Evaluation of combined therapeutic effects of hydrogen sulfide donor sodium hydrogen sulfide and phosphodiesterase type‐5 inhibitor tadalafil on erectile dysfunction in a partially bladder outlet obstructed rat model

Abstract

Aims: To evaluate the impacts of hydrogen sulfide (H 2 S) donor, sodium hydrogen sulfide (NaHS), and phosphodiesterase type-5 inhibitor (PDE5i), tadalafil per se and their combination treatment on partial bladder outlet obstruction (PBOO)-induced erectile dysfunction (ED). Methods: Sprague-Dawley rats were equally divided into five groups: (a) shamoperated control; (b) PBOO; (c) PBOO-treated with NaHS (5.6 mg/kg/day, ip); (d) PBOO-treated with tadalafil (2 mg/kg/day, oral); and (e) PBOO-treated with combination of NaHS and tadalafil. The obstruction was created by urethral ligation for 6 weeks. In vivo erectile responses, in vitro relaxant and contractile responses in penile tissue as well as protein expression of nitric oxide synthases (NOS), H 2 S synthesis enzymes, oxidative stress, hypoxia, fibrosis markers, and the smooth muscle/collagen ratio and apoptosis were analyzed. Results: Combined treatment entirely returned increased bladder mass, reduced erectile responses, relaxation responses to acetylcholine, and electrical field stimulation in obstructed rats, while partial amelioration was observed after mono-treatment. Decreased neuronal NOS and 3-mercaptopiruvate transferase enzyme expressions in penile tissue from obstructed rats were also entirely restored by the combined treatment. Mono-treatment partially improved increased hypoxia, oxidative stress, fibrosis markers, decreased smooth muscle mass, and H 2 S levels, while combined therapy completely recovered. Conclusions: The combination therapy with H 2 S donor and PDE5i had positive effects on erectile responses through the improvement of ischemiainduced morphological and functional penile alterations in obstruction. H 2 S and NO may likely play a synergistic role in the regulation of erectile function and have constructive effects on clinical outcomes in male patients with ED and benign prostatic hyperplasia/lower urinary tract symptoms.

Sodium butyrate ameliorates erectile dysfunction through fibrosis in a rat model of partial bladder outlet obstruction

“…30,36,37 Penile fibrosis in the PBOO animal model has been demonstrated in previous studies. 9,10 Supporting these data, results of our study have demonstrated a significant upregulation of TGF-β1 gene and protein expression with collagen formation in the obstructed group. NaBu, a HDAC inhibitor, attenuated fibrosis in the penile tissues of the obstructed rats by decreasing the gene and protein expression of TGF-β1 and increasing smooth muscle/collagen ratio.…”

“…As reported previously, lower nNOS protein levels in penile tissue of animals with PBOO seem to be responsible for the impaired erectile function. 6,8,10,30 In the present study, PBOO diminished relaxation responses induced by ACh (an endothelium-dependent vasodilator), which was corrected by NaBu treatment. Similarly, another HDAC inhibitor, trichostatin A increased endothelium-dependent relaxation induced by ACh in mesenteric artery from spontaneous hypertensive rats.…”

“…31 Besides, increased eNOS gene expression in penile tissue from PBOO rats was decreased by NaBu treatment and there was no change in eNOS protein levels among groups, which is similar to previous studies. 10,30 eNOS uncoupling together with loss of NO bioavailability may have major consequences on the endothelial function. 32 Both enhanced eNOS expression and impaired eNOS functionality have been observed in patients with endothelial dysfunction due to hypertension and diabetes.…”

“…[6][7][8] Also, preclinical studies have shown that increased levels of markers of fibrosis [transforming growth factor (TGF)-β1], oxidative stress [malondialdehyde (MDA)], and inflammation [inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-κB)] in the penile tissue of the PBOO model may play a role in ED. 9,10 There is a cross-talk between NF-κB and nuclear factor erythroid 2-related factor 2 (Nrf2) response pathways. 11 Nrf2 is a main regulator of cellular response via counteracting oxidative stress and NF-κB-mediated inflammation.…”

3-Mercaptopyruvate sulfurtransferase: an enzyme at the crossroads of sulfane sulfur trafficking

“…Furthermore, a decrease in MPST expression was linked to erectile dysfunction, which is common in men who have diabetes. Rats with erectile dysfunction showed a decrease of MPST protein levels in penile tissue, which could be partially countermanded by tadalafil, a drug used to treat erectile dysfunction (Yilmaz-Oral et al 2020;Zhang et al 2016).…”