Machado Natália T, Maciel Priscilla M P, Alustau Maria C, Queiroz Thyago M, Furtado Fabíola F, Assis Valéria L, Veras Robson C, Araújo Islânia G A, Athayde-Filho Petrônio F, Medeiros Isac A
Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba 58.059-900, Brazil.
Departamento de Química, Universidade Federal da Paraíba (UFPB), João Pessoa, Paraíba, Brazil.
Eur J Pharm Sci. 2014 Oct 1;62:317-25. doi: 10.1016/j.ejps.2014.06.012. Epub 2014 Jun 22.
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.
在大鼠中研究了一种新型有机硝酸盐引起的心血管效应。（Z）-12-硝基氧基-9-十八烯酸乙酯（NCOE）由蓖麻油的主要成分蓖麻油酸合成。NCOE在正常血压大鼠中引起显著的剂量依赖性低血压和心动过缓。在用NCOE（60mg/kg，静脉注射，每天一次）连续预处理4天的大鼠中，该硝酸盐引起的低血压与未用该化合物预处理的大鼠中观察到的相似。在预先用去氧肾上腺素（1μM）预收缩的有或无内皮的大鼠肠系膜动脉环中，该化合物引起的血管舒张呈浓度依赖性（10（-10）-10（-3）M）。用PTIO（300μM）（一种一氧化氮（NO）自由基清除剂）预孵育减弱了NCOE的血管舒张效力。然而，在存在L-半胱氨酸（3mM）（一种一氧化氮（NO-）还原形式清除剂）的情况下，NCOE反应增强。在存在细胞色素P450抑制剂丙胺卡因（10μM）的情况下，NCOE的作用没有改变。另一方面，在存在线粒体醛脱氢酶抑制剂（mtALDH）氰胺（1mM）、可溶性鸟苷酸环化酶抑制剂（sGC）ODQ（10μM）和非选择性钾通道阻滞剂TEA（3mM）的情况下，血管舒张作用减弱。此外，NCOE诱导的血管舒张被大电导钙激活钾通道（BKCa）阻断剂iberiotoxin（100nM）和ATP敏感性钾通道（KATP）选择性阻断剂格列本脲（10μM）减弱，然而该作用未被钾通道（KV）阻断剂4-氨基吡啶（1mM）改变。此外，通过流式细胞术用对NO敏感的探针DAF-2DA检测发现，NCOE增加了大鼠主动脉平滑肌培养细胞中的NO水平。这些结果共同表明，NCOE诱导短暂的低血压和心动过缓，并通过经由mtALDH的化合物代谢释放NO，进而激活sGC、KATP和BKCa，从而促进血管舒张。此外，该化合物不能诱导耐受性。
