EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN MICE - PHARMACOLOGICAL EVALUATION OF ADENOSINE RECEPTOR AGONISTS

Inhibition of inducible nitric oxide (NO) synthase during endotoxaemia may be of therapeutic value. We have previously shown that pretreatme nt of mice with adenosine receptor agonists 1 h before lipopolysacchar ide administration results in a dose-dependent reduction of plasma nit rite and nitrate (NOx-) levels. This report examines the effects of ad enosine receptor agonists, 5'-N-ethylcarboxamidoadenosine (NECA), N-6- cyclohexyladenosine (CHA), R-phenylisopropyl-adenosine(R-PIA) and 5'-( N-cyclopropyl)carboxamidoadenosine (CPCA), on the level of inducible N O synthase expression in a model of liver inflammation induced by lipo polysaccharide. Following lipopolysaccharide administration (10 mg/kg, i.p.), liver mRNA expression peaked at 3 h and declined to 35% of max imal level after 24 h. Pretreatment with adenosine receptor agonists ( 0.001 mg/kg to 5 mg/kg, i.p.) depressed inducible NO synthase mRNA exp ression significantly. Down-regulation of inducible NO synthase mRNA e xpression corresponded with changes in plasma NOx- level as well as ac tivity of NO synthase in the liver. Administration of R-PIA (5 mg/kg, i.p.) increased the survival of animals injected with a lethal dose of lipopolysaccharide. Thus adenosine receptor agonists may useful as an ti-inflammatory agents in the treatment of endotoxaemia.