Acute tadalafil administration increases plasma fatty acids without changes in inflammatory response in healthy men
Purpose: The phosphodiesterase type 5 inhibitor (PDE5I) tadalafil has been shown to reduce visceral adipose tissue in rabbit and to improve lean mass content in non-obese men. In order to clarify this effect in humans, in the present study we determined the impact of an acute oral tadalafil administration on lipolysis by evaluating plasma free fatty acids (FFAs) and glycerol. FFAs are potential modulator of inflammation response that we evaluated through tumor necrosis factor alpha (TNFa), interleukin 6 (IL6), interleukin 8 (IL8) and interleukin 10 (IL10) plasma levels. Moreover, we determined whether the effects of tadalafil would be reflected in variation of plasma levels of cGMP and NO, twoimportant molecules involved in PDE5Is signaling.
Methods: Twelve healthy subjects were supplemented with tadalafil 20 mg or a placebo, in a double-blind, randomized, cross-over design. Blood samples were collected immediately before, and at 2, 6, and 24 hours post ingestion, and assayed for biochemical analysis.
Results: A condition effect was noted for FFAs and glycerol with values higher for tadalafil compared to placebo group at 2 and 6 hours post ingestion. No statistically significant effects were noted for glucose, cGMP, nitrate and nitrite. No inflammatory response was induced by tadalafil.
Conclusion: Tadalafil, in human subjects, increases lipolysis as evidenced by a significant increase in circulating FFAs and glycerol without affecting plasma cGMP and NO levels, noticeable the increase in FFAs did not develop an inflammatory response. Further well-controlled studies are warranted to assess the impact of tadalafil administration on weight/fat loss.
Aldridge J, Measham F (1999) Sildenafil (Viagra) is used as a recreational drug in England. British Medical Journal 318(7184):669.
Armani A, Marzolla V, Rosano GM, Fabbri A, Caprio M (2011) Phosphodiesterase type 5 (PDE5) in the adipocyte: a novel player in fat metabolism? Trends in Endocrinology and Metabolism 22(10):404-11. doi: 10.1016/j.tem.2011.05.004
Aversa A, Fittipaldi S, Francomano D, Bimonte VM, Greco EA, Crescioli C, Di Luigi L, Lenzi A, Migliaccio S (2017) Tadalafil improves lean mass and endothelial function in nonobese men with mild ED/LUTS: in vivo and in vitro characterization. Endocrine 56(3):639-648. doi: 10.1007/s12020-016-1208-y.
Aversa A (2010) Systemic and metabolic effects of PDE5-inhibitor drugs. World Journal of Diabetes, 15(1):3-7.
Beavo JA, Brunton LL (2002) Cyclic nucleotide research -- still expanding after half a century. Nature Reviews Molecular Cell Biology 3(9):710-8.
Bechara A, Casabe´ A, De Bonis W, Helien A, Bertolino MV (2010) Recreational use of phosphodiesterase type 5 inhibitors by healthy young men. Journal of Sexual Medicine 7:3736-42
Ceci R, Duranti G, Sgrò P, Sansone M, Guidetti L, Baldari C, Sabatini S, Di Luigi L (2015) Effects of tadalafil administration on plasma markers of exercise-induced muscle damage, IL6 and antioxidant status capacity. European Journal of Applied Physiology 115(3):531-9.
Corbin JD, Francis SH (2002) Pharmacology of phosphodiesterase-5 inhibitors. International Journal of Clinical Practice 56:453–459.
Crescioli C, Sturli N, Sottili M, Bonini P, Lenzi A, Di Luigi L (2013) Insulin-like effect of the phosphodiesterase type 5 inhibitor tadalafil onto male human skeletal muscle cells. Journal of Endocrinological Investigation 36(11):1020-6. doi: 10.3275/9034
Dai Z, Wu Z, Yang Y, Wang J, Satterfield MC, Meininger CJ, Bazer FW, Wu G (2013) Nitric oxide and energy metabolism in mammals. Biofactors 39(4):383-91. doi: 10.1002/biof.1099.
Di Luigi L, Baldari C, Pigozzi F, Emerenziani GP, Gallotta MC, Iellamo F, Ciminelli E, Sgrò P, Romanelli F, Lenzi A, Guidetti L (2008) The long-acting phosphodiesterase inhibitor tadalafil does not influence athletes' VO2max, aerobic, and anaerobic thresholds in normoxia. International Journal of Sports Medicine 29(2):110-5.
Di Luigi L, Sgrò P, Baldari C, Gallotta MC, Emerenziani GP, Crescioli C, Bianchini S, Romanelli F, Lenzi A, Guidetti L (2012) The phosphodiesterases type 5 inhibitor tadalafil reduces the activation of the hypothalamus-pituitary-adrenal axis in men during cycle ergometric exercise. American Journal of Physiology - Endocrinology and Metabolism 302(8):E972–E978.
Di Luigi L (2008) Supplements and the endocrine system in athletes. Clinics in Sports Medicine 27(1):131-51.
Duranti G, Ceci R, Sgrò P, Sabatini S, Di Luigi L (2017) Influence of the PDE5 inhibitor tadalafil on redox status and antioxidant defense system in C2C12 skeletal muscle cells. Cell stress and chaperones 22(3):389-396. doi: 10.1007/s12192-017-0778-9.
Fiore D, Gianfrilli D, Giannetta E, Galea N, Panio G, di Dato C, Pofi R, Pozza C, Sbardella E, Carbone I, Naro F, Lenzi A, Venneri MA, Isidori AM (2016) PDE5 inhibition ameliorates visceral adiposity targeting the miR-22/SIRT1 pathway: evidence from the CECSID Trial. The Journal of Clinical Endocrinology and Metabolism 101:1525–1534.
