Pentoxifylline alleviates vascular impairment in insulin resistance via TNF-alpha inhibition

Deterioration of vascular reactivity plays a pivotal role in vascular complications. Pentoxifylline (PTX) is a well-tolerated drug used to treat vascular insufficiency. We investigated the protective effect of PTX against vascular impairment in insulin resistance. Insulin resistance was induced by fructose (10\%) in drinking water while PTX was concurrently administered (50 mg/kg(-1)) for 8 weeks. Serum levels of glucose, insulin, tumor necrosis factor alpha (TNF-alpha) were determined. Isolated aorta reactivity to phenylephrine (PE), potassium chloride (KCl), and acetylcholine (ACh) was studied, as was nitric oxide (NO) generation and histopathology. Insulin resistance was accompanied with a significant elevation in serum TNF-alpha level, marked leukocytes infiltration, and endothelial pyknosis. PTX inhibited insulin resistance and prevented TNF-alpha elevation, leukocyte infiltration and endothelial pyknosis. Vascular dysfunction was evident in insulin resistance as increased vascular contractility to PE and decreased relaxation to ACh, whereas PTX protected against this dysfunction. Notably, in vitro incubation with TNF-alpha (1 ng/ml(-1)) increased contractility to PE and decreased relaxation to ACh while concomitant PTX (1 mM) incubation partially restored response to ACh but not to PE. Furthermore, TNF-alpha reduced ACh-induced NO generation, whereeas PTX restored it. In conclusion, PTX protects from the impairment in vascular reactivity in insulin resistance, by a mechanism involving TNF-alpha inhibition.