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 i n-vitro experiments, but the role of chymase in vivo has been unclear. In t his 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 d og, the concentration of NK3201 in blood was about 10 muM at 24 h after ora l administration of the drug (5 mg/kg). In the group treated with NK3201, e ach dog was administered orally 5 mg/kg per day from 5 days before to the d ay 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 obser ved in the grafted veins and the chymase activity was also increased signif icantly. Treatment with chymase inhibitor significantly suppressed the prol iferation of the grafted veins and the increased chymase activity. In this study, we demonstrate for the first time that oral administration of a spec ific chymase inhibitor, NK3201, appears useful for preventing vascular prol iferation. (C) 2001 Elsevier Science Inc. All rights reserved.