Francis SH, Corbin JD (2003) Molecular mechanisms and pharmacokinetics of phosphodiesterase-5 antagonists. Curr Urol Rep 4:457-465
Frappier J, Toupin I, Levy JJ, Aubertin-Leheudre M, Karelis AD (2013) Energy expenditure during sexual activity in young healthy couples. PLoS One 8(10):e79342. doi: 10.1371/journal.pone.0079342
Grant RW, Stephens JM (2015) Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis. American Journal of Physiology - Endocrinology and Metabolism 309(3):E205-13. doi: 10.1152/ajpendo.00053.2015
Guilherme A, Virbasius JV, Puri V, Czech MP (2008) Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nature Reviews Molecular Cell Biology 9(5):367-77. doi: 10.1038/nrm2391
Jobgen WS, Fried SK, Fu WJ, Meininger CJ, Wu G (2006) Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. Journal of Nutritional Biochemistry 17(9):571-88.
Koka S, Aluri HS, Xi L, Lesnefsky EJ, Kukreja RC (2014) Chronic inhibition of phosphodiesterase 5 with tadalafil attenuates mitochondrial dysfunction in type 2 diabetic hearts: potential role of NO/SIRT1/PGC-1α signaling. American Journal of Physiology - Heart and Circulatory Physiology 306(11):H1558-68.
Lafontan M, Moro C, Berlan M, Crampes F, Sengenes C, Galitzky J (2008) Control of lipolysis by natriuretic peptides and cyclic GMP. Trends in Endocrinology and Metabolism 19(4):130-7. doi: 10.1016/j.tem.2007.11.006
Mammi C, Pastore D, Lombardo MF, Ferrelli F, Caprio M, Consoli C, Tesauro M, Gatta L, Fini M, Federici M, Sbraccia P, Donadel G, Bellia A, Rosano GM, Fabbri A, Lauro D (2011) Sildenafil reduces insulin-resistance in human endothelial cells. PLoS One 6(1):e14542. doi: 10.1371/journal.pone.0014542.
Maneschi E, Cellai I, Aversa A, Mello T, Filippi S, Comeglio P, Bani D, Guasti D, Sarchielli E, Salvatore G, Morelli A, Mazzanti B, Corcetto F, Corno C, Francomano D, Galli A, Vannelli GB, Lenzi A, Mannucci E, Maggi M, Vignozzi L (2016) Tadalafil reduces visceral adipose tissue accumulation by promoting preadipocytes differentiation towards a metabolically healthy phenotype: Studies in rabbits. Molecular and Cellular Endocrinology 424:50-70. doi: 10.1016/j.mce.2016.01.015
Metzger IF, Sertorio JT, Tanus-Santos JE (2006) Relationship between systemic nitric oxide metabolites and cyclic GMP in healthy male volunteers. Acta Physiologica 188:123–7.
Moro C, Lafontan M (2013) Natriuretic peptides and cGMP signaling control of energy homeostasis. American Journal of Physiology - Heart and Circulatory Physiology 304(3):H358-68. doi: 10.1152/ajpheart.00704.2012
Sabatini S, Sgrò P, Duranti G, Ceci R, Di Luigi L (2011) Tadalafil alters energy metabolism in C2C12 skeletal muscle cells. Acta Biochimica Polonica 58(2):237-41.
Saponaro C, Gaggini M, Carli F, Gastaldelli A (2015) The Subtle Balance between Lipolysis and Lipogenesis: A Critical Point in Metabolic Homeostasis. Nutrients 7(11):9453-74. doi: 10.3390/nu7115475
Savary S, Trompier D, Andréoletti P, Le Borgne F, Demarquoy J, Lizard G (2012) Fatty acids - induced lipotoxicity and inflammation. Current Drug Metabolism 13(10):1358-70.
Sears B, Perry M (2015) The role of fatty acids in insulin resistance. Lipids in Health and Disease 14:121. doi: 10.1186/s12944-015-0123-1.
Venneri MA, Giannetta E, Panio G, De Gaetano R, Gianfrilli D, Pofi R, Masciarelli S, Fazi F, Pellegrini M, Lenzi A, Naro F, Isidori AM (2015) Chronic Inhibition of PDE5 Limits Pro-Inflammatory Monocyte-Macrophage Polarization in Streptozotocin-Induced Diabetic Mice. PLoS One 10(5):e0126580. doi: 10.1371/journal.pone.0126580.
Vignozzi L, Gacci M, Cellai I, Santi R, Corona G, Morelli A, Rastrelli G, Comeglio P, Sebastanelli A, Maneschi E, Nesi G, De Nunzio C, Tubaro A, Mannucci E, Carini M, Maggi M (2013) Fat boosts, while androgen receptor activation counteracts, BPH-associated prostate inflammation. Prostate 73(8):789-800. doi: 10.1002/pros.22623.
Zhang X, Ji J, Yan G, Wu J, Sun X, Shen J, Jiang H, Wang H (2010) Sildenafil promotes adipogenesis through a PKG pathway. Biochemical and Biophysical Research Communications 396(4):1054-9. doi: 10.1016/j.bbrc.2010.05.064.
Acta Biochimica Polonica is an open access quarterly and publishes four issues a year. All contents are distributed under the Creative Commons Attribution-ShareAlike 4.0 International (CC BY-SA 4.0) license. Everybody may use the content following terms: Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made, ShareAlike — If you remix, transform, or build upon the material, you must distribute your contributions under the same license as the original. There are no additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
Copyright for all published papers © stays with the authors.
Copyright for the journal: © Polish Biochemical Society.