1. Testosterone/Estradiol Ratio Regulates NO‐Induced Bladder Relaxation and Responsiveness to PDE5 Inhibitors
- Author
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Linda Vignozzi, Rosa Mancina, Gabriella B. Vannelli, Mario Maggi, Sandra Filippi, Erica Sarchielli, Annamaria Morelli, Mauro Gacci, Elena Maneschi, Ilaria Cellai, and Paolo Comeglio
- Subjects
Male ,Muscle Relaxation ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Gene Expression ,Piperazines ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Endocrinology ,Testosterone ,Sulfones ,Progesterone ,Estradiol ,Aromatase Inhibitors ,Triazines ,Imidazoles ,Biological activity ,Psychiatry and Mental health ,Letrozole ,Androgens ,Ovariectomized rat ,Female ,Sodium nitroprusside ,medicine.drug ,Nitroprusside ,medicine.medical_specialty ,Ovariectomy ,Urology ,Urinary Bladder ,Steroid ,Sex Factors ,Vardenafil Dihydrochloride ,Lower urinary tract symptoms ,Internal medicine ,Nitriles ,medicine ,Animals ,Nitric Oxide Donors ,RNA, Messenger ,Cyclic guanosine monophosphate ,Cyclic Nucleotide Phosphodiesterases, Type 5 ,Estrogens ,Muscle, Smooth ,Phosphodiesterase 5 Inhibitors ,Triazoles ,medicine.disease ,Rats ,Reproductive Medicine ,chemistry ,Vardenafil ,Progestins - Abstract
Introduction 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. Aim To investigate sex differences in PDE5 expression and biological activity in female bladder, as opposed to the male counterpart. Main Outcome Measure Gene and protein expression and enzymatic activity of PDE5. Methods 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. Results 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. Conclusion 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. Vignozzi L, Filippi S, Morelli A, Comeglio P, Cellai I, Sarchielli E, Maneschi E, Mancina R, Gacci M, Vannelli GB, and Maggi M. Testosterone/estradiol ratio regulates NO‐induced bladder relaxation and responsiveness to PDE5 inhibitors. J Sex Med 2012;9:3028–3040.
- Published
- 2012