Biomedical subjects

William C de Groat

Publications and source records attributed to William C de Groat.

At least 19 recordsLinked to original sources

PubMed2007

Mechanisms of disease: involvement of the urothelium in bladder dysfunction.

Although the urinary bladder urothelium has classically been thought of as a passive barrier to ions and solutes, a number of novel properties have been recently attributed to urothelial cells. Studies have revealed that the urothelium is involved in sensory mechanisms (i.e. the ability to express a number of sensor molecules or respond to thermal, mechanical and chemical stimuli) and can release chemical mediators. Localization of afferent nerves next to the urothelium suggests that urothelial cells could be targets for neurotransmitters released from bladder nerves or that chemicals released by urothelial cells could alter afferent nerve excitability. Taken together, these and other findings highlighted in this article suggest a sensory function for the urothelium. Elucidation of mechanisms that influence urothelial function might provide insights into the pathology of bladder dysfunction.

Humans↗

PubMed2006

Ex vivo biomechanical properties of the female urethra in a rat model of birth trauma.

Stress urinary incontinence (SUI) is the involuntary release of urine during sudden increases in abdominal pressures. SUI is common in women after vaginal delivery or pelvic trauma and may alter the biomechanical properties of the urethra. Thus we hypothesize that injury due to vaginal distension (VD) decreases urethral basal tone and passive stiffness. This study aimed to assess the biomechanical properties of the urethra after VD in the baseline state, where basal muscle tone and extracellular matrix (ECM) are present, and in the passive state, where inactive muscle and ECM are present. Female rat urethras were isolated in a rat model of acute SUI induced by simulated birth trauma. Our established ex vivo system was utilized, wherein we applied intraluminal static pressures ranging from 0 to 20 mmHg. Outer diameter was measured via a laser micrometer. Measurements were recorded via computer. Urethral thickness was assessed histologically. Stress-strain responses of the urethra were altered by VD. Quantification of biomechanical parameters indicated that VD decreased baseline stiffness. The passive peak incremental elastic modulus of the distal segment in VD urethras was less than for controls (1.84 +/- 0.67 vs. 1.19 +/- 0.70 x 10(6) dyne/cm(2), respectively; P = 0.016). An increase was noted in passive low-pressure compliance values in proximal VD urethras compared with controls (9.44 +/- 2.43 vs. 4.62 +/- 0.60 mmHg(-1), respectively; P = 0.04). Biomechanical analyses suggest that VD alters urethral basal tone, proximal urethral compliance, and distal stiffness. Lack of basal smooth muscle tone, in combination with these changes in the proximal and distal urethra, may contribute to SUI induced by VD.

Animals↗

PubMed2006

Bladder overactivity and hyperexcitability of bladder afferent neurons after intrathecal delivery of nerve growth factor in rats.

Nerve growth factor (NGF) has been proposed as an important mediator inducing bladder overactivity under pathological conditions such as spinal cord injury, bladder outlet obstruction, or cystitis. We therefore examined the effects of chronic NGF treatment on bladder activity and the properties of bladder afferent neurons. In adult female rats, NGF (2.5 microg/microl) was infused continuously into the intrathecal space at the L6-S1 level of spinal cord for 1 or 2 weeks using osmotic pumps (0.5 microl/h). Bladder afferent neurons were labeled with axonal transport of Fast Blue injected into the bladder wall. After intrathecal injection of NGF, cystometrograms under an awake condition showed bladder overactivity revealed by time-dependent reductions in intercontraction intervals and voided volume. ELISA analyses showed significant increases in NGF levels in L6-S1 dorsal root ganglia of NGF-treated rats. In patch-clamp recordings, dissociated bladder afferent neurons exhibiting tetrodotoxin (TTX)-resistant action potentials from NGF-treated animals were larger in diameter and had significantly lower thresholds for spike activation compared with sham rats. In addition, the number of TTX-resistant action potentials during 600 ms depolarizing pulses was significantly increased time dependently after 1 or 2 weeks of NGF application. The density of slowly inactivating A-type K+ currents was decreased by 52% in bladder afferent neurons with TTX-resistant spikes after 2 week NGF treatment. These results indicate that increased NGF levels in bladder afferent pathways and NGF-induced reduction in A-type K+ current density could contribute to the emergence of bladder overactivity as well as somal hypertrophy and hyperexcitability of bladder afferent neurons.

