l-Citrulline ameliorates cerebral blood flow during cortical spreading depression in rats: Involvement of nitric oxide- and prostanoids-mediated pathway.
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.
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: kurauchy@kumamoto-u.ac.jp.
Yuki
Y
Kurauchi
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Koichi
K
Mokudai
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Asami
A
Mori
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Kenji
K
Sakamoto
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Tsutomu
T
Nakahara
Healthcare Products Development Center, Kyowa Hakko Bio Co., Ltd., 2 Miyukigaoka, Tsukuba-shi, Ibaraki 305-0841, Japan.
Masahiko
M
Morita
Healthcare Products Development Center, Kyowa Hakko Bio Co., Ltd., 2 Miyukigaoka, Tsukuba-shi, Ibaraki 305-0841, Japan.
Ayako
A
Kamimura
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Kunio
K
Ishii
D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002956:Citrulline / Q000494:pharmacology*; D013181:Cortical Spreading Depression / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D011453:Prostaglandins / Q000502:physiology*; D017207:Rats, Sprague-Dawley
D011453:Prostaglandins; D002956:Citrulline; D009569:Nitric Oxide; D006152:Cyclic GMP
Cerebral blood flow; Cortical spreading depression; Nitric oxide; Prostanoids; l-Citrulline