A novel chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[[,4-dioxo-1-phenyl-7-(2-pyridyloxy)]2-heptyl]acetamide (NK3201), suppressed intimal hyperplasia after balloon injury.
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.
Takai
Shinji
S
Department of Pharmacology, Osaka Medical College, Takatsuki City, Osaka, Japan. pha010@art.osaka-med.ac.jp
Sakonjo
Hiroshi
H
Fukuda
Kohzo
K
Jin
Denan
D
Sakaguchi
Masato
M
Kamoshita
Keiichi
K
Ishida
Koichi
K
Sukenaga
Yoshikazu
Y
Miyazaki
Mizuo
M
D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D002404:Catheterization / Q000009:adverse effects*; D053818:Chymases; D004285:Dogs; D006965:Hyperplasia; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017539:Tunica Intima / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000473:pathology*
D000081:Acetamides; C437945:NK3201; D011743:Pyrimidines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D053818:Chymases