Animals↗

PubMed2006

Serotonergic drugs and spinal cord transections indicate that different spinal circuits are involved in external urethral sphincter activity in rats.

Lower urinary tract function is regulated by spinal and supraspinal reflexes that coordinate the activity of the urinary bladder and external urethral sphincter (EUS). Two types of EUS activity (tonic and bursting) have been identified in rats. This study in urethane-anesthetized female rats used cystometry, EUS electromyography, spinal cord transection (SCT) at different segmental levels, and analysis of the effects of 5-HT(1A) receptor agonist (8-OH-DPAT) and antagonist (WAY100635) drugs to examine the origin of tonic and bursting EUS activity. EUS activity was elicited by bladder distension or electrical stimulation of afferent axons in the pelvic nerve (pelvic-EUS reflex). Tonic activity evoked by bladder distension was detected in spinal cord-intact rats and after acute and chronic T8-9 or L3-4 SCT but was abolished after L6-S1 SCT. Bursting activity was abolished by all types of SCT except chronic T8-9 transection. 8-OH-DPAT enhanced tonic activity, and WAY100635 reversed the effect of 8-OH-DPAT. The pelvic-EUS reflex consisted of an early response (ER) and late response (LR) when the bladder was distended in spinal cord-intact rats. ER remained after acute or chronic T8-9 and L3-4 SCT, but was absent after L6-S1 SCT. LR occurred only in chronic T8-9 SCT rats where it was enhanced or unmasked by 8-OH-DPAT. The results indicate that spinal serotonergic mechanisms facilitate tonic and bursting EUS activity. The circuitry for generating different patterns of EUS activity appears to be located in different segments of the spinal cord: tonic activity at L6-S1 and bursting activity between T8-9 and L3-4.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2006

Role of noradrenergic pathways in sneeze-induced urethral continence reflex in rats.

To clarify the role of noradrenergic pathways in preventing stress urinary incontinence (SUI) during sneezing, we investigated the effect of the norepinephrine reuptake inhibitor nisoxetine and alpha-adrenoceptor antagonists phentolamine (nonspecific blocker) and prazosin (alpha(1)-receptor-selective blocker) on the neurally evoked urethral continence reflex induced by sneezing in rats. The amplitude of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats and rats with SUI induced by vaginal distention (VD). In normal rats, intrathecal (it) phentolamine (0.02 nmol) and prazosin (0.02 nmol) decreased A-URS by 11.9 and 15.7%, respectively, without affecting UBP. In both normal and VD rats, intravenous (iv) application of nisoxetine (1 mg/kg) increased A-URS by 17.2 and 18.3% and UBP by 23.7 and 32.7%, respectively. Phentolamine or prazosin (both it) eliminated nisoxetine-induced increases in A-URS, but not the increases in UBP, which were, however, suppressed by iv phentolamine (5 mg/kg) or prazosin (1 mg/kg). Sneezing induced fluid leakage from the urethral orifice in VD rats, but not in normal rats. In VD rats, S-LPP was increased by 30.2% by iv nisoxetine. Application of phentolamine and prazosin (both it) decreased S-LPP by 15.7 and 20.6%, respectively, and nisoxetine induced increases in S-LPP to 13.2 and 12.3%, respectively. These results indicate that activation of the noradrenergic system by a norepinephrine reuptake inhibitor can prevent SUI via alpha(1-)adrenoceptors by enhancing the sneeze-induced active urethral closure mechanism at the spinal level and augmenting UBP at the periphery.

Adrenergic Uptake Inhibitors↗

PubMed2006

Expression of hyperpolarization-activated cyclic nucleotide-gated cation channels in rat dorsal root ganglion neurons innervating urinary bladder.

