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We investigated the actions of Gosha-jinki-gan, a traditional Japanese medicine containing processed Aconiti tubers, on urinary bladder function in anesthetized rats. In cystometrical investigations, Gosha-jinki-gan (1.0 g/kg, i.d.) increased bladder capacity as well as micturition threshold pressure. In addition, it decreased the frequency of distension-induced rhythmic bladder contractions. However, it did not influence the amplitude of bladder contractions induced by electrical stimulation of the pontine micturition center. The inhibitory effect of Gosha-jinki-gan on bladder motility was abolished by pretreatment with nor-binaltorphimine (10 mg/kg, s.c.), and was diminished by the concomitant use of anti-dynorphin A antiserum (10 μg, i.t.), yohimbine (10 μg, i.t.), or methysergide (20 μg, i.t.). Processed Aconiti tuber extract (27 mg/kg, i.d.) also suppressed bladder motility, and the effect was abolished by nor-binaltorphimine. These results suggest that Gosha-jinki-gan attenuates bladder sensation via the kappa-opioid receptor-stimulating action of processed Aconiti tuber. Gosha-jinki-gan may be a useful anti-pollakiuria agent that does not influence bladder contractility at micturition. Keywords:: Gosha-jinki-gan, anti-pollakiuria effect, micturition reflex, kappa-opioid receptor, processed Aconiti tuber

Background: We examined the influence of rectal distention on the spinal micturition reflex and the mechanism underlying its inhibition of bladder contraction. Methods: Fourteen conscious female Sprague-Dawley rats were used in this study after transection of the lower thoracic cord. Isovolumetric cystometry was performed before and after distention of the rectum by inflation of a rectal balloon, followed by intrathecal injection of strychnine (a selective glycine receptor antagonist) or bicuculline (a GABAA receptor antagonist) into the lumbosacral cord. Results: Rectal distention (1.0–3.0 cm3) prolonged the interval, decreased the amplitude, and shortened the duration of bladder contraction, and eventually almost abolished bladder activity. After intrathecal injection of strychnine (0.001–10 µg) or bicuculline (0.001–1 µg) in animals with inhibition of bladder activity by rectal distention, the interval, amplitude, and duration of bladder contraction returned to baseline. Conclusion: These results suggest that there is an inhibitory rectovesical reflex in the lumbosacral cord of rats with spinal cord injury, which modulates the spinal micturition reflex via glycinergic or GABAergic mechanisms.

Intravesical electrical stimulation (IVES) has been used in treatment of patients with urinary bladder dysfunctions for more than four decades. While some investigators have reported excellent results others have observed less convincing effects or outright failures. The discrepancies may reflect differences in patient selection or stimulation procedure. A better theoretical understanding of the IVES working mechanism might help to improve the success rate of the treatment. The aims of the present study were to provide such information. Experiments were performed on adult female cats and rats under /alpha/-chloralose anesthesia. IVES was delivered by a catheter electrode in the bladder. At proper intensity and frequency, IVES evoked reflex detrusor contractions that were abolished by bilateral rhizotomy of sacral dorsal roots. Stimulation parameters and response characteristics revealed that bladder mechanoreceptor A/delta/ afferents were activated by the IVES, the same afferents that drive the normal micturition reflex. Five minutes of continues IVES at 20 Hz induced a prolonged, significant decrease in the micturition threshold volume of anesthetized rats. Similarly, selective bladder A/delta/ afferent stimulation induced a long-lasting enhancement of micturition reflex discharges in cats. A comparable prolonged inhibitory effect on the micturition reflex was demonstrated after ano-genital afferent stimulation. Both modulatory effects occurred without changes in response sensitivity of stimulated afferents. The IVES induced modulation was prevented by transient exposure of the bladder to a local anesthetic and by systemic administration of a glutamate NMDA receptor antagonist. In conclusion, IVES induces a prolonged modulation of the micturition reflex by an LTP like enhancement of excitatory synaptic transmission in the central micturition reflex pathway. The findings provide an experimental explanation for the neuronal mechanisms underlying the curative effect of IVES in patients with bladder evacuation problems. On the day of the public defence the status of article V was: Accepted.

The central pathway of the micturition reflex in the rat was investigated functionally by acute blockade of synaptic neurotransmission using microinjection of cobalt chloride into the periaqueductal gray or pontine tegmental region. In 27 urethan-anesthetized (1.2 g/kg ip) rats, the bladder pressure response to continuous infusion of the bladder with saline (0.1–0.25 ml/min) was assessed. Electromyographic activity of external urethral sphincter and arterial blood pressure were also monitored. Bladder contractions and external urethral sphincter activity were reversibly attenuated after unilateral or bilateral stereotaxic injections of 10 mM cobalt chloride into the caudal (bregma −7.80 to −8.80) ventrolateral periaqueductal gray as well as into Barrington’s nucleus. Blood pressure was not affected by injection into either area. The results demonstrate that the caudal ventrolateral periaqueductal gray, in addition to Barrington’s nucleus, is a critical part of the long-routed micturition reflex circuitry in the anesthetized rat.

This unit describes a conscious rat model that allows the investigation of compounds administered by various routes (e.g., oral, intravenous and subcutaneous). This procedure can be used to examine the effects of agents on supraspinal, spinal and peripheral control of the micturition reflex, in addition to effects on parasympathetic neurotransmission and detrusor relaxation. One advantage to this procedure over anesthetized dog and rat models is the ability to determine pharmacological effects in the absence of possible interfering effects of anesthetics.

This study was undertaken to examine the change in intravesical saline volume during isovolumetric cystometry in the urethane anesthetized female rat. The ureters were transected bilaterally and their distal ends were ligated. To prevent leakage of intravesical fluid, the proximal urethra was ligated after inserting a urethral catheter into the bladder. In 13 rats in which the bladder was filled with different volumes of saline between 0.3 and 2.0 ml and maintained under isovolumetric conditions for 3 hours, intravesical volume decreased (4-79%) when initial intravesical saline volume was equal to or greater than 0.6 ml (n = 9). In 9 rats in which intravesical volume decreased, mean final volume was 0.68 +/- 0.09 ml. The percentage change in intravesical volume (y) significantly depended on initial volume (x) (y = -42x + 17, n = 13). In 7 rats in which the proximal urethra was ligated and the bladder was filled with different volumes of soybean oil between 0.25 and 2.0 ml, intravesical volume did not change. In 8 rats in which the bladder neck was ligated around a urethral catheter to block blood flow to the bladder and in which the bladder was filled with different volumes of saline (0.3-1.8 ml), intravesical volume decreased when initial volume was equal to or greater than 1.35 ml. These results demonstrate that intravesical saline is absorbed from the normal bladder wall when intravesical volume is greater than the volume (0.6 ml) necessary to evoke the micturition reflex in urethane anesthetized rats.

The mechanisms governing development of diseases causing lower urinary tract disorders, such as overactive bladder and bladder pain syndrome/interstitial cystitis, remain unclear. Although several mechanisms have been proposed, currently available experimental models to investigate such mechanisms are insufficient. However, this situation could be set to change with the development of a novel rat model enabling investigation of the effects of stretch, electrical and pharmacological stimulation of the bladder in vivo and in situ.

Objective To investigate the effects of activation of somatostatin subtype 4 (SST4) on the micturition reflex in rats. Methods Continuous cystometrograms (0.04 mL/min infusion rate) were performed in female Sprague-Dawley rats (242-265 g) under urethane anesthesia. After stable micturition cycles were established, a selective SST4 receptor agonist, NNC 26-9100, was administered intravenously in normal rats or rats pretreated with capsaicin 4 days before the experiments. The micturition parameters were recorded and compared before and after drug administration. Results Intravenous administration of NNC 26-9100 (10-300 μg/kg) significantly increased the intercontraction interval in a dose-dependent fashion. Intravenous administration of NNC 26-9100 (10-300 μg/kg) also significantly increased the pressure threshold in a dose-dependent fashion. No significant changes were seen in the baseline pressure, maximum voiding pressure, or postvoid residual urine volume. However, NNC 26-9100-induced increases in the intercontraction intervals and pressure threshold were not seen in rats with C-fiber desensitization induced by capsaicin pretreatment. Conclusion These results indicate that in urethane-anesthetized rats, activation of the SST4 receptor can inhibit the micturition reflex by suppression of capsaicin-sensitive C-fiber afferent pathways. Thus, the SST4 receptor could be a potential target for the treatment of C-fiber afferent-mediated bladder dysfunction.

Polygraphic exploration during sleep using cystomanometry was performed in 20 patients aged 7-17 years with primary (17) or secondary (3) enuresis. In this group of patients, 9 presented with isolated nocturnal enuresis while 11 patients had associated diurnal micturition troubles. During this study we documented 24 episodes of enuresis. There was no disturbance in sleep architecture or correlation between the uncontrolled micturition and any particular state or stage of sleep. Most episodes of enuresis occurred in a unique pattern in which a sudden or progressive intravesical increased pressure was associated with an awakening reaction. From a physiopathologic point of view, our findings are in favor of immaturity of the central system of inhibition of micturition reflex during sleep.

