Tadalafil improves bladder dysfunction and object recognition in rats with pelvic venous congestion.

OBJECTIVES: To examine the effects of tadalafil on bladder function and object recognition ability in rats with alterations in urinary frequency and locomotor activity as a result of pelvic venous congestion. METHODS: A total of 48 female rats were divided into three groups (sham, pelvic venous congestion and pelvic venous congestion/tadalafil groups). In the pelvic venous congestion and pelvic venous congestion/tadalafil groups, the bilateral common iliac veins and uterine veins were ligated under anesthesia. Rats in the pelvic venous congestion/tadalafil group received a diet containing tadalafil, and the other rats were fed a normal diet. After 4 weeks, rats underwent analysis of voiding behavior, locomotor activity, a novel object recognition test, continuous cystometry, measurement of plasma monoamines, and measurement of plasma and urinary nitric oxide metabolites. Expression of nitric oxide synthase messenger ribonucleic acid in the bladder wall was also assessed, along with histological examination of the bladder. RESULTS: Rats with pelvic venous congestion showed a higher urinary frequency, lower locomotor activity, and lower plasma and urinary nitric oxide levels than sham rats. The bladder wall endothelial nitric oxide synthase messenger ribonucleic acid level was low and object recognition was impaired. Pelvic venous congestion/tadalafil rats showed improvement in locomotor activity, bladder function and object recognition compared with pelvic venous congestion rats, as well as elevation of plasma and urinary nitric oxide, plasma monoamines, and bladder neuronal nitric oxide synthase messenger ribonucleic acid expression. Bladder wall vascularity was greater in pelvic venous congestion/tadalafil rats compared with sham rats. CONCLUSIONS: In rats with pelvic venous congestion, tadalafil might improve bladder function and the general condition by increasing blood flow to the bladder and brain, and by increasing dopamine levels.

Action of naftopidil on spinal serotonergic neurotransmission for inhibition of the micturition reflex in rats.

AIMS: We examined the mechanism of action of naftopidil, an α1D/A blocker, on spinal descending serotonergic neurotransmission for the micturition reflex. METHODS: We examined (1) urinary 5-hydroxyindole acetic acid (5-HIAA) after intraperitoneal administration of saline, para-chlorophenylalanine (PCPA; a serotonin synthetic enzyme inhibitor), and/or 5-hydroxytryptophan (5-HTP; a serotonin precursor); (2) isovolumetric cystometry after intraperitoneal administration of saline, PCPA, and/or 5-HTP and intravenous injection of naftopidil; and (3) isovolumetric cystometry before and after intrathecal administration of serotonin (5-HT) receptor antagonists and intravenous injection of naftopidil. RESULTS: PCPA decreased and 5-HTP increased urinary 5-HIAA/creatinine. Intraperitoneal injection of PCPA did not influence cystometric parameters. Intraperitoneal injection of 5-HTP significantly shortened the interval between bladder contractions. Intravenous injection of naftopidil transiently abolished bladder contractions. However, the duration of abolishment of bladder contractions after injection of naftopidil in rats given PCPA was significantly shorter than that in rats given vehicle, but significantly longer than that in rats given PCPA and 5-HTP. Intrathecal injection of 5-HT1B, 5-HT3, or 5-HT7 receptor antagonists significantly prolonged the interval between bladder contractions. Intrathecal injection of 5-HT1D or 5-HT2B receptor antagonists significantly shortened the interval between bladder contractions. Combined administration of the maximum non-effective dose of 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, or 5-HT3 receptor antagonists and intravenous injection of naftopidil significantly shortened the duration of abolishment of bladder contraction compared to intravenous injection of naftopidil alone. CONCLUSIONS: Naftopidil may inhibit the micturition reflex via 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT3 receptors in the spinal cord. Neurourol. Urodynam. 36:604-609, 2017. © 2016 Wiley Periodicals, Inc.

