Differential effects of nitric oxide synthase inhibitors in an in vivo allergic rat model

The in vivo role of nitric oxide in inflammatory cell migration, vascular p ermeability and the development of hyperresponsiveness to methacholine (MCh ) was studied in rats 24h following ovalbumin (OVA) challenge, The NO synthase (NOS) inhibitors N-G-mono-methyl-L-arginine (L-NMMA; nonsel ective), aminoguanidine (two-fold inducible NOS-selective), N-omega-nitro-L -arginine methyl ester (L-NAME; 2000-fold endothelial cell NOS-selective) o r S-methyt-L-thiocitrulline (100-fold neuronal NOS-selective) were administ ered (100 mg.kg(-1) sc.) to OVA-sensitized Piebald-Virol-Glaxo rats on 3 co nsecutive days during which they were challenged with allergen (1% OVA). Re sponses to inhaled MCh were measured in anaesthetized animals 24 h after OV A challenge. Cellular inflammation and vascular permeability were assessed using bronchoalveolar lavage (BAL) fluid collected 30 min after administrat ion of Evans blue (50 mg.kg(-1) iv.). OVA challenge in sensitized animals induced hyperresponsiveness to MCh, inf lammatory cell influx and increased leakage of Evans blue into the BAL flui d (n=9, p<0.001). Aminoguanidine was effective in inhibiting the allergen-i nduced cellular influx and microvascular leakage (n=9, p<0.001) without alt ering 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 inflamma tion. L-NMMA attenuated both the OVA-induced cellular influx and Evans blue leakage (n=8, p<0.001) as well as further potentiating the hyperresponsive ness to MCh (p<0.05). From these studies, it is suggested that, in allergic Piebald-Virol-Glaxo r ats, nitric oxide production by inducible nitric oxide synthase plays a rol e in the migration of inflammatory cells and increase in vascular permeabil ity following allergen challenge, whereas nitric oxide produced by the cons titutively expressed neuronal nitric oxide synthase limits hyperresponsiven ess to methacholine.