Nitric oxide as a target for the hypotensive and vasorelaxing effects induced by (Z)-ethyl 12-nitrooxy-octadec-9-enoate in rats

作者：Machado Natalia T; Maciel Priscilla M P; Alustau Maria C; Queiroz Thyago M; Furtado Fabiola F; Assis Valeria L; Veras Robson C; Araujo Islania G A; Athayde Filho Petronio F; Medeiros Isac A^*

来源：European Journal of Pharmaceutical Sciences, 2014, 62: 317-325.

DOI：10.1016/j.ejps.2014.06.012

• Organic nitrate
• Nitric oxide
• Mesenteric artery
• Vasorelaxation
• (Z)-ethyl 12-nitrooxy-octadec-9-enoate

The cardiovascular effects induced by a new organic nitrate were investigated in rats. The (Z)-ethyl 12nitrooxy-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_b0_10_3 M) in rat mesenteric artery rings, pre-contracted with phenylephrine (1 WI with or without endothelium. Pre-incubation with PTIO (300 [tM), a free radical form of NO (NOV) scavenger, attenuated the NCOE vasorelaxation potency. However, in the presence of t-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 (101.IM). 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 pM); and non-selective K+ channels blocker, TEA (3 mM). In addition the NCOE-induced vasorelaxation was reduced by BKca (iberiotoxin, 100 nM) and KAT? selective (glibenclamide, 10 jaM) 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 BICca activation. Furthermore, the compound was not able to induce tolerance.

• 出版日期2014-10-1