Proceedings of The Physiological Society

Physiology 2014 (London, UK) (2014) Proc Physiol Soc 31, PCB187

Poster Communications

Investigation of Kv7 (KCNQ) modulators on contractility of normal and overactive rat bladder

L. Baysting1, K. D. McCloskey1

1. Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Belfast, Northern Ireland, United Kingdom.

Introduction: Kv7 channels have recently been shown to be functionally expressed in smooth muscle1,2 and interstitial cells3 from normal rat and guinea-pig bladder. Inhibition of Kv7 channels results in depolarization and enhanced contractility whereas Kv7 channel activation decreases contractility with hyperpolarization. Kv7 activators may therefore present promising pharmacological tools for the development of treatments for overactive bladder. It is not currently known whether Kv7 activation impacts contractility in overactive bladder. The present study examined the effect of Kv7 modulators on contractility in normal and overactive bladder from spontaneously hypertensive rats (SHR).Materials and Methods: Wistar (normal) and SHR rats were killed by cervical dislocation in accordance with Schedule 1 (UK Animals Scientific Procedures Act) and approval from QUB Animal Ethics and Welfare Committee. Bladders were removed, opened longitudinally and full thickness strips cut for in vitro myography. Results are presented as mean ± SEM, n and N denote the number of strips and animals respectively. Data were analysed by ANOVA with post-hoc Dunnett's test or paired t-tests with P<0.05 considered to be significant.Results: Spontaneous myogenic contractions developed in the majority of tissues (approx. 80%) from normal and SHR bladders in the presence of tetrodotoxin (500nM). Application of the Kv7 inhibitor, XE991 (1, 3, 10, 30 µM) enhanced spontaneous activity measured as Area Under Curve (AUC) in both normal (n=16, N=4, control 7,550 ± and SHR strips (n=12, N=3, control 5,527g ± 1, with significant increases at 10 µM (P<0.05; normal 30,104 ± 9,; SHR 12,967 ±3, and 30 µM (P<0.05; normal 36,309 ± 11,; SHR, 14,704 ± 3, The Kv7 activator, flupirtine (20 µM) significantly decreased spontaneous activity in normal (P<0.05, n=16, N=4) and SHR (P<0.05, n=12, N=3) strips. Neurogenic contractions were evoked by electrical field stimulation (0.5, 1, 2, 4, 8, 16Hz; 10s duration; 0.3ms pulse-width and were sensitive to tetrodotoxin (500nM). XE991 (10 µM) did not significantly affect neurogenic contractions across the frequencies tested either in normal (n=9, N=3) or SHR (n=11, N=3) bladder strips (P>0.05).Conclusions: Kv7 modulators impact the contractility of overactive bladder strips from SHRs and normal rats. These findings indicate that spontaneous activity is sensitive to Kv7 modulation, however, neurogenic contractions are insensitive. This is promising as development of Kv7 treatments to target non-voiding (overactive) contractions may spare neurogenic contraction which would be desirable for effective bladder emptying.

Where applicable, experiments conform with Society ethical requirements