Effects of silodosin on bladder activity in rats with frequent urination induced by pelvic venous congestion.

OBJECTIVE: To examine the effects of silodosin on bladder activity using female rats with frequent urination induced by pelvic venous congestion. METHODS: A total of 24 female rats were divided into three groups: sham, pelvic venous congestion and pelvic venous congestion/silodosin group. Rats in the pelvic venous congestion and pelvic venous congestion/silodosin groups were anesthetized with isoflurane, after which the bilateral common iliac veins and uterine veins were ligated. In the pelvic venous congestion/silodosin group, silodosin (0.3 mg/kg/day) was given using an osmotic pump implanted into the subcutaneous space of the back. After 5-6 weeks, analysis of voiding behavior, measurements of urinary 8-hydroxydeoxyguanosine and nitric oxide metabolites, continuous cystometry under urethane anesthesia, and Evans blue dye extravasation test of the bladder were carried out. RESULTS: In comparison with sham rats, pelvic venous congestion rats showed an increase in urination frequency with a concomitant increase in urine volume, a shorter interval between bladder contractions on continuous cystometry, an increase in urinary 8-hydroxydeoxyguanosine, a decrease in urinary nitric oxide metabolites and an increase in vesical vascular permeability. In comparison with pelvic venous congestion rats, pelvic venous congestion/silodosin rats showed a decrease in urination frequency with a concomitant decrease in urine volume, a lower maximum bladder contraction pressure, a longer interval between bladder contractions, an increase in urinary nitric oxide metabolites and a decrease in vascular permeability. CONCLUSION: Silodosin might improve both bladder dysfunction caused by pelvic venous congestion, and the pelvic venous congestion itself.

Propiverine increases urethral wall catecholamine levels and bladder leak point pressure in rats.

OBJECTIVE: To investigate whether propiverine has a noradrenaline re-uptake inhibitor and whether it acts on the lumbosacral cord or the urethral wall. In addition, we aimed to examine the effect of propiverine on leak point pressure in rats. METHODS: A total of 72 female and 30 male rats were used to examine the following: (i) the change of leak point pressure caused by intravenous agents in rats with vaginal distention; (ii) the change of leak point pressure caused by intrathecal agents in rats with vaginal distention; (iii) the noradrenaline re-uptake inhibitor action of propiverine; and (iv) catecholamine levels in the bladder wall, urethral wall, cerebrospinal fluid and plasma after oral administration of propiverine. RESULTS: Intravenous injection of propiverine, imipramine and duloxetine increased the leak point pressure in rats with vaginal distention. Intrathecal naftopidil decreased the leak point pressure, whereas subsequent intravenous propiverine restored the leak point pressure to the level before intrathecal naftopidil in rats with vaginal distention. Propiverine acted like a noradrenaline re-uptake inhibitor, increasing noradrenaline and/or dopamine levels in the plasma, cerebrospinal fluid, and urethral wall perfusion fluid. CONCLUSION: Propiverine inhibits noradrenaline re-uptake, as well as having antimuscarinic and Ca-antagonist actions. The inhibition of noradrenaline re-uptake by propiverine mainly occurs at the urethral level and partially in the central nervous system, and might stimulate the smooth muscle of the bladder neck and proximal urethra through α1-adrenergic receptors, as well as stimulating the striated muscle of the urethra and pelvic floor by activation of spinal motoneurons. Therefore, propiverine might be effective for both stress and urge incontinence.

Pelvic venous congestion with castration causes chronic prostatitis in rats.

OBJECTIVE: To determine whether castration combined with pelvic congestion could cause chronic prostatitis, and to examine the effect of eviprostat in this rat model. METHODS: Male rats were divided into three groups, which were the sham, castration combined with pelvic congestion and castration combined with pelvic congestion plus eviprostat groups. Rats in the castration combined with pelvic congestion and castration combined with pelvic congestion plus eviprostat groups were anesthetized with isoflurane, after which ligation of the bilateral common iliac veins and castration were carried out. The sham and castration combined with pelvic congestion groups were fed a standard diet, whereas the castration combined with pelvic congestion plus eviprostat group was fed the same diet containing 0.1% eviprostat. After 4 weeks, continuous cystometry was carried out under urethane anesthesia. Then the bladder and the prostate gland were subjected to histological examination. RESULTS: There was no significant difference of the interval between bladder contractions in the sham and castration combined with pelvic congestion plus eviprostat groups, but the interval in the castration combined with pelvic congestion group was significantly shorter than the other groups. There was no difference in the maximum bladder contraction pressure among the three groups. Pathological inflammatory changes of the bladder wall were slightly more severe in the castration combined with pelvic congestion and castration combined with pelvic congestion plus eviprostat groups than in the sham group, whereas bladder vascularity was increased in the castration combined with pelvic congestion plus eviprostat group. In addition, pathological inflammatory changes and glandular atrophy of the prostate were more severe in the castration combined with pelvic congestion and castration combined with pelvic congestion plus eviprostat groups than in the sham group. CONCLUSION: This rat model of pelvic congestion with castration might assist in the development of new treatments for chronic prostatitis and frequency.

Intravenous or local injections of flavoxate in the rostral pontine reticular formation inhibit urinary frequency induced by activation of medial frontal lobe neurons in rats.

PURPOSE: The rostral pontine reticular formation has a strong inhibitory effect on micturition by facilitating lumbosacral glycinergic neurons. We assessed the influence of the rostral pontine reticular formation on the micturition reflex after noradrenaline injection in the medial frontal lobe. We also examined the relation between the medial frontal lobe and the rostral pontine reticular formation. MATERIALS AND METHODS: Continuous cystometry was performed in 28 female rats. After the interval between bladder contractions was shortened by noradrenaline injection in the medial frontal lobe we injected glutamate or flavoxate hydrochloride in the rostral pontine reticular formation or intravenously injected flavoxate or propiverine. The change in bladder activity was examined. RESULTS: Noradrenaline injection in the medial frontal lobe shortened the interval between bladder contractions. In contrast to the bladder contraction interval before and after noradrenaline injection in the medial frontal lobe, the interval was prolonged after noradrenaline injection when glutamate or flavoxate was injected in the rostral pontine reticular formation, or flavoxate was injected intravenously. Noradrenaline injection in the medial frontal lobe plus intravenous propiverine injection also prolonged the interval compared to that after noradrenaline injection alone. However, the interval after noradrenaline injection in the medial frontal lobe plus intravenous injection of propiverine was shorter than that before noradrenaline injection only. CONCLUSIONS: Medial frontal lobe neurons excited by noradrenaline may facilitate the micturition reflex via activation of inhibitory interneurons, which inhibit descending rostral pontine reticular formation neurons that innervate the lumbosacral glycinergic inhibitory neurons. Therefore, the mechanism of micturition reflex facilitation by the activation of medial frontal lobe neurons involves the rostral pontine reticular formation.

Effect of carbazochrome sodium sulfonate on refractory chronic prostatitis.

OBJECTIVES: To study the effect of carbazochrome sodium sulfonate, an agent that reduces capillary permeability, on refractory chronic prostatitis. METHODS: Patients with prostatitis refractory to at least 8 weeks of routine therapy and with urinalysis positive for microhematuria were considered for the present study. In addition to their prior therapy, the patients received carbazochrome at a dose of 30 mg three times a day. The severity of pain (score 0-10), daytime and night-time frequency, international prostate symptom score, global self-assessment, urine occult blood positivity, and adverse events were assessed after 4 and 8 weeks of treatment, and compared with baseline findings. RESULTS: A total of 50 patients (mean age 68.6 ± 8.5 years) were evaluable. The pain score decreased significantly from 3.2 ± 2.1 at baseline to 1.7 ± 1.4 after 4 weeks of treatment and to 1.1 ± 1.8 after 8 weeks. Daytime and night-time frequency, storage symptoms, post-micturition symptoms, and urine occult blood positivity also significantly improved. More than 36% of the patients gave a global self-assessment rating of "improved" or "better" after both 4 and 8 weeks of treatment. Mild adverse events occurred in three patients; one had nausea and two developed drug rash. CONCLUSIONS: Carbazochrome seems to effectively improve pain as well as storage and post-micturition symptoms in patients with refractory chronic prostatitis.

