title: Direct gas measurements indicate that the novel cyclooxygenase inhibitor AZD3582 is an effective nitric oxide donor in vivo.
abstract: 1. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donor that inhibits COX-1 and COX-2. It is as effective as naproxen in models of pain and inflammation, but causes less gastroduodenal damage. Nitric oxide (NO) is generated from AZD3582 in vitro, and this study sought to show that the drug donates NO in vivo. 2. In anaesthetised male New Zealand white rabbits, the endogenous NO concentration in exhaled air was reduced by N(G)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(- 1) i.v.) from 33.5+/-1.0 ppb (mean+/-s.e.m.; n=6 per group) to 3.0+/-1.0 ppb, while increasing blood pressure and reducing heart rate. AZD3582 (0.2, 0.6, 2.0 or 6.0 micromol kg(- 1) min(- 1)) given 30 min after L-NAME increased the concentration of NO in exhaled air (P<0.05), decreased blood pressure and increased heart rate in a dose-dependent manner versus L-NAME control values. The peak mean NO concentration obtained was 44+/-8.0 ppb. 3. In in situ-perfused rabbit lungs, L-NAME (185 micromol l(- 1)) reduced the NO concentration in exhaled air from 106+/-13 to 4.0+/-0.4 ppb (n=5). Addition of AZD3582 (6 micromol min(- 1)) to the perfusate produced an initial rapid increase in the NO concentration in exhaled air, followed by a sustained, but lower plateau. Infusion of L-NAME increased, and AZD3582 decreased, pulmonary arterial pressure. 4. In both anaesthetised rabbits and in the perfused lungs, brief periods of hypoxia increased NO concentrations generated by AZD3582. 5. We conclude that, in rabbits, AZD3582 donates NO in vivo with characteristics similar to those reported for nitroglycerin and isosorbide nitrates
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: L Christofer
authors.initials: LC
authors.lastname: Adding
authors.forename: Per
authors.initials: P
authors.lastname: Agvald
authors.forename: Lars I
authors.initials: LI
authors.lastname: Andersson
authors.forename: Bror
authors.initials: B
authors.lastname: Jonzon
authors.forename: Janet
authors.initials: J
authors.lastname: Hoogstraate
authors.forename: Lars E
authors.initials: LE
authors.lastname: Gustafsson
mesh_terms: D000136:Acid-Base Equilibrium / Q000187:drug effects; D000388:Air / Q000032:analysis*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005740:Gases / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology*; D009288:Naproxen / Q000031:analogs & derivatives; D009569:Nitric Oxide / Q000032:analysis* / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005740:Gases; D006454:Hemoglobins; D009281:Naphthalenes; D014665:Vasodilator Agents; C111751:naproxen-n-butyl nitrate; D009569:Nitric Oxide; D009288:Naproxen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005996:Nitroglycerin; D019331:NG-Nitroarginine Methyl Ester