Inhibitory effects of cyclic AMP elevating agents on lipopolysaccharide (LPS)-induced microvascular permeability change in mouse skin

1 Anti-inflammatory effects of cyclic AMP elevating agents were examined in a mouse model of lipopolysaccharide (LPS)-induced microvascular permeability change. 2 Vascular permeability on the back skin was measured by the local accumulation of Pontamine sky blue (PSB) after subcutaneous injection of LPS (400 mug site(-1)) from Salmonella typhimurium. 3 Dye leakage in the skin was significantly increased 2 h after injection of LPS. This LPS-induced dye leakage was suppressed by phosphodiesterase inhibitors, including pentoxifylline (160 mg kg(-1)), milrinone (5-10 mg kg(-1)), rolipram (0.5-10 mg kg(-1)) and zaprinast (5-10 mg kg(-1)). The dye leakage was also inhibited by P-adrenoceptor agonists, including isoproterenol (0.5-5 mg kg(-1))and salbutamol (0.05-5 mg kg(-1)), an adenylate cyclase activator, forskolin (5 mg kg(-1)), and a cell permeable cyclic AMP analogue, 8-bromo-cyclic AMP (8-Br-cAMP, 10 mg kg(-1)). 4 LPS caused a transient increase in serum TNF-alpha level peaking at 1 h after the injection. This increase in serum TNF-alpha was completely blocked by a pretreatment with pentoxifylline (160 mg kg(-1)), milrinone (5 mg kg(-1)), rolipram (1 mg kg(-1)), zaprinast (10 mg kg(-1)), salbutamol (0.5 mg kg(-1)), forskolin (1 mg kg(-1)) and 8-Br-cAMP (10 mg kg(-1)). 5 LPS caused an increase in serum IL-1 alpha level peaking at 3 h after injection. This increase in serum IL-1 alpha was not significantly suppressed by the cyclic AMP elevating agents. 6 Our study suggests that cyclic AMP elevating agents attenuate LPS-induced microvascular permeability change by suppressing TNF-alpha up regulation.