Effects of Phosphodiesterase Inhibitors on the Inflammatory Response of Endothelial Cells Stimulated by Myeloperoxidase-Modified Low-Density Lipoprotein or Tumor Necrosis Factor Alpha

BackgroundSildenafil, vardenafil, and tadalafil are phosphodiesterase type 5 inhibitors (PDE5-Is) usually used in the treatment of erectile dysfunction (ED). Previously, we have shown the presence of myeloperoxidase-modified low-density lipoprotein (Mox-LDL) in the penises of patients with ED, and we have shown the impact of Mox-LDL on cyclic monophosphate (cGMP) level. In vitro, Mox-LDL triggered the inflammatory response by increasing the release of both interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-α) by endothelial cells (ECs) and monocytes respectively.ObjectiveTo determine whether or not the three therapeutically PDE5-Is protect against the proinflammatory effects of Mox-LDL or TNF-α on ECs.Design, setting, and participantsECs (EA.hy926) were incubated in the presence of either TNF-α (100 pg/ml) or Mox-LDL (200 μg/ml) with each of the three PDE5-Is (1 μM, 5 μM, and 10 μM) respectively. IL-8 production was measured in the supernatant after 48 h of incubation.MeasurementsAll experiments were repeated at least three times. Statistical analysis was performed with an ANOVA.Results and limitationsTwo-way ANOVA analysis showed that TNF-α alone (p < 0.001) or Mox-LDL alone (p < 0.001) increased IL-8 production. Sildenafil, vardenafil, or tadalafil alone did not generate an increase of IL-8 production. Tadalafil in combination with Mox-LDL and TNF-α showed a decrease of IL-8 (p < 0.05) compared with sildenafil and vardenafil.ConclusionsAmong the three available PDE5-Is, tadalafil showed an additional potentially anti-inflammatory effect on relaxation. Those data could be considered for the chronic use of PDE5-Is, but extrapolations of experimental evidence to the clinical setting should be made cautiously.