title: Nitric oxide as a target for the hypotensive and vasorelaxing effects induced by (Z)-ethyl 12-nitrooxy-octadec-9-enoate in rats.
abstract: The cardiovascular effects induced by a new organic nitrate were investigated in rats. The (Z)-ethyl 12-nitrooxy-octadec-9-enoate (NCOE) was synthesized from ricinoleic acid, the major compound of the castor oil. NCOE induced significant and dose-dependent hypotension and bradycardia in normotensive rats. In rats pretreated with NCOE (60 mg/kg, i.v., once a day) for 4 consecutive days, hypotension induced by the nitrate was similar to that observed in rats that were not pretreated with the compound. The vasorelaxation induced by the compound was concentration-dependent (10(-10)-10(-3) M) in rat mesenteric artery rings, pre-contracted with phenylephrine (1 μM), with or without endothelium. Pre-incubation with PTIO (300 μM), a free radical form of NO (NO) scavenger, attenuated the NCOE vasorelaxation potency. However, in the presence of L-cysteine (3 mM), a reduced form of NO (NO-) scavenger, NCOE response was potentiated. NCOE effect was not changed in the presence of an inhibitor of cytochrome P450, proadifen (10 μM). On the other hand, the vasodilation was reduced in the presence of mitochondrial aldehyde dehydrogenase inhibitor (mtALDH), cyanamide (1 mM); soluble guanylyl cyclase inhibitor (sGC), ODQ (10 μM); and non-selective K+ channels blocker, TEA (3 mM). In addition the NCOE-induced vasorelaxation was reduced by BKCa (iberiotoxin, 100 nM) and KATP selective (glibenclamide, 10 μM) blockers, however the effect was not modified by a KV blocker (4-aminopyridine, 1 mM). Furthermore, NCOE increased NO levels in rat aortic smooth muscle cultured cells, detected by NO-sensitive probe DAF-2DA, by flow cytometry. These results together suggest that NCOE induces short-lasting hypotension and bradycardia, and promotes vasorelaxation due to NO release through the compound metabolism via mtALDH and consequent sGC, KATP and BKCa activation. Furthermore, the compound was not able to induce tolerance.
authors: Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba 58.059-900, Brazil.
authors: Natália T
authors: NT
authors: Machado
authors: Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba 58.059-900, Brazil.
authors: Priscilla M P
authors: PM
authors: Maciel
authors: Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba 58.059-900, Brazil.
authors: Maria C
authors: MC
authors: Alustau
authors: Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba 58.059-900, Brazil.
authors: Thyago M
authors: TM
authors: Queiroz
authors: Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba 58.059-900, Brazil.
authors: Fabíola F
authors: FF
authors: Furtado
authors: Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba 58.059-900, Brazil.
authors: Valéria L
authors: VL
authors: Assis
authors: Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba 58.059-900, Brazil.
authors: Robson C
authors: RC
authors: Veras
authors: Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba 58.059-900, Brazil.
authors: Islânia G A
authors: IG
authors: Araújo
authors: Departamento de Química, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba, Brazil.
authors: Petrônio F
authors: PF
authors: Athayde-Filho
authors: Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba 58.059-900, Brazil. Electronic address: isacmed@uol.com.br.
authors: Isac A
authors: IA
authors: Medeiros
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D001919:Bradycardia / Q000139:chemically induced; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D007022:Hypotension / Q000139:chemically induced; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D017208:Rats, Wistar; D012277:Ricinoleic Acids / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D009566:Nitrates; D020030:Nitric Oxide Donors; D012277:Ricinoleic Acids; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C000596112:ethyl 12-nitrooxyoctadec-9-enoate; D010656:Phenylephrine; D009569:Nitric Oxide
keywords: (Z)-ethyl 12-nitrooxy-octadec-9-enoate; Mesenteric artery; Nitric oxide; Organic nitrate; Vasorelaxation