Mirabegron is a selective β3-adrenoceptor agonist that is clinically used for the treatment of overactive bladder. Accumulating evidence suggests that bladder ischemia is involved in the pathogenesis of overactive bladder (1). However, it is unknown whether mirabegron has a positive impact on bladder blood flow. Therefore, we have evaluated the effects of mirabegron on bladder blood flow in a rat model of bladder outlet obstruction (BOO).

Adult female Sprague-Dawley rats were divided into 3 groups: sham, BOO, and BOO + mirabegron. In the sham group, rats underwent a sham operation, whereas in the BOO and the BOO + mirabegron group, rats underwent an operation to establish partial BOO. After the surgery, the BOO + mirabegron group was treated with mirabegron (0.3 mg/kg/h, subcutaneously) using an osmotic pump for 14 days, whereas the sham and the BOO groups were similarly treated with the vehicle. The following experiments were performed after the 14 days-treatment: (1) continuous cystometry in awake state; (2) measurement of bladder blood flow with a 2D laser blood flow imager (OMEGAZONE); (3) hematoxylin-eosin staining of bladder tissue; and (4) malondialdehyde (MDA) measurement in bladder tissue.

The bladder weight was significantly increased in the BOO and the BOO + mirabegron groups compared to the sham group (p = 0.001 and 0.02, respectively). There was no significant difference in blood pressure among the three groups, 14 days after the treatment.
(1)	Continuous cystometry in awake state
The BOO group showed significantly higher baseline and peak pressure, more residual urine volume, lower voiding efficiency, and more frequent non-voiding contractions in comparison to the sham group (p = 0.04, < 0.001, 0.007, 0.02, 0.01, respectively). In addition, the BOO + mirabegron group showed significantly higher peak pressure, more residual urine volume and lower voiding efficiency than the sham group. The BOO + mirabegron group had significantly fewer non-voiding contractions than the BOO group (Table).
(2) Measurement of bladder blood flow  
There was no significant difference among the three groups, regarding the bladder blood flow with intravesical volume at 0 mL. In contrast, at 0.4 mL intravesical volume, the BOO and BOO + mirabegron group had significantly decreased bladder blood flow than the sham group (p < 0.001 and 0.006), whereas the BOO + mirabegron group showed significantly (p = 0.01) increased bladder blood flow, as compared to the BOO group (figure).
(2)	Hematoxylin-eosin staining 
The bladder tissue in the BOO group had a tendency to contain more hypertrophic detrusor muscle and inflammatory cells when compared to those of the control group, while mirabegron treatment suppressed these histological changes.
(4) MDA measurement
In the BOO group significantly increased MDA levels were detected, as compared to the sham group (p = 0.02). Moreover, significantly decreased MDA was observed in the BOO + mirabegron than the BOO group. (p = 0.04)

These results indicate that: (1) BOO surgery caused high micturition pressure, low voiding efficiency, large residual urine volume and increased the frequency of non-voiding contractions; (2) BOO surgery decreased bladder blood flow, which led to the generation of oxidative stress in the bladder. (3) Mirabegron treatment significantly improved these pathological changes.

Mirabegron treatment significantly improved BOO-induced bladder dysfunction through the amelioration of bladder blood flow.

The link between vascular dysfunction, bladder ischemia, and aging bladder dysfunction.  Andersson KE, Boedtkjer DB, Forman A. Ther Adv Urol. 2017 Jan;9(1):11-27.