Chymase inhibitor suppressed intimal hyperplasia after balloon injury

In clinical studies and dog models, angiotensin 11 receptor blocker was successful in preventing restenosis after percutaneous transluminal coronary angioplasty in a clinical study, but angiotensin-converting enzyme (ACE) inhibitor was not. These reports strongly suggest that chymase-dependent Ang II formation may play an important role in vascular proliferation. In this study, we investigated whether an orally active chymase inhibitor, 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, the renin and ACE activities and blood pressure were same levels between the placebo- and NK3201-treated groups. However, in the placebo-treated group, the chymase activity was significantly increased in the injured arteries. In the NK3201-treated group, the chymase activity in the injured arteries was reduced significantly, and the percent inhibition of chymase activity by treatment with NK3201 was 66.4%. On the other hand, the ACE activity tended to be increased in the injured arteries, while it was not affected by treatment with NK3201. The intimal area in the placebo-treated group was significantly reduced compared with that in the NK3201-treated group. Here we demonstrated for the first time that a chymase inhibitor prevented the development of intimal hyperplasia in the balloon-injured arteries.