Motor effects of K V 7 channel modulators in the human detrusor

D Currò1, R Bientinesi2, E Sacco2, PF Bassi2. 1Institute of Pharmacology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy, 2Department of Urology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy

The voltage-dependent K+ (KV) channels encoded by the KCNQ gene family (KV7.1–7.5) are delayed rectifier K+ channels with important functional roles in regulating the membrane potential of various cell types, including cardiomyocytes, neurons and smooth muscle cells (1). The opening of KV7.2-7.3 channels in neurons gives rise to the M current, that modulates excitability and firing pattern. KV7 channels also regulate smooth muscle activity in different systems (2). The aim of the present study was to investigate the motor effects of KV7 channel modulators in the human detrusor. Detrusor specimens were obtained from patients undergoing surgical resections for urinary bladder cancer. The study was approved by the Ethics Committee of the Catholic University and all patients signed an informed consent. Muscle strips prepared from the detrusor were suspended under isotonic conditions (9.8-mN load) in Krebs solution maintained at 37° C and bubbled with carbogen inside 5 ml organ baths. The effects of the KV7 blocker XE-991 and the KV7.2-7.5 channel activators retigabine and flupirtine were investigated. XE-991 (1-100 μM) produced concentration-dependent contractions, with mean EC50 and Emax of 14.1±3.7 μM and 28.8±4.6 % of the maximal contraction induced by bethanechol (100 μM), respectively (n=6). Retigabine and flupirtine (both 1-100 μM) induced concentration-dependent relaxations of bethanecol (5 μM)-precontracted strips. Retigabine (100 μM)- and flupirtine (100 μM)-induced relaxations were 51.8±5.3 % (n=6) and 51.6±11.6 % (n=5) of bethanecol (5 μM)-produced precontraction, respectively. DMSO, the solvent in which retigabine and flupirtine were dissolved, at the maximal concentration used (0.5 %) relaxed bethanechol-precontracted strips by 17.5±0.9 % (n=4, P<0.05 vs. 100 μM retigabine and flupirtine). XE-991 (20 μM) reduced retigabine (100 μM)-induced relaxation to levels very close to those produced by DMSO (47.0±5.6 % and 20.8±9.0 % of bethanechol-produced precontraction without and with XE-991, n=4, P<0.01). The relaxation produced by retigabine (100 μM) was not significantly affected by tetrodotoxin (1 μM) and ω-conotoxin GVIA (30 nM) (n=3 each). Our results seem to indicate that KV7 channels regulate the smooth muscle tone in the human detrusor. Thus, KV7 channel activators could be useful detrusor relaxant agents for the treatment of urinary bladder motor disturbances.

(1) Soldovieri et al. (2011). Physiology (Bethesda) 26: 365-376.

(2) Stott et al. (2014). Drug Discov Today 19: 413–424.