Knockout of Vascular Smooth Muscle Inward‐Rectifier K + Channels Causes Symptoms of Overactive Bladder in Mice

The urinary bladder is highly vascularized, and chronic decreases in blood flow are linked to bladder dysfunction. Interestingly, bladder arterioles do not constrict in response to changes in intraluminal pressure (“myogenic tone”), due to a maintained membrane hyperpolarization regulated by inward‐rectifier K + (K IR 2.1) channels. We developed a tamoxifen‐inducible, smooth muscle‐specific K IR 2.1 channel knockout (K IR 2.1 SMKO ) mouse to provide additional support that vascular smooth muscle K IR 2.1 channels are responsible for this lack of myogenic tone (Tykocki et al . AJP Renal Physiol, 2017). It is, however, unknown if increased vascular myogenic tone alone can alter bladder function. Unlike vascular smooth muscle, detrusor smooth muscle normally lacks functional K IR 2.1 channels. Thus, we tested the hypothesis that knockout of smooth muscle K IR 2.1 channels can cause bladder overactivity solely by increasing vascular tone. Voiding behavior was measured using the UroVoid ® System: a novel tool for chronic, non‐invasive measurements of bladder function (void volume and frequency) in mice. At 6 weeks of age, K IR 2.1 SMKO mice underwent either sham surgery or surgical implantation of a 21‐day tamoxifen‐eluting pellet (10 mg/kg). Bladder function and water intake were measured before (at 4 weeks of age), during (at 8 weeks of age) and after (at 12 weeks of age) tamoxifen treatment. Prior to tamoxifen treatment, void frequency and volume did not differ between groups. At 8 and 12 weeks, sham K IR 2.1 SMKO mice showed an age‐dependent decrease in void frequency that correlated with an increase in void volume; this was indicative of a normal, age‐dependent increase in bladder size and voiding control. When compared to sham mice, K IR 2.1 SMKO mice receiving tamoxifen had increased void frequency and decreased void volume during tamoxifen treatment (8 weeks), which remained elevated at 12 weeks. This was not due to increased diuresis, as no differences in water intake were noted between groups. This suggests that increased vascular tone leads to symptoms of overactive bladder in mice, and that bladder blood flow plays an integral role in regulating bladder function. Support or Funding Information Supported by NIH K01‐DK103840 (NRT) and R37‐DK053832 (MTN). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .