Abstract
We conducted this study to examine whether acid-sensing ion channels (ASICs) are involved in the modulation of urinary bladder activity with or without intravesical irritation induced by acetic acid. All in vivo evaluations were conducted during continuous infusion cystometry in decerebrated unanesthetized female mice. During cystometry with a pH 6.3 saline infusion, an i.p. injection of 30 μmol/kg A-317567 (a potent, non-amiloride ASIC blocker) increased the intercontraction interval (ICI) by 30% (P < 0.001), whereas vehicle injection had no effect. An intravesical acetic acid (pH 3.0) infusion induced bladder hyperactivity, with reductions in ICI and maximal voiding pressure (MVP) by 79% (P < 0.0001) and 29% (P < 0.001), respectively. A-317567 (30 μmol/kg i.p.) alleviated hyperreflexia by increasing the acid-shortened ICI by 76% (P < 0.001). This dose produced no effect on MVP under either intravesical pH condition. Further analysis in comparison with vehicle showed that the increase in ICI (or bladder capacity) by the drug was not dependent on bladder compliance. Meanwhile, intravesical perfusion of A-317567 (100 μM) had no effect on bladder activity during pH 6.0 saline infusion cystometry, and drug perfusion at neither 100 μM nor 1 mM produced any effects on bladder hyperreflexia during pH 3.0 acetic acid infusion cystometry. A-317567 has been suggested to display extremely poor penetrability into the central nervous system and thus to be a peripherally active blocker. Taken together, our results suggest that blockade of ASIC signal transduction increases bladder capacity under normal intravesical pH conditions and alleviates bladder hyperreflexia induced by intravesical acidification and that the site responsible for this action is likely to be the dorsal root ganglia.
Highlights
Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder healthcare issue comprising severe refractory bladder symptoms such as suprapubic pain and urinary frequency and urgency, without a specific identifiable cause (Yoshimura et al, 2002)
We evaluated bladder compliance (BCP; μl/mmHg), which was calculated as the ratio of infused volume to the pressure difference between time points of resting pressure (RP) and the following pressure threshold (PT), i.e.,/(PT - previous RP)
The present study showed that i.p. administration of A-317567, a potent non-amiloride acid-sensing ion channels (ASICs) blocker, increases urinary bladder capacity during normal saline infusion cystometry and alleviates bladder hyperreflexia induced by intravesical infusion of acetic acid in decerebrated, unanesthetized mice
Summary
Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder healthcare issue comprising severe refractory bladder symptoms such as suprapubic pain and urinary frequency and urgency, without a specific identifiable cause (Yoshimura et al, 2002). Transient receptor potential vanilloid receptor 1 (TRPV1) has been suggested to be a candidate target in the treatment of IC/BPS (Liu et al, 2014; Grundy et al, 2018; Rosen et al, 2018). Previous studies have shown a possible involvement of TRPV1 in the modulation of irritated urinary bladder activity via signal transduction in the urothelium and via vesical afferent C-fiber transmission (Birder et al, 2002; Dinis et al, 2004; Wang et al, 2008), suggesting a potential therapeutic use of TRPV1 antagonists for IC/BPS. TRPV1 antagonists, have been found to significantly affect body temperature (Garami et al, 2020), contraindicating their clinical use and impeding further development of their applicability
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