Choreito, a Kampo medicine attenuates detrusor overactivity and bladder pain symptoms in rat tranilast-induced interstitial cystitis/bladder pain syndrome-like model.

AIMS: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory condition of the bladder. However, there are only a few medicines that are of pharmaceutical grade and reliably effective for IC/BPS symptoms. Choreito (CRT) is a pharmaceutical-grade Kampo medicine and has been widely prescribed for patients of lower urinary tract symptoms (LUTS) and BPS in Japan. In this study, we exploratory investigated the effects of CRT on the IC/BPS-like symptoms induced by tranilast. METHODS: The rat IC/BPS-like model was induced by feeding administration with 0.4% tranilast. The rats were divided into the three following treatment groups: normal diet (Normal), tranilast treatment (Control), and the groups of 1% CRT (CRT) treatment for IC/BPS-like model. After 4 weeks, continuous cystmetry, locomotor, and vascular permeability was assessed. Furthermore, the cytokine levels in bladder were analyzed by the Bio-Plex suspension array system and plasma monoamine were measured. RESULTS: Control group exhibited 14.3% decrease of locomotor activity in the dark period, and which were 20.3% increase by 1%CRT treatment. The voiding interval was shorter in control than in other groups. 1%CRT suppressed the shortening of voiding interval. Evans blue leakage of bladder wall observed 44.8% higher in control group than in the normal group. The leakage of 1%CRT group was 33.3% less than in the control group. The cytokine level of IFNγ and VEGF were elevated in the control, and CRT treatment suppressed the elevation of IFNγ in the bladder. Plasma noradrenaline was significantly reduced by CRT treatment compared normal group. CONCLUSION: These results suggest that CRT can be an effective therapeutic agent for the treatment of IC/BPS-like symptoms.

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.

Spinal glycinergic and gamma-aminobutyric acid-ergic neurons inhibit the micturition reflex after electrical stimulation of the perineum in rats with pelvic venous congestion.

OBJECTIVES: To examine whether electrical stimulation of the perineum inhibited urinary frequency in rats with pelvic venous congestion, and whether electrical stimulation influences spinal glycinergic/gamma-aminobutyric acid-ergic neurons. METHODS: Bilateral common iliac veins and bilateral uterine veins were ligated to create pelvic venous congestion rats. At 4 weeks after ligation, cystometry was carried out before and after electrical stimulation with/without intrathecal injection of strychnine (a glycine receptor antagonist) and/or bicuculline (a gamma-aminobutyric acid type A receptor antagonist). In addition, measurement of amino acid levels in the lumbosacral cord was carried out with/without electrical stimulation, and cystometry was carried out after oral administration of glycine. RESULTS: Continuous cystometry showed that the interval between bladder contractions was shorter in pelvic venous congestion rats than in sham rats. Electrical stimulation did not change cystometric parameters in sham rats, but the interval between bladder contractions was increased by electrical stimulation in pelvic venous congestion rats. Electrical stimulation increased the levels of glutamic acid, glycine, gamma-aminobutyric acid, and taurine in the lumbosacral cord of pelvic venous congestion rats. Intrathecal strychnine abolished the effects of electrical stimulation in pelvic venous congestion rats, and intrathecal administration of both strychnine and bicuculline shortened the interval between bladder contractions more than before electrical stimulation. Oral administration of glycine (3%) to pelvic venous congestion rats increased bladder capacity. CONCLUSIONS: Electrical stimulation of the perineum inhibits urinary frequency mainly through activation of spinal glycinergic neurons, and partly through activation of gamma-aminobutyric acid-ergic neurons in a rat model of pelvic venous congestion.

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.

Mechanisms by which a phytotherapeutic drug influences bladder activity in rats.

PURPOSE: We investigated the mechanisms by which Eviprostat, a phytotherapeutic drug for benign prostatic hyperplasia, influences bladder activity in rats. MATERIALS AND METHODS: A total of 42 female rats were divided into a control group and an Eviprostat group. Rats in the control group were fed a standard diet, while animals in the Eviprostat group were fed a diet containing 0.1% Eviprostat. After 2 weeks 14 rats (7 rats per group) underwent continuous cystometry with physiological saline or 0.1% acetic acid solution and bladder activity was recorded. Body weight, blood pressure, plasma monoamines and adenosine triphosphate were measured in another 14 rats (7 per group). In the remaining 14 rats (7 per group) 0.1% acetic acid solution was infused into the bladder and urinary adenosine triphosphate was measured before and after stimulation. RESULTS: During cystometry with acetic acid the interval between bladder contractions was shorter and maximum bladder contraction pressure was higher in the control group compared with results obtained using physiological saline but such differences were not seen in the Eviprostat group. Plasma adrenaline and noradrenaline were lower in the Eviprostat group than the control group but no difference in blood pressure was observed. Urinary adenosine triphosphate was higher in the 2 groups than before stimulation but the increase was smaller in the Eviprostat group than in the control group. CONCLUSIONS: These results suggest that Eviprostat acts to maintain low catecholamine and also inhibit pathological bladder activity by decreasing adenosine triphosphate release from the bladder.

