Presentation Authors: Didem Yilmaz-Oral*, Adana, Turkey, Ecem Kaya-Sezginer, Nur Bayatli, Serap Gur, Ankara, Turkey
Introduction: Lower urinary tract symptoms (LUTS) in men are strictly linked to benign prostatic hyperplasia (BPH), which may lead to bladder outlet obstruction (BOO). The phosphodiesterase type 5 inhibitor, tadalafil has been approved for the treatment of BPH/LUTS. Hydrogen sulfide (H2S), an endogenous gasotransmitter, is generated by cystathionine-Î²-synthase (CBS), cystathionine-Î³-lyase (CSE) as well as 3-mercaptopyruvate sulfurtransferase (3-MST) and involved in pathological disorders of the BPH/LUTS. The present study aimed to investigate the possible restorative effect of combined treatment with a H2S donor, sodium hydrosulfide (NaHS) and tadalafil on the bladder dysfunction in a rat model of partial BOO (PBOO).
Methods: Adult Sprague-Dawley rats (n=75) were equally divided into five groups: 1) sham-operated control, 2) PBOO (6-wk), 3) NaHS (6-wk, 5.6 mg/kg/day, i.p.)-PBOO, 4) tadalafil (6-wk, 2 mg/kg/day, oral)-PBOO and 5) combined treatment with NaHS and tadalafil in PBOO. Rats underwent PBOO surgery by partial ligation of the urethra. The contractile responses of detrusor muscle were obtained from in vitro studies. Bladder tissues were processed for Western blotting, malondialdehyde (MDA) and H2S assay.
Results: Combined treatment prevented increased bladder weight as well as decreased contractile responses in the detrusor smooth muscle of PBOO rats. The increased protein expression of neuronal, endothelial and inducible nitric oxide synthase (nNOS, eNOS and iNOS) in obstructed rats was normalized by combination treatment. CSE, CBS and nuclear factor kappa B (NF-&[kappa]B) protein levels were not significantly different among groups. Surprisingly, decreased 3-MST protein expression was normalized by tadalafil and combined treatment. NaHS or tadalafil monotherapy partially improved increased MDA levels and decreased H2S levels in obstructed rats, while combination therapy normalized both MDA and H2S levels.
Conclusions: Significant alterations in the expression of nNOS, eNOS and iNOS as well as MDA and H2S levels may contribute to functional impairment in bladder induced by PBOO. We firstly demonstrated that combination therapy improved bladder dysfunction in PBOO rats by modulation of H2S/nitric oxide (NO) pathway and oxidative stress. The synergistic effect and crosstalk between H2S and NO can control the molecular regulation of bladder function, which supports combined treatment for improving clinical outcomes in men with BPH/LUTS.
Source of Funding: The present study was supported by Tubitak, Scientific and Technological Research Council of Turkey with 216S813 project number.