Limitations of in vitro experiments on isolated human bladders included the inability to assess the full spectrum of TREK-1 related effects on voiding function as the channel is also expressed in the nervous system and therefore, may indirectly participate in micturition modulation via a neural pathway. Additionally, DO specimens had an increased basal tone and increased spontaneous contractile activity suggestive that TREK-1 channels affect bladder compliance during storage phase of the micturition cycle. Experimental data obtained by our group in bladder specimens from patients with idiopathic DO confirmed a decreased expression of TREK-1 channels along with an altered response to pharmacological stimulation and diminished smooth muscle relaxation. Interestingly, TREK-1 expression levels declined by the time of labor. In humans, increased expression of TREK-1 was detected in pregnant women’s myometrium. Ī decrease in functional expression of TREK-1 channel in the bladder smooth muscle was shown to be associated with detrusor overactivity (DO) in the animal model of partial bladder outlet obstruction. Further, expression of TREK-1 channels in vascular smooth muscle suggests a role in the regulation of the vascular tone and endothelial production of nitric oxide. TREK-1 has also been detected in the human myometrium, where it participates in the maintenance of uterine relaxation during pregnancy. Our previous studies confirmed that bladder capacity and detrusor relaxation in the human urinary bladder depends on the expression and function of TREK-1 channel, one of the members of the K 2P channel family. The family of mechano-gated K 2P channels is highly expressed in the smooth muscle of visceral hollow organs where they regulate smooth muscle excitability by controlling the resting membrane potential. Previous animal studies provided evidence that bladder stretch can activate mechanosensitive two-pore domain potassium (K 2P) channels. The urinary bladder undergoes slow mechanical stretch during the storage phase of the micturition cycle without significant changes in intravesical pressure. The observed differences are likely due to expression of TREK-1 channel not only in detrusor myocytes but also in afferent and efferent neural pathways involved in regulation of micturition which may underly the “mixed” voiding phenotype in TREK-1 KO mice. Our results provide evidence that global down-regulation of TREK-1 channels has dual effects on detrusor contractility and micturition patterns in vivo. However, cystometric recordings from TREK-1 KO mice revealed a significant increase in the duration of the intermicturition interval, enhanced bladder capacity and increased number of non-voiding contractions in comparison to WT mice. The detrusor strips from TREK-1 KO mice also generated more contractile force in response to electric field stimulation and high potassium concentration in comparison to WT group (p ≤ 0.05 for both tests). Stretch applied to isolated detrusor strips increased the amplitude of spontaneous contractions by 109% in the TREK-1 KO group in contrast to a 61% increase in WT mice ( p ≤ 0.05 to respective baseline for each group).
TREK-1 KO animals had an elevated basal muscle tone and enhanced spontaneous activity in the detrusor without detectable changes in bladder morphology/histology. The overall phenotype and bladder function were evaluated by gene and protein expression of TREK-1 channel, in vitro contractile experiments using detrusor strips in response to stretch and pharmacological stimuli, and cystometry in unanesthetized animals. MethodsĪdult C57BL/6 J wild-type (WT, N = 32) and TREK-1 KO ( N = 33) mice were used in this study. Therefore, in the present study, we aimed to assess the role of TREK-1 channel in bladder function and voiding patterns in vivo by using TREK-1 knockout (KO) mice. One of the limitations of in vitro experiments on isolated human detrusor included inability to evaluate in vivo effects of TREK-1 on voiding function, as the channel is also expressed in the nervous system, and may modulate micturition via neural pathways. Previously published results from our laboratory identified a mechano-gated two-pore domain potassium channel, TREK-1, as a main mechanosensor in the smooth muscle of the human urinary bladder.