Interaction of Pentoxifylline and Adenosine in the Inhibition of Superoxide Anion Production of Human Polymorphonuclear Leukocytes

Abstract

The nucleoside adenosine (ADO) has been shown to inhibit several leukocyte functions, such as the production of superoxide anions, degranulation, adherence, and cell-mediated cytotoxicity, and can enhance the chemotactic response of polymorphonuclear leukocytes (PMNL). These pharmacodynamic effects are also shared by pentoxifylline (PTX). ADO acts via specific receptors on the outer surface of the PMNL leading to the activation of the adenylate cyclase system. In contrast, the action of PTX has not yet been fully understood. In general, two modes of action might be considered in the inhibition of leukocyte functions. While the alkylxanthine PTX could act as an inhibitor of phosphodiesterases, it is also likely that PTX interferes with the specific ADO receptors thereby increasing intracellular cyclic adenosine monophosphate (cAMP). This latter possibility was supported by the findings that the specific ADO receptor antagonist BW A1433U was able to block PTX in restoring the chemotactic response of human PMNL after inhibition by tumor necrosis factor a (TNF-a) [12]. In order to elucidate these mechanisms, the influence of the combined action of PTX and ADO on the superoxide anion production was investigated in formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated PMNL. The pharmacological analysis [8] of the dose-response curves of ADO and PTX provide insight into the type of action of both substances. In addition, the effect of the ADO receptor antagonist 8-phenyltheophylline (8-PT) was compared with the ADO- and PTX-mediated inhibition.