Yuji Ishibashi1, Takanori Matsui1, Takafumi Matsumoto2, Hiroshi Kato3, Sho-Ichi Yamagishi4. 1. Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan. 2. Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, Osaka, Japan. 3. Drug Development Division, Sumitomo Dainippon Pharma Co., Ltd, Tokyo, Japan. 4. Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan shoichi@med.kurume-u.ac.jp.
Abstract
OBJECTIVE: Under diabetic conditions, glucose is converted to sorbitol via aldose reductase, whose process could contribute to diabetic vascular complications. However, effects of aldose reductase inhibitors are modest in diabetic patients. This may be attributed to weak inhibitory activity of aldose reductase inhibitors. We compared effects of ranirestat on endothelial cell damage with those of epalrestat. MATERIALS AND METHODS: Intracellular formations of sorbitol and superoxide were measured by liquid chromatography-mass spectrometry-mass spectrometry and dihydroethidium staining, respectively. Vascular cell adhesion molecule-1 gene expression was analysed by reverse transcription polymerase chain reaction. THP-1 cell adhesion to human umbilical vein endothelial cells was evaluated using a fluorescent probe. RESULTS: High glucose significantly increased sorbitol levels, superoxide generation and vascular cell adhesion molecule-1 mRNA levels in, and THP-1 cell adhesion to, human umbilical vein endothelial cells, all of which were prevented by 500 nM ranirestat, but not epalrestat except for superoxide production. CONCLUSION: Our present results suggest that ranirestat has a stronger inhibitory activity on aldose reductase than epalrestat and suppresses inflammatory reactions in high glucose-exposed human umbilical vein endothelial cells.
OBJECTIVE: Under diabetic conditions, glucose is converted to sorbitol via aldose reductase, whose process could contribute to diabetic vascular complications. However, effects of aldose reductase inhibitors are modest in diabeticpatients. This may be attributed to weak inhibitory activity of aldose reductase inhibitors. We compared effects of ranirestat on endothelial cell damage with those of epalrestat. MATERIALS AND METHODS: Intracellular formations of sorbitol and superoxide were measured by liquid chromatography-mass spectrometry-mass spectrometry and dihydroethidium staining, respectively. Vascular cell adhesion molecule-1 gene expression was analysed by reverse transcription polymerase chain reaction. THP-1 cell adhesion to human umbilical vein endothelial cells was evaluated using a fluorescent probe. RESULTS: High glucose significantly increased sorbitol levels, superoxide generation and vascular cell adhesion molecule-1 mRNA levels in, and THP-1 cell adhesion to, human umbilical vein endothelial cells, all of which were prevented by 500 nM ranirestat, but not epalrestat except for superoxide production. CONCLUSION: Our present results suggest that ranirestat has a stronger inhibitory activity on aldose reductase than epalrestat and suppresses inflammatory reactions in high glucose-exposed human umbilical vein endothelial cells.