Pentoxifylline potentiates nitric oxide production in interleukin-1β-stimulated vascular smooth muscle cells through cyclic AMP-dependent protein kinase A pathway

In the present study, we observed that pentoxifylline (PTX) significantly augmented the nitric oxide (NO) production and the iNOS gene expression by interleukin-1β (IL-1β)-stimulated vascular smooth muscle cells (VSMCs). The enhancing effects of PTX on the IL-1β-induced NO production was associated with an increased intracellular cyclic AMP (cAMP) levels, and the synergistic effects of PTX on the IL-1β-induced NO production was blocked by cAMP-dependent protein kinase A (PKA) inhibitors. PKA inhibitors, KT5720 and H89, markedly decreased the augmented expression of iNOS gene whereas ODQ, a soluble guanylate cyclase inhibitor, did not affect the enhancing effect. In addition, the pretreatment with KT5720 or H89 abolished the increased translocation of the p65 subunit of NF-κB into the nucleus by PTX in the IL-1β-stimulated VSMCs. These results suggest that enhancing effects of PTX on the iNOS gene expression in the IL-1β-stimulated VSMCs is mediated predominantly through the activation of NF-κB via cAMP-dependent PKA pathway.