sirolimus and oxybutynin

Bladder deterioration after partial outlet obstruction (pBOO) occurs commonly and has significant clinical implications. Our previous animal model results described the progression of pBOO to hypertrophy and fibrosis. We wished to determine if the pathologic process of pBOO can be altered with rationally chosen oral medications.. Female Sprague-Dawley rats underwent controlled surgically induced pBOO. Rats were maintained for a period of 16 weeks at which point urodynamics were performed, and organs harvested. Rats were divided into four groups, each receiving different daily treatment: control (saline), oxybutynin (3 mg/kg), rapamycin (2 mg/kg), and tadalafil (2 mg/kg). Outcomes were assessed after 4,8,12, or 16 weeks. Measures included animal health, urodynamics, histology, mass spectrometry for collagen content, and rtPCR for inflammatory mediators.. Rapamycin treated animals exhibited significant mortality at later time points. Oxybutinin and tadalafil treated bladders demonstrated significant improvements in bladder capacity and compliance, with less detrusor hypertrophy than controls. Tadalafil also resulted in a significant down-regulation of HIF-1α, while decorin, biglycan, and TGF-β were upregulated in treated animals. Tadalafil treated bladders measured lower collagen content towards the end of the study, indicating an antifibrotic effect.. Our study has effectively demonstrated that deleterious changes secondary to pBOO can be altered pharmacologically. Oxybutinin and tadalafil seem to have a time-dependent protective effect on the detrusor muscle, although with different mechanisms of action. Tadalafil treatment in this setting appears to have an antifibrotic effect. This work has the potential to seed important clinical studies and improve clinical practice.

Topics: Administration, Oral; Animals; Carbolines; Disease Models, Animal; Female; Mandelic Acids; Muscarinic Antagonists; Phosphodiesterase 5 Inhibitors; Rats; Rats, Sprague-Dawley; Sirolimus; Tadalafil; Urinary Bladder Neck Obstruction; Urodynamics