Effects of a calcineurin inhibitor, tacrolimus, on glutamate-dependent potentiation in pelvic-urethral reflex in anesthetized rats

Kamo I, Hashimoto T. Involvement of reflex urethral closure mechanisms in urethral resistance under momentary stress condition induced by electrical stimulation of rat abdomen. Am J Physiol Renal Physiol 293: F920-F926, 2007. First published July 11, 2007; doi:10.1152/ajprenal.00466.2006.-A novel method for evaluating the urethral resistance during abrupt elevation of abdominal pressure was developed in spinalized female rats under urethane anesthesia. Electrical stimulation of abdominal muscles for 1 s induced increases in both the intra-abdominal and the intravesical pressure in a stimulusdependent manner, and the bladder response was almost lost when the abdomen was opened. The lowest intravesical pressure during electrical stimulation that induced fluid leakage from the urethral orifice (leak point pressure) and the maximal intravesical pressure without urine leakage below the leak point pressure were evaluated as the indexes of urethral resistance. Lower urethral resistance was obtained in the rats whose pelvic nerves or somatic nerves containing pudendal nerves and nerves to iliococcygeus/pubococcygeus muscles were transected bilaterally. In contrast, transection of bilateral hypogastric nerves showed smaller effects. Duloxetine, a drug for stress urinary incontinence, enlarged the reflex urethral closing contractions that were induced by an increase in intravesical pressure and measured using a microtip transducer catheter in the middle urethra. This drug also increased the urethral resistance (leak point pressure), whereas it did not show any effect in the rats whose pelvic nerves were bilaterally transected, showing that the augmentation of the reflex urethral closure by the drug resulted in the elevation of the urethral resistance. From these findings, it was concluded that during momentary elevation of abdominal pressure, the reflex urethral closure mechanisms via bladder-spinal cord-urethral sphincter and pelvic floor muscles greatly contribute to the increase in the urethral resistance to prevent the urinary incontinence. stress urinary incontinence; leak point pressure; reflex urethral closing responses; duloxetine STRESS URINARY INCONTINENCE (SUI) is defined as the involuntary loss of urine during increments of abdominal pressure (stress condition) such as sneezing and coughing in the absence of bladder contractions (5,22). This disorder is very common in women over middle age and generally occurs as a result of defects in the various passive and reflex mechanisms that maintain urethral closure in the presence of elevated abdominal pressure (1, 4, 23). Recently, the nerve-mediated reflex urethral closure mechanisms have been considered to contribute to the urethral resistance during events causing elevation of intravesical pressure (P ves ) in rats (14). Electrophysiological studies also have provided evidence indicating functions of the glutamate-mediated bladder-to-urethra reflexes in rats (6,16,17). With the accumulation of findings of active urethral closure mechanisms, pharmacotherapy by dr...

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confidence: 99%

Involvement of reflex urethral closure mechanisms in urethral resistance under momentary stress condition induced by electrical stimulation of rat abdomen

Izumi¹,

Hashimoto²

2007

“…At the end of the experiments, the location of the injection site was marked by an injection of Alcian blue (10 l, 2%), followed by a laminectomy to verify the location of the cannula tip. The volume of drug injected in the spinal cord in this experiment may spread from 0.5 to 1.5 mm from the site of injection, as previously described (12).…”

Section: Methodsmentioning

confidence: 99%

“…Using in vivo animal preparations, we demonstrated that low-frequency repetitive stimulations (RS) on the pelvic afferent nerve elicited a form of activity-dependent reflex plasticity, spinal reflex potentiation (SRP) in the pelvic-urethra reflex activities (12,13,41,42,43,44,45). Such in vivo preparations used in these studies maintained the whole neural network within the the central nervous system intact, thus offering an animal model to explore the possibility that activity-dependent reflex plasticity can be regulated by a specific nucleus that projects nerve fibers to the site where plasticity occurs.…”

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confidence: 99%

Nicotine-activated descending facilitation on spinal NMDA-dependent reflex potentiation from pontine tegmentum in rats

