Role of TREK-1 Potassium Channel in Bladder Overactivity After Partial Bladder Outlet Obstruction in Mouse

Purpose

Mouse models of partial bladder outlet obstruction cause bladder hypertrophy. Expression of a number of ion channels is altered in hypertrophic detrusor muscle, resulting in bladder dysfunction. We determined whether mechanosensitive TREK-1 channels are present in the murine bladder and whether their expression is altered in partial bladder outlet obstruction, resulting in abnormal filling responses.

Materials and Methods

Partial bladder outlet obstruction was surgically induced in CD-1 mice and the mice recovered for 14 days. Cystometry was done to evaluate bladder pressure responses during filling at 25 μl per minute in partial bladder outlet obstruction mice and sham operated controls. TREK-1 channel expression was determined at the mRNA and protein levels by quantitative reverse transcriptase-polymerase chain reaction and Western blotting, respectively, and localized in the bladder wall using immunohistochemistry.

Results

Obstructed bladders showed about a 2-fold increase in weight vs sham operated bladders. TREK-1 channel protein expression on Western blots from bladder smooth muscle strip homogenates was significantly decreased in obstructed mice. Immunohistochemistry revealed a significant decrease in TREK-1 channel immunoreactivity in detrusor smooth muscle in obstructed mice. On cystometry the TREK-1 channel blocker L-methioninol induced a significant increase in premature contractions during filling in sham operated mice. L-methioninol had no significant effect in obstructed mice, which showed an overactive detrusor phenotype.

Conclusions

TREK-1 channel down-regulation in detrusor myocytes is associated with bladder overactivity in a murine model of partial bladder outlet obstruction.

Key Words: urinary bladder, overactive, urinary bladder neck obstruction, hypertrophy, potassium channel protein TREK-1, mice

Abbreviations and Acronyms: GAPDH, glyceraldehyde-3-phosphate dehydrogenase, MHC, myosin heavy chain, NVC, nonvoiding contraction, PBOO, partial bladder outlet obstruction, PBS, phosphate buffered saline, SDK, stretch dependent potassium channels, TREK-1, TWIK-related K⁺-1 channel, TREK-1-LI, TREK-1-like immunoreactivity