INHIBITION OF FIBROPROLIFERATION BY PENTOXIFYLLINE - ACTIVITY OF METABOLITE-1 AND LACK OF ROLE OF ADENOSINE RECEPTORS

We have reported previously that pentoxifylline and adenosine decrease platelet-derived growth factor- (PDGF) stimulated fibroproliferation. To determine the role of adenosine receptors in the inhibition of fib roproliferation observed with pentoxifylline, we used a non-selective adenosine receptor antagonist, 8-phenyltheophylline, and specific A(1) and A(2) adenosine receptor antagonists. Ii the A(2) receptor, which is present on fibroblasts, mediates the inhibition of fibroproliferati on which occurs with pentoxifylline, then pretreatment of fibroblasts with receptor antagonists Drier to the addition of pentoxifylline shou ld prevent the action of pentoxifylline. The results indicated that pr etreatment of fibroblasts with 8-phenyltheophylline (100 mu M) did not alter the inhibitory effect of pentoxifylline on PDGF-stimulated fibr oproliferation. These results argue against a mechanism involving inhi bition of adenosine reuptake as the mechanism for pentoxifylline's eff ect in this system. 8-Phenyltheophylline also did not alter the effect of pentoxifylline on baseline proliferation, suggesting that these ef fects of pentoxifylline are not mediated by adenosine receptors. Pento xifylline is metabolized to several metabolites including 1-(5-hydroxy hexyl)-3,7-dimethylxanthine (metabolite-1). Metabolite-1 significantly reduced PDGF-stimulated fibroproliferation and was as effective as pe ntoxifylline. The combination of pentoxifylline and metabolite-1 had a n additive effect. Metabolite-1 and pentoxifylline also reduced baseli ne proliferation. Preincubation of fibroblasts with 8-phenyltheophylli ne did not prevent the inhibitory action of metabolite-1 on PDGF-stimu lated proliferation or on basal proliferation of fibroblasts, suggesti ng that the action of metabolite-1 on fibroproliferation was not media ted by adenosine receptors. Results using A(1) and A(2) adenosine rece ptor antagonists further suggest that the effect of pentoxifylline was not mediated by adenosine receptors.