Effect of GsMTx4 on Mouse Urinary Bladder Smooth Muscle (UBSM) Contractility

Abstract

Urinary incontinence is a common problem with limited treatment options. Stretch‐activated channels (SACs) enhance UBSM excitability, and have been proposed as a novel target for reducing overactive bladder. The goal of this study was to determine whether an inhibitor of SACs (GsMTx4) decreased UBSM contractions in wild‐type (WT) and BK KO (Kcnma1−/−) bladders, a mouse model for urinary incontinence which harbors a deletion of the BK K+ channel. GsMTx4 was applied to isolated UBSM strips at 0.1–10 μM and spontaneous (phasic) and nerve‐evoked (EFS) contractions were investigated using isometric tension recordings. As expected, baseline BK KO contractile amplitudes were significantly larger than WT. Application of 5 μM GsMTx4 induced a smaller reduction in BK KO phasic amplitude than in WT (KO: −12 ± 0.22%, WT: −31 ± 0.04%), and reliably decreased phasic frequency in BK KO strips (KO: −14 ± 9%, WT: +11 ± 4%). Additionally, 10 μM GsMTx4 suppressed EFS evoked contractions (10 Hz amplitude, BK KO: −19 ± 12%, WT: −4 ± 1%). This data suggests that GsMTx4 may be effective at reducing spontaneous and nerve evoked contractions in overactive UBSM, while having a limited effect on normal UBSM. This work was funded by NIDDK R21–089337 (A.L.M.) and the APS UGSRF (Z.K.).