Control of rat bladder neck relaxation with NORD-1, a red light-reactive nitric oxide releaser: In vitro study.

We aimed to control the relaxation of rat bladder neck specimens by using NORD-1, a red light-reactive nitric oxide (NO) releaser. Female and male 10-11-week-old Wistar/ST rats were divided into three groups: NORD-1, vehicle, and NORD-1+[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; a soluble guanylyl cyclase inhibitor). We infused 10-4 M NORD-1 into the bladders of NORD-1 and NORD-1+ODQ group rats and the vehicle into those of vehicle group rats. Isometric tension was analyzed using circular bladder neck specimens with 10-5 M NG-nitro-l-arginine methyl ester, an NO synthase inhibitor. Moreover, 10-5 M ODQ was added into the NORD-1+ODQ group bath. After precontraction with 10-5 M carbachol, the specimens were irradiated with red light and their relaxation responses were measured. We evaluated NORD-1 tissue permeability by observing the sliced bladder neck specimens. The NORD-1 group specimens relaxed during red light irradiation; the relaxation response increased with the increase in light intensity. The vehicle and NORD-1+ODQ group specimens did not respond to irradiation. Sex-related differences in responsiveness were not noted. NORD-1 permeated into the urothelium of NORD-1 group specimens. Rat bladder neck relaxation was controlled by NORD-1 and light irradiation in vitro. NORD-1 might be a novel therapeutic agent for voiding dysfunction.

Detrusor underactivity causes neurogenic voiding dysfunction in a rat bilateral accessory nerve-injury model.

We aimed to investigate detrusor function in a previously developed rat neurogenic voiding dysfunction model that we have developed previously. We performed sham or bilateral accessory nerve injury (BACNI) surgeries on ten-week-old male Wistar/ST rats. One week after surgery, we evaluated detrusor contractility in the bladder using isometric tension and mRNA expression assays. Cholinergic contraction was attenuated in the injury model, whereas carbachol-evoked contraction was enhanced, and mRNA expression of the cholinergic receptor increased. These findings suggest that there was a reduction in neurotransmitter release causing detrusor underactivity.

Effects of High Salt Intake on Detrusor Muscle Contraction in Dahl Salt-Sensitive Rats.

High salt intake has been reported as a risk factor for urinary storage symptoms. However, the association between high salt intake and detrusor muscle contraction is not clear. Therefore, we investigated the effects of high salt intake on the components of detrusor muscle contraction in rats. Six-week-old male Dahl salt-resistant (DR; n = 5) and Dahl salt-sensitive (DS; n = 5) rats were fed a high salt (8% NaCl) diet for one week. The contractile responses of the detrusor muscle to the cumulative administration of carbachol and electrical field stimulation (EFS) with and without suramin and atropine were evaluated via isometric tension study. The concentration-response curves of carbachol were shifted more to the left in the DS group than those in the DR group. Contractile responses to EFS were more enhanced in the DS group than those in the DR group (p < 0.05). Cholinergic component-induced responses were more enhanced in the DS group than those in the DR group (p < 0.05). High salt intake might cause urinary storage symptoms via abnormalities in detrusor muscle contraction and the enhancement of cholinergic signals. Excessive salt intake should be avoided to preserve bladder function.

Impairment of accessory nerves around major pelvic ganglion leading to overflow urinary incontinence in rats.

AIMS: To investigate the relationship between lower urinary tract function and the accessory nerve (ACN) arising from the major pelvic ganglion (MPG). METHODS: Ten-week-old male Wistar/ST rats were randomly divided into eight groups according to the type of treatment (sham or bilateral accessory nerve injury [BACNI]) and the duration of observation (3 days, 1 week, 2 weeks, or 4 weeks: Sham-3d, Sham-1w, Sham-2w, Sham-4w, BACNI-3d, BACNI-1w, BACNI-2ws, and BACNI-4w. BACNI was induced in the following manner: the ACN was crushed for 1 min (2 mm away from the MPG) using reverse-action tweezers. The same procedure was performed on both sides. On the last day of each observation period, the bladder function was measured by awake cystometry, and histological evaluation was performed. RESULTS: All rats in the Sham groups micturated normally. In the BACNI-3d and BACNI-1w groups, all rats showed symptoms of overflow urinary incontinence (OUI). This OUI improved gradually over time. The bladder's size in the BACNI group was significantly larger than that in the Sham group (p < .01). In addition, fibrosis was observed in the subserosa of the bladder of rats in BACNI groups. CONCLUSION: The BACNI model rats exhibited OUI, suggesting that ACN is involved in the lower urinary tract function. It might be possible that ACN controls the function of either the bladder, the urethra, or both.

