The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats

YAMAN, Selma; Altıntaş Aykan, Duygun; ESER, Nadire; seyithanoğlu, muhammed; YAYLALI, ASLI; Aykan, Ahmet

doi:10.14744/nci.2020.30906

The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats

Duygun ALTINTAŞ AYKAN, (Kahramanmaraş Sütçü İmam Üniversitesi, Tıp Fakültesi, Farmakoloji Anabilim Dalı, Kahramanmaraş, Türkiye)

Aslı YAYLALI, (Kahramanmaraş Sütçü İmam Üniversitesi, Tıp Fakültesi, Histoloji ve Embriyoloji Anabilim Dalı, Kahramanmaraş, Türkiye)

Nadire ESER, (Kahramanmaraş Sütçü İmam Üniversitesi Tıp Fakültesi, Farmakoloji Anabilim Dalı, Kahramanmaraş, Türkiye)

Muhammed SEYİTHANOĞLU, (Kahramanmaraş Sütçü İmam Üniversitesi, Tıp Fakültesi, Biyokimya Anabilim Dalı, Kahramanmaraş, Türkiye)

Selma YAMAN, (Kahramanmaraş Sütçü İmam Üniversitesi, Tıp Fakültesi, Biyofizik Anabilim Dalı, Kahramanmaraş, Türkiye)

Ahmet Çağrı AYKAN (Kahramanmaraş Sütçü İmam Üniversitesi, Tıp Fakültesi, Kardiyoloji Anabilim Dalı, Kahramanmaraş, Türkiye)

İstanbul Kuzey Klinikleri

5 2

Yıl: 2020 Cilt: 7 Sayı: 5 Sayfa Aralığı: 425 - 432 Metin Dili: İngilizce DOI: 10.14744/nci.2020.30906 İndeks Tarihi: 16-05-2021

The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats

Öz:

Objective: Renin angiotensinogen system (RAS) inhibitors, ramipril and sacubitril/valsartan are frequently used in the treatment of cardiovascular diseases. Although they are known as contraindicated during pregnancy in hypertensive women, there is not any outcome of their safety in male fertility after exposure to ramipril or sacubitril/valsartan. In this study, we aimed to evaluate the effects of ramipril and sacubitril/valsartan to highlight their safety in the male fertility in normotensive and hypertensive rats.Methods: Adult male normotensive and dexamethasone-induced hypertensive rats were treated with sacubitril/valsartan, ramipril and saline for 18 days. Arterial blood pressures were verified using carotid artery cannulation. Male fertility parameters, including the testis weights, histopathologic scoring of the testis, sperm count, sperm motility, morphology, and serum testosterone levels, were analyzed in treated and nontreated normotensive/hypertensive rats.Results: Sacubitril/valsartan or ramipril treatments did not reveal a significant difference in sperm production, testicular morphology, and radioimmunoassay of serum testosterone levels compared to the control group. However, sperm motility was significantly reduced in rats under RAS inhibition.Conclusion: This finding was likely mediated by the identification of Ang receptors in the tails of rat sperm given that Ang receptors may play a role in the modulation of sperm motility. Identification of RAS-related proteins involved in sperm motility may help to explain their roles in motility. Our data provide general safety evidence for the male fertilization ability after paternal sacubitril/valsartan and ramipril exposure.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

