Effects of phosphodiesterase inhibitors on the inflammatory response of endothelial cells stimulated by myeloperoxidase-modified low-density lipoprotein or tumor necrosis factor alpha.
BACKGROUND
Sildenafil, 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-alpha) by endothelial cells (ECs) and monocytes respectively.


OBJECTIVE
To determine whether or not the three therapeutically PDE5-Is protect against the proinflammatory effects of Mox-LDL or TNF-alpha on ECs.


METHODS
ECs (EA.hy926) were incubated in the presence of either TNF-alpha (100 pg/ml) or Mox-LDL (200 microg/ml) with each of the three PDE5-Is (1 microM, 5 microM, and 10 microM) respectively. IL-8 production was measured in the supernatant after 48 h of incubation.


METHODS
All experiments were repeated at least three times. Statistical analysis was performed with an ANOVA.


CONCLUSIONS
Two-way ANOVA analysis showed that TNF-alpha 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-alpha showed a decrease of IL-8 (p<0.05) compared with sildenafil and vardenafil.


CONCLUSIONS
Among 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.
Roumeguère
Thierry
T
Laboratory of Experimental Medicine, Unit 222, CHU Charleroi, Free University of Brussels, Montigny-le-Tilleul, Belgium. thierry.roumeguere@ulb.ac.be
Zouaoui Boudjeltia
Karim
K
Babar
Sajida
S
Nuyens
Vincent
V
Rousseau
Alexandre
A
Van Antwerpen
Pierre
P
Ducobu
Jean
J
Wespes
Eric
E
Vanhaeverbeek
Michel
M
D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009195:Peroxidase / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D008077:Lipoproteins, LDL; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase