AMRINONE SUPPRESSES THE SYNTHESIS OF TUMOR-NECROSIS-FACTOR-ALPHA IN HUMAN MONONUCLEAR-CELLS

Tumor necrosis factor-alpha (TNF) exerts a wide spectrum of biological activities and contributes to the pathophysiology of septic shock. El evated circulating levels of TNF have also been reported in patients w ith severe chronic heart failure. We studied the effect of amrinone, a class III cyclic nucleotide phosphodiesterase inhibitor used in the t reatment of acute heart failure, on the synthesis of TNF in vitro. Per ipheral blood mononuclear cells from healthy volunteers or cells of a permanent monoblast cell line were stimulated for 20 h with bacterial lipopolysaccharide and different doses of amrinone. TNF production is suppressed in a dose-dependent manner to a minimum of 9% of controls w ith 1000 muM of amrinone, reaching half-maximal inhibition at 80 muM a mrinone. This effect appears to be mediated via cAMP, which accumulate d nearly twofold in the presence of amrinone. Suppression of TNF synth esis by therapeutically administered phosphodiesterase inhibitors such as amrinone may contribute to their beneficial effect in the treatmen t of heart failure.