Effect of propiverine hydrochloride on stress urinary incontinence.

OBJECTIVES: To investigate whether the anticholinergic agent, propiverine hydrochloride, is clinically effective for stress urinary incontinence. METHODS: The participants were adult female patients with the chief complaint of stress incontinence. Propiverine (20 mg once daily) was given for 8 weeks. If the response was inadequate after 4 weeks of treatment, the dose was increased to 40 mg/day. Before and after 4 and 8 weeks of treatment, lower urinary tract symptoms were assessed. The urethral pressure and blood catecholamine levels were also measured. RESULTS: A total of 37 patients (mean age 69 ± 11 years) were enrolled, including 15 patients with stress incontinence and 22 with mixed incontinence. The number of episodes of stress incontinence decreased significantly from 2.6 ± 2.3 times per day to 1.3 ± 2.2 times per day after 4 weeks, and 0.4 ± 0.6 times per day after 8 weeks. The daytime and night-time frequency of urination, and quality of life score showed significant improvement. The maximum urethral closing pressure and the functional urethral length increased significantly after treatment, but blood catecholamine levels, blood pressure and pulse rate at 8 weeks were not significantly different from those at baseline. CONCLUSIONS: Propiverine could be an effective drug for stress urinary incontinence by increasing urethral closing pressure without increasing blood catecholamine levels.

[Effect of distigmine at 5 mg daily in patients with detrusor underactivity].

PURPOSE: Since distigmine can cause the serious side effect of cholinergic crisis, its dosage regimen has been reduced to 5 mg/day for patients with difficulty in urination due to detrusor underactivity. Therefore, the efficacy and safety of add-on therapy with distigmine at 5 mg daily were examined in patients with persistent urination problems due to detrusor underactivity despite administration of alpha1-blockers. PATIENTS AND METHODS: The subjects were 39 patients with underactive bladder (18 men and 21 women with an average age of 75 years) who showed no improvement of difficulty in urination or had a residual urine volume > or = 50 ml despite the administration of alpha1-blockers for more than 4 weeks. They received treatment with distigmine (5 mg daily after breakfast) in addition to their alpha1-blockers for 8 weeks. The international prostate symptom score (IPSS), quality-of-life (QOL) score, residual urine volume, blood pressure, and biochemistry tests were investigated before and after addition of distigmine. RESULTS: After four and eight weeks of distigmine administration, all items of the IPSS and QOL score, as well as the residual urine volume, showed a significant decrease. In contrast, the pressure and pulse rate were unchanged. Serum creatinine showed a slight but significant decreased. As adverse events, frequent defecation, fecal incontinence, diarrhea, frequent urination and poor physical condition were recognized in 4 patients, but there was no serious event. CONCLUSION: For difficulty in urination due to detrusor underactivity, the combination of an alpha1-blocker with distigmine at 5 mg daily showed early efficacy and good safety.

Effect of chemical stimulation of the medial frontal lobe on the micturition reflex in rats.

