AMRINONE AND THEOPHYLLINE DIFFERENTIALLY REGULATE CYTOKINE AND NITRIC-OXIDE PRODUCTION IN ENDOTOXEMIC MICE

Intracellular cyclic nucleotide levels play an important role in the r egulation of several immunological processes. Since elevation of intra cellular cyclic adenosine monophosphate and/or cyclic guanosine monoph osphate concentration by inhibition of phosphodiesterase (PDE) is know n to modulate the inflammatory response, we compared the effect of amr inone, an inhibitor of the PDE III isoenzyme, and of theophylline, a n onspecific PDE inhibitor, on the plasma tumor necrosis factor-alpha (T NF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), and nitric ox ide response in mice to intraperitoneal injection of bacterial lipopol ysaccharide (LPS). Intraperitoneal treatment of animals with amrinone (100 mg/kg) 30 min before LPS administration decreased both plasma IL- 6 and IL-10 concentrations in the first phase of the response, but enh anced plasma levels of these cytokines in the second part. In contrast , pretreatment of the animals with theophylline (100 mg/kg) enhanced L PS-induced plasma IL-6 and IL-10 levels during the whole response. How ever, pretreatment with both PDE inhibitors resulted in a marked inhib ition of LPS-evoked plasma concentrations of TNF-alpha and nitrite/nit rate (breakdown products of nitric oxide) throughout the response. Thi s study demonstrates for the first time that amrinone and theophylline possess differential, but primarily anti-inflammatory, properties dur ing LPS-induced systemic inflammation in the mouse.