title: Gender-specific immunological effects of the phosphodiesterase 5 inhibitor sildenafil in healthy mice.
abstract: Phosphodiesterase 5 (PDE5) is a pharmacological target in erectile dysfunction, pulmonary hypertension and in other indications. In tumor-bearing mice an inhibition of PDE5 with sildenafil prolongs survival of the animals through the augmentation of antitumor immunity, indicating the immunomodulatory properties of this drug. Effects of sildenafil on the immune system in healthy organisms are poorly investigated. In this work we showed that chronic application of sildenafil in healthy mice leads to opposite gender-dependent effects on NK cells, subpopulations of CD4(+) and CD8(+) T cells, activated conventional T cells, and to a decrease in Gr-1(+)CD11b(+) immature myeloid cells. Besides, sildenafil treatment decreases the serum concentration of interleukin-6. Ex vivo cultivation of isolated splenocytes with sildenafil results in an increase in CD4(+) T cells and a concomitant decrease in B cells and central memory CD8(+) T cells. Ex vivo modulatory properties of sildenafil are not gender-specific, indicating the importance of sildenafil's pharmacokinetics for it immunomodulatory activity in vivo. While the PDE5 expression is equal in the splenocytes from both genders, splenocytes from female mice possess higher basal level of cGMP compared to the male ones. Moreover, cultivation of splenocytes obtained from female but not male mice with sildenafil leads to an increase in cGMP concentration, making sildenafil's pharmacodynamics also responsible for gender-specific effects of the drug. Thus, this work secures conclusive evidence that the PDE5 inhibitor sildenafil possesses immunomodulatory properties and these effects are gender-specific. Immunological clinical trials are needed to prove the potential immunomodulatory effects of sildenafil in humans.
authors.affiliation: Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Karakhanova
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Yang
authors.forename: Julia
authors.initials: J
authors.lastname: Link
authors.forename: Sabine
authors.initials: S
authors.lastname: Soltek
authors.forename: Katharina
authors.initials: K
authors.lastname: von Ahn
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
authors.forename: Jens
authors.initials: J
authors.lastname: Werner
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Bazhin
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D015850:Interleukin-6 / Q000097:blood; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects* / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D000068677:Sildenafil Citrate; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D015850:Interleukin-6; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D019707:Receptors, Chemokine; D013450:Sulfones; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP
keywords: FACS; GC; Gender-specific effects; IL; Immune cells; Immunomodulation; NK cells; NO; PDE5; Phosphodiesterase 5; Sildenafil; T cell receptor; TCR; cGMP; cyclic guanosine monophosphate; fluorescence activated cell sorting; guanylyl cyclases; interleukin; mAbs; monoclonal antibodies; nature killer cells; nitric oxide; phosphodiesterase 5