Afferent pathways innervating the urinary bladder consist of myelinated Adelta- and unmyelinated C-fibers, the neuronal cell bodies of which correspond to medium and small-sized cell populations of dorsal root ganglion (DRG) neurons, respectively. Since hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel currents have been identified in various peripheral sensory neurons, we examined the expression of isoforms of HCN channels in the L6-S1 spinal cord and bladder afferent neurons from L6-S1 DRG in rats. Among HCN-1, HCN-2 and HCN-4 channel subtypes, positive staining with HCN-2 antibodies was found in the superficial dorsal horn of the spinal cord and small- and medium-sized unidentified DRG neurons. In dye-labeled bladder afferent neurons, HCN-2-positive cells were found in approximately 60% of neurons, and HCN-2 was expressed in both small- and medium-sized neurons with a higher ratio (expression ratio: 61% and 50% of neurons, respectively) compared with unidentified DRG neurons, in which the HCN expression ratio was 47% and 21% of small- and medium-sized cells, respectively. These results suggest that HCN-2 is the predominant subtype of HCN channels, which can control neuronal excitability, in small-sized C-fiber and medium-sized Adelta fiber DRG neurons including bladder afferent neurons, and might modulate activity of bladder afferent pathways controlling the micturition reflex.

Animals↗

PubMed2006

Characterization of hyperpolarization-activated current (Ih) in dorsal root ganglion neurons innervating rat urinary bladder.

Afferent pathways innervating the urinary bladder consist of myelinated Adelta-fibers and unmyelinated C-fibers. Normal voiding is dependent on mechanoceptive Adelta-fiber bladder afferents that respond to bladder distention. However, the mechanisms for controlling the excitability of Adelta-fiber bladder afferents are not fully understood. We therefore used whole cell patch-clamp techniques to investigate the properties of hyperpolarization-activated, cyclic nucleotide-gated (HCN) currents (I(h)) in dorsal root ganglion (DRG) neurons innervating the urinary bladder of rats. The neurons were identified by axonal tracing with a fluorescent dye, Fast Blue, injected into the bladder wall. Hyperpolarizing voltage step pulses from -40 to -130 mV produced voltage- and time-dependent inward I(h) currents in bladder afferent neurons. The amplitude and current density of I(h) at a holding potential of -130 mV was significantly larger in medium-sized bladder afferent neurons (diameter: 37.8 +/- 0.3 microm), a small portion (19%) of which were sensitive to capsaicin (1 microM), than in uniformly capsaicin-sensitive small-sized (27.6 +/- 0.5 microm) bladder neurons. In medium-sized bladder neurons, a selective HCN channel inhibitor, ZD7288, dose-dependently inhibited I(h) currents. ZD7288 (10 microM) also increased the time constant of the slow depolarization phase of spike after-hyperpolarization from 91.8 to 233.0 ms. These results indicate that I(h) currents are predominantly expressed in medium-sized bladder afferent neurons innervating the bladder and that inhibition of I(h) currents delayed recovery from the spike after-hyperpolarization. Thus, it is assumed that I(h) currents could control excitability of mechanoceptive Adelta-fiber bladder afferent neurons, which are usually capsaicin-insensitive and larger in size than capsaicin-sensitive C-fiber bladder afferent neurons.

Action Potentials↗

PubMed2006

Muscarinic regulation of neonatal rat bladder spontaneous contractions.

In vitro preparations of whole urinary bladders of neonatal rats exhibit prominent myogenic spontaneous contractions, the amplitude and frequency of which can be increased by muscarinic agonists. The muscarinic receptor subtype responsible for this facilitation was examined in the present experiments. Basal spontaneous contractions in bladders from 1- to 2-wk-old Sprague-Dawley rats were not affected by M2 or M3 receptor antagonists. However, administration of 0.5 microM physostigmine, an anticholinesterase agent that increases the levels of endogenous acetylcholine, or 50-100 nM carbachol, a cholinergic agonist at low concentrations, which did not cause tonic contractions, significantly augmented the frequency and amplitude of spontaneous contractions. Blockade of M2 receptors with 0.1 microM AF-DX 116 or 1 microM methoctramine or blockade of M3 receptors with 50 nM 4-diphenylacetoxy-N-methylpiperidine methiodide or 0.1 microM 4-diphenylacetoxy-N-(2-chloroethyl)piperidine hydrochloride (4-DAMP mustard) reversed the physostigmine and carbachol responses. M2 and M3 receptor blockade did not alter the facilitation of spontaneous contractions induced by 10 nM BAY K 8644, an L-type Ca2+ channel opener, or 0.1 microM iberiotoxin, a large-conductance Ca2+-activated K+ channel blocker. NS-1619 (30 microM), a large-conductance Ca2+-activated K+ channel opener, decreased carbachol-augmented spontaneous contractions. These results suggest that spontaneous contractions in the neonatal rat bladder are enhanced by activation of M2 and M3 receptors by endogenous acetylcholine released in the presence of an anticholinesterase agent or a cholinergic receptor agonist.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2006

Suppression of bladder reflex activity in chronic spinal cord injured cats by activation of serotonin 5-HT1A receptors.