Effect of Gosha-jinki-gan, a blended herbal medicine, on bladder activity in rats.

PURPOSE: We investigated the effect of the blended herbal medicine Gosha-jinki-gan on bladder activity and the autonomic nervous system in rats. MATERIALS AND METHODS: A total of 42 female rats were divided into a control diet group of 21 and a Gosha-jinki-gan diet group of 21. Rats in the control diet group were fed a standard diet, while animals in the Gosha-jinki-gan were fed a special diet containing 1.08% Gosha-jinki-gan (TJ107, Tsumura Co., Tokyo, Japan). After 4 weeks 28 rats, including 14 in the control and 14 in the Gosha-jinki-gan group, underwent continuous cystometry with physiological saline or 0.1% acetic acid solution and bladder activity was recorded. The remaining 14 rats were anesthetized with halothane, and body weight, serum amino acid (glutamate and glycine) and plasma monoamine (noradrenaline, adrenaline, dopamine and serotonin) levels were measured. RESULTS: The amplitude of bladder contraction on continuous cystometry with physiological saline was lower in the Gosha-jinki-gan diet group than in the control diet group, and plasma dopamine and serotonin levels were also lower in the Gosha-jinki-gan group. When cystometry was done with 0.1% acetic acid, the interval between bladder contractions was shortened in the control and Gosha-jinki-gan groups. However, the interval and duration of bladder contractions were longer in the Gosha-jinki-gan than in the control group. CONCLUSIONS: These results suggest that Gosha-jinki-gan inhibits bladder activity by maintaining the balance of the sympathetic and parasympathetic nervous systems at a low level.

Intrathecal or dietary glycine inhibits bladder and urethral activity in rats with spinal cord injury.

PURPOSE: We examined the influence of intrathecal or dietary glycine on bladder and urethral activity in rats with spinal cord injury. MATERIALS AND METHODS: A total of 20 female Sprague-Dawley rats were used 4 weeks after lower thoracic spinal cord injury. The rats were divided into standard and 1% glycine diet groups. In the standard diet group isovolumetric cystometry and urethral pressure measurement were performed before and after intrathecal injection of glycine. In the 1% glycine diet group bladder and urethral activity were compared with control recordings in the standard diet group. RESULTS: In the standard diet group intrathecal injection of glycine prolonged the interval and decreased the amplitude of bladder contractions, decreased baseline urethral pressure and altered urethral activity during bladder contraction from a pattern of detrusor-sphincter dyssynergia to detrusor-sphincter synergy at 100 mug glycine. In the 1% glycine diet group the interval and amplitude of bladder contractions were prolonged and decreased, respectively, compared with those in the standard diet group. Baseline urethral pressure was lower than in the standard diet group even after intrathecal injection of 100 mug glycine. Urethral pressure did not change during bladder contraction and it was the same as baseline pressure. Residual urine volume was lower than in the standard diet group. CONCLUSIONS: Intrathecal or dietary glycine inhibits bladder and urethral activity, and improves detrusor hyperreflexia and detrusor-sphincter dyssynergia.

Urinary response to an oxalic acid load is influenced by the timing of calcium loading in rats.

