title: Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo.
abstract: Nitric oxide (NO)-derived products may modify tissue constituents, forming S- and N-nitroso adducts and metal nitrosyls implicated in NO signaling. Nitrovasodilator drugs have been in widespread use for more than a century, yet their biotransformation pathways to NO and their effects as NO donors across tissues remain ill defined. By using a metabonomics approach (termed "NObonomics") for detailing the global NO-related metabolism of the cornerstone nitrovasodilator, glyceryl trinitrate (GTN; 0.1-100 mg/kg), in the rat in vivo, we find that GTN biotransformation elicits extensive tissue nitros(yl)ation throughout all major organ systems. The corresponding reaction products remained detectable hours after administration, and vascular tissue was not a major nitros(yl)ation site. Extensive heart and liver modifications involved both S- and N-nitrosation, and RBC S-nitrosothiol formation emerged as a sensitive indicator of organic nitrate metabolism. The dynamics of GTN-derived oxidative NO metabolites in blood did not reflect the nitros(yl)ation patterns in the circulation or in tissues, casting doubt on the usefulness of plasma nitrite/nitrate as an index of NO/NO-donor biodynamics. Target-tissue NO metabolites varied in amount and type with GTN dose, suggesting a dose-sensitive shift in the prevailing routes of GTN biotransformation ("metabolic shunting") from thiol nitrosation to heme nitrosylation. We further demonstrate that GTN-induced nitros(yl)ation is modulated by a complex, tissue-selective interplay of enzyme-catalyzed pathways. These findings provide insight into the global in vivo metabolism of GTN at pharmacologically relevant doses and offer an additional experimental paradigm for the NObonomic analysis of NO-donor metabolism and signaling.
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Janero
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Bryan
authors.forename: Fumito
authors.initials: F
authors.lastname: Saijo
authors.forename: Vijay
authors.initials: V
authors.lastname: Dhawan
authors.forename: David J
authors.initials: DJ
authors.lastname: Schwalb
authors.forename: Michael C
authors.initials: MC
authors.lastname: Warren
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
mesh_terms: D000818:Animals; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage; D005996:Nitroglycerin / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D005996:Nitroglycerin