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. 2025 Sep;182(18):4343-4362.
doi: 10.1111/bph.70092. Epub 2025 Jun 2.

Role of sacubitril/valsartan in testicular ischaemia reperfusion injury via modulation of AngII/ASK/NF-κB and JAK/STAT pathways in juvenile rats

Marwa Monier Mahmoud Refaie  1 , Elshymaa A Abdel-Hakeem  2 , Randa Ahmed Ibrahim  3 , Zamzam Hassan Mohamed  4 , Sayed Shehata  5 , Hoda Soltan Shrekawy El Bakry  6 , Doaa Mohamed Elroby Ali  7
Affiliations

Role of sacubitril/valsartan in testicular ischaemia reperfusion injury via modulation of AngII/ASK/NF-κB and JAK/STAT pathways in juvenile rats

Marwa Monier Mahmoud Refaie et al. Br J Pharmacol. 2025 Sep.

Abstract

Background and purpose: Testicular torsion is a common urological emergency that affects children and young males and requires immediate surgical intervention and adequate management, or it may lead to male subfertility and infertility with remote effects on vital organs including the heart. To date, there has been no sufficient treatment for these cases, and further studies are highly recommended. Thus, our study aimed to evaluate the effect of sacubitril/valsartan (SV) on testicular ischaemia/reperfusion (TIR)-induced testicular damage and remote cardiac effect in juvenile rats.

Experimental approach: Forty juvenile Wistar albino rats were divided into five groups (n = 8) as control; SV (60 mg kg-1); TIR-induced group; TIR plus SV low-dose (30 mg kg-1); TIR plus SV high-dose (60 mg kg-1).

Key results: TIR induced testicular injury with remote cardiac effects, as we found a significant decrease in serum testosterone, increased cardiac enzyme levels and marked disturbances in oxidative stress parameters. Moreover, there are increases in angiotensin II (Ang II), neprilysin and apoptosis signal-regulating kinase 1 (ASK1). In addition, there is a disturbance in phosphor-nuclear factor kappa B (p-NF-κB p65), tumour necrosis factor alpha (TNFα), Janus kinase 1 (JAK1), signal transducer and activator of transcription 4 (STAT4) and cleaved caspase 3 with abnormal histological features. However, SV co-administration reversed damaging effect of TIR by regulating the renin angiotensin aldosterone system (RAAS), and anti-inflammatory, anti-oxidant, and anti-apoptotic pharmacological and physiological properties, and by modulation of different pathways.

Conclusions and implications: SV has protective properties against TIR-induced damage.

Keywords: angiotensin II; sacubtril/valsartan; signal transducer and activator of transcription; testicular ischaemia reperfusion.

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References

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