The effects of 8-OH-DPAT (5-HT1A receptor agonist) and WAY100635 (5-HT1A receptor antagonist) on reflex bladder activity were investigated in alpha-chloralose anesthetized or conscious chronic spinal cord injured cats. The results were similar in both anesthetized and conscious animals. Cystometrograms revealed that 8-OH-DPAT (0.5 mg/kg, s.c.) significantly increased the bladder volume threshold for eliciting a large amplitude micturition contraction, but only slightly reduced the amplitude of the contractions and did not alter the small amplitude pre-micturition contractions. 8-OH-DPAT also reduced the amplitude of isovolumetric bladder contractions. The inhibitory effect of 8-OH-DPAT was reversed by WAY100635 (0.5 mg/kg) or blocked by pre-treatment with WAY100635. Reflex bladder contractions evoked by tactile stimulation of the perigenital region were not altered by 8-OH-DPAT. These results suggest that the inhibitory effect of 8-OH-DPAT is mediated by an action on interneuronal pathways in the spinal cord or on the C-fiber afferent limb of the spinal micturition reflex and not on bladder smooth muscle or the efferent limb of the reflex pathway. Drugs that activate 5-HT1A receptors might be useful in treating detrusor overactivity after spinal cord injury.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2006

Roles of glutamatergic and serotonergic mechanisms in reflex control of the external urethral sphincter in urethane-anesthetized female rats.

This study was conducted to examine reflex mechanisms that mediate urinary bladder and external urethral sphincter (EUS) coordination in urethane-anesthetized female Sprague-Dawley rats. We investigated the properties of EUS reflexes elicited by electrical stimulation of pelvic nerve afferent axons (pelvic-EUS reflex). The changes in the reflexes induced by bladder distension and administration of agonists or antagonists for glutamatergic or serotonergic receptors were examined. The reflexes consisted of an early response (ER, 18- to 22-ms latency) and a late, long-duration (>100-ms latency) response (LR), which consisted of bursts of activity at 20- to 160-ms interburst intervals. In a few experiments, a reflex with an intermediate (40- to 70-ms) latency was also identified. With the bladder empty, the ER, but not the LR, was detected in the majority of experiments. The LR was markedly enhanced when the bladder was distended. The ER remained, but the LR was abolished, after spinal cord transection at T8-T9. The ER and LR were significantly decreased 75 and 35%, respectively, by the N-methyl-D-aspartate receptor antagonist MK-801 (0.3 mg/kg iv), but only decreased 18 and 14%, respectively, by the alpha-amino-5-methylisoxazole-4-propionate receptor antagonist LY-215490 (3 mg/kg iv). The serotonin (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (1 mg/kg iv) enhanced spontaneous EUS activity and the pelvic-EUS reflex. WAY-100635 (0.1-1 mg/kg iv), a 5-HT1A antagonist, reversed the effect of 8-hydroxy-2-(di-n-propylamino)-tetralin and suppressed EUS activity and the pelvic-EUS reflex. These results indicate that glutamatergic and serotonergic mechanisms are important in the reflex pathways underlying bladder- sphincter coordination in rats.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2006

Release of GABA from sensory neurons transduced with a GAD67-expressing vector occurs by non-vesicular mechanisms.

