Mori Asami, Takei Toshiaki, Suzuki Namiko, Sakamoto Kenji, Morita Masahiko, Nakagawa Satoshi, Nakahara Tsutomu, Ishii Kunio
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Research & Innovation Center, KYOWA HAKKO BIO CO., LTD, 2 Miyukigaoka, Tsukuba-shi, Ibaraki, 305-0841, Japan.
Heliyon. 2021 Mar 21;7(3):e06532. doi: 10.1016/j.heliyon.2021.e06532. eCollection 2021 Mar.
In our previous study, we found that the vasodilation of retinal arterioles induced by acetylcholine and BMS-191011, a large-conductance Ca-activated K (BK) channel opener, were diminished in diabetic rats. Currently, few agents ameliorate the impaired vasodilator responses of retinal blood vessels. Our recent finding that the intravenous infusion of L-citrulline dilated retinal arterioles, suggests that L-citrulline could be a potential therapeutic agent for circulatory disorders of the retina. In this study, we determined the effect of an oral L-citrulline treatment on impaired acetylcholine- and BMS-191011-induced vasodilation in the retinal arterioles of diabetic rats. To induce diabetes, rats were administered an intravenous dose of streptozotocin (65 mg/kg) and a 5% D-glucose solution as drinking water. The L-citrulline (2 g/kg/day) and L-arginine (2 g/kg/day) treatments commenced either 15 days before or just after the streptozotocin injection and continued throughout the experimental period. A 29-day treatment with L-citrulline, but not L-arginine, significantly ameliorated the impaired acetylcholine- and BMS-191011-induced retinal vasodilation in diabetic rats without affecting their plasma glucose levels. The 2-week L-citrulline treatment tended to ameliorate the dysfunction of the acetylcholine-induced retinal vasodilation in diabetic rats. In conclusion, these results showed that the retinal blood vessel dysfunction induced by diabetes mellitus could be prevented by the long-term administration of L-citrulline and suggest that the latter could play a potentially prophylactic role in diabetic retinopathy.
在我们之前的研究中，我们发现，在糖尿病大鼠中，乙酰胆碱和大电导钙激活钾（BK）通道开放剂BMS-191011所诱导的视网膜小动脉血管舒张作用减弱。目前，很少有药物能改善视网膜血管受损的血管舒张反应。我们最近发现静脉输注L-瓜氨酸可使视网膜小动脉扩张，这表明L-瓜氨酸可能是治疗视网膜循环障碍的一种潜在治疗药物。在本研究中，我们确定了口服L-瓜氨酸治疗对糖尿病大鼠视网膜小动脉中乙酰胆碱和BMS-191诱导的血管舒张功能受损的影响。为诱导糖尿病，给大鼠静脉注射链脲佐菌素（65mg/kg），并给予5% D-葡萄糖溶液作为饮用水。L-瓜氨酸（2g/kg/天）和L-精氨酸（2g/kg/天）治疗在链脲佐菌素注射前15天或注射后立即开始，并在整个实验期间持续。L-瓜氨酸治疗29天，但L-精氨酸治疗无效，可显著改善糖尿病大鼠乙酰胆碱和BMS-191011诱导的视网膜血管舒张功能受损，且不影响其血糖水平。L-瓜氨酸治疗2周倾向于改善糖尿病大鼠乙酰胆碱诱导视网膜血管舒张功能障碍。总之，这些结果表明，长期给予L-瓜氨酸可预防糖尿病引起的视网膜血管功能障碍，并提示L-瓜氨酸可能在糖尿病视网膜病变中发挥潜在的预防作用。
