Voiding Interval Research Articles

Selective Pharmacological Blockade of the TRPV1 Receptor Suppresses Sensory Reflexes of the Rodent Bladder

We investigated the pharmacological effect of TRPV1 antagonists in anesthetized rodent models of bladder function. The TRPV1 antagonists JNJ17203212 and JYL1421 were evaluated in the anesthetized rat volume induced micturition reflex model. JNJ17203212 was further evaluated in this model in capsaicin (Sigma) desensitized rats, and in rat capsaicin and mouse citric acid models of irritant induced detrusor overactivity. Systemic JNJ17203212 and JYL1421 administration in the anesthetized rat volume induced micturition reflex model resulted in an increased micturition threshold volume. JNJ17203212 also decreased bladder contraction amplitude but JYL1421 had no effect. Capsaicin desensitization significantly increased baseline micturition threshold volume and decreased bladder contraction amplitude in the volume induced micturition reflex model compared to those in sham treated controls and JNJ17203212 produced no further effect after capsaicin desensitization. JNJ17203212 was also effective in 2 models of irritant induced detrusor overactivity, preventing the decrease in micturition threshold volume and the increase in bladder contraction amplitude observed with intravesical instillation of 10 microM capsaicin, and the decreased voiding interval induced by intravesical citric acid. The TRPV1 antagonists JNJ17203212 and JYL1421 increased the threshold for activation of the micturition reflex in the anesthetized rat volume induced micturition reflex model. This effect appeared to be mediated by capsaicin sensitive afferents. JNJ17203212 also inhibited detrusor overactivity induced by intravesical capsaicin and intravesical citric acid. These data extend our understanding of the role of TRPV1 in sensory modulation of the micturition reflex under nonirritant and inflammatory conditions.

Role of α1‐adrenergic receptors in detrusor overactivity induced by cold stress in conscious rats

alpha(1)-Adrenergic receptors (ARs) are involved in micturition control both centrally and peripherally. alpha(1)-AR antagonists improve not only voiding but also storage symptoms in patients with bladder outlet obstruction. We investigated the role of alpha(1)-AR mechanisms involved in detrusor overactivity induced by cold stress in conscious rats. Continuous cystometry was performed at room temperature (RT, 28 +/- 2 degrees C) and for 40 min at cold temperature (CT, 4 +/- 2 degrees C). Voiding interval (VI), micturition volume (MV), and bladder capacity (BC) were evaluated before and after intravenous administration of KMD-3213 (selective alpha(1A)-AR antagonist), naftopidil (selective alpha(1D)-AR antagonist), tamsulosin (selective alpha(1A/1D)-AR antagonist), and prazosin (non-selective alpha(1)-AR antagonist). Blood pressure (BP), cumulative voided volume and body temperature were also evaluated. At RT, none of the AR antagonists caused significant change in the cystometric parameters. During 40 min of cold stress cumulative voided volume and body temperature did not change, but there were significant decreases in VI, MV, and BC. Low doses of the AR antagonists had no effect on CT-induced decreases of these variables. However, high doses of KMD-3213, tamsulosin, naftopidil and prazosin significantly inhibited the CT-induced decreases in VI, MV, and BC. CT caused a significant increase in BP, and this was not affected by low doses of the AR antagonists. However, high doses of prazosin significantly lowered the CT-induced increase of BP. Cold stress induces detrusor overactivity and increases BP in conscious rats. These effects are mediated, at least in part, by alpha(1A)-AR and alpha(1D)-AR subtypes and can be prevented/reduced by alpha(1)-AR antagonists.

61 Visceral Hypersensitivity and Altered 5-HT Dynamics in the Intestine of Rats with a Loss of Function Mutation in the Serotonin Transporter