We have demonstrated that dorsal root ganglion neurons transduced with a recombinant replication-defective herpes simplex virus vector coding for glutamic acid decarboxylase (QHGAD67) release GABA to produce an analgesic effect in rodent models of pain. In this study, we examined the mechanism of transgene-mediated GABA release from dorsal root ganglion neurons in vitro and in vivo. Release of GABA from dorsal root ganglion neurons transduced with QHGAD67 was not increased by membrane depolarization induced by 60 mM extracellular K+ nor reduced by the removal of Ca2+ from the medium. Release of GABA from transduced dorsal root ganglion neurons was, however, blocked in a dose-dependent manner by NO-711, a selective inhibitor of the GABA transporter-1. The amount of GABA released from a spinal cord slice preparation, prepared from animals transduced by subcutaneous inoculation of QHGAD67 in the hind paws, was substantially increased compared to animals transduced with control vector Q0ZHG or normal animals, but the amount of GABA released was not changed by stimulation of the dorsal roots at either low (0.1 mA, 0.5-ms duration) or high (10 mA, 0.5-ms duration) intensity. We conclude that QHGAD67-mediated GABA release from dorsal root ganglion neurons is non-vesicular, independent of electrical depolarization, and that this efflux is mediated through reversal of the GABA transporter.

Analysis of Variance↗

PubMed2006

External urethral sphincter activity in a rat model of pudendal nerve injury.

AIMS: Pudendal nerve injury in the rat has been a useful animal model for studying stress urinary incontinence (SUI). However, the effect of pudendal nerve injury on activity of the external urethral sphincter (EUS) is relatively unexplored. The aims of this study were to examine voiding and the EUS electromyogram (EMG) in a durable SUI model in rats with bilateral or unilateral pudendal nerve transections. In addition, the effects of denervation on urethral anatomy were investigated. METHODS: A leak point pressure (LPP) test was first used to demonstrate that pudendal nerve transection induced SUI. Cystometry exhibited changes in voiding function and EUS-EMG measurements provided a quantitative evaluation of EUS activity during voiding. The morphological changes in sections through the mid-urethra were assessed with hematoxylin and eosin (H&E) staining. RESULTS: A significant decrease in average LPP was detected in rats 6 weeks after bilateral pudendal nerve transection (BPNT). Abnormal urodynamic measurements including a decrease in contraction amplitude and voided volume as well as an increase in contraction duration, and residual volume all indicated inefficient voiding. In addition EUS-EMG silent periods were reduced and the frequency of EUS-EMG bursting during voiding was increased. Atrophy of striated muscle in the EUS was also detected in rats with pudendal nerve transection(s). CONCLUSIONS: Our results indicate that pudendal nerve transection in rats decreases urethral outlet resistance and causes striated muscle atrophy in the EUS, EUS-EMG abnormalities and inefficient voiding. The results demonstrate that BPNT is a durable model for SUI.

Animals↗

PubMed2006

Dopaminergic mechanisms controlling urethral function in rats.

AIMS: To investigate the role of dopamine receptor subtypes in the control of urethral activity. METHODS: Simultaneous recordings of intravesical and urethral perfusion pressure (UPP) were performed in rats under urethane anesthesia. Changes in coordinated activity of the bladder and urethral sphincter were examined following intravenous (i.v.), intrathecal (i.t.), or intracerebroventricular (i.c.v.) administration of dopamine D1- and D2-like receptor agonists (SKF38393 and quinpirole, respectively) and antagonists (SCH23390 and remoxipride, respectively). RESULTS: Quinpirole (0.03, 0.1, and 0.3 mg/kg i.v.) dose-dependently decreased baseline urethral pressure to 45.33 +/- 5.8, 33.7 +/- 3.3 (P < 0.05, n = 6), and 27.7 +/- 3.3 cm H(2)O (P < 0.05, n = 5) from the control value (46.0 +/- 4.0 cm H(2)O), respectively. i.c.v. injection of quinpirole (1 microg) decreased baseline urethral pressure to 33.6 +/- 5.0 cm H(2)O (P < 0.05, n = 4) from the control value (51.4 +/- 4.9 cm H(2)O) in contrast to the insignificant effects of i.t. administration of the drug (3 microg). The decrement of baseline pressure induced by quinpirole (0.1 mg/kg i.v.) was suppressed by alpha-bungarotoxin (BGT), a neuromuscular blocking agent. SCH23390 (1 and 3 mg/kg, i.v.) dose-dependently decreased the frequency of high frequency oscillation (HFO) of the urethral sphincter. SKF38393 or remoxipride did not have significant effects on any parameters of bladder and urethral activity. CONCLUSIONS: These results indicate that activation of D2-like dopamine receptors at a supraspinal site can suppress activity of the striated muscle urethral sphincter. Thus, decreased urethral resistance induced by D2 dopamine receptor activation might aggravate urge incontinence symptoms often seen in patients with Parkinson's disease (PD).

