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Role of the soluble guanylyl cyclase α1-subunit in murine bladder function
Saman Shafaat Talab, MD1, Emmanuel S. Buys, Phd1, Maryrose P. Sullivan, Phd2, Juan Cheng, MD1, Marielle Scherrer-Crosbie, MD1, Warren M. Zapol, MD1, Shahin Tabatabaei, MD1.
1Massachusetts General Hospital, Boston, MA, USA, 2VA Boston Healthcare System and Harvard Medical School, Boston, MA, USA.

BACKGROUND:Nitric oxide (NO) signaling plays an important role in urethral and bladder function. NO-dependent smooth muscle relaxation is mediated by cGMP through activation of soluble guanylyl cyclase (sGC). In this study we aim to investigate the importance of sGC in lower urinary tract function in mice by studying healthy wild-type (WT) animals and mice with a congenital absence of sGCα1.
METHODS:We studied 20 female sGCα1−/− mice and 20 of their WT littermates (C57BL/6, 20-25 g). Bladder function was evaluated by cystometry under anesthesia (Urethane 1000 mg/kg, IP) with a continuous infusion (15 μL/min) of saline or the NO donor, sodium nitroprusside (SNP, 0.1 mM) in both WT and sGCα1−/− mice, (n=6). We also examined the voiding pattern of awake WT and sGCα1−/− mice using voided urine stains on paper experiment (VSOP) (n=4): animals were individually housed in metabolic cages for 8 hrs and their voiding pattern was evaluated by measuring the number and surface area of urine stains on filter paper. In separate studies, under light sedation, bladder volume was measured by transabdominal ultrasound in both WT and sGCα1−/− mice.
RESULTS:In the cystometry study with a normal saline infusion, the bladder capacity and compliance was significantly higher in sGCα1−/− mice than in WT mice ((mean ± SD) 113.64±13.88 μl vs. 49.14±12.01 μl and 17.33±1.3 μl/mmHg vs. 4.04±1.23 μl/mmHg, respectively) (P < 0.01). The maximum voiding pressure during cystometry was similar in both sGCα1−/− and WT mice (31.4±4.1 mmHg and 35.4±7.61 mmHg). NO administration did not alter cystometric parameters including bladder capacity, bladder compliance, and maximum voiding pressure in both sGCα1−/− or WT mice. Non-voiding contractions were more frequent per voiding cycle in sGCα1−/− mice (4.6±2.3 vs. 2.1±0.4) (P<0.05). SNP infusion in the bladder significantly reduced the frequency of non-voiding contractions in WT animals (0.4±0.4) but not in sGCα1−/− mice. In awake mice, the voiding frequency was lower and the mean voiding volume was greater in sGCα1−/− than in WT mice. The micturition pattern evidences bladder hyperactivity in sGCα1−/− mice. Bladder volume, assessed in vivo by ultrasound, was significantly higher in sGCα1−/− than in WT mice (109.3±40.4 vs. 42.4±35.5 μl, respectively) (P<0.05).
CONCLUSIONS:sGCα1-deficiency in female mice is associated with a larger bladder size, greater bladder compliance, and bladder hyperactivity. These observations in sGCα1−/− mice suggest that the NO-sGC pathway plays a key role in bladder development and function and impaired NO-sGC signaling is associated with voiding disturbances.


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