PURPOSE: We assessed the influence of the medial frontal lobe on micturition after chemical stimulation. We also examined the relation between the medial frontal lobe and the rostral pontine reticular formation, which has a strong inhibitory effect on micturition. MATERIALS AND METHODS: A total of 35 female rats underwent continuous cystometry. Bladder activity changes were examined after physiological saline, glutamate, the glutamate receptor antagonist MK-801, noradrenaline or the adrenergic α-1 receptor antagonist naftopidil was injected in the medial frontal lobe. When glutamate was injected in the medial frontal lobe, MK-801 was also injected in the rostral pontine reticular formation. RESULTS: Glutamate injection in the medial frontal lobe prolonged the interval between bladder contractions while injection of the glutamate antagonist MK-801 shortened the interval. Glutamate injection in the medial frontal lobe just after MK-801 injection in the ipsilateral rostral pontine reticular formation also prolonged the interval between bladder contractions. However, after prior injection of MK-801 in the bilateral rostral pontine reticular formation glutamate injection in the medial frontal lobe did not influence cystometric parameters. Noradrenaline injection in the medial frontal lobe shortened the interval between bladder contractions while injection of its antagonist naftopidil prolonged the interval. CONCLUSIONS: Medial frontal lobe neurons excited by glutamate inhibited the micturition reflex via activation of the rostral pontine reticular formation by glutamatergic projection while medial frontal lobe neurons excited by noradrenaline facilitated the micturition reflex. Thus, the medial frontal lobe may be an important integration center for the initiation of micturition and urine storage mechanisms.

Excitatory effect of propiverine hydrochloride on urethral activity in rats.

OBJECTIVES: To investigate the effects of the antimuscarinic agent, propiverine, on the bladder and urethra in rats. METHODS: A total of 54 female rats were given propiverine, imidafenacin (an antimuscarinic agent), or distilled water by gavage once or twice daily. After 2 weeks, bladder and urethral activity were recorded under urethane anesthesia. In the propiverine group, the changes of bladder and urethral activity before and after intravenous injection of α(1) -adrenergic antagonists (prazosin, silodosin and naftopidil) were also recorded. Furthermore, the leak point pressure after electrical stimulation of abdominal wall muscles was measured in rats with vaginal distension from the control and propiverine groups. RESULTS: Intravesical baseline pressure was significantly lower in the propiverine and imidafenacin groups compared with the control group, whereas the urethral baseline pressure was significantly higher in the propiverine group compared with the control or imidafenacin groups. Intravenous injection of prazosin (an α(1) -receptor antagonist) significantly decreased the urethral baseline pressure in both of the propiverine and control groups. Intravenous injection of silodosin and naftopidil (α(1A) - and α(1D) -receptor antagonists, respectively) significantly decreased the maximum contraction pressure and the urethral baseline pressure in the propiverine group. The leak point pressure of the propiverine group was significantly higher than that of the control group. CONCLUSIONS: An increase of catecholamines after propiverine administration might activate smooth muscle of the proximal urethra via α(1A) - and α(1D) -adrenergic receptors, as well as activating urethral and pelvic floor striated muscle via the spinal motoneurons.

Effect of distigmine combined with propiverine on bladder activity in rats with spinal cord injury.

It is not uncommon for patients with spinal cord injury to have both detrusor overactivity during the storage phase and detrusor underactivity during the voiding phase. However, there has been no information about the efficacy of combined treatment with cholinesterase inhibitors and anti-muscarinic agents for this condition. Therefore, the effect of co-administration of distigmine bromide (a cholinesterase inhibitor) and propiverine hydrochloride (an anti-muscarinic agent) on bladder activity was examined in rats with spinal cord injury. Rats were anesthetized with isoflurane and the lower thoracic spinal cord was transected. The bladder was emptied by abdominal compression twice a day for 14 days after surgery. A total of 4 weeks after surgery, the animals were anesthetized with urethane, and the effect of intravenous injection of distigmine (0.01-1 mg/kg) followed by propiverine (1 mg/kg) on continuous cystometry parameters was examined. After injection of distigmine (0.1 and 1 mg/kg), the maximum bladder contraction pressure was significantly increased, and the duration of bladder contraction and the interval between bladder contractions were significantly prolonged. The baseline bladder pressure was not changed by injection of distigmine. After the addition of propiverine, the interval between bladder contractions was significantly further prolonged without any change of the maximum contraction pressure, baseline pressure or duration of bladder contraction. The residual volume after voiding bladder contraction was less than 0.1 mL in all animals. In conclusion, co-administration of distigmine with propiverine might improve both bladder underactivity during the voiding phase and bladder overactivity during the storage phase.