PURPOSE: Dietary intake of calcium or dairy products has been shown to decrease urinary oxalate excretion by limiting its intestinal absorption. However, not enough attention has been given to whether there is any benefit from altering the schedule of ingesting calcium and oxalate. Therefore, we investigated the effects of changes in the timing of calcium and oxalate loading on urinary oxalate excretion. MATERIALS AND METHODS: Male Wistar rats weighing 180 to 200 gm were fasted and randomized into several groups. They were then administered normal saline or oxalic acid with or without calcium or milk. Calcium or milk was given immediately, or 5, 10, 15 or 30 minutes before or after the oxalate load. All treatments were given via gastrostomy. Urine samples were collected by bladder puncture just before administration and at hourly intervals up to 5 hours afterward. Urinary oxalate was measured by capillary electrophoresis. RESULTS: Urinary oxalate increased after the administration of oxalate alone, while it decreased when oxalate was combined with calcium or milk. Urinary oxalate showed a smaller increment when calcium or milk was given before than after oxalate loading, and it was much smaller when calcium or milk was given immediately before oxalate. CONCLUSIONS: Prior calcium loading appears to have a positive influence on decreasing oxalic acid absorption from the intestinal tract. Therefore, calcium or dairy products should always be ingested before a meal rich in oxalate to prevent oxalate absorption and decrease urinary oxalate excretion.

Major factors modulating the serum oxalic acid level in hemodialysis patients.

Ascorbic acid overload and vitamin B6 deficiency have been implicated in the development of hyperoxalemia in dialysis patients, but there is still disagreement about this. Hemodialysis patients who are exposed long-term hyperoxalemia may develop secondary oxalosis with an increased risk of cardiac, vascular, and bone disease, and thus may benefit from maintaining a low serum oxalic acid level. In 452 hemodialysis patients, the serum level of oxalic acid was 47.2 +/- 22.9 micromol /l before and 16.9 +/- 10.5 micromol/l after a 4-hour dialysis session, while the ascorbic acid levels were 39.0 +/- 92.7 micromol/l and 6.5 +/- 18.6 micromol/l, the glycolic acid levels were 7.3 +/- 10.1 micromol/l and 0.6 +/- 2.3 micromol/l, and the citric acid levels were 141.3 +/- 54.7 micromol/l and 117.6 +/- 37.2 micromol/l, respectively. Most patients (65.3 percent) had low serum ascorbic acid levels (less than 10 micromol/l) before hemodialysis. The serum level of oxalic acid [Ox] showed a significant positive correlation with the levels of ascorbic acid [AA], glycolic acid [Gly], and creatinine [Cre]: [Ox] = 21.711 + 0.181 x [AA] + 0.174 x [Gly] + 0.171 x [Cre], (all micromol/l, p less than 0.05). In 124 dialysis patients, the 4-pyridoxic acid level was 8.9 +/- 19.6 micromol /l before and 3.9 +/- 8.8 micromol/l after dialysis, and it was not correlated with oxalic acid or glycolic acid. Most dialysis patients (65.3 percent) had low serum levels of ascorbic acid, but a subgroup of patients (12 percent) had high serum ascorbic acid levels (more than 100 micromol/l) associated with hyperoxalemia (88.2 +/- 24.5 micromol/l). High-dose vitamin C supplementation may aggravate hyperoxalemia in hemodialysis patients, so attention should be paid to avoiding this risk.

Urinary oxalic acid excretion differs after oral loading of rats with various oxalate salts.

BACKGROUND: To compare urinary oxalate excretion after the oral administration of oxalic acid, disodium oxalate, or calcium oxalate in rats. METHODS: Male Wistar rats were divided into four groups of six rats each and were intravenously hydrated with normal saline, and then were administered normal saline (control group), 10 mg of oxalic acid, equimolar disodium oxalate, or equimolar calcium oxalate via a gastrostomy. Urine specimens were collected just before administration and at hourly intervals up to 5 h afterwards. The urinary oxalate, calcium, magnesium and phosphorus levels were measured. RESULTS: Urinary oxalate excretion peaked at 1-2 h after administration of oxalic acid or equimolar disodium oxalate, while administration of calcium oxalate only caused a small increase of urinary oxalate excretion. Cumulative urinary oxalate excretion during 5 h was 1.69 +/- 0.10 mg (mean +/- SD; 17%), 1.43 +/- 0.13 mg (13%), and 0.22 +/- 0.03 mg (2%) after the administration of oxalic acid, disodium oxalate, and calcium oxalate, respectively. Urinary calcium excretion showed a decrease in the oxalic acid and disodium oxalate groups, while urinary magnesium or phosphorus excretion did not change significantly. CONCLUSION: The upper gastrointestinal tract seems to be the major site of oxalic acid absorption and only free oxalate is absorbed irrespective of whether it is the sodium salt or not. After binding to calcium in the gut, oxalic acid absorption seems to be inhibited in the presence of calcium and this means that calcium oxalate is poorly absorbed (at least in the upper gastrointestinal tract).