BACKGROUND: The β3-adrenoceptor (AR) agonist mirabegron has been introduced as a treatment for the overactive bladder. Its effects on the function of the ischemic bladder are not known. OBJECTIVE: To investigate the effect of mirabegron in a rat model of chronic ischemia-related bladder dysfunction. DESIGN, SETTING, AND PARTICIPANTS: Male Sprague-Dawley rats were divided into three groups: control (n=10), arterial endothelial injury (AI; n=16), and AI with mirabegron treatment (AI-mirabegron; n=10). AI and AI-mirabegron groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-mirabegron rats received mirabegron (10mg/kg/d) orally for 8 wk. The control group received a regular diet. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: After 8 wk, urodynamic investigation was performed in awake animals. Pharmacologic in vitro studies and histologic examination of the iliac arteries and bladders were performed. RESULTS AND LIMITATIONS: Iliac arteries from both AI and AI-mirabegron rats displayed neointimal formation and luminal occlusion. Micturition interval (MI), bladder capacity (Bcap), and voided volume (VV) in the AI group were significantly less than in the control group (p<0.01). In the AI-mirabegron group, MI, Bcap, and VV were significantly larger than in the AI group (p<0.05) but significantly less than in the control group (p<0.05). Contractile responses of bladder strips to potassium chloride, electrical field stimulation, and carbachol were significantly lower after AI than in controls; responses in preparations from AI-mirabegron-treated animals were similar to those of controls. The AI group showed a significantly higher percentage of collagen (28.6 ± 1.57%) compared with the controls (8.65 ± 0.67%) and AI-mirabegron-treated animals (17.2 ± 2.32%). The mirabegron dose used in this study may potentially limit the translational value of the results. CONCLUSIONS: In the chronically ischemic rat bladder, treatment with mirabegron seems to protect bladder function and morphology, resulting in reduced bladder hyperactivity. If the results are valid for humans, they support β3-AR agonism as a potential treatment of chronic ischemia-related bladder dysfunction.
BACKGROUND: The β3-adrenoceptor (AR) agonist mirabegron has been introduced as a treatment for the overactive bladder. Its effects on the function of the ischemic bladder are not known. OBJECTIVE: To investigate the effect of mirabegron in a rat model of chronic ischemia-related bladder dysfunction. DESIGN, SETTING, AND PARTICIPANTS: Male Sprague-Dawley rats were divided into three groups: control (n=10), arterial endothelial injury (AI; n=16), and AI with mirabegron treatment (AI-mirabegron; n=10). AI and AI-mirabegron groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-mirabegron rats received mirabegron (10mg/kg/d) orally for 8 wk. The control group received a regular diet. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: After 8 wk, urodynamic investigation was performed in awake animals. Pharmacologic in vitro studies and histologic examination of the iliac arteries and bladders were performed. RESULTS AND LIMITATIONS: Iliac arteries from both AI and AI-mirabegron rats displayed neointimal formation and luminal occlusion. Micturition interval (MI), bladder capacity (Bcap), and voided volume (VV) in the AI group were significantly less than in the control group (p<0.01). In the AI-mirabegron group, MI, Bcap, and VV were significantly larger than in the AI group (p<0.05) but significantly less than in the control group (p<0.05). Contractile responses of bladder strips to potassium chloride, electrical field stimulation, and carbachol were significantly lower after AI than in controls; responses in preparations from AI-mirabegron-treated animals were similar to those of controls. The AI group showed a significantly higher percentage of collagen (28.6 ± 1.57%) compared with the controls (8.65 ± 0.67%) and AI-mirabegron-treated animals (17.2 ± 2.32%). The mirabegron dose used in this study may potentially limit the translational value of the results. CONCLUSIONS: In the chronically ischemic rat bladder, treatment with mirabegron seems to protect bladder function and morphology, resulting in reduced bladder hyperactivity. If the results are valid for humans, they support β3-AR agonism as a potential treatment of chronic ischemia-related bladder dysfunction.
Authors: Zachary E Cullingsworth; Naveen Nandanan; Natalie R Swavely; Konstantin Frolov; Randy Vince; Rebecca Zee; Theodore Cisu; Adam P Klausner; John E Speich Journal: Transl Androl Urol Date: 2021-06