Losartan Improves Erectile Function Through Suppression of Corporal Apoptosis and Oxidative Stress in Rats with Cavernous Nerve Injury

Overview

Journal Asian J Androl

Specialty Urology

Date 2019 Mar 19

PMID 30880689

Citations 7

Authors

Yi Wang

Xiang-Hu Meng

Qi-Jie Zhang

Ya-Min Wang

Chen Chen

Yi-Chun Wang

Xiang Zhou

Cheng-Jian Ji

Ning-Hong Song

Affiliations

Soon will be listed here.

Abstract

This study aimed to investigate the functional and morphological changes in the corpus cavernosum after cavernous nerve (CN) injury or neurectomy and then reveal whether treatment with the angiotensin II Type 1 receptor antagonist losartan would improve erectile function as well as its potential mechanisms. A total of 48 10-week-old Sprague-Dawley male rats, weighing 300-350 g, were randomly divided into the following four groups (n = 12 per group): sham operation (Sham) group, bilateral cavernous nerve injury (BCNI) group, losartan-treated BCNI (BCNI + Losartan) group, and bilateral cavernous neurectomy (Neurectomy) group. Losartan was administered once daily by oral gavage at a dose of 30 mg kg day for 4 weeks starting on the day of surgery. The BCNI and the Neurectomy groups exhibited decreases in erectile response and increases in apoptosis and oxidative stress, compared with the Sham group. Treatment with losartan could have a modest effect on erectile function and significantly prevent corporal apoptosis and oxidative stress. The phospho-B-cell lymphoma 2 (Bcl-2)-associated death promoter (p-Bad)/Bad and phospho-the protein kinase B (p-AKT)/AKT ratios were substantially lower, while the Bcl-2-associated X protein (Bax)/Bcl-2 ratio, nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap-1), transforming growth factor-β 1 (TGF-β 1) and heme oxygenase-1 (HO-1) levels, and caspase-3 activity were higher in the BCNI and Neurectomy groups than in the Sham group. After 4 weeks of daily administration with losartan, these expression levels were remarkably attenuated compared with the BCNI group. Taken together, our results suggested that early administration of losartan after CN injury could slightly improve erectile function and significantly reduce corporal apoptosis and oxidative stress by inhibiting the Akt/Bad/Bax/caspase-3 and Nrf2/Keap-1 pathways.

Citing Articles

Mitochondria-Rich Microvesicles Alleviate CNI ED by Transferring Mitochondria and Suppressing Local Ferroptosis.

Liang Z, Chen Z, Zhang C, Chen C, Yang W, Zhang Y Int J Nanomedicine. 2024; 19:11745-11765.

PMID: 39558916 PMC: 11570538. DOI: 10.2147/IJN.S488163.

Adipose Derived Mesenchymal Stem Cells-Derived Mitochondria Transplantation Ameliorated Erectile Dysfunction Induced by Cavernous Nerve Injury.

Zhai J, Chen Z, Chen P, Yang W, Wei H World J Mens Health. 2023; 42(1):188-201.

PMID: 37382278 PMC: 10782119. DOI: 10.5534/wjmh.220233.

Lacosamide alleviates bilateral cavernous nerve injury-induced erectile dysfunction in the rat model by ameliorating pathological changes in the corpus cavernosum.

Yao L, Cong R, Zhou X, Zhou X, Ji C, Wei X Int J Impot Res. 2023; 36(3):283-290.

PMID: 36922697 DOI: 10.1038/s41443-023-00674-9.

Comparison of the therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells and adipose-derived stem cells on erectile dysfunction in a rat model of bilateral cavernous nerve injury.

Ti Y, Yang M, Chen X, Zhang M, Xia J, Lv X Front Bioeng Biotechnol. 2022; 10:1019063.

PMID: 36277409 PMC: 9585154. DOI: 10.3389/fbioe.2022.1019063.

Relaxin-2 Prevents Erectile Dysfunction by Cavernous Nerve, Endothelial and Histopathological Protection Effects in Rats with Bilateral Cavernous Nerve Injury.

Liu K, Sun T, Xu W, Song J, Chen Y, Ruan Y World J Mens Health. 2022; 41(2):434-445.

PMID: 36047071 PMC: 10042645. DOI: 10.5534/wjmh.220003.

References

Liu C, Cao Y, Ko T, Chen M, Zhou X, Wang R . The Changes of MicroRNA Expression in the Corpus Cavernosum of a Rat Model With Cavernous Nerve Injury. J Sex Med. 2018; 15(7):958-965. DOI: 10.1016/j.jsxm.2018.05.006. View

Bella A, Fandel T, Tantiwongse K, Brant W, Klein R, Garcia C . Neurturin enhances the recovery of erectile function following bilateral cavernous nerve crush injury in the rat. J Brachial Plex Peripher Nerve Inj. 2007; 2:5. PMC: 1820781. DOI: 10.1186/1749-7221-2-5. View

Toblli J, Cao G, Lombrana A, Rivero M . Functional and morphological improvement in erectile tissue of hypertensive rats by long-term combined therapy with phosphodiesterase type 5 inhibitor and losartan. J Sex Med. 2007; 4(5):1291-303. DOI: 10.1111/j.1743-6109.2007.00567.x. View

