Differential effects of nitric oxide synthase inhibitors in an <I>in vivo</I> allergic rat model

Abstract

The in vivo role of nitric oxide in inflammatory cell migration, vascular permeability and the development of hyperresponsiveness to methacholine (MCh) was studied in rats 24h following ovalbumin (OVA) challenge.The NO synthase (NOS) inhibitorsv -nitro-L-arginine methyl ester (L-NAME; 2000-fold endothelial cell NOS-selective) or S-methyl-L-thiocitrulline (100-fold neuronal NOS-selective) were administered (100 mg . kg -1 s.c.) to OVA-sensitized Piebald-Virol-Glaxo rats on 3 consecutive days during which they were challenged with allergen (1% OVA). Responses to inhaled MCh were measured in anaesthetized animals 24 h after OVA challenge. Cellular inflammation and vascular permeability were assessed using bronchoalveolar lavage (BAL) fluid collected 30 min after administration of Evans blue (50 mg . kg -1 i.v.). OVA challenge in sensitized animals induced hyperresponsiveness to MCh, inflammatory cell influx and increased leakage of Evans blue into the BAL fluid (n=9, p<0.001). Aminoguanidine was effective in inhibiting the allergen-induced cellular influx and microvascular leakage (n=9, p<0.001) without altering responses to MCh. This effect was reserved by L-arginine. L-NAME (n=5, p<0.01) and S-methyl-L-thiocitrulline (n=6, p<0.001) further potentiated the allergen-induced hyperresponsiveness without altering cellular inflammation. L-NMMA attenuated both the OVA-induced cellular influx and Evans blue leakage (n=8, p<0.001) as well as further potentiating the hyperresponsiveness to MCh (p<0.05).From these studies, it is suggested that, in allergic Piebald-Virol-Glaxo rats, nitric oxide production by inducible nitric oxide synthase plays a role in the migration of inflammatory cells and increase in vascular permeability following allergen challenge, whereas nitric oxide produced by the constitutively expressed neuronal nitric oxide synthase limits hyperresponsiveness to methacholine. Eur Respir J 2000; 15: 870±877.

Selective Release System for Antioxidative and Anti-Inflammatory Activities Using H2O2-Responsive Therapeutic Nanoparticles

“…Harmful substances, pathogens, and active oxygen cause the macrophages in the skin to initiate an inflammatory reaction, which can lead to oxidative damage. In particular, NO induces the inflammatory responses of macrophages to free radicals produced by the reaction of nitric oxide synthase (NOS) with l -arginine . It is also known to increase with the expression level of iNOS and reacts with reactive oxygen radicals to generate peroxynitrite, a powerful oxidant, which causes disease .…”