrinitrate-tolerant rat femoral arteries.
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.
authors.affiliation: Clinical Pharmacology Unit, University of Edinburgh, Department of Biomedical Sciences, Western General Hospital, EH4 2LH, Scotland, UK. m.r.miller@sms.ed.ac.uk
authors.forename: M R
authors.initials: MR
authors.lastname: Miller
authors.forename: M J
authors.initials: MJ
authors.lastname: Roseberry
authors.forename: F A
authors.initials: FA
authors.lastname: Mazzei
authors.forename: A R
authors.initials: AR
authors.lastname: Butler
authors.forename: D J
authors.initials: DJ
authors.lastname: Webb
authors.forename: I L
authors.initials: IL
authors.lastname: Megson
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005263:Femoral Artery / Q000187:drug effects* / Q000502:physiology; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008297:Male; D008706:Methemoglobin / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D005996:Nitroglycerin / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000737:chemistry / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine; D026422:S-Nitrosoglutathione; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010069:Oxadiazoles; D011810:Quinoxalines; C109931:RIG 200; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D026422:S-Nitrosoglutathione; D026423:S-Nitroso-N-Acetylpenicillamine; D008706:Methemoglobin; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D005978:Glutathione; D010396:Penicillamine; D005944:Glucosamine