Oral administration of a specific chymase inhibitor, NK3201, inhibits vascular proliferation in grafted vein.
Chymase may play an important role in vascular proliferation, as shown by in-vitro experiments, but the role of chymase in vivo has been unclear. In this study, we investigated the effect of a novel chymase inhibitor, NK3201, on this proliferation in dog grafted veins. NK3201 inhibited human and dog chymases, but not rabbit ACE. NK3201 suppressed the Ang I-induced vascular contraction in isolated dog arteries in the presence of an ACE inhibitor, and the IC50 value of chymostatin and NK3201 in dog artery was 320 nM. In dog, the concentration of NK3201 in blood was about 10 microM at 24 h after oral administration of the drug (5 mg/kg). In the group treated with NK3201, each dog was administered orally 5 mg/kg per day from 5 days before to the day before the removal of the grafted veins. Each dog underwent right common carotid artery bypass grafting with the ipsilaterial external jugular vein. By 28 days after grafting, a significant vascular proliferation was observed in the grafted veins and the chymase activity was also increased significantly. Treatment with chymase inhibitor significantly suppressed the proliferation of the grafted veins and the increased chymase activity. In this study, we demonstrate for the first time that oral administration of a specific chymase inhibitor, NK3201, appears useful for preventing vascular proliferation.
Takai
S
S
Department of Pharmacology, Osaka Medical College, Takatsuki City, Japan. pha010@art.osaka-med.ac.jp
Jin
D
D
Nishimoto
M
M
Yuda
A
A
Sakaguchi
M
M
Kamoshita
K
K
Ishida
K
K
Sukenaga
Y
Y
Sasaki
S
S
Miyazaki
M
M
D000081:Acetamides / Q000494:pharmacology*; D000284:Administration, Oral; D000803:Angiotensin I / Q000494:pharmacology; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D053818:Chymases; D046508:Culture Techniques; D004285:Dogs; D004336:Drug Antagonism; D006083:Graft Occlusion, Vascular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009119:Muscle Contraction / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013045:Species Specificity; D014680:Veins / Q000473:pathology / Q000637:transplantation*
D000081:Acetamides; C437945:NK3201; D011743:Pyrimidines; D015842:Serine Proteinase Inhibitors; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases