ECE2007 Poster Presentations (1) (659 abstracts)
Characterization and functional role of an androgen-dependent PDE5 activity in bladder
Sandra Filippi 1 , Annamaria Morelli 2 , Peter Sandner 6 , Benedetta Fibbi 2 , Rosa Mancina 2 , Mirca Marini 4 , Mauro Gacci 5 , Linda Vignozzi 2 , Gabriella Barbara Vannelli 4 , Marco Carini 5 , Gianni Forti 3 & Mario Maggi 1
1University of Florence, Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Departments of Pharmacology and Clinical Physiopathology, Florence, Italy; 2University of Florence, Department of Clinical Physiopathology, Andrology Unit, Florence, Italy; 3University of Florence,Department of Clinical Physiopathology, Endocrinology Unit, Florence, Italy; 4University of Florence, Department of Anatomy, Histology and Forensic Medicine, Florence, Italy; 5University of Florence,Department of Urology, Florence, Italy; 6Bayer Healthcare, Wuppertal, Germany.
Benign prostate hyperplasia (BPH) is the most common disease in the aging male, often comorbid with erectile dysfunction (ED). PDE5 inhibitors (PDE5i, sildenafil, tadalafil and vardenafil) decrease lower urinary tract symptoms (LUTS) in patients with ED and BPH. We studied PDE5 expression and activity in the human bladder and PDE5i effects both in vitro (human and rat) and in vivo (rat). PDE5 is highly expressed in rat and human bladder and immunolocalized in vascular endothelium and muscle fibers. Sildenafil, tadalafil and vardenafil blocked 70% of the total cGMP catabolizing activity, with vardenafil being the most potent (IC50=0.3 nM). In human bladder cells and in rat strips, a PDE-resistant cGMP analogue, SP-8-Br-PET-cGMPS, induced, respectively, a consistent anti-proliferative and relaxant effect. In contrast, the nitric oxide (NO) donor sodium nitroprusside (SNP) was almost ineffective. However, blocking PDE5 with vardenafil increased SNP anti-proliferative and relaxant activity up to the level observed with SP-8-Br-PET-cGMPS. We also found that castration decreased, and T supplementation restored, PDE5 gene expression in rat bladder. Accordingly, bladder strips from castrated rats were more sensitive to SNP- induced relaxation than strips from control or T-replaced rats, while in the presence of vardenafil, all groups showed the same SNP sensitivity. To discover whether vardenafil affects bladder activity in vivo, the rat bladder outlet obstruction (BOO) model was used. Chronic treatment with 10 mg/kg/d vardenafil significantly reduced non-voiding contractions (47%, P<0.05 vs. placebo) up to tamsulosin level (51%). Overall, these results demonstrate that PDE5 regulates bladder smooth muscle tone, strongly limiting the NO/cGMP signalling, and that vardenafil, by blocking PDE5, may be a possible therapeutic option for bladder dysfunction, by ameliorating irritative LUTS.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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