Sildenafil does not affect the proliferation of human lymphocytes in the in vitro transplant model

  • Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland
  • Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland

Abstract

Sildenafil is used in the treatment of erectile dysfunction and pulmonary arterial hypertension. Numerous  studies revealed beneficial effects of its use in renal, liver, heart and bone marrow transplant recipients. Some reports suggested that the drug modulates the function of the immune system, however, its influence on antigen-induced proliferation of lymphocytes remains unknown. Thus, the aim of the study was to investigate the effects of sildenafil on human peripheral blood mononuclear cells (PBMCs) proliferation in a mixed lymphocyte reaction. It was demonstrated that the drug did not affect auto- and alloantigen-induced proliferation of PBMCs and showed no cytotoxic effect.

References

Boffini M, Sansone F, Ceresa F, Ribezzo M, Patanè F, Comoglio C, Rinaldi M (2009) Role of oral sildenafil in thetreatment of right ventricular dysfunction after heart transplantation. Transplant Proc 41: 1353-1356. doi: 10.1016/j.transproceed.2009.03.042.

Boguska A, Kaleta B, Kniotek M, Górski A (2018) Sildenafil, a selective phosphodiesterase type 5 inhibitor, downregulates natural killer cells activity in healthy men in vitro. Acta Pol Pharm 1: 211-216.

Boswell-Smith V, Spina D, Page CP (2006) Phosphodiesterase inhibitors. Br J Pharmacol 147: S252- S257.

De Santo LS, Mastroianni C, Romano G, Amarelli C, Marra C, Maiello C, Galdieri N, Della Corte A, Cotrufo M, Caianiello G (2008). Role of sildenafil in acute posttransplant right ventricular dysfunction: successful experience in 13 consecutive patients. Transplant Proc 40: 2015-2018. doi: 10.1016/j.transproceed.2008.05.055.

Doganci S, Yildirim V, Yesildal F, Erol G, Kadan M, Ozkan G, Avcu F, Ozgurtas T (2015) Comparison of angiogenic and proliferative effects of three commonly used agents for pulmonary artery hypertension (sildenafil, iloprost, bosentan): is angiogenesis always beneficial? Eur Rev Med Pharmacol Sci 19: 1900-1906.

Erdogan A, Luedders DW, Muenz BM, Schaefer CA, Tillmanns H, Wiecha J, Kuhlmann CR (2007) Sildenafil inhibits the proliferation of cultured human endothelial cells. Int J Biomed Sci 3: 93-96.

Essayan DM (2001) Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol 108: 671-680.

He X, Liu Y, Li K, Yang A, Wang R, Liu S (2017) Sildenafil suppresses the proliferation and enhances the apoptosis of hemangioma endothelial cells. Exp Ther Med. 13: 2645-2650. doi: 10.3892/etm.2017.4306.

Ho JK, Ko HH, Schaeffer DF, Erb SR, Wong C, Buczkowski AK, Scudamore CH, Yoshida EM (2006) Sexual health after orthotopic liver transplantation. Liver Transpl 12: 1478-1484.

Kaleta B, Boguska A, Borysowski J, Górski A (in press) Sildenafil upregulates tumor necrosis factor α production in peripheral blood mononuclear cells of healthy men – preliminary report. Acta Pol Pharm (in press).

Kaleta B, Boguska A (2017) Sildenafil, a phosphodiesterase type 5 inhibitor, downregulates osteopontin in human peripheral blood mononuclear cells. Arch Immunol Ther Exp (Warsz) 65: 347-353. doi: 10.1007/s00005-017-0455-9.

Kobayashi Y (2010) The regulatory role of nitric oxide in proinflammatory cytokine expression during the induction and resolution of inflammation. J Leukoc Biol 88: 1157-1162. doi: 10.1189/jlb.0310149.

Kukreja RC, Salloum F, Das A, Ockaili R, Yin C, Bremer YA, Fisher PW, Wittkamp M, Hawkins J, Chou E, Kukreja AK, Wang X, Marwaha VR, Xi L (2005) Pharmacological preconditioning with sildenafil: basic mechanisms and clinical implications. Vascul Pharmacol 42: 219-232.

Lasaponara F, Sedigh O, Pasquale G, Bosio A, Rolle L, Ceruti C, Timpano M, Negro CL, Paradiso M, Abbona A, Segoloni GP, Fontana D (2013) Phosphodiesterase type 5 inhibitor treatment for erectile dysfunction in patients with end-stage renal disease receiving dialysis or after renal transplantation. J Sex Med 10: 2798-2814. doi: 10.1111/jsm.12038.

Li B, Yang L, Shen J, Wang C, Jiang Z (2007) The antiproliferative effect of sildenafil on pulmonary artery smooth muscle cells is mediated via upregulation of mitogen-activated protein kinase phosphatase-1 and degradation of extracellular signal-regulated kinase 1/2 phosphorylation. Anesth Analg 105: 1034-1041.

