K_v7 Positive Modulators Reduce Detrusor Overactivity and Increase Bladder Capacity in Rats

Abstract

The effects of the K v 7 channel modulators retigabine (opener) and XE991 (blocker) on rat bladder function were investigated ex vivo and in vivo to assess the potential of K v 7 openers for the treatment of overactive bladder. In organ bath studies, capsaicin-stimulated rat urinary bladder rings were exposed to retigabine and XE991 and the effect on tension and amplitude was evaluated. In anaesthetized rats, retigabine (0.01-1 mg ⁄ kg, i.v.) effects on bladder function, in which overactivity was induced by continuous infusion of 0.5% acetic acid, were assessed. The effect of retigabine (10 mg ⁄ kg, p.o.) on cystometric parameters was also measured in conscious rats with capsaicin-induced irritated bladders. Localization of K v 7 subunits within bladder tissue was analysed by RT-qPCR and western blotting. In organ bath studies, retigabine robustly reduced capsaicin-induced contractility of bladder rings and this effect was blocked by XE991 confirming the specificity of action via K v 7 channels. In anaesthetized rats with acetic acid-irritated bladders, retigabine markedly increased bladder capacity with no concomitant reduction in blood pressure. Retigabine also reduced bladder pressure and delayed voiding in conscious rats with capsaicin-irritated bladders. K v 7

Molecular Expression and Pharmacological Evidence for a Functional Role of Kv7 Channel Subtypes in Guinea Pig Urinary Bladder Smooth Muscle

“…As illustrated in Figure 2, we could not detect any specific staining for Kv7.4 in DSM cells but did so for Kv7.1, Kv7.2, Kv7.3, and Kv7.5 channel subtypes. Our findings further extend and complement the recent observations in guinea pig, pig, and rat DSM [23,25,28]. In guinea pigs, all five Kv7 channel subtypes were detected by RT-PCR and immunohistochemistry [28] confirming our findings for Kv7.1, Kv7.2, Kv7.3, and Kv7.5 channel subtypes.…”

“…This finding and sporadic few other studies suggest that Kv7 channels might be important regulators of DSM function. Specifically, acute retigabine exposure has been shown to increase micturition volume and voiding intervals in rats [22,23], reduce the contractility and tone of rat and pig DSM isolated strips [23,24,25], and enhance Kv7 currents in guinea pig urinary bladder interstitial cells [26]. In addition, chronic exposure to retigabine resulted in a higher incidence of distended urinary bladders in a pre-clinical study [21].…”

“…In addition, chronic exposure to retigabine resulted in a higher incidence of distended urinary bladders in a pre-clinical study [21]. Kv7 channel subtype expression has been previously studied in rats by qRT-PCR, demonstrating the highest mRNA expression for Kv7.4 channels followed by detectable levels of Kv7.5 and Kv7.1 and minimal expression of Kv7.2 and Kv7.3 channel subtypes in whole bladder tissues [23]. Another study, also in rats, failed to detect any transcripts for Kv7.1, Kv7.2, or Kv7.3 channel subtypes by RT-PCR in whole bladder tissues; however, positive expression of KCNE1 and KCNE2 mRNAs was found [27].…”

The Novel KV7.2/KV7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

“…1, A and B), consistent with the previous reports by our group and others using immunohistochemistry (Afeli et al, 2013;Anderson et al, 2013). K V 7 channel activators and inhibitors such as retigabine and XE991 have provided a useful pharmacological approach for elucidating K V 7 channel roles in urinary bladder function Sheldon et al, 2002;Streng et al, 2004;Rode et al, 2010;Svalø et al, 2012Svalø et al, , 2013Svalø et al, , 2015Petkov, 2012;Afeli et al, 2013;Anderson et al, 2013). However, retigabine and XE991 do not effectively distinguish among K V 7.2-K V 7.5 and K V 7.1-K V 7.5 channel subtypes, respectively.…”

“…Patients undergoing treatment reported an increased occurrence of urinary retention compared with the placebo (Brickel et al, 2012). These findings correspond with in vivo studies in rodents, in which retigabine increased bladder capacity while decreasing voiding frequency (Streng et al, 2004;Svalø et al, 2012).…”