Kurauchi Yuki, Mokudai Koichi, Mori Asami, Sakamoto Kenji, Nakahara Tsutomu, Morita Masahiko, Kamimura Ayako, Ishii Kunio
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
J Pharmacol Sci. 2017 Mar;133(3):146-155. doi: 10.1016/j.jphs.2017.02.004. Epub 2017 Feb 17.
l-Citrulline is a potent precursor of l-arginine, and exerts beneficial effect on cardiovascular system via nitric oxide (NO) production. Migraine is one of the most popular neurovascular disorder, and imbalance of cerebral blood flow (CBF) observed in cortical spreading depression (CSD) contributes to the mechanism of migraine aura. Here, we investigated the effect of l-citrulline on cardiovascular changes to KCl-induced CSD. in rats. Intravenous injection of l-citrulline prevented the decrease in CBF, monitored by laser Doppler flowmetry, without affecting mean arterial pressure and heart rate during CSD. Moreover, l-citrulline attenuated propagation velocity of CSD induced by KCl. The effect of l-citrulline on CBF change was prevented by l-NAME, an inhibitor of NO synthase, but not by indomethacin, an inhibitor of cyclooxygenase. On the other hand, attenuation effect of l-citrulline on CSD propagation velocity was prevented not only by l-NAME but also by indomethacin. In addition, propagation velocity of CSD was attenuated by intravenous injection of NOR3, a NO donor, which was diminished by ODQ, an inhibitor of soluble guanylyl cyclase. These results suggest that NO/cyclic GMP- and prostanoids-mediated pathway differently contribute to the effect of l-citrulline on the maintenance of CBF.
L-瓜氨酸是L-精氨酸的有效前体，通过一氧化氮（NO）的产生对心血管系统发挥有益作用。偏头痛是最常见的神经血管疾病之一，在皮层扩散性抑制（CSD）中观察到的脑血流（CBF）失衡是偏头痛先兆机制的一部分。在此，我们研究了L-瓜氨酸对氯化钾诱导的大鼠CSD心血管变化的影响。静脉注射L-瓜氨酸可防止激光多普勒血流仪监测到的CBF下降，且在CSD期间不影响平均动脉压和心率。此外，L-瓜氨酸减弱了氯化钾诱导的CSD的传播速度。L-瓜氨酸对CBF变化的影响可被NO合酶抑制剂L-NAME阻断，但不能被环氧化酶抑制剂吲哚美辛阻断。另一方面，L-瓜氨酸对CSD传播速度的减弱作用不仅被L-NAME阻断，也被吲哚美辛阻断。此外，静脉注射NO供体NOR3可减弱CSD的传播速度，而该作用可被可溶性鸟苷酸环化酶抑制剂ODQ减弱。这些结果表明，NO/环鸟苷酸和前列腺素介导的途径对L-瓜氨酸维持CBF的作用有不同贡献。
