title: Characterization of the influence of nitric oxide donors on intestinal absorption of macromolecules.
abstract: To characterize the influence of nitric oxide (NO) donors on the intestinal absorption of macromolecules, the relationship between the release rate of NO from NO donors and their absorption-enhancing effects and the effects of several scavengers and generators on the absorption-enhancing effects of NO donor were investigated. The t1/2 values of the NO release rate from 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)-1-propanamine (NOC5), 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)-N-methyl-1-propanamine (NOC7) and N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine (NOC12) are 25, 5 and 100min, respectively. The absorption-enhancing effects of NO donors on the absorption of fluorescein isothiocyanate dextrans with an average molecular weight of 4400 (FD-4) are NOC5 > NOC7 > NOC12 in the colon. The lowest enhancing effect of NOC12 may be due to the slow rate of NO release. The enhancing effect of NOC7 rapidly disappeared compared with the effect of NOC5. The results raise the possibility that the difference between NOC5 and NOC7 on enhancing effect is related to the t1/2 of the NO release. The NOC7-induced enhancing effect was prevented by the co-administration of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide sodium salt (C-PTIO), an NO scavenger; tiron, an O2(-) scavenger; mannitol, an OH* scavenger, and deferoxamine, peroxynitrate scavenger. Pyrogallol, an O2(-) generator, potentiated the NOC7-induced enhancing effect. These results support a role for peroxynitrate, and possibly OH*, in the NO donor-induced intestinal enhancing effect.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68, Koshien, Kyuban-cho, Nishinomiya, Hyogo 663-8179, Japan. koichi@mwu.mukogawa-u.ac.jp
authors.forename: Koichi
authors.initials: K
authors.lastname: Takahashi
authors.forename: Nanako
authors.initials: N
authors.lastname: Numata
authors.forename: Natsumi
authors.initials: N
authors.lastname: Kinoshita
authors.forename: Naoki
authors.initials: N
authors.lastname: Utoguchi
authors.forename: Tadanori
authors.initials: T
authors.lastname: Mayumi
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Mizuno
mesh_terms: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000378:metabolism / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003911:Dextrans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology; D006834:Hydrazines / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D046911:Macromolecular Substances / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000145:classification / Q000378:metabolism* / Q000494:pharmacology; D009603:Nitroso Compounds / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D014226:Triazenes / Q000378:metabolism / Q000494:pharmacology
chemical_list: C114535:1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene; C115239:3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamine; D001565:Benzoates; D003911:Dextrans; D016166:Free Radical Scavengers; D006834:Hydrazines; D007093:Imidazoles; D046911:Macromolecular Substances; C118603:NOC 12; D009566:Nitrates; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D014226:Triazenes; C015219:fluorescein isothiocyanate dextran; D013481:Superoxides; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; C039642:peroxynitric acid; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D000255:Adenosine Triphosphate; D016650:Fluorescein-5-isothiocyanate