Acetic acid opens large-conductance Ca2+-activated K+ channels in guinea pig detrusor smooth muscle cells
Introduction
Urinary incontinence is characterized by the involuntary loss of urine and is frequently associated with hyperactivity of bladder detrusor muscle. Over 51 million Americans are reported to have these conditions. Both males and females are affected, with the highest prevalence observed in age groups > 60 years. Recent therapeutic advances have improved treatment of this patient population; however, efficacy and side effect profiles of current therapeutics are far from ideal. As such, treatment of overactive bladder continues to represent a significant medical challenge.
Animal models can reveal the phenomena involved in the bladder that are related to the origin of incontinence. However, there is an unmet need of an ideal animal model for urinary incontinence. Chemical irritants are frequently used in animal models to simulate the signs of urinary incontinence. Direct intravesical instillation of acetic acid (up to 1.0%) has been widely used as a method to produce bladder irritation (Chang et al., 1998). Acetic acid is also used to prevent bladder infections from indwelling urinary catheters in humans.
Large-conductance, calcium-activated K+ channels (BKCa) play critical roles in regulating human, rat, and guinea-pig detrusor smooth muscle reactivity (Herrera et al., 2000, Hashitani and Brading, 2003, Meredith et al., 2004). While examining the effects of NS 1619, a BKCa channel opener, on bladder function in the acetic acid irritation model, we found, unexpectedly, that acetic acid activated BKCa channels of detrusor smooth muscle cells. These effects of acetic acid were also confirmed in the recombinant human BKCa channels expressed in CHO cells. Direct effects of the acetic acid on BKCa channels of detrusor smooth muscle cells would affect bladder function and complicate pharmacological manipulation in the acetic acid irritant models of overactive bladder. Precaution needs to be taken when interpreting results obtained from these models.
Section snippets
Single cell isolation
The studies were carried out in accordance with the US NIH Guide for the Care and Use of Laboratory Animals and the GlaxoSmithKline Animal Care and Use Committee. The urinary bladder was removed from adult guinea pigs euthanized by sodium pentobarbital overdose. The bladder was washed in cold, nominal Ca2+-free solution containing (in mM): 137 NaCl, 5 KH2PO4, 1 MgSO4, 10 glucose, 5 HEPES, 8 taurine and 1 mg/ml bovine serum albumin; pH 7.4. Fat, connective tissue, and urothelium were largely
Effect of acetic acid on BKCa current in detrusor smooth muscle cells
Acetic acid activated BKCa current in freshly isolated guinea pig detrusor smooth muscle cells (Fig. 1). The selective BKCa channel blocker, iberiotoxin (100 nM), partially reversed the activation induced by 0.05% acetic acid on BKCa current (Fig. 1A). The % increase of BKCa current induced by 0.05% acetic acid at different membrane potentials was bell shaped, with a maximal response (2764 ± 918%, n = 8) at + 30 mV (Fig. 1B). The concentration-dependent responses at + 30 mV are illustrated in Fig. 1C.
Discussion
In the present study we have demonstrated that acetic acid, commonly used as an irritant to simulate overactive bladder in animal models, activated BKCa channels in detrusor smooth muscle cells. The effects of acetic acid were observed in native guinea pig (frequently used for in vivo and in vitro bladder studies) detrusor smooth muscle cells and CHO cells expressing recombinant human BKCa channels. These data suggest that acetic acid and related derivatives (e.g., butyric acid) have complex
Acknowledgement
The authors are grateful to their colleagues at Tanabe Pharmaceutical Company, Japan for their help.
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