title: Activity of nicorandil, a nicotinamide derivative with a nitrate group, in the experimental model of pain induced by formaldehyde in mice.
abstract: Nicorandil (2-nicotinamide ethyl nitrate), an antianginal drug characterized by the coupling of nicotinamide with a nitric oxide (NO) donor, activates guanylyl cyclase and opens ATP-dependent K(+) channels. In the present study, we investigated the effects induced by per os (p.o.) administration of nicorandil (12.5, 25 or 50 mg/kg) or equimolar doses (corresponding to the highest dose of nicorandil) of N-(2-hydroxyethyl) nicotinamide (NHN), its main metabolite, or nicotinamide in the model of nociceptive response induced by formaldehyde in mice. Nicorandil, but not NHN or nicotinamide, inhibited the second phase of the nociceptive response. This activity was observed when nicorandil was administered between 30 and 120 min before the injection of formaldehyde. Ipsilateral intraplantar injection of nicorandil (125, 250 or 500 μg/paw) did not inhibit the nociceptive response. After p.o. administration of nicorandil (50 mg/kg), peak plasma concentrations of this compound and NHN were observed 0.63 and 4 h later, respectively. Nicotinamide concentrations were not increased after administration of nicorandil. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 or 2 mg/kg), a guanylyl cyclase inhibitor, partially attenuated the antinociceptive activity of nicorandil. However, this activity was not changed by glibenclamide (30 or 60 mg/kg), an inhibitor of ATP-dependent K(+) channels. In conclusion, we demonstrated the antinociceptive activity of nicorandil in a model of pain that exhibits both a nociceptive and an inflammatory profile. This activity is not mediated by nicotinamide or NHN. The coupling of an NO-donor to nicotinamide results in a compound with an increased potency. The NO-cGMP pathway, but not ATP-dependent K(+) channels, partially mediates the antinociceptive activity of nicorandil.
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Marcela M G B
authors.initials: MM
authors.lastname: Dutra
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Godin
authors.forename: Isabela C
authors.initials: IC
authors.lastname: César
authors.forename: Elias B
authors.initials: EB
authors.lastname: Nascimento
authors.forename: Raquel R
authors.initials: RR
authors.lastname: Menezes
authors.forename: Wallace C
authors.initials: WC
authors.lastname: Ferreira
authors.forename: Darly G
authors.initials: DG
authors.lastname: Soares
authors.forename: João Gabriel T
authors.initials: JG
authors.lastname: Seniuk
authors.forename: Débora P
authors.initials: DP
authors.lastname: Araújo
authors.forename: Leandro F S
authors.initials: LF
authors.lastname: Bastos
authors.forename: Gerson A
authors.initials: GA
authors.lastname: Pianetti
authors.forename: Ângelo
authors.initials: Â
authors.lastname: de Fátima
authors.forename: Renes R
authors.initials: RR
authors.lastname: Machado
authors.forename: Márcio M
authors.initials: MM
authors.lastname: Coelho
mesh_terms: D000700:Analgesics / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000633:toxicity*; D005905:Glyburide / Q000494:pharmacology; D008297:Male; D051379:Mice; D020108:Nicorandil / Q000097:blood / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D000700:Analgesics; D010069:Oxadiazoles; D005557:Formaldehyde; D020108:Nicorandil; D005905:Glyburide