Fr146801, A Novel Nitric Oxide Donating Agent, Prevents Neointimal Formation After Balloon Injury In Rats

FR 146801 (+/-)-N-[(E)-4-ethyl-3-[(Z)-hydroxyimino]-6-methyl-5-nitro-3-heptenyl]-3-pyridinecarboxamide is a novel nitric oxide (NO) donating agent. In the present study, we examined the effect of FR146801, a slow NO releaser, on intimal thickening of rat carotid arteries following balloon injury, in comparison with FK409, a rapid NO releaser. In this model, vehicle or each drug was administered orally, twice daily from 2 days before to 13 days after injury and the intimal thickening was assessed at 14 days after injury. FR146801 suppressed neointimal formation after balloon injury dose-dependently and significantly. FR146801 (32 mg/kg) decreased neointima/media ratio by 36.4% (P<0.05) vs. vehicle-treated group. FR146801 (1-100 muM) inhibited the growth of cultured rat vascular smooth muscle cells concentration-dependently. in measurements of mean blood pressure with conscious rats, FR146801 showed no hypotensive effect at 32 mg/kg p.o., the dose required for significant suppression of intimal thickening. In contrast, FK409 showed hypotensive effect at 10 mg/kg p.o. at which it suppressed neointimal formation with almost the same efficacy as FIR 146801. These data demonstrate that FR146801 could be a useful inhibitor of intimal hyperplasia after vascular injury and, moreover, that its inhibitory effect could be separated from its hypotensive effect. (C) 2004 Wiley-Liss, Inc.