Anagliptin, a dipeptidyl peptidase-4 inhibitor, improved bladder function and hemodynamics in rats with bilateral internal iliac artery ligation.

AIMS: To investigate the effect of anagliptin (Ana), a dipeptidyl peptidase-4 (DPP-4) inhibitor, on acute ischemia-induced bladder dysfunction in rats. METHODS: Eight-week-old female Wistar-ST rats were randomly assigned into four groups: (a) sham; (b) ligation (Lig); (c) Lig + Ana; and (d) Lig + Liraglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist; Lira). Rats in the Lig, Lig + Ana, and Lig + Lira groups underwent ligature of the bilateral internal iliac arteries. Ana was orally administered mixed with the CE-2 diet. Lira was subcutaneously administered once a day. Blood glucose levels, plasma dipeptidyl peptidase 4 (DPP-4) activity, GLP-1 levels, and bladder function were measured in all groups. Bladder blood flow was measured in the sham, Lig, and Lig + Ana groups, 4 weeks postsurgery. RESULTS: No differences in blood glucose levels among the groups were observed. DPP-4 activity decreased in the Lig + Ana group (P < .01). GLP-1 levels in the Lig + Ana and Lig + Lira groups were higher than those in the sham and Lig groups (P < .01). Intercontraction intervals (ICIs) were longer in the Lig and Lig + Lira groups than in the sham group (P < .05), but similar to those observed in the Lig + Ana and sham groups. The Lig group exhibited reduced bladder blood flow relative to the sham group (P < .01); however, this measure improved in the Lig + Ana group (P < .01). CONCLUSIONS: Ana administration improved ICIs and bladder blood flow after acute bladder ischemia through a GLP-1 receptor-independent signaling pathway, without altering the blood glucose levels. Therefore, Ana dosing might be useful to prevent ischemia-induced bladder dysfunctions.

High salt loading induces urinary storage dysfunction via upregulation of epithelial sodium channel alpha in the bladder epithelium in Dahl salt-sensitive rats.

We aimed to investigate whether high salt intake affects bladder function via epithelial sodium channel (ENaC) by using Dahl salt-resistant (DR) and salt-sensitive (DS) rats. Bladder weight of DR + high-salt diet (HS, 8% NaCl) and DS + HS groups were significantly higher than those of DR + normal-salt diet (NS, 0.3% NaCl) and DS + NS groups after one week treatment. We thereafter used only DR + HS and DS + HS group. Systolic and diastolic blood pressures were significantly higher in DS + HS group than in DR + HS group after the treatment period. Cystometrogram showed the intercontraction intervals (ICI) were significantly shorter in DS + HS group than in DR + HS group during infusion of saline. Subsequent infusion of amiloride significantly prolonged ICI in DS + HS group, while no intra-group difference in ICI was observed in DR + HS group. No intra- or inter-group differences in maximum intravesical pressure were observed. Protein expression levels of ENaCα in the bladder were significantly higher in DS + HS group than in DR + HS group. ENaCα protein was localized at bladder epithelium in both groups. In conclusion, high salt intake is considered to cause urinary storage dysfunction via upregulation of ENaC in the bladder epithelium with salt-sensitive hypertension, suggesting that ENaC might be a candidate for therapeutic target for urinary storage dysfunction.

Mineralocorticoid receptor stimulation induces urinary storage dysfunction via upregulation of epithelial sodium channel expression in the rat urinary bladder epithelium.

We aimed to evaluate mineralocorticoid receptor (MR) expression in rat bladder and the physiological role of the MR-epithelial sodium channel (ENaC) pathway in controlling bladder function in 10-12-week-old, male Sprague-Dawley rats. First, we examined the mRNA expression of MR and localization of MR and ENaC-α proteins in the urinary bladder. MR mRNA expression was observed in untreated-rat urinary bladders, and MR and ENaC-α proteins were localized in the epithelium. Next, rats were treated with vehicle (controls) or fludrocortisone (an MR agonist) for 3 days, and ENaC-α protein expression levels and bladder function were evaluated on day 4. ENaC-α protein expression was significantly higher in fludrocortisone-treated rats than in controls. In addition, cystometry was performed during intravesical infusion of saline and amiloride (an ENaC inhibitor). While intercontraction intervals (ICIs) during saline infusion were significantly shorter in the fludrocortisone group than in the controls, infusion of amiloride normalized the ICIs in the fludrocortisone group. However, no intra- or inter-group differences in maximum intravesical pressure were observed. Taken together, MR protein is localized in the rat urinary bladder epithelium, and may regulate ENaC expression and bladder afferent input. The MR-ENaC pathway may be a therapeutic target for ameliorating storage symptoms.