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CARDIOVASCULAR

A Novel Chymase Inhibitor, 2-(5-Formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl]acetamide (NK3201), Suppressed Intimal Hyperplasia after Balloon Injury

Department of Pharmacology, Osaka Medical College, Takatsuki City, Osaka, Japan (S.T., H.S., K.F., D.J., M.S., M.M.); Environmental Biological Life Science Research Center (BILIS), Minakuchi-cho, Koka-gun, Shiga, Japan (H.S., K.F.); Research and Development Division, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan (K.K., Y.S.)

In this study, we investigated whether an orally active chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl]acetamide (NK3201), prevents intimal hyperplasia in carotid arteries injured by a balloon catheter in dog. Each dog was administered NK3201 (1 mg/kg per day, p.o.) or placebo beginning 5 days before balloon injury and continuing through the experiments. Four weeks after balloon injury, NK3201 did not affect the plasma renin and angiotensin-converting enzyme activities. The chymase activity was significantly increased in the injured arteries, whereas the angiotensin-converting enzyme activity was not. NK3201 significantly reduced the chymase activity in the injured arteries. The intimal area in the placebo- and NK3201-treated group and was 0.46 ± 0.06 and 0.24 ± 0.04 mm², respectively, and this difference was significant. In this study, we demonstrated for the first time that a chymase inhibitor prevented the development of intimal hyperplasia in the balloon-injured arteries.

Address correspondence to: Dr. Shinji Takai, Department of Pharmacology, Osaka Medical College, Takatsuki City, Osaka 569-8686, Japan. E-mail: pha010{at}art.osaka-med.ac.jp

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