1. De Santis M, Cesari E, Cavaliere A, Ligato MS, Nobili E, Visconti D, et al. Paternal exposure and counselling: experience of a Teratology Information Service. Reprod Toxicol 2008;26:42–6.
2. Gianzo M, Muñoa-Hoyos I, Urizar-Arenaza I, Larreategui Z, Quintana F, Garrido N, Subirán N, et al. Angiotensin II type 2 receptor is expressed in human sperm cells and is involved in sperm motility. Fertil Steril 2016;105:608–16.
3. Reis AB, Araújo FC, Pereira VM, Dos Reis AM, Santos RA, Reis FM. Angiotensin (1-7) and its receptor Mas are expressed in the human testis: implications for male infertility. J Mol Histol 2010;41:75–80.
4. Leal MC, Pinheiro SV, Ferreira AJ, Santos RA, Bordoni LS, Alenina N, et al. The role of angiotensin-(1-7) receptor Mas in spermatogenesis in mice and rats. J Anat 2009;214:736–43.
5. Pan PP, Zhan QT, Le F, Zheng YM, Jin F. Angiotensin-converting enzymes play a dominant role in fertility. Int J Mol Sci 2013;14:21071– 86.
6. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:1122–31.
7. European Society of Gynecology (ESG); Association for European Paediatric Cardiology (AEPC); German Society for Gender Medicine (DGesGM), Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira R, Foidart JM, et al; ESC Committee for Practice Guidelines. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J 2011;32:3147–97.
8. Kruger TF, DuToit TC, Franken DR, Acosta AA, Oehninger SC, Menkveld R, et al. A new computerized method of reading sperm morphology (strict criteria) is as efficient as technician reading. Fertil Steril 1993;59:202–9.
9. Bilanda DC, Dimo T, Dzeufiet Djomeni PD, Bella NM, Aboubakar OB, Nguelefack TB, et al. Antihypertensive and antioxidant effects of Allanblackia floribunda Oliv. (Clusiaceae) aqueous extract in alcohol- and sucrose-induced hypertensive rats. J Ethnopharmacol 2010;128:634–40.
10. d’Emmanuele di Villa Bianca R, Mitidieri E, Donnarumma E, Tramontano T, Brancaleone V, Cirino G, et al. Hydrogen sulfide is involved in dexamethasone-induced hypertension in rat. Nitric Oxide 2015;46:80–6.
11. Aykan DA, Koca TT, Yaman S, Eser N. Angiotensin converting enzyme and neprilysin inhibition alter pain response in dexhamethasoneinduced hypertensive rats. Pharmacol Rep 2019;71:306–10.
12. Johnsen SG. Testicular biopsy score count--a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Hormones 1970;1:2–25.
13. Yokoi K, Uthus EO, Nielsen FH. Nickel deficiency diminishes sperm quantity and movement in rats. Biol Trace Elem Res 2003;93:141–54.
14. Seely EW, Ecker J. Chronic hypertension in pregnancy. Circulation 2014;129:1254–61.
15. Leung PS, Sernia C. The renin-angiotensin system and male reproduction: new functions for old hormones. J Mol Endocrinol 2003;30:263– 70.
16. Trasler JM, Doerksen T. Teratogen update: paternal exposures-reproductive risks. Teratology 1999;60:161–72.
17. Doerksen T, Trasler JM. Developmental exposure of male germ cells to 5-azacytidine results in abnormal preimplantation development in rats. Biol Reprod 1996;55:1155–62.
18. Barton TS, Robaire B, Hales BF. Epigenetic programming in the preimplantation rat embryo is disrupted by chronic paternal cyclophosphamide exposure. Proc Natl Acad Sci U S A 2005;102:7865–70.
19. Kedia-Mokashi NA, Kadam L, Ankolkar M, Dumasia K, Balasinor NH. Aberrant methylation of multiple imprinted genes in embryos of tamoxifen-treated male rats. Reproduction 2013;146:155–68.
20. Sabanegh ES Jr, Ragheb AM. Male fertility after cancer. Urology 2009;73:225–31.
21. Howell S, Shalet S. Gonadal damage from chemotherapy and radiotherapy. Endocrinol Metab Clin North Am 1998;27:927–43.
22. Jin M, Lou J, Yu H, Miao M, Wang G, Ai H, et al. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin promotes inflammation in mouse testes: The critical role of Klotho in Sertoli cells. Toxicol Lett 2018;295:134–43.
23. Meistrich ML. Effects of chemotherapy and radiotherapy on spermatogenesis in humans. Fertil Steril 2013;100:1180–6.
24. Wankeu-Nya M, Florea A, Bâlici S, Watcho P, Matei H, Kamanyi A. Dracaena arborea alleviates ultra-structural spermatogenic alterations in streptozotocin-induced diabetic rats. BMC Complement Altern Med 2013;13:71.
25. Supriya Ch, Reddy PS. Prenatal exposure to aflatoxin B1: developmental, behavioral, and reproductive alterations in male rats. Naturwissenschaften 2015;102:26.
26. Ma Y, Yang HZ, Xu LM, Huang YR, Dai HL, Kang XN. Testosterone regulates the autophagic clearance of androgen binding protein in rat Sertoli cells. Sci Rep 2015;5:8894.
27. Bechara GR, de Souza DB, Simoes M, Felix-Patrício B, Medeiros JL Jr, Costa WS, et al. Testicular Morphology and Spermatozoid Parameters in Spontaneously Hypertensive Rats Treated with Enalapril. J Urol 2015;194:1498–503.
28. Bielas W, Niżański W, Nicpoń J, Nicpoń JE, Partyka A, Mordak R, et al. Effect of zearalenone on circulating testosterone concentration, testicular and epididymal morphology and epididymal sperm characteristics in wild boars. Theriogenology 2017;102:59–66.
29. Kwok T, Ohlsson C, Vandenput L, Tang N, Zhang YF, Tomlinson B, et al. ACE inhibitor use was associated with lower serum dehydroepiandrosterone concentrations in older men. Clin Chim Acta 2010;411:1122–5.
30. Schunkert H, Ingelfinger JR, Hirsch AT, Pinto Y, Remme WJ, Jacob H, et al. Feedback regulation of angiotensin converting enzyme activity and mRNA levels by angiotensin II. Circ Res 1993;72:312–8.
31. Koshida H, Takeda R, Miyamori I. Lisinopril decreases plasma free testosterone in male hypertensive patients and increases sex hormone binding globulin in female hypertensive patients. Hypertens Res 1998;21:279–82.
32. Grönroos PE, Irjala KM, Vesalainen RK, Kantola IM, Leinonen VM, Helenius TI, et al. Effects of ramipril on the hormone concentrations in serum of hypertensive patients. Eur J Clin Chem Clin Biochem 1997;35:411–4.
33. Ravaux B, Garroum N, Perez E, Willaime H, Gourier C. A specific flagellum beating mode for inducing fusion in mammalian fertilization and kinetics of sperm internalization. Sci Rep 2016;6:31886.
34. Publicover SJ, Barratt CL. Sperm motility: things are moving in the lab!. Mol Hum Reprod 2011;17:453–6.
35. Sabeur K, Vo AT, Ball BA. Effects of angiotensin II on the acrosome reaction in equine spermatozoa. J Reprod Fertil 2000;120:135–42.
36. Vinson GP, Mehta J, Evans S, Matthews S, Puddefoot JR, Saridogan E, et al. Angiotensin II stimulates sperm motility. Regul Pept 1996;67:131–5.
37. Dzau VJ, Brody T, Ellison KE, Pratt RE, Ingelfinger JR. Tissuespecific regulation of renin expression in the mouse. Hypertension 1987;9:III36–41.
38. Krege JH, John SW, Langenbach LL, Hodgin JB, Hagaman JR, Bachman ES, et al. Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature 1995;375:146–8.
39. Kim HS, Krege JH, Kluckman KD, Hagaman JR, Hodgin JB, Best CF, et al. Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci U S A. 1995;92:2735–9.

