Horinouchi Yuya, Tsuchiya Koichiro, Taoka Chiaki, Tajima Soichiro, Kihira Yoshitaka, Matsuda Yuko, Shishido Kozo, Yoshida Masahiro, Hamano Shuichi, Kawazoe Kazuyoshi, Ikeda Yasumasa, Ishizawa Keisuke, Tomita Shuhei, Tamaki Toshiaki
Department of Pharmacology, The Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Japan.
Chem Pharm Bull (Tokyo). 2011;59(2):208-14. doi: 10.1248/cpb.59.208.
Recently, increasing evidence suggests that the antihypertensive drug nifedipine acts as a protective agent for endothelial cells, and that the activity is unrelated to its calcium channel blocking. Nifedipine is unstable under light and reportedly decomposes to a stable nitrosonifedipine (NO-NIF). NO-NIF has no antihypertensive effect, and it has been recognized as a contaminant of nifedipine. The present study for the first time demonstrated that NO-NIF changed to a NO-NIF radical in a time-dependent manner when it interacted with human umbilical vein endothelial cells (HUVECs). The electron paramagnetic resonance (EPR) signal of NO-NIF radicals in HUVECs showed an asymmetric pattern suggesting that the radicals were located in the membrane. The NO-NIF radicals had radical scavenging activity for 1,1-diphenyl-2-picrylhydrazyl, whereas neither NO-NIF nor nifedipine did. In addition, the NO-NIF radical more effectively quenched lipid peroxides than NO-NIF or nifedipine. Furthermore, NO-NIF attenuated the superoxide-derived free radicals in HUVECs stimulated with LY83583, and suppressed iron-nitrilotriacetic acid (Fe-NTA)-induced cytotoxicity in rat pheochromocytoma (PC12) cells. Our findings suggest that NO-NIF is a candidate for a new class of antioxidative drugs that protect cells against oxidative stress.
最近，越来越多的证据表明，抗高血压药物硝苯地平可作为内皮细胞的保护剂，且该活性与其钙通道阻滞作用无关。硝苯地平在光照下不稳定，据报道会分解为稳定的亚硝基硝苯地平（NO-NIF）。NO-NIF没有抗高血压作用，并且已被认为是硝苯地平的一种污染物。本研究首次证明，NO-NIF与人脐静脉内皮细胞（HUVECs）相互作用时会随时间变化转变为NO-NIF自由基。HUVECs中NO-NIF自由基的电子顺磁共振（EPR）信号呈现不对称模式，表明这些自由基位于细胞膜中。NO-NIF自由基对1,1-二苯基-2-苦基肼具有自由基清除活性，而NO-NIF和硝苯地平都没有。此外，NO-NIF自由基比NO-NIF或硝苯地平更有效地淬灭脂质过氧化物。此外，NO-NIF可减轻LY83583刺激的HUVECs中超氧化物衍生的自由基，并抑制铁-次氮基三乙酸（Fe-NTA）诱导的大鼠嗜铬细胞瘤（PC12）细胞的细胞毒性。我们的研究结果表明，NO-NIF是一类新型抗氧化药物的候选物，可保护细胞免受氧化应激。