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2006

Functional analysis of active urethral closure mechanisms under sneeze induced stress condition in a rat model of birth trauma.

PURPOSE: We evaluated changes in the urethral closure mechanism under a sneeze induced stress condition in a rat model of birth trauma. MATERIALS AND METHODS: Four days after vaginal distention induced by balloon catheter inflation in the vagina sneezing was induced while recording intravesical pressure with the rat under urethane anesthesia to evaluate sneeze induced leak point pressure, defined as the lowest pressure inducing fluid leakage from the urethral meatus during sneezing. Sneeze induced responses in the bladder and proximal or mid urethra were also measured using microtip transducer catheters. RESULTS: In 5 sham operated rats no leakage was observed from the urethral meatus during sneezing, which produced an increase in intravesical pressure of up to 34 cm H(2)O. However, in 5 of 6 rats with vaginal distention leakage during sneezing was observed with a sneeze leak point pressure of 26.2 cm H(2)O. In the mid urethra microtip transducer catheters revealed that pressure increases during sneezing were greater than those in the bladder but they were significantly decreased in the 5 incontinent vaginal distention rats. However, sneeze induced responses at the proximal urethra, which were similar to those in the bladder, were not different in sham operated and incontinent vaginal distention rats. CONCLUSIONS: Sneeze induced stress urinary incontinence in a rat model of birth trauma was caused by decreased active closure mechanisms at the mid urethra without affecting the passive transmission of abdominal pressure in the proximal urethra.

Animals↗

PubMed2006

Activation of alpha1D adrenergic receptors in the rat urothelium facilitates the micturition reflex.

PURPOSE: Previous studies have revealed that the activation of alpha(1) adrenergic receptors in urothelial cells releases neurotransmitters. We determined if alpha(1D) adrenergic receptors are expressed in the urothelium of the rat bladder and if inhibition of these receptors affects reflex voiding. MATERIALS AND METHODS: Female Wistar rats were used in the experiments. Receptor expression was evaluated by Western blot. The effects of receptor activation were studied using cystometrograms, measurement of adenosine triphosphate concentrations in the bladder lumen and afferent nerve recording. The alpha(1D) antagonist naftopidil (0.75 to 1.66 mg/kg) was administered intravenously into the external jugular vein. RESULTS: The expression of alpha(1D) adrenergic receptors was detected in urothelial tissue with Western blot and immunohistochemistry. The alpha(1D) receptor antagonist naftopidil prolonged the intercontraction interval during continuous infusion cystometrograms in conscious rats (143% of the control value) and suppressed the excitatory effect of intravesical infusion of acetic acid (0.1%) on the intercontraction interval (220%). Naftopidil inhibited the bladder afferent nerve activity induced by bladder distention (32.0%) and acetic acid infusion (30.4%), and decreased adenosine triphosphate levels in the bladder perfusate during bladder distention (36.6%). CONCLUSIONS: Endogenous catecholamines appear to act on alpha(1D) receptors in the urothelium to facilitate mechanosensitive bladder afferent nerve activity and reflex voiding.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2006

Maternal separation uncouples reflex from spontaneous voiding in rat pups.

PURPOSE: Rat pups only void when the perigenital-bladder reflex is activated by the mother rat licking the perineum. Maternal separation causes bladder distention as well as stress responses and anxiety behaviors in adult rats. We determined if MS would change voiding reflex maturation in neonatal rats. MATERIALS AND METHODS: A total of 14 Sprague-Dawley rat pups were subjected to 6 hours of daily MS and 17 were subjected to 6 hours of MS with bladder emptying by perigenital stimulation at 3 hours on postnatal days 2 to 14. Age matched controls for the 2 groups remained with the mother. Spontaneous voiding in awake pups from 1 to 3 weeks was monitored in a metabolic cage and perigenital-bladder reflex latency was determined from 1 to 7 weeks. Cystometry was performed at 9 weeks with the rats under urethane anesthesia. RESULTS: Spontaneous voiding began at 3 weeks in all animals. The latency of the perigenital-bladder reflex at 3 weeks was shorter than the latency at 2 days in MS animals (3.3 vs 6.4 seconds, p < 0.01) but not in control or MSPG animals. MS animals maintained the perigenital-bladder reflex 2 weeks longer than control animals. The spontaneous voiding behavior of MSPG animals was similar to that in controls. CONCLUSIONS: Intermittent bladder distention delays withdrawal of the spinal perigenital-bladder reflex but it does not affect maturation of the supraspinal bladder-bladder reflex that controls spontaneous voiding in older rats. This suggests that increased bladder afferent firing can selectively modulate spinal but not supraspinal mechanisms controlling postnatal changes in voiding function.

