Testosterone/Estradiol Ratio Regulates NO‐Induced Bladder Relaxation and Responsiveness to PDE5 Inhibitors

Abstract

The efficacy of phosphodiesterase type 5 inhibitors (PDE5i) in treating lower urinary tract symptoms is supported by the extremely high expression and activity of PDE5 in male bladder. Although bladder function regulation is similar among genders, no data are available on PDE5 expression and activity in female bladder. To investigate sex differences in PDE5 expression and biological activity in female bladder, as opposed to the male counterpart. Gene and protein expression and enzymatic activity of PDE5. We studied gene and protein expression, and enzymatic activity of PDE5 in bladder of male and female rats. A subgroup of female rats was ovariectomized and alternatively replaced with estradiol (E2), progesterone, and testosterone (T) alone or in combination with letrozole to completely abrogate T-induced E formation. As a readout of PDE5 activity, we studied vardenafil efficacy in potentiating sodium nitroprusside (SNP)-induced relaxation in bladder of the different experimental groups. SNP was three-log unit less potent in relaxing the male bladder than the female one. On the contrary, the PDE5-resistant cyclic guanosine monophosphate (cGMP) analog (Bromo-β-phenyl-1, N(2) -ethenoguanosine-3', 5'-cyclic monophosphorothioate, Sp-isomer [SP-8-Br-PET-cGMPS]) was equipotent in relaxing male and female bladder. Vardenafil was more effective in potentiating SNP-induced bladder relaxation in male than in female. Accordingly, the cGMP-hydrolyzing activity of PDE5 was higher in male vs. female homogenates. In ovariectomized female rats, with or without sex-steroid replacement, vardenafil activity in potentiating SNP-induced bladder relaxation was associated with an increased T/E2 ratio. In particular, masculinization of ovariectomized rats--by the administration of T + letrozole--dramatically increased vardenafil capacity to potentiate SNP-induced relaxation. In this study, we demonstrated that PDE5 activity is more pronounced in male as compared with female bladder and that T/E ratio positively regulates responsiveness to PDE5i, thus suggesting that male bladder is a more suitable target for PDE5i than the female counterpart.