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

Br J Pharmacol. 2001 May;133(2):237-42. doi: 10.1038/sj.bjp.0704073.


Anti-inflammatory effects of cyclic AMP elevating agents were examined in a mouse model of lipopolysaccharide (LPS)-induced microvascular permeability change. Vascular permeability on the back skin was measured by the local accumulation of Pontamine sky blue (PSB) after subcutaneous injection of LPS (400 microg site-1) from Salmonella typhimurium. 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 beta-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). 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). LPS caused an increase in serum IL-1alpha level peaking at 3 h after injection. This increase in serum IL-1alpha was not significantly suppressed by the cyclic AMP elevating agents. Our study suggests that cyclic AMP elevating agents attenuate LPS-induced microvascular permeability change by suppressing TNF-alpha up regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Adenylyl Cyclases / metabolism
  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Capillary Permeability / drug effects*
  • Colforsin / pharmacology
  • Cyclic AMP / agonists*
  • Cyclic AMP / analogs & derivatives
  • Enzyme Activators / pharmacology
  • Interleukin-1 / metabolism
  • Lipopolysaccharides / pharmacology*
  • Male
  • Mice
  • Phosphodiesterase Inhibitors / pharmacology
  • Salmonella typhimurium
  • Skin / drug effects
  • Skin / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism


  • Adrenergic beta-Agonists
  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Activators
  • Interleukin-1
  • Lipopolysaccharides
  • Phosphodiesterase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Colforsin
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Cyclic AMP
  • Adenylyl Cyclases