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 fibroproliferation observed with pentoxifylline, we used a non-selective adenosine receptor antagonist, 8-phenyltheophylline, and specific A1 and A2 adenosine receptor antagonists. If the A2 receptor, which is present on fibroblasts, mediates the inhibition of fibroproliferation which occurs with pentoxifylline, then pretreatment of fibroblasts with receptor antagonists prior to the addition of pentoxifylline should prevent the action of pentoxifylline. The results indicated that pretreatment of fibroblasts with 8-phenyltheophylline (100 microM) did not alter the inhibitory effect of pentoxifylline on PDGF-stimulated fibroproliferation. These results argue against a mechanism involving inhibition of adenosine reuptake as the mechanism for pentoxifylline's effect in this system. 8-Phenyltheophylline also did not alter the effect of pentoxifylline on baseline proliferation, suggesting that these effects of pentoxifylline are not mediated by adenosine receptors. Pentoxifylline is metabolized to several metabolites including 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (metabolite-1). Metabolite-1 significantly reduced PDGF-stimulated fibroproliferation and was as effective as pentoxifylline. The combination of pentoxifylline and metabolite-1 had an additive effect. Metabolite-1 and pentoxifylline also reduced baseline proliferation. Preincubation of fibroblasts with 8-phenyltheophylline did not prevent the inhibitory action of metabolite-1 on PDGF-stimulated proliferation or on basal proliferation of fibroblasts, suggesting that the action of metabolite-1 on fibroproliferation was not mediated by adenosine receptors. Results using A1 and A2 adenosine receptor antagonists further suggest that the effect of pentoxifylline was not mediated by adenosine receptors.
Peterson
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Department of Medicine, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D010431:Pentoxifylline / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects*; D013936:Thymidine / Q000494:pharmacology
D010431:Pentoxifylline; D013936:Thymidine