capsaicin-sensitive afferents was clearly demonstrated, as capsaicin pretreatment prevented the development of cross-sensitization and the associated bladder mastocytosis. Furthermore, acute bladder afferent sensitization was noted at 1 hr, while sub-acutely, the degree of bladder mast cell migration was directly and temporally associated with increases in bladder permeability and decreases in bladder voiding intervals (irritative voiding). A causal role of mast cells could not be established. We hypothesize that pelvic organ mast cell infiltration, mediator release, and consequential afferent modulation are the primary mechanisms responsible for chronic pelvic organ sensitization. Methods: Intra-colonic TNBS (or vehicle) was administered to mast cell deficient mice (W/Wv) and wild type (WT) littermates. Eight days later, colonic and bladder mast cells were quantified, and under urethane anesthesia, bladder voiding intervals and permeability were measured using saline cystometry and fluorescein, respectively. Animal weights were recorded daily throughout the experiment. Results: Animal weights were decreased following intra-colonic TNBS beginning as early as day 2 and peaking at 15-20% on day 4 (p<0.05). By day 6, weights had normalized and were no different from untreated controls. Histologic colitis paralleled decreases in weight and was no different in the c-kit deficient mice as compared to WT whose mast cell counts were elevated three-fold (p<0.05). Colonic mast cell counts in W/Wv mice were significantly less at baseline compared to WT mice, and there was no change following TNBS. In the bladder, mast cell responses paralleled those of the colon despite the lack of any acute inflammatory changes. Voiding intervals were decreased by 33% in TNBS-treated WT mice (p<0.05) (irritative voiding) but were unchanged inW/Wvmice. Likewise, bladder permeability was increased 4-fold (p<0.05) in TNBS-treated WT mice but unchanged in W/Wv mice. Conclusion: Mast cells and afferent nerves both play important roles in the development and maintenance of pelvic organ sensitization. Although afferent nerves and neuropeptide release are likely response for the acute effects, it would appear that the mast cells and their effects play an important role in maintaining pelvic organ sensitization.

Duloxetine compared with placebo for treating women with symptoms of overactive bladder

To evaluate duloxetine (a serotonin-noradrenaline reuptake inhibitor) in women with symptoms of overactive bladder (OAB), as it has been shown to increase the bladder capacity in an animal model. In all, 306 women (aged 21-84 years) were recruited and randomly assigned to placebo (153) or duloxetine (80-mg/day for 4 weeks increased to 120-mg/day for 8 weeks; 153). Symptoms of OAB were defined as bothersome urinary urgency and/or urge urinary incontinence (UI) for > or =3 months. Participants were also required to have a mean daytime voiding interval (VI) of < or=2 h and urodynamic observations of either detrusor overactivity (DOA) or urgency which limited bladder capacity to <400 mL, both with no stress UI (SUI). The primary efficacy analysis compared the treatment effects on mean change from baseline to endpoint in the mean number of voiding episodes (VE)/24 h. The secondary efficacy analyses compared the treatment effects on the number of UI episodes (IE)/24 h, in the Incontinence Quality of Life questionnaire (I-QOL) score, and on the mean daytime VI. Safety was assessed with vital signs, adverse event reporting, routine laboratory testing, electrocardiogram, and the measurement of postvoid residual urine volumes (PVR). Patients randomized to duloxetine had significant improvements over those randomized to placebo for decreases in VE and IE, for increases in the daytime VI, and for improvements in I-QOL scores at both doses of duloxetine. Urodynamic studies showed no significant increases in maximum cystometric capacity or in the volume threshold for DOA. The most common treatment-emergent adverse events with duloxetine (nausea, 31%; dry mouth, 16%; dizziness, 14%; constipation, 14%; insomnia, 13%; and fatigue, 11%) were the same as those reported by women with SUI and were significantly more common with duloxetine than placebo. Laboratory assessments, vital signs and electrocardiograms were stable relative to baseline, with no relevant differences detected between groups. There was a significant difference in the change in PVR with duloxetine (<5 mL mean increase) but no patient reported hesitancy or retention. In this trial, duloxetine was better than placebo for treating women with 'wet' and 'dry' symptoms of OAB associated with DOA or a bladder capacity of <400 mL.