Vickers M, Satyanarayana R . Phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction in patients with diabetes mellitus. Int J Impot Res. 2002; 14(6):466-71. DOI: 10.1038/sj.ijir.3900910. View

Yang R, Yang B, Wen Y, Fang F, Cui S, Lin G . Losartan, an Angiotensin type I receptor, restores erectile function by downregulation of cavernous renin-angiotensin system in streptozocin-induced diabetic rats. J Sex Med. 2009; 6(3):696-707. DOI: 10.1111/j.1743-6109.2008.01054.x. View

Wang X, Liu C, Xu Y, Chen P, Shen Y, Xu Y . Combination of mesenchymal stem cell injection with icariin for the treatment of diabetes-associated erectile dysfunction. PLoS One. 2017; 12(3):e0174145. PMC: 5369760. DOI: 10.1371/journal.pone.0174145. View

Noldus J, Michl U, Graefen M, Haese A, Hammerer P, Huland H . Patient-reported sexual function after nerve-sparing radical retropubic prostatectomy. Eur Urol. 2002; 42(2):118-24. DOI: 10.1016/s0302-2838(02)00219-1. View

Silva F, Monica F, Bau F, Brugnerotto A, Priviero F, Toque H . Superoxide anion production by NADPH oxidase plays a major role in erectile dysfunction in middle-aged rats: prevention by antioxidant therapy. J Sex Med. 2013; 10(4):960-71. DOI: 10.1111/jsm.12063. View

Hu W, Hu L, Li S, Zheng X, Tian B . Expression of transforming growth factor-beta1 in penile tissue from rats with bilateral cavernosal nerve ablation. BJU Int. 2004; 94(3):424-8. DOI: 10.1111/j.1464-410X.2004.04969.x. View

10.

Jin H, Chung Y, Kim W, Zhang L, Piao S, Tuvshintur B . A mouse model of cavernous nerve injury-induced erectile dysfunction: functional and morphological characterization of the corpus cavernosum. J Sex Med. 2010; 7(10):3351-64. DOI: 10.1111/j.1743-6109.2010.01942.x. View

11.

Hu W, Hu L, Song J, Li S, Zheng X, Cheng B . Fibrosis of corpus cavernosum in animals following cavernous nerve ablation. Asian J Androl. 2004; 6(2):111-6. View

12.

Leungwattanakij S, Bivalacqua T, Usta M, Yang D, Hyun J, Champion H . Cavernous neurotomy causes hypoxia and fibrosis in rat corpus cavernosum. J Androl. 2003; 24(2):239-45. DOI: 10.1002/j.1939-4640.2003.tb02668.x. View

13.

Ruan Y, Li M, Wang T, Yang J, Rao K, Wang S . Taurine Supplementation Improves Erectile Function in Rats with Streptozotocin-induced Type 1 Diabetes via Amelioration of Penile Fibrosis and Endothelial Dysfunction. J Sex Med. 2016; 13(5):778-85. DOI: 10.1016/j.jsxm.2016.02.164. View

14.

Jia L, Zhang Y, Ji W, Li H . Angiotensin II Silencing Alleviates Erectile Dysfunction Through Down-Regulating the Rhoa/Rho Kinase Signaling Pathway in Rats with Diabetes Mellitus. Cell Physiol Biochem. 2018; 45(1):419-427. DOI: 10.1159/000486919. View

15.

Park K, Shin J, Oh J, Ryu K, Kim S, Paick J . Restoration of erectile capacity in normotensive aged rats by modulation of angiotensin receptor type 1. J Androl. 2004; 26(1):123-8. View

16.

Bakircioglu M, Lin C, Fan P, Sievert K, Kan Y, Lue T . The effect of adeno-associated virus mediated brain derived neurotrophic factor in an animal model of neurogenic impotence. J Urol. 2001; 165(6 Pt 1):2103-9. DOI: 10.1097/00005392-200106000-00078. View

17.

Cho M, Park K, Kim S, Paick J . Restoration of erectile function by suppression of corporal apoptosis, fibrosis and corporal veno-occlusive dysfunction with rho-kinase inhibitors in a rat model of cavernous nerve injury. J Urol. 2014; 193(5):1716-23. DOI: 10.1016/j.juro.2014.10.099. View

18.

Bella A, Hayashi N, Carrion R, Price R, Lue T . FK1706 enhances the recovery of erectile function following bilateral cavernous nerve crush injury in the rat. J Sex Med. 2007; 4(2):341-6. DOI: 10.1111/j.1743-6109.2007.00438.x. View

19.

Canguven O, Lagoda G, Sezen S, Burnett A . Losartan preserves erectile function after bilateral cavernous nerve injury via antifibrotic mechanisms in male rats. J Urol. 2009; 181(6):2816-22. DOI: 10.1016/j.juro.2009.01.097. View

20.

Klein L, Miller M, Buttyan R, Raffo A, Burchard M, Devris G . Apoptosis in the rat penis after penile denervation. J Urol. 1997; 158(2):626-30. View