Dietary glycine improves urine storage symptoms in urology outpatients.

OBJECTIVES: Spinal glycinergic mechanisms inhibit the micturition reflex, and administration of glycine inhibits bladder activity in rats. Therefore, we examined whether dietary glycine would improve storage symptoms in urological outpatients. METHODS: We enrolled 20 participants (16 men and four women) with an overactive bladder symptom score (OABSS) ≥ 3. All participants took 3 g of glucose (placebo) twice a day for the first four weeks, then 3 g of glycine twice a day for the next four weeks. We evaluated blood pressure, international prostate symptom score (IPSS), nocturia quality of life (N-QOL) score, OABSS, frequency of urination, sleep latency, time to first nighttime void, bladder pain, global self-assessment (GSA) evaluated urinary symptom improvement, and adverse events. RESULTS: Glucose administered as a placebo improved urinary frequency, urine force on the IPSS, and five of the 13 items on the N-QOL. However, compared to the results before and after glucose administration, glycine treatment decreased the number of nocturnal voids, urgency, and total score for urine storage items on the IPSS. It also reduced blood pressure and improved IPSS-QOL. For the OABSS, improvements with glycine were noted in the number of nocturnal urinations, urinary urgency, urge incontinence, and total score. For the N-QOL, eight of 13 items, and the total score, improved. The actual number of nighttime urinations, sleep latency, latency to first nighttime urination, bladder pain, and GSA also improved. There were no adverse events. CONCLUSIONS: Glycine might improve urine storage symptoms, cardiovascular function, pain, and sleep.

[ASSOCIATION OF BREATH HYDROGEN CONCENTRATION WITH ORAL INTAKE AND URINARY DISEASES].

(Purpose) Ingestion of hydrogen is said to prevent oxidation in the body, but hydrogen is produced by intestinal bacterial flora and excreted in the exhaled breath. We investigated how breath hydrogen concentrations change with the diurnal cycle and under various conditions, including after consuming food or drink, and in people with urological disease. (Subjects and methods) Participants were healthy volunteers (40 men, 45 women; 30-83 years old) and urological outpatients (40 men with benign prostatic hyperplasia, 30 women with overactive bladder; 60 years or older). Breath hydrogen levels were measured before and after eating and drinking in three volunteers, and its diurnal variation was examined in one. The relationship between breath hydrogen and age or urological disease status was also analyzed by gender. Additional measurements were taken in the person with the highest breath hydrogen concentration and the person with the lowest; in these two people, breath hydrogen was measured at the same time for 10 or more days to determine the fluctuation range. (Results) Breath hydrogen concentration increased temporarily after ingestion of tap water, hydrogen water or food. It also increased with food intake and in cases of flatulence with intestinal gas accumulation, but decreased after defecation. In the person with the highest breath hydrogen, concentrations were 11.2-188.6 ppm, whereas in the person with the lowest, they were 0.4-2.3 ppm. Breath hydrogen increased significantly with age in healthy female volunteers. There was no association between breath hydrogen and benign prostatic hyperplasia, overactive bladder or constipation. (Conclusion) Breath hydrogen concentration increases with eating, drinking and aging, and is not associated with benign prostatic hyperplasia, overactive bladder or constipation. Breath hydrogen concentration varies widely between individuals, which may be due to differences in intestinal flora.

Mechanisms underlying the effects of propiverine on bladder activity in rats with pelvic venous congestion and urinary frequency.