Age Factors↗

PubMed2006

Roles of peripheral and central nicotinic receptors in the micturition reflex in rats.

PURPOSE: We investigated the effects of nicotinic acetylcholine receptor activation in the bladder and central nervous system on the micturition reflex in urethane anesthetized rats. MATERIALS AND METHODS: The effects of nicotinic acetylcholine receptor activation on bladder activity were examined during continuous infusion cystometrogram. Nicotine with or without the nicotinic acetylcholine receptor antagonist mecamylamine (Sigma Chemical Co., St. Louis, Missouri) was administered intravesically, intrathecally or intracerebroventricularly in normal or capsaicin pretreated rats. We also examined nicotine induced responses in dissociated bladder afferent neurons from L6 to S1 dorsal root ganglia that were sensitive to capsaicin using whole cell patch clamp recordings. RESULTS: Intravesical nicotine (1 to 10 mM) significantly decreased intercontraction intervals in dose dependent fashion. This excitatory effect was abolished by co-application of mecamylamine (3 mM) as well as by capsaicin pretreatment. On patch clamp recordings 300 muM nicotine evoked rapid inward currents that were antagonized by mecamylamine in capsaicin sensitive bladder afferent neurons. Intrathecal and intracerebroventricular administration of nicotine (10 mug) decreased and increase intercontraction intervals, respectively. Each effect was antagonized by mecamylamine (50 mug) administered intrathecally and intracerebroventricularly. The spinal excitatory effect was significantly inhibited by the N-methyl-D-aspartate receptor antagonist (+)-MK-801 hydrogen maleate (20 mug) given intrathecally or by capsaicin pretreatment, although the effects of capsaicin pretreatment were significantly smaller than those of (+)-MK-801 hydrogen maleate. CONCLUSIONS: These results indicate that nicotinic acetylcholine receptor activation in capsaicin sensitive C-fiber afferents in the bladder can induce detrusor overactivity. In the central nervous system nicotinic acetylcholine receptor activation in the spinal cord and brain has an excitatory and an inhibitory effect on the micturition reflex, respectively. In addition, the nicotine induced spinal excitatory effect may be mediated by the activation of glutamatergic mechanisms.

Administration, Intravesical↗

PubMed2006

Mechanisms underlying the recovery of lower urinary tract function following spinal cord injury.

The lower urinary tract has two main functions, the storage and periodic expulsion of urine, which are regulated by a complex neural control system in the brain and lumbosacral spinal cord. This neural system coordinates the activity of two functional units in the lower urinary tract: (1) a reservoir (the urinary bladder) and (2) an outlet (consisting of bladder neck, urethra and striated muscles of the pelvic floor). During urine storage the outlet is closed and the bladder is quiescent, thereby maintaining a low intravesical pressure over a wide range of bladder volumes. During micturition the outlet relaxes and the bladder contracts to promote the release of urine. This reciprocal relationship between bladder and outlet is generated by visceral reflex circuits, some of which are under voluntary control. Experimental studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through a coordination center (the pontine micturition center) located in the rostral brainstem. This reflex pathway is in turn modulated by higher centers in the cerebral cortex that are presumably involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter functions. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. Studies in animals indicate that the recovery of bladder function after spinal cord injury is dependent in part on plasticity of bladder afferent pathways and the unmasking of reflexes triggered by capsaicin-sensitive C-fiber bladder afferent neurons. The plasticity is associated with changes in the properties of ion channels and electrical excitability of afferent neurons, and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs.

Adrenergic Fibers↗