APA	Altıntaş Aykan D, YAYLALI A, ESER N, seyithanoğlu m, YAMAN S, Aykan A (2020). The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats. , 425 - 432. 10.14744/nci.2020.30906
Chicago	Altıntaş Aykan Duygun,YAYLALI ASLI,ESER Nadire,seyithanoğlu muhammed,YAMAN Selma,Aykan Ahmet The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats. (2020): 425 - 432. 10.14744/nci.2020.30906
MLA	Altıntaş Aykan Duygun,YAYLALI ASLI,ESER Nadire,seyithanoğlu muhammed,YAMAN Selma,Aykan Ahmet The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats. , 2020, ss.425 - 432. 10.14744/nci.2020.30906
AMA	Altıntaş Aykan D,YAYLALI A,ESER N,seyithanoğlu m,YAMAN S,Aykan A The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats. . 2020; 425 - 432. 10.14744/nci.2020.30906
Vancouver	Altıntaş Aykan D,YAYLALI A,ESER N,seyithanoğlu m,YAMAN S,Aykan A The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats. . 2020; 425 - 432. 10.14744/nci.2020.30906
IEEE	Altıntaş Aykan D,YAYLALI A,ESER N,seyithanoğlu m,YAMAN S,Aykan A "The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats." , ss.425 - 432, 2020. 10.14744/nci.2020.30906
ISNAD	Altıntaş Aykan, Duygun vd. "The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats". (2020), 425-432. https://doi.org/10.14744/nci.2020.30906

APA	Altıntaş Aykan D, YAYLALI A, ESER N, seyithanoğlu m, YAMAN S, Aykan A (2020). The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats. İstanbul Kuzey Klinikleri, 7(5), 425 - 432. 10.14744/nci.2020.30906
Chicago	Altıntaş Aykan Duygun,YAYLALI ASLI,ESER Nadire,seyithanoğlu muhammed,YAMAN Selma,Aykan Ahmet The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats. İstanbul Kuzey Klinikleri 7, no.5 (2020): 425 - 432. 10.14744/nci.2020.30906
MLA	Altıntaş Aykan Duygun,YAYLALI ASLI,ESER Nadire,seyithanoğlu muhammed,YAMAN Selma,Aykan Ahmet The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats. İstanbul Kuzey Klinikleri, vol.7, no.5, 2020, ss.425 - 432. 10.14744/nci.2020.30906
AMA	Altıntaş Aykan D,YAYLALI A,ESER N,seyithanoğlu m,YAMAN S,Aykan A The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats. İstanbul Kuzey Klinikleri. 2020; 7(5): 425 - 432. 10.14744/nci.2020.30906
Vancouver	Altıntaş Aykan D,YAYLALI A,ESER N,seyithanoğlu m,YAMAN S,Aykan A The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats. İstanbul Kuzey Klinikleri. 2020; 7(5): 425 - 432. 10.14744/nci.2020.30906
IEEE	Altıntaş Aykan D,YAYLALI A,ESER N,seyithanoğlu m,YAMAN S,Aykan A "The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats." İstanbul Kuzey Klinikleri, 7, ss.425 - 432, 2020. 10.14744/nci.2020.30906
ISNAD	Altıntaş Aykan, Duygun vd. "The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats". İstanbul Kuzey Klinikleri 7/5 (2020), 425-432. https://doi.org/10.14744/nci.2020.30906