We investigated the mechanisms by which propiverine hydrochloride influenced bladder activity in rats with pelvic venous congestion (PC) and urinary frequency. To create PC rats, female rats were anesthetized with isoflurane and the bilateral common iliac veins and bilateral uterine veins were ligated. At 4 weeks after ligation, we assessed voiding behaviour, locomotor activity, and urinary 8-hydroxydeoxyguanosine (8-OHdG) and nitric oxide metabolites (NOx). We also performed cystometry and measured mRNAs for nitric oxide synthase (NOS) and several receptors in the bladder wall. PC rats showed a decrease in locomotor activity and an increased frequency of urination. There was a decrease in endothelial NOS (eNOS), M3, and TRPV1 mRNA expression in the bladder wall, as well as an increase in inducible NOS (iNOS) mRNA. Administration of propiverine to PC rats increased locomotor activity to the level in sham rats, improved bladder function, decreased urinary 8-OHdG excretion, and increased urinary NOx excretion. In addition, propiverine increased neuronal NOS (nNOS) mRNA expression, and decreased expression of iNOS, M3 and TRPV1 mRNA in the bladder wall. Therefore, propiverine not only improved bladder dysfunction through its previously reported actions (anti-muscarinic effect, Ca antagonist effect, and inhibition of noradrenaline re-uptake), but also by reducing inflammation.

Relationship of blood flow in the common iliac vein to lower urinary tract disease.

PURPOSE: The relationship between blood flow and lower urinary tract disease was explored by measuring blood flow in the common iliac vein to examine the influence of pelvic congestion on lower urinary tract symptoms. METHODS: Color Doppler ultrasonography of the right common iliac vein was performed in 113 men and 60 women, who were outpatients of two Japanese hospitals. Average blood flow velocity and cross-sectional area of the vein were measured, and blood flow volume was calculated. The relationship between these parameters and age or urological diseases was then examined. RESULTS: There was no relation between age and average blood flow velocity or blood flow volume of the common iliac vein in either men or women. However, average common iliac vein blood flow velocity was significantly lower in men with chronic prostatitis and in women with overactive bladder than in other male and female patients, respectively. Common iliac vein blood flow volume was also significantly lower in men with chronic prostatitis than in other male patients. CONCLUSIONS: Men with chronic prostatitis and women with overactive bladder have low blood flow in the common iliac vein, suggesting that pelvic congestion may be related to these two conditions.

Evaluation of a rat model of functional urinary bladder outlet obstruction produced by chronic inhibition of nitric oxide synthase.

AIMS: Ligation of the urethra to create partial bladder outlet obstruction has widely been used as an animal model of bladder obstruction, although obstructive bladder dysfunction may be due to both mechanical and functional obstruction. Previous studies in rodents have demonstrated that long-term nitric oxide (NO) deficiency can lead to detrusor overactivity, and lack of NO may thus cause impairment of bladder outlet relaxation. The aim of this study was to define the characteristics of bladder and urethral dysfunction induced by chronic NO deficiency through both in vivo and in vitro investigations. MAIN METHODS: Rats were divided into two groups, and one group received an NO synthase inhibitor (Nω-nitro-L-arginine methyl ester hydrochloride: L-NAME) in the drinking water for 4 weeks. Bladder and urethral function were evaluated by continuous cystometry and isovolumetric cystometry. In vitro functional studies of detrusor strips and measurement of the mRNA and protein expression of an ischemic marker and a gap junction protein were also performed in separate rats. KEY FINDINGS: L-NAME administration raised blood pressure and decreased plasma nitrite/nitrate level compared to the control group. L-NAME treatment increased the frequency of bladder contractions and the residual volume, and elevated urethral pressure and bladder contraction pressure. In addition, carbachol-induced contraction was reduced in isolated detrusor strips from the L-NAME group, and bladder expression of HIF-1 and connexin 43 showed upregulation. SIGNIFICANCE: These findings suggest that chronic administration of L-NAME to rats induces bladder hyperactivity with residual urine, and may provide a useful model of functional bladder obstruction.