Pan

Peng

Chen³

et al. 2008

This study was conducted to investigate the possible neurotransmitter that activates the descending pathways coming from the dorsolateral pontine tegmentum (DPT) to modulate spinal pelvic-urethra reflex potentiation. External urethra sphincter electromyogram (EUSE) activity in response to test stimulation (TS, 1/30 Hz) and repetitive stimulation (RS, 1 Hz) on the pelvic afferent nerve of 63 anesthetized rats were recorded with or without microinjection of nicotinic cholinergic receptor (nAChR) agonists, ACh and nicotine, to the DPT. TS evoked a baseline reflex activity with a single action potential (1.00 Ϯ 0.00 spikes/stimulation, n ϭ 40), whereas RS produced a long-lasting reflex potentiation (16.14 Ϯ 0.96 spikes/stimulation, n ϭ 40) that was abolished by D-2-amino-5-phosphonovaleric acid (1.60 Ϯ 0.89 spikes/ stimulation, n ϭ 40) and was attenuated by 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline (7.10 Ϯ 0.84 spikes/stimulation, n ϭ 40). ACh and nicotine microinjections to DPT both produced facilitation on the RS-induced reflex potentiation (23.57 Ϯ 2.23 and 28.29 Ϯ 2.36 spikes/stimulation, P Ͻ 0.01, n ϭ 10 and 20, respectively). Pretreatment of selective nicotinic receptor antagonist, chlorisondamine, reversed the facilitation on RS-induced reflex potentiation caused by nicotine (19.41 Ϯ 1.21 spikes/stimulation, P Ͻ 0.01, n ϭ 10) Intrathecal WAY-100635 and spinal transection at the T1 level both abolished the facilitation on reflex potentiation resulting from the DPT nicotine injection (12.86 Ϯ 3.13 and 15.57 Ϯ 1.72 spikes/stimulation, P Ͻ 0.01, n ϭ 10 each). Our findings suggest that activation of nAChR at DPT may modulate N-methyl-D-aspartic acid-dependent reflex potentiation via descending serotonergic neurotransmission. This descending modulation may have physiological/ pathological relevance in the neural controls of urethral closure.acetylcholine; serotonin; WAY-100635; intrathecal; rats; N-methyl-D-aspartic acid; spinal reflex potentiation THE IMPORTANCE OF UNDERSTANDING the descending innervations coming from the brain stem to the spinal circuitry involved in the micturition function has been emphasized because it may offer the strategy for developing pharmacological therapy in micturition disorders (38). Researchers applied electric shocks to the pontine reticular formation to relate this site with micturition function and revealed that the pontine reticular formation plays an important role in descending control on the functions of the lower urinary tract (30,31,54,55,67). The cholinergic system in brain areas of the central nervous system regulates physiological functions, including micturition (18, 21, 40). Administration of cholinergic agonists to the pontine tegmentum affected urodynamic parameters in reflexive micturition cycles (31, 67). In addition, pharmacological blockage of the nicotinic cholinergic receptors (nAChR) in the pontine tegmentum using chlorisondamine, a nicotinic receptor antagonist, abolished the modulation exhibited by cholinergic agonists (40, 56), suggesting that...

“…Recent studies on pelvic-urethra reflex, using intact spinal cord preparations, have demonstrated a glutamatergic N-methyl-D-aspartate (NMDA)-dependent spinal reflex potentiation in which the activity of this reflex was dynamically potentiated by repetitive (29) and tetanic (30) afferent inputs. Because pathological potentiation in this reflex activity was suggested to underlie the hyperactive urethra (10, 11, 26 -28), the activity-dependent spinal reflex potentiation seems to be a novel animal model for studying urethra continent function (12,13,28,39,(41)(42)(43)(44).…”

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confidence: 99%

Acute anal stretch inhibits NMDA-dependent pelvic-urethra reflex potentiation via spinal GABAergic inhibition in anesthetized rats

Chen

Huang

Kao

et al. 2008

The impact of acute anal stretch on the pelvic-urethra reflex potentiation was examined in urethane-anesthetized rats by recording the external urethra sphincter electromyogram activity evoked by the pelvic afferent stimulation. Test stimulation (1 stimulation/30 s) evoked a baseline reflex activity with a single action potential that was abolished by gallamine (5 mg/kg iv). On the other hand, the repetitive stimulation (1 stimulation/1 s) induced spinal reflex potentiation (SRP) that was attenuated by intrathecal 6-cyano-7-nitroquinoxaline-2,4-dione (a glutamatergic ␣-amino-3-hydroxy-5-methyl-4-isoxazoleproprionat receptor antagonist, 100 M, 10 l) and D-2-amino-5-phosphonovalerate [a glutamatergic N-methyl-D-aspartate (NMDA) antagonist, 100 M, 10 l]. Acute anal stretch using a mosquito clamp with a distance of 4 mm exhibited no effect, whereas distances of 8 mm attenuated and 12 mm abolished the repetitive stimulation-induced SRP. Intrathecal NMDA (100 M, 10 l) reversed the abolition on SRP caused by anal stretch. On the other hand, pretreated bicuculline [␥-aminobutyric acid (GABA) A receptor antagonist, 100 M, 10 l] but not hydroxysaclofen (GABA B receptor antagonist) counteracted the abolition on the repetitive stimulation-induced SRP caused by the anal stretch. All of the results suggested that anal stretch may be used as an adjunct to assist voiding dysfunction in patients with overactive urethra sphincter and that GABAergic neurotransmission is important in the neural mechanisms underlying external urethra sphincter activity inhibited by anal stretch. spinal cord; voiding dysfunction; glutamate; bicuculline; hydroxysaclofen THE MECHANISM INVOLVED IN micturition, which is the result of coordination between bladder detrusor and outlet, is intricate. Both elements, the detrusor and outlet, maintain a sound cycle of storage and evacuation that is controlled by a group of reflex and voluntary actions (54). During the storage phase of a micturition cycle, detrusor relaxes and urethra contracts to produce continence; while the detrusor contracts, with sphincter relaxes to void urine during the evacuation phase. Inhibition of external urethra sphincter (EUS) activity during evacuation is essential for sufficient bladder emptying (18, 49). The absence of suppression on EUS activity during voiding is one feature of the pathological condition referred to as detrusor-sphincter dyssynergia (51). Such a dyssynergic sphincter contraction results in high intravesical pressure and residual urine. Therefore, to achieve near-normal voiding function in patients with detrusor-sphincter dyssynergia, outlet resistance should be reduced.Arising from the puborectalis muscle, EUS innervated by the perineal branch of the pudendal nerve and external anal sphincter (EAS) innervated by the rectal branch of the pudendal nerve are both striated skeletal muscles that contract and relax voluntarily. A study investigating the coordination between the EUS and EAS muscles demonstrated these muscles shared in reflex actions as in dilatation a...