We studied the effect of MK-801, a potent non-competitive NMDA receptor antagonist, on the micturition reflex in anesthetized rats. Pretreatment with MK-801 (0.1-1 mg/kg i.v.) dose dependently increased the bladder capacity and reduced the micturition contraction. The ability of MK-801 to inhibit bladder voiding was confirmed in additional experiments in which the compound (30-50 micrograms/kg i.v.) transiently suppressed established bladder voiding produced by continuous bladder filling. MK-801 (1 microM) did not affect nerve-mediated contractions of the rat bladder or inhibit the response to capsaicin. These findings provide pharmacological evidence for an involvement of NMDA receptors in the micturition reflex pathways.

1. 1. Intravesical adminstration of hyperosmolar NaCl or urea solutions produced a concentration-dependent stimulatory action on the micturition reflex in urethane-anesthetized rats. This effect was not modified in rats pretreated with capsaicin as adults (50 mg/kg s.c. 4 days before). 2. 2. Hyperosmolar NaCl also produced Evans blue leakage (plasma extravasation) in the rat bladder. This effect was greatly reduced by extrinsic bladder denervation and in rats desensitized to capsaicin as newborns but not as adults. 3. 3. Cumulative addition of NaCl produced a concentration-dependent increase in tone and biphasic effects on neurogenic contractions of the rat isolated bladder. These effects were not modified by in vitro capsaicin desensitization. 4. 4. These findings do not support the idea that true osmoreceptors are present in the rat urinary bladder. The neurogenic component of the inflammatory response to hyperosmolar NaCl could involve activation of a subpopulation of bladder sensory fibers susceptible to the neurotoxic action of capsaicin in the early postnatal period only.

In our years of observation, confirmed over a large population of cows, suckling of the udder by the calf invariably leads to micturition in the cow, especially during the early postpartum period. We undertook a study to explain this suckling–micturition reflex. In our study, we monitored 30 cows for the suckling–micturition reflex without a local anesthesia to the udder, 10 cows with a local anesthesia to the udder, and 50 lactating women (after breastfeeding their infants) via a questionnaire. Our results showed that 27 of the 30 cows without local anesthesia urinated upon suckling, whereas the 10 cows under local anesthesia never urinated. Lactatingwomen never reported having a sensation to urinate during breastfeeding. It could not be a hormonal (oxytocin)-mediated response because the reflex is absent in humans. Because the reflex disappears in cows under local anesthesia to the udder, we attribute this to a nerve-mediated response. Hence, we propose that the anatomical location of the micturition center is in the lumbo-sacral segments (Swenson, 1984), and that lumbo-sacral nerve innervations of the udder of the

Indications, technique and results of a modified approach to an extended sphincterotomy in spinal cord injury patients with voiding dysfunctions is presented. There were 32 patients who underwent surgery and were subjected to analysis for their dysfunctional bladder and bladder-neck problems. Overall satisfactory results were obtained in about 90 per cent patients following sphincterotomy. Early recognition of patients where intermittent catheterisation may not succeed is presented to intervene and establish an early catheter-free status in such patients. Foley indwelling catheter in ten patients, being worn from seven months to four years, where intermittent catheterisation had not succeeded elsewhere, were decatheterised following surgery. Excellent results were obtained in ten patients with vesico-urethral reflux; external sphincterotomy, therefore, seems to be the treatment of choice for complete spinal cord transection with vesico-ureteral reflux. An attempt has also been made to present physiology of micturition reflex in spinal cord injury patients.

SUMMARY— The effect of 4 weeks' treatment with emepronium bromide in 20 incontinent female patients with detrusor hyperreflexia was compared to the effect in 20 patients who did not have uninhibited detrusor contractions during filling cystometry but who were unable to suppress a voluntarily induced detrusor contraction. In both groups, 65% benefited from the drug and no statistically significant differences were seen in the decrease in frequency of voiding and incontinence episodes during treatment. There were no differences between the groups for age, type and degree of urinary incontinence, and radiological findings of bladder suspension defects. In these patients it is important to perform cystometry, including detrusor reflex activation procedures and the testing of their ability to suppress a voluntarily induced detrusor contraction.