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Functional constipation induces bladder overactivity associated with upregulations of Htr2 pathways
Nao Iguchi, PhD1, Alonso Carrasco, Jr., MD2, Alison X. Xie, PhD1, Ricardo H. Pineda, PhD1, Anna P. Malykhina, PhD1, Duncan T. Wilcox, MBBS, MD3.
1University of Colorado AMC, Aurora, CO, USA, 2Children's Mercy Kansas City, Kansas City, MO, USA, 3Children's Hospital Colorado, Aurora, CO, USA.

BACKGROUND: Bladder and Bowel Dysfunction (BBD) is a common yet underdiagnosed pediatric entity that describes lower urinary tract symptoms (LUTS) accompanied by abnormal bowel patterns manifested as constipation and/or encopresis. LUTS usually manifest as urgency, urinary frequency, incontinence, and urinary tract infections (UTI). Despite increasing recognition of BBD as a risk factor for long-term urinary tract problems including recurrent UTI, vesicoureteral reflux, and renal scarring, the mechanisms underlying BBD have been unclear, and treatment remains empirical.
METHODS: Juvenile male mice (C57BL/6J, 4-week-old) were divided into two groups: constipation model, and sham group. Constipation was induced by surgical reduction of external anal sphincter opening. At 4 days post-op, LUT function was evaluated in vivo by awake cystometry and in vitro assessment of detrusor physiology and calcium imaging using isolated bladder strips. Changes in gene expression in bladders were examined by quantitative real-time PCR (qPCR) and immunostaining.
RESULTS: Animals in the constipation group developed the fecal impaction with a significant decrease in fecal output compared to the sham operated control group (4.0 ▒ 1.0 mg vs. 8.6 ▒ 0.5 mg, p=0.0025). This verified that our murine model replicated clinical characteristics of functional constipation in children. Animals with constipation developed LUTS including urinary frequency and bladder instability evaluated by awake cystometry (Table). Physiological examination of detrusor function in vitro demonstrated a significant increase in spontaneous contractions compared to the control group (frequency, 9.2 ▒ 0.5 vs. 6.7 ▒ 0.4 min−1, p=0.0015, and amplitude, 35.6 ▒ 5.8 vs. 14.2 ▒ 1.0 mg, p=0.0013) without affecting contractile force in response to electrical field stimulation, carbachol, and KCl. Likewise, a significant elevation of unprovoked spontaneous intracellular Ca2+ transients was observed in detrusor myocytes from the constipation group compared to those from the control animals (incidence, 6.7 ▒ 1.7 vs. 3.4 ▒ 1.2 min−1, p = 0.037). A significant upregulation of serotonin receptors, Htr2a and Htr2c, was observed in the bladders from mice with constipation. Pre-incubation of the bladder strips with 5‑HT (0.5 ÁM, corresponding to normal serum level) induced contraction response and exacerbated increases in spontaneous contractions in the constipation group, while no notable changes were observed in the control group. The selective Htr2 antagonist, ketanserin, reversed the 5-HT-induced detrusor overactivity in the constipation group (Figure).
CONCLUSIONS: Our results suggest that constipation induced detrusor overactivity and increased excitatory serotonin receptor activation in the urinary bladder, which contributes to the development of BBD. The data obtained in this study suggest that local administration of selective antagonists of Htr2 may offer therapeutic options for BBD patients.


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