Pelvic venous congestion induces lower urinary tract dysfunction in rats.

Pelvic venous congestion (PC) is thought to be related to several diseases of the lower urinary tract (LUT). We examined the characteristics of the LUT in rats with PC. To create PC, female rats were anesthetized with isoflurane, and the bilateral common iliac veins and bilateral uterine veins were ligated. At 1-8 weeks after either ligation or sham surgery, we performed cystometry with or without administration of carbazochrome sodium sulfonate hydrate or propiverine hydrochloride, histologic examination of the bladder, blood flow imaging, assessment of locomotor activity, measurement of urinary 8-hydroxydeoxyguanosine (8-OHdG) and nitric oxide metabolites (NOx), and the Evans blue dye extravasation test. PC elevated frequency of urination after 2-6 weeks, and caused a decrease of spontaneous locomotor activity. In addition, there was a decrease of bladder blood flow, an increase of bladder vascular permeability, an increase of urinary 8-OHdG, a decrease of urinary NOx, and mild inflammatory changes of the bladder. In rats with PC, frequency of urination was normalized by administration of propiverine or carbazochrome. Rats with PC may be used as a model of PC associated with high frequency of urination, and this model may be useful when developing treatment for LUT symptoms associated with PC.

Naftopidil Improves Symptoms in a Rat Model of Tranilast-Induced Interstitial Cystitis.

OBJECTIVE: The effect of naftopidil on symptoms of tranilast-induced interstitial cystitis (IC) was examined in rats. METHODS: Thirty-two female rats were divided into four groups (control, naftopidil, tranilast, and combination groups). Rats in the control group were fed a standard diet, while rats in the naftopidil, tranilast, and combination groups were fed diets containing naftopidil, tranilast, or naftopidil + tranilast, respectively. After 4 weeks of treatment, locomotor activity was measured and continuous cystometry was performed. RESULTS: During the light period, locomotor activity was lower in the tranilast group than in the control, naftopidil, and combination groups. During the dark period, locomotor activity was higher in the naftopidil group than in the other three groups. The combination group showed higher locomotor activity than the tranilast group, but significantly lower activity than the naftopidil group. Continuous cystometry revealed that the interval between bladder contractions was shorter in the tranilast group than in the other three groups. The combination group also had a shorter interval between contractions than the control group. CONCLUSION: Naftopidil improved the symptoms of tranilast-induced IC, such as reduced locomotor activity due to pelvic pain and a shortened interval between bladder contractions. Therefore, naftopidil may be a potential treatment for IC.

Naftopidil improves locomotor activity and urinary frequency in rats with pelvic venous congestion.

The α1D/A receptor antagonist, naftopidil, inhibits micturition reflex by acting on various different sites. We examined the effects of naftopidil on bladder activity and changes in the induced urinary frequency using female rats with pelvic venous congestion (PC). Twenty-four female rats were divided into sham, PC, and PC/naftopidil groups. After anesthetizing rats in the PC and PC/naftopidil groups, the bilateral common iliac veins and uterine veins were ligated. Rats in the sham and PC groups were fed a standard diet, while rats in the PC/naftopidil group were fed diets containing 0.04% naftopidil. After 4 weeks of treatment, locomotor activity, urinary nitric oxide metabolites (NOx), continuous cystometry, and plasma monoamine measurements were performed. PC rats exhibited a decrease of locomotor activity, a shorter interval between bladder contractions on continuous cystometry, and decreased urinary NOx and plasma serotonin levels than the sham rats. The PC/naftopidil rats exhibited an increase of locomotor activity, a longer interval between bladder contractions, and increased urinary NOx and plasma serotonin levels. Therefore, naftopidil might improve bladder dysfunction induced by pelvic venous congestion due to several actions in the central nervous system and bladder tissue, as well as acting as an α1 blocker to cause pelvic venous dilation.