Liu XM, Peyton KJ, Wang X, Durante W (2012) Sildenafil stimulates the expression of gaseous monoxide-generating enzymes in vascular smooth muscle cells via distinct signaling pathways. Biochem Pharmacol 84: 1045-1054. doi: 10.1016/j.bcp.2012.07.023.

Lledo-Garcia E, Rodriguez-Martinez D, Cabello-Benavente R, Moncada-Iribarren I, Tejedor-Jorge A, Dulin E, Hernandez-Fernandez C, Del Canizo-Lopez JF (2007) Sildenafil improves immediate posttransplant parameters in warm-ischemic kidney transplants: experimental study. Transplant Proc 39: 1354-1356.

Nichols DJ, Muirhead GJ, Harness JA (2002) Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol 53 (Suppl. 1): 5S-12S.

Pifarré P, Gutierrez-Mecinas M, Prado J, Usero L, Roura-Mir C, Giralt M, Hidalgo J, García A (2014) Phosphodiesterase 5 inhibition at disease onset prevents experimental autoimmune encephalomyelitis progression through immunoregulatory and neuroprotective actions. Exp Neurol 251: 58-71. doi: 10.1016/j.expneurol.2013.10.021.

Pifarre P, Prado J, Baltrons MA, Giralt M, Gabarro P, Feinstein DL, Hidalgo J, Garcia A (2011) Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis. Acta Neuropathol 121: 499-508. doi: 10.1007/s00401-010-0795-6.

Potter MR, Moore M (1977) Human mixed lymphocyte culture using separated lymphocyte populations. Immunology 32: 359-365.

Russo D, Musone D, Alteri V, Cindolo L, Lanzillo B, Federico S, Andreucci VE (2004) Erectile dysfunction in kidney transplanted patients: efficacy of sildenafil. J Nephrol 17: 291-295.

Santos AI, Carreira BP, Nobre RJ, Carvalho CM, Araújo IM (2014) Stimulation of neural stem cell proliferation by inhibition of phosphodiesterase 5. Stem Cells Int 2014: 878397. doi: 10.1155/2014/878397.

Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, Dolcetti L, Bronte V, Borrello I (2006) Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 203: 2691-2702.

Sharma RK, Prasad N, Gupta A, Kapoor R (2006) Treatment of erectile dysfunction with sildenafil citrate in renal allograft recipients: a randomized, double-blind, placebo-controlled, crossover trial. Am J Kidney Dis 48: 128-133.

Sherman LA, Chattopadhyay S (1993) The molecular basis of allorecognition. Annu Rev Immunol 11: 385-402.

Singh RK, Richmond ME, Zuckerman WA, Lee TM, Giblin TB, Rodriguez R, Chen JM, Addonizio LJ (2014) The use of oral sildenafil for management of right ventricular dysfunction after pediatric heart transplantation. Am J Transplant 14: 453-458. doi: 10.1111/ajt.12552.

Sun L, Quan H, Xie C, Wang L, Hu Y, Lou L (2014) Phosphodiesterase 3/4 inhibitor zardaverine exhibits potent and selective antitumor activity against hepatocellular carcinoma both in vitro and in vivo independently of phosphodiesterase inhibition. PLoS One 9: e90627. doi: 10.1371/journal.pone.0090627.

Szczypka M, Obmińska-Mrukowicz B (2010) Modulating effects of nonselective and selective phosphodiesterase inhibitors on lymphocyte subsets and humoral immune response in mice. Pharmacol Rep 62: 1148-1158.

Wang C, Wang J, Zhao L, Wang Y, Liu J, Shi L, Xu M, Wang C (2008) Sildenafil inhibits human pulmonary artery smooth muscle cell proliferation by decreasing capacitative Ca2+ entry. J Pharmacol Sci 108: 71-78.

Yamamura A, Fujitomi E, Ohara N, Tsukamoto K, Sato M, Yamamura H (2017) Tadalafil induces antiproliferation, apoptosis, and phosphodiesterase type 5 downregulation in idiopathic pulmonary arterial hypertension in vitro. Eur J Pharmacol 5: 44-50. doi: 10.1016/j.ejphar.2017.06.010.

Yoo AR, Koh SH, Cho GW, Kim SH (2010) Inhibitory effects of cilostazol on proliferation of vascular smooth muscle cells (VSMCs) through suppression of the ERK1/2 pathway. J Atheroscler Thromb 17: 1009-1018.

Zhang Y, Guan DL, Ou TW, Wang Y, Chen X, Xing NZ, Zhang XD, Yang Y (2005) Sildenafil citrate treatment for erectile dysfunction after kidney transplantation. Transplant Proc 37: 2100-2103.

Published
2019-02-28
Section
Articles