BENEFICIAL-EFFECTS OF THE PHOSPHODIESTERASE INHIBITORS BRL-61063, PENTOXIFYLLINE, AND ROLIPRAM IN A MURINE MODEL OF ENDOTOXIN-SHOCK

Three inhibitors of calcium-dependent cyclic adenosine 3'5'-monophosph ate (cAMP) dependent phosphodiesterase IV (PDE IV) were evaluated for their effects on lipopolysaccharide (LPS)-induced tumor necrosis facto r (TNF) production in vitro and in vivo and for their ability to prote ct mice from LPS-induced lethality in D-galactosamine (D-gal) sensitiz ed mice. In vitro, on LPS-stimulated murine peritoneal macrophages (PE M), BRL 61063 (1,3-di(cyclopropylmethyl)-8-aminoxanthine) and rolipram -(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) had similar TNF in hibitory activity with an IC50 ranging from 0.1 to 0.5 mu M. Pentoxify lline (PTX), (3,7-dimethyl-1-(5-oxohexyl)xanthine) was less potent wit h an IC50 = 100 mu M. in vivo, there was a rank order potency on serum TNF levels in LPS challenged D-gal sensitized mice. BRL 61063 inhibit ed TNF production with an ID50 of 0.1 mg/kg, rolipram at 1 mg/kg, and PTX at 200 mg/kg. Thus, BRL 61063 is 2,000 times more potent than PTX in reducing TNF serum levels in this model. Interestingly, TNF is impl icated as having a central pathogenic role in the LPS/D-gal model, sin ce survival of animals correlated directly with reduction of serum TNF levels for all three compounds tested. It is proposed that potent inh ibitors of TNF may have therapeutic activity in disease states where T NF appears to play a role in the pathogenesis of the disease. (C) 1995 Wiley-Liss, inc.