title: Direct demonstration of nitric oxide formation in organs of rabbits treated by transdermal glyceryl trinitrate using an in vivo spin trapping technique.
abstract: Glyceryl trinitrate (GTN) is commonly delivered by a patch for the treatment of angina pectoris. The idea is now generally accepted that GTN requires a biotransformation process that activates the drug, in particular through nitric oxide (NO) generation. However, the pharmacokinetics of NO delivery from GTN still remains obscure. The objective of this study was to assess GTN-derived NO formation in vascular tissues and organs in rabbit given GTN patches. NO levels were evaluated in rabbits after 3 h of treatment with a 10 mg GTN patch (GTN group; n = 7) or a placebo patch (CTL; n = 7). Nitrosylhaemoglobin (HbNO) was evaluated by electron spin resonance (ESR) spectroscopy in red cell suspension. In vivo spin trapping technique using FeMGD as a spin trap, associated with ESR was used to quantify NO in tissues. The NO-spin trap complex, which is a relatively stable product, has been measured in several tissues. The ESR spectrum corresponding to HbNO was not found in red cell of GTN or CTL rabbits. The spectrum corresponding to the NO-spin trap complex was observed in all analysed tissues of CTL rabbits. The signal was significantly increased in liver, renal medulla, heart left ventricle and spleen of GTN-treated rabbits, and to a lesser extent in right ventricle and lung. No difference was shown between NO-spin trap levels measured in aorta or inferior vena cava from GTN or CTL rabbits. These data suggest that GTN patch treatment induced NO release, and that tissue-specific differences in transdermal GTN-derived NO exist. The GTN-NO pathway appears to be largely involved in organs such as the liver, kidney and heart.
authors.affiliation: LPPCE, Faculty of Medicine, 7 Bd Jeanne d'Arc, BP 87900, 21079 Dijon Cedex--IFR Santé no. 100, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Clermont
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lecour
authors.forename: Catherine
authors.initials: C
authors.lastname: Vergely
authors.forename: Marianne
authors.initials: M
authors.lastname: Zeller
authors.forename: Caroline
authors.initials: C
authors.lastname: Perrin
authors.forename: Véronique
authors.initials: V
authors.lastname: Maupoil
authors.forename: Olivier
authors.initials: O
authors.lastname: Bouchot
authors.forename: Luc
authors.initials: L
authors.lastname: Rochette
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004304:Dosage Forms; D005296:Ferrous Compounds / Q000737:chemistry; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry; D007275:Injections, Intravenous; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000097:blood* / Q000493:pharmacokinetics; D009573:Nitrites / Q000097:blood; D005996:Nitroglycerin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D009928:Organ Specificity / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D013012:Sorbitol / Q000819:agonists / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013113:Spin Labels; D019097:Spin Trapping / Q000379:methods*; D013154:Spleen / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013859:Thiocarbamates / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D014682:Vena Cava, Inferior / Q000187:drug effects / Q000378:metabolism
chemical_list: D004304:Dosage Forms; D005296:Ferrous Compounds; D006454:Hemoglobins; D009566:Nitrates; D009573:Nitrites; D013113:Spin Labels; D013859:Thiocarbamates; D014665:Vasodilator Agents; C008657:nitrosyl hemoglobin; D009569:Nitric Oxide; D013012:Sorbitol; C041262:N-methyl-D-glucamine dithiocarbamate; D005996:Nitroglycerin