URODYNAMIC EFFECTS OF THE K+ CHANNEL (KCNQ) OPENER RETIGABINE IN FREELY MOVING, CONSCIOUS RATS

Retigabine is a novel anticonvulsant drug that not only augments gamma-aminobutyric acid mechanisms, but also opens voltage gated K+ channels (KCNQ). In this study we investigated the effects of retigabine on detrusor activity in rats. To conscious, female Sprague-Dawley rats undergoing continuous cystometry retigabine was given intravenously (0.5, 1 and 5 mg/kg(-1)). The KCNQ channel blocker linopirdine was given intravenously (2 mg/kg(-1)) 5 minutes prior to retigabine (1 mg/kg(-1)). In addition, retigabine was given intracerebroventricularly (1, 5 and 10 microg) and intravesically (100, 500 and 1,000 ng ml(-1)). The effects of the drug (intravesical administration) on capsaicin induced bladder overactivity were also tested. Retigabine given intravenously (1 mg/kg(-1)) decreased baseline and maximal bladder pressures, increased voided and infused volumes, and increased voiding intervals. Retigabine (10 microg) given intracerebroventricularly decreased baseline pressure and increased voided and infused volumes as well as voiding intervals. However, bladder pressures were not significantly affected. Intravesical retigabine (1,000 ng.ml(-1)) decreased maximal bladder pressure, increased voided and infused volumes, and increased voiding intervals. Given intravesically for 30 minutes prior to intravesical capsaicin (30 microM) instillation retigabine (1,000 ng.ml(-1)) decreased the detrusor overactivity induced by capsaicin. The KNCQ channel blocker linopirdine (2 mg/kg(-1)) completely blocked the effects of intravenous retigabine (1 mg/kg(-1)). Retigabine given intravenously, intracerebroventricularly and intravesically increased micturition volume and voiding intervals and, when given intravesically, it decreased capsaicin induced detrusor overactivity, suggesting that KCNQ channels can be interesting targets for drugs aiming at micturition control. Retigabine may be a candidate to test as a treatment for detrusor overactivity in humans.

Effects of resiniferatoxin desensitization of capsaicin-sensitive afferents on detrusor over-activity induced by intravesical capsaicin, acetic acid or ATP in conscious rats.

Recent studies have provided evidence for a major role of urothelially released ATP acting on a subpopulation of pelvic afferent nerves in mechano-afferent transduction in the bladder. We investigated whether desensitization of capsaicin-sensitive nerve fibres by systemic resiniferatoxin (RTX)-pretreatment can counteract the detrusor over-activity induced by intravesical capsaicin, acetic acid or ATP. Cystometric investigations were performed on awake female Sprague-Dawley rats before and 24 h after injection of RTX (0.3 mg/kg s.c.) or vehicle. The effects of intravesically instilled ATP (0.1 or 1.0 mM), capsaicin (30 microM) or acetic acid (pH 4.0) were compared with those of intravesical saline. RTX, but not its vehicle, significantly increased threshold pressure, voiding interval, micturition volume and bladder capacity. In the vehicle-pretreated rats, intravesical instillation of capsaicin or acetic acid significantly decreased voiding interval, micturition volume, and bladder capacity. However, in the RTX-pretreated rats, neither capsaicin nor acetic acid affected any parameter. On the other hand, intravesical ATP (0.1 mM) significantly decreased voiding interval and micturition volume in both groups of animals. At 1.0 mM, ATP also increased basal pressure and decreased the pressure threshold for micturition in both groups. The present results support the view that increased extracellular ATP has a role in mechano-afferent transduction in the rat bladder and that ATP-induced facilitation of the micturition reflex is mediated, at least partly, by nerves other than capsaicin-sensitive afferent nerves.

Interstitial cystitis: Successfulmanagement by increasing urinary voiding intervals

A variant of the interstitial cystitis (IC) syndrome, minimal or no pain or significant pain that has been lessened by another therapy, can be clinically improved by retraining of the individual's voiding pattern. Patients with greater pain but capable of completing this protocol also may be helped. While this group of patients fills the diagnostic criteria of IC and has many of the classic changes, many differ in that they have minimal or no pain, while simultaneously they have a dysfunctional bladder as expected from long-term low-volume voiding. All patients were placed on a protocol which focused on progressively increasing intervals between voids. Fifteen to thirty minutes initially were added to their present voiding time. The same increase was added to the voiding pattern every three or four weeks until an interval of three to four hours between voids was achieved. Twenty-one patients fit the criteria to be entered into this study. Overall 71 percent (15/21) had successful management of their symptoms and reported a 50 percent decrease in their symptoms of urinary urgency, frequency, and nocturia. Nineteen percent (4/21) reported 25 percent decrease in symptoms and 10 percent had no change. Presence of significant pain adversely affects outcome, 3/7 (with pain) improvements versus 12/14 (without pain). For all patients there was a significant increase in bladder capacity (92 mL average before study and 179 mL after) and average daily voids (13.2/day prestudy and 7.4 post-therapy). These differences in voided profiles were statistically significant (p value less than 0.01).