Hypothesis / aims of study
The pharmacotherapy for acontractile detrusor (AD) is still disappointing. Previous studies have demonstrated the functional role of calcium activated chloride channel (CaCC) on bladder smooth muscle. We investigated the effects of activation of TMEM16A, a CaCC, on detrusor strips and voiding cycle presented in cystometry (CMG) using a model of metabolic syndrome (MetS) induced AD in rats.
Study design, materials and methods
Fructose feeding rats were fed a fructose rich diet while control animals received standard rat chow for 6 months. Based on the results of cystometric presentation at month 6, rats in NDF group (normal detrusor function) and AD group were selected. We conducted a strategy using a TMEM16A activator (N-(2-methoxyethyl)-N-(4-phenyl-2-thiazolyl)- 2,3,4-trimethoxybenzeneacetamide (Eact )) as a reagent to involve ①Organ bath isometric tension experiments of harvested bladder smooth tissue to construct concentration-response curve (CRC). ②Continuous infusion CMG under anesthesia with replacement of infused physiological saline by Eact solution at different concentrations. The results of CRC and the CMG parameters including maximum bladder voiding pressure (MBVP) and intercontraction interval (ICI) were recorded and compared among control, NDF and AD groups.
Interpretation of results
In our organ bath study, rat detrusor contractions could be induced by treatment of Eact in AD group in a concentration dependent manner. In the continuous infusion CMG study, significantly decreased MBVP and increased ICI could be found in AD group which could also be ameliorated by intravesical administration of Eact in a concentration dependent manner. Both in vitro and in vivo studies showed the positive effect of TMEM16A chloride channel activator on bladder contraction in rats with MetS induced AD.