Testosterone (T) deficiency is associated with erectile dysfunction (ED). The relaxant response of T on the corporal smooth muscle through a non-genomic pathway has been reported; however, the in vitro modulating effects of T on human corpus cavernosum (HCC) have not been studied.
To compare the effects of various concentrations of T on nitric oxide (NO)-dependent and -independent relaxation in organ bath studies and elucidate its mode of action, specifically targeting the cavernous NO/cyclic guanosine monophosphate (cGMP) pathway.
HCC samples were obtained from men undergoing penile prosthesis implantation (n = 9). After phenylephrine (Phe) precontraction, the effects of various relaxant drugs of HCC strips were performed using organ bath at low (150ng/dL), eugonadal (400ng/dL), and hypergonadal (600ng/dL) T concentrations. The penile tissue measurements of endothelial nitric oxide synthase (eNOS), neuronal (n)NOS and phosphodiesterase type 5 (PDE5)A were evaluated via immunostaining, Western blot, cGMP and nitrite/nitrate (NOx) assays.
Relaxation responses to ACh and EFS in isolated HCC strips were significantly increased at all T levels compared with untreated tissues. The sildenafil-induced relaxant response was significantly increased at both eugonadal and hypergonadal T levels. Normal and high levels of T are accompanied by increased eNOS, nNOS, cGMP and nitrate/nitrite (NOx) levels, along with reduced PDE5 protein expression.
This study reveals an important role of short-term and modulatory effects of different concentrations of T in HCC. T positively regulates functional activities, inhibition of PDE5 expression and formation of cGMP and NOx in HCC. These results demonstrate that T indirectly contributes to HCC relaxation via downstream effects on nNOS, eNOS, and cGMP and by inhibiting PDE5. This action provides a rationale for normalizing T levels in hypogonadal men with ED, especially when PDE5 inhibitors are ineffective. T replacement therapy may improve erectile function by modulating endothelial function hypogonadal men.
Andrology. 2020 Jul 16 [Epub ahead of print]
Serap Gur, Laith Alzweri, Didem Yilmaz-Oral, Ecem Kaya-Sezginer, Asim Abdel-Mageed, Suresh C Sikka, Volkan Cetin Oztekin, Wayne J G Hellstrom
Tulane University Health Sciences Center, Department of Urology and Pharmacoloz, New Orleans, LA, USA., Cukurova University, Department of Pharmacology, Faculty of Pharmacy, Adana, Turkey., Ankara University, Faculty of Pharmacy, Department of Biochemistry, Ankara, Turkey., Department of Urology, Faculty of Medicine, University of Kyrenia, Girne, Turkish Republic of North Cyprus, Mersin, Turkey.