Bladder smooth muscle contractility is inhibited by HC030031 independently of TRPA1
Sources of Funding: none
Introduction
TRPA1, a member of the Transient Receptor Potential (TRP) ion channel superfamily, is expressed in sensory afferents innervating the bladder, and activation of this channel induces urinary frequency in mice and rats. To investigate the role of TRPA1 in bladder physiology, researchers have often used HC030031 as a selective TRPA1 antagonist. In organ bath studies, concentrations between 1 and 100 μM are typically used. Preliminary data from our lab indicated inhibition of detrusor contractility with HC03031 (100 μM) in TRPA1 knock out mice. _x000D_ Our aim is to evaluate if HC030031 (100 μM) inhibits detrusor contractility in a TRPA1-independent manner.
Methods
The effect of HC030031 on detrusor contractility was examined in an organ bath study in wild type (WT) and TRPA1 knock-out (KO) C57Bl/6 mice. Contractile forces to cold (10°C), KCl (120 mM), carbachol (10 μM) and electrical field stimulation (EFS: 50V, 20Hz, 0,5ms, 10s) were recorded before, and after addition of HC030031 (100 μM), and following wash out. Contractile responses are reported as percentage of the first stimulus with the respective agonist. Statistical analyses were performed using Mann-Whitney U test and Kruskal-Wallis test.
Results
In WT animals, HC030031 (100 μM) partially inhibited all tested agonist-induced detrusor contractions. We observed a 46 ± 5 % reduction of the contractile response to KCl, a 45 ± 4 % reduction to carbachol and a 32 ± 6 % reduction to EFS. Importantly, similar blocking potency was observed in TRPA1 KO-animals, where HC030031 (100 μM) inhibited the contractile response to KCl by 59 ± 5 % and to carbachol by 61 ± 4 %.
Conclusions
HC030031 (100 μM) inhibits detrusor contractility independent of TRPA1. Further research is necessary to investigate the target of HC030031.
Funding
none
Jan Franken
Pieter Uvin
Yves Deruyver
Wouter Everaerts
Dirk De Ridder
Thomas Voets