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 permeability and the development of hyperresponsiveness to methacholine (MCh) was studied in rats 24 h following ovalbumin (OVA) challenge. The NO synthase (NOS) inhibitors N(G)-mono-methyl-L-arginine (L-NMMA; nonselective), aminoguanidine (two-fold inducible NOS-selective), N(omega)-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 x 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 x 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.
Tulić
M K
MK
TVW Telethon Institute for Child Health Research and Dept of Paediatrics, University of Western Australia, Perth, Australia.
Wale
J L
JL
Holt
P G
PG
Sly
P D
PD
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D016085:Bronchoconstrictor Agents; D002956:Citrulline / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006967:Hypersensitivity / Q000276:immunology*; D008297:Male; D016210:Methacholine Chloride; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D016085:Bronchoconstrictor Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D016210:Methacholine Chloride; D019323:omega-N-Methylarginine; D002956:Citrulline; D019001:Nitric Oxide Synthase; D013890:Thiourea; C086717:S-methylthiocitrulline; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester