Sildenafil citrate long-term treatment effects on cardiovascular reactivity in a SHR experimental model of metabolic syndrome

Autoři: Yosra Doghri aff001;  Fabien Chetaneau aff001;  Moez Rhimi aff002;  Aicha Kriaa aff002;  Valérie Lalanne aff001;  Chantal Thorin aff001;  Emmanuelle Maguin aff002;  M. Yassine Mallem aff001;  Jean-Claude Desfontis aff001
Působiště autorů: UPSP NP3 (2017.B146), Nutrition, Pathophysiology and Pharmacology, Oniris, College of Veterinary Medicine, Food Sciences and Engineering, Atlanpôle—La Chantrerie, Route de Gachet, 5 BP, Nantes, France aff001;  UMR 1319 Micalis, INRA, Microbiota Interaction with Human and Animal Team (MIHA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France aff002
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223914


Much evidence indicates that metabolic syndrome is strongly correlated with a decrease in nitric oxide and an increase in oxidative stress leading to cardiovascular alterations. In recent years, gut microbiota has emerged as a new contributor to the metabolic syndrome establishment and associated cardiovascular diseases, but the underlying mechanisms remain unclear. We hypothesized that a positive modulation of cyclic guanosine monophosphate (cGMP) pathway, through phosphodiesterase type 5 (PDE5) inhibition could prevent cardiovascular alterations and gut dysbiosis that may be associated to metabolic syndrome. Spontaneously hypertensive rats (SHR) were randomly divided into 4 groups: control, cafeteria diet (CD) and sildenafil citrate treated groups (5mg/kg per os) were given either a CD or a standard chow diet for 10 weeks. Body weight, arterial blood pressure and glucose tolerance test were monitored. At the 10th week, cardiac inotropy and coronary perfusion pressure were evaluated on isolated heart according to Langendorff method. Cumulative concentration response curves to phenylephrine and acetylcholine were determined on thoracic aorta rings for vascular reactivity evaluation. Faecal samples were collected for the gut microbiota analysis. Compared to the control group, CD-fed rats showed a significant increase in body weight gain, arterial blood pressure and were glucose intolerant. This group showed also a decrease in β-adrenoceptor-induced cardiac inotropy and coronary vasodilation. Gut microbiota analysis revealed a significant reduction in the abundance of Lactobocillus spp in cafeteria diet-fed rats when compared to the control ones. Sildenafil citrate long-term treatment decreased weight gain and arterial blood pressure, improved coronary vasodilation and reduced α1-adrenoceptor-induced vasoconstriction in CD group. However, it did not reverse gut dysbiosis induced by chronic CD feeding. These results suggest that cGMP pathway targeting may be a potential therapeutic strategy for the management of the metabolic syndrome and associated cardiovascular disorders.

Klíčová slova:

Acetylcholine – Aorta – Blood pressure – Diet – Fats – Gut bacteria – Metabolic syndrome – Vasodilation


1. Weiss R, Bremer AA, Lustig RH. What is metabolic syndrome, and why are children getting it? Ann N Y Acad Sci. 2013 Apr;1281:123–40. doi: 10.1111/nyas.12030 23356701

2. Rentoukas E, Tsarouhas K, Kaplanis I, Korou E, Nikolaou M, Marathonitis G, et al. Connection between telomerase activity in PBMC and markers of inflammation and endothelial dysfunction in patients with metabolic syndrome. PLoS ONE. 2012;7(4):e35739. doi: 10.1371/journal.pone.0035739 22558213

3. Ahirwar AK, Jain A, Singh A, Goswami B, Bhatnagar MK, Bhatacharjee J. The study of markers of endothelial dysfunction in metabolic syndrome. Horm Mol Biol Clin Investig. 2015 Dec;24(3):131–6. doi: 10.1515/hmbci-2015-0039 26516933

4. Ayala JE, Bracy DP, Julien BM, Rottman JN, Fueger PT, Wasserman DH. Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice. Diabetes. 2007 Apr;56(4):1025–33. doi: 10.2337/db06-0883 17229936

5. Johann K, Reis MC, Harder L, Herrmann B, Gachkar S, Mittag J, et al. Effects of sildenafil treatment on thermogenesis and glucose homeostasis in diet-induced obese mice. Nutr Diabetes. 2018 Mar 13;8(1):9. doi: 10.1038/s41387-018-0026-0 29549244

6. Goldstein I, Tseng L-J, Creanga D, Stecher V, Kaminetsky JC. Efficacy and Safety of Sildenafil by Age in Men With Erectile Dysfunction. J Sex Med. 2016;13(5):852–9. doi: 10.1016/j.jsxm.2016.02.166 27114196

7. Everard A, Cani PD. Diabetes, obesity and gut microbiota. Best Pract Res Clin Gastroenterol. 2013 Feb;27(1):73–83. doi: 10.1016/j.bpg.2013.03.007 23768554

8. Festi D, Schiumerini R, Eusebi LH, Marasco G, Taddia M, Colecchia A. Gut microbiota and metabolic syndrome. World J Gastroenterol. 2014 Nov 21;20(43):16079–94. doi: 10.3748/wjg.v20.i43.16079 25473159

9. Round JL, Palm NW. Causal effects of the microbiota on immune-mediated diseases. Sci Immunol. 2018 Feb 9;3(20).

10. He M, Shi B. Gut microbiota as a potential target of metabolic syndrome: the role of probiotics and prebiotics. Cell Biosci. 2017;7:54. doi: 10.1186/s13578-017-0183-1 29090088

11. Okubo H, Nakatsu Y, Kushiyama A, Yamamotoya T, Matsunaga Y, Inoue M-K, et al. Gut Microbiota as a Therapeutic Target for Metabolic Disorders. Curr Med Chem. 2018;25(9):984–1001. doi: 10.2174/0929867324666171009121702 28990516

12. Velasquez MT. Altered Gut Microbiota: A Link Between Diet and the Metabolic Syndrome. Metab Syndr Relat Disord. 2018 Sep;16(7):321–8. doi: 10.1089/met.2017.0163 29957105

13. Bleau C, Karelis AD, St-Pierre DH, Lamontagne L. Crosstalk between intestinal microbiota, adipose tissue and skeletal muscle as an early event in systemic low-grade inflammation and the development of obesity and diabetes. Diabetes Metab Res Rev. 2015 Sep;31(6):545–61. doi: 10.1002/dmrr.2617 25352002

14. Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Nageshwar Reddy D. Role of the normal gut microbiota. World J Gastroenterol. 2015 Aug 7;21(29):8787–803. doi: 10.3748/wjg.v21.i29.8787 26269668

15. Arshad N, Visweswariah SS. Cyclic nucleotide signaling in intestinal epithelia: getting to the gut of the matter. Wiley Interdiscip Rev Syst Biol Med. 2013 Aug;5(4):409–24. doi: 10.1002/wsbm.1223 23610087

16. Buglioni A, Burnett JC. New Pharmacological Strategies to Increase cGMP. Annu Rev Med. 2016;67:229–43. doi: 10.1146/annurev-med-052914-091923 26473417

17. Yaguas K, Bautista R, Quiroz Y, Ferrebuz A, Pons H, Franco M, et al. Chronic sildenafil treatment corrects endothelial dysfunction and improves hypertension. Am J Nephrol. 2010;31(4):283–91. doi: 10.1159/000279307 20110668

18. Skrzypiec-Spring M, Grotthus B, Szelag A, Schulz R. Isolated heart perfusion according to Langendorff—still viable in the new millennium. J Pharmacol Toxicol Methods. 2007 Apr;55(2):113–26. doi: 10.1016/j.vascn.2006.05.006 16844390

19. Sauvaget F, Mallem MY, Bucas V, Gogny M, Desfontis J-C, Noireaud J. Positive influence of AT(1) receptor antagonism upon the impaired celiprolol-induced vasodilatation in aorta from spontaneously hypertensive rats. Eur J Pharmacol. 2010 Oct 10;644(1–3):169–75. doi: 10.1016/j.ejphar.2010.07.003 20637193

20. Kanso H, Mallem MY, Rabesona H, Thorin C, Haertle T, Chobert J-M, et al. Vasorelaxant effects of camel and bovine casein hydrolysates in rat thoracic aorta and mesenteric artery. International Dairy Journal. 2014 Nov 1;39(1):113–20.

21. Thorin C, Mallem MY, Noireaud J, Gogny M, Desfontis J-C. Nonlinear mixed effects models applied to cumulative concentration-response curves. J Pharm Pharmacol. 2010 Mar;62(3):339–45. doi: 10.1211/jpp.62.03.0008 20487217

22. Benjamini Y, Hochberg Y. Controlling the false discovery rate: A Practical and powerful approach to multiple testing. JRoyStatistSoc. 1995;57:289–300.

23. Miesel A, Müller H, Thermann M, Heidbreder M, Dominiak P, Raasch W. Overfeeding-induced obesity in spontaneously hypertensive rats: an animal model of the human metabolic syndrome. Ann Nutr Metab. 2010;56(2):127–42. doi: 10.1159/000278748 20134158

24. Moreno-Fernández S, Garcés-Rimón M, Vera G, Astier J, Landrier JF, Miguel M. High Fat/High Glucose Diet Induces Metabolic Syndrome in an Experimental Rat Model. Nutrients. 2018 Oct 14;10(10).

25. Rehakova R, Klimentova J, Cebova M, Barta A, Matuskova Z, Labas P, et al. Effect of deuterium-depleted water on selected cardiometabolic parameters in fructose-treated rats. Physiol Res. 2016 Oct 24;65(Supplementum 3):S401–7. 27775425

26. Wong SK, Chin K-Y, Suhaimi FH, Fairus A, Ima-Nirwana S. Animal models of metabolic syndrome: a review. Nutr Metab (Lond). 2016;13:65.

27. Lorkowska B, Bartus M, Franczyk M, Kostogrys RB, Jawien J, Pisulewski PM, et al. Hypercholesterolemia does not alter endothelial function in spontaneously hypertensive rats. J Pharmacol Exp Ther. 2006 Jun;317(3):1019–26. doi: 10.1124/jpet.105.098798 16547168

28. Ryu SY, Choi YJ, Park SY, Kim JY, Kim YD, Kim YW. Udenafil, a Phosphodiesterase 5 Inhibitor, Reduces Body Weight in High-Fat-Fed Mice. World J Mens Health. 2018 Jan;36(1):41–9. doi: 10.5534/wjmh.17028 29164831

29. Brandt N, De Bock K, Richter EA, Hespel P. Cafeteria diet-induced insulin resistance is not associated with decreased insulin signaling or AMPK activity and is alleviated by physical training in rats. Am J Physiol Endocrinol Metab. 2010 Aug;299(2):E215–224. doi: 10.1152/ajpendo.00098.2010 20484011

30. Ho JE, Arora P, Walford GA, Ghorbani A, Guanaga DP, Dhakal BP, et al. Effect of phosphodiesterase inhibition on insulin resistance in obese individuals. J Am Heart Assoc. 2014 Sep 11;3(5):e001001. doi: 10.1161/JAHA.114.001001 25213566

31. Lambert GW, Straznicky NE, Lambert EA, Dixon JB, Schlaich MP. Sympathetic nervous activation in obesity and the metabolic syndrome—causes, consequences and therapeutic implications. Pharmacol Ther. 2010 May;126(2):159–72. doi: 10.1016/j.pharmthera.2010.02.002 20171982

32. Rengo G. The adrenergic system in cardiovascular pathophysiology: a translational science point of view. Front Physiol. 2014;5:356. doi: 10.3389/fphys.2014.00356 25278905

33. Jiang C, Carillion A, Na N, De Jong A, Feldman S, Lacorte J-M, et al. Modification of the β-Adrenoceptor Stimulation Pathway in Zucker Obese and Obese Diabetic Rat Myocardium. Crit Care Med. 2015 Jul;43(7):e241–249. doi: 10.1097/CCM.0000000000000999 26079096

34. Nevelsteen I, Bito V, Van der Mieren G, Vanderper A, Van den Bergh A, Sipido KR, et al. ACE-inhibition, but not weight reduction restores cardiomyocyte response to β-adrenergic stimulation in the metabolic syndrome. BMC Cardiovasc Disord. 2013 Jul 12;13:51. doi: 10.1186/1471-2261-13-51 23848952

35. Lima-Leopoldo AP, Leopoldo AS, Sugizaki MM, Bruno A, Nascimento AF, Luvizotto RAM, et al. Myocardial dysfunction and abnormalities in intracellular calcium handling in obese rats. Arq Bras Cardiol. 2011 Sep;97(3):232–40. doi: 10.1590/s0066-782x2011005000061 21584481

36. Teixeira-da-Silva JJ, Nunes-Moreira HS, Silva CO, Lahlou S, Naro F, Xavier FE, et al. Chronic administration of sildenafil improves endothelial function in spontaneously hypertensive rats by decreasing COX-2 expression and oxidative stress. Life Sci. 2019 May 15;225:29–38. doi: 10.1016/j.lfs.2019.03.074 30940538

37. Lunardi CN, Vercesi JA, da Silva RS, Bendhack LM. Vasorelaxation induced by the new nitric oxide donor cis-[Ru(Cl)(bpy)(2)(NO)](PF(6)) is due to activation of K(Ca) by a cGMP-dependent pathway. Vascul Pharmacol. 2007 Sep;47(2–3):139–44. doi: 10.1016/j.vph.2007.05.003 17602893

38. Andric SA, Janjic MM, Stojkov NJ, Kostic TS. Sildenafil treatment in vivo stimulates Leydig cell steroidogenesis via the cAMP/cGMP signaling pathway. Am J Physiol Endocrinol Metab. 2010 Oct;299(4):E544–550. doi: 10.1152/ajpendo.00337.2010 20663985

39. Yu J, Zhang B, Su X-L, Tie R, Chang P, Zhang X-C, et al. Natriuretic peptide resistance of mesenteric arteries in spontaneous hypertensive rat is alleviated by exercise. Physiol Res. 2016 Jun 20;65(2):209–17. 26447511

40. Sannajust F, Barrès C, Koenig-Bérard E, Sassard J. Sympathoinhibitory effects of rilmenidine may be mediated by sites located below the brainstem. Br J Pharmacol. 1992 Mar;105(3):535–41. doi: 10.1111/j.1476-5381.1992.tb09015.x 1352718

41. Schirner M, Taube C. Different effects of aspirin on blood pressure of spontaneously hypertensive rats (SHR) with high and spontaneously low levels of blood pressure. Br J Pharmacol. 1993 Aug;109(4):900–1. doi: 10.1111/j.1476-5381.1993.tb13704.x 8401941

42. Mergia E, Stegbauer J. Role of Phosphodiesterase 5 and Cyclic GMP in Hypertension. Curr Hypertens Rep. 2016 Apr;18(5):39. doi: 10.1007/s11906-016-0646-5 27079836

43. Graham DA, Rush JWE. Exercise training improves aortic endothelium-dependent vasorelaxation and determinants of nitric oxide bioavailability in spontaneously hypertensive rats. J Appl Physiol. 2004 Jun;96(6):2088–96. doi: 10.1152/japplphysiol.01252.2003 14752124

44. Kim J-A, Jang H-J, Hwang DH. Toll-like receptor 4-induced endoplasmic reticulum stress contributes to impairment of vasodilator action of insulin. Am J Physiol Endocrinol Metab. 2015 Nov 1;309(9):E767–776. doi: 10.1152/ajpendo.00369.2015 26522062

45. Berenyiova A, Dovinova I, Kvandova M, Kristek F, Jansen E, Majzunova M, et al. The Effect of Chronic NO Synthase Inhibition on the Vasoactive and Structural Properties of Thoracic Aorta, NO Synthase Activity, and Oxidative Stress Biomarkers in Young SHR. Oxid Med Cell Longev. 2018;2018:2502843. doi: 10.1155/2018/2502843 30050647

46. Del Bas JM, Guirro M, Boqué N, Cereto A, Ras R, Crescenti A, et al. Alterations in gut microbiota associated with a cafeteria diet and the physiological consequences in the host. Int J Obes (Lond). 2018 Apr;42(4):746–54.

47. Bortolin RC, Vargas AR, Gasparotto J, Chaves PR, Schnorr CE, Martinello KB, et al. A new animal diet based on human Western diet is a robust diet-induced obesity model: comparison to high-fat and cafeteria diets in term of metabolic and gut microbiota disruption. Int J Obes (Lond). 2018 Mar;42(3):525–34.

48. Moreno-Indias I, Cardona F, Tinahones FJ, Queipo-Ortuño MI. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. Front Microbiol. 2014;5:190. doi: 10.3389/fmicb.2014.00190 24808896

49. Yang T, Santisteban MM, Rodriguez V, Li E, Ahmari N, Carvajal JM, et al. GUT MICROBIOTA DYSBIOSIS IS LINKED TO HYPERTENSION. Hypertension. 2015 Jun;65(6):1331–40. doi: 10.1161/HYPERTENSIONAHA.115.05315 25870193

50. Lecomte V, Kaakoush NO, Maloney CA, Raipuria M, Huinao KD, Mitchell HM, et al. Changes in gut microbiota in rats fed a high fat diet correlate with obesity-associated metabolic parameters. PLoS ONE. 2015;10(5):e0126931. doi: 10.1371/journal.pone.0126931 25992554

51. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007 Jul;56(7):1761–72. doi: 10.2337/db06-1491 17456850

52. Tanida M, Shen J, Maeda K, Horii Y, Yamano T, Fukushima Y, et al. High-fat diet-induced obesity is attenuated by probiotic strain Lactobacillus paracasei ST11 (NCC2461) in rats. Obes Res Clin Pract. 2008 Sep;2(3):I–II.

Článek vyšel v časopise


2019 Číslo 11