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Vol. 297, Issue 3, 933-939, June 2001
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Y.I., M.Y., O.Y., W.C.deG.); and Department of Urology, Kanazawa University School of Medicine, Kanazawa, Japan (Y.I., O.Y., M.N.)
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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The influence of muscarinic receptor stimulation and blockade on the
central regulation of micturition was evaluated in conscious female
rats. Saline was infused into the bladder to induce repeated bladder
contractions and voiding. Increasing doses of a muscarinic agonist,
oxotremorine-M (OXO-M; 0.01 to 1 µg/rat) or antagonist, atropine (0.1 to 30 µg/rat) were administered. Intrathecal OXO-M (0.1 µg)
increased bladder capacity (BC; 85 ± 17%), but did not change
maximal voiding pressure (MVP), pressure threshold (PT), postvoiding
intravesical pressure, or voiding efficiency (VE). Intracerebroventricular OXO-M (0.1 µg) increased BC (97 ± 6%), MVP (45 ± 19%), PT (158 ± 49%), and reduced VE (
17 ± 5%). A larger dose of OXO-M (1 µg, either i.c.v. or i.t.)
produced greater changes. These effects were not reproduced by i.v.
injections of OXO-M. The effects of OXO-M were blocked by pretreatment
with atropine in a dose (1 µg i.c.v. or i.t.), which alone had no
effect on voiding parameters. A larger dose of atropine (10 µg)
reduced MP (31 ± 7% i.c.v. and 34 ± 6% i.t.) and VE
(21 ± 3% i.c.v. and 25 ± 5% i.t.) but increased BC
(52 ± 8% i.c.v.). These results indicate that activation of
muscarinic receptors in the brain or spinal cord can suppress voluntary
voiding, but also stimulates bladder activity during bladder filling.
The muscarinic inhibitory mechanisms do not appear to be tonically
active. The effects of atropine (i.c.v. and i.t.) indicate that
muscarinic excitatory mechanisms are tonically active. These findings
raise the possibility that voiding function is regulated by both
inhibitory and excitatory cholinergic mechanisms in the central nervous system.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Muscarinic and anti-muscarinic
agents have been used clinically for many years to treat disorders of
the lower urinary tract (Chapple, 2000
). Although the effects of these
agents are usually attributed to their action on peripheral muscarinic
receptors, it is also possible that they have effects on central
muscarinic receptors located in the brain and spinal cord (Li et al.,
1991; Zhou and Gebhart, 1991; Bartolini et al., 1992; Aagaard and
McKinney, 1993; Iwamoto et al., 1993; McKinney et al., 1993).
Previous studies in animals revealed excitatory and inhibitory effects
of cholinergic drugs on central neural pathways controlling lower
urinary tract function. In decerebrate cats, injection of the
cholinergic agonist, carbachol, into the region of the locus coeruleus
alpha (the pontine micturition center) evoked bladder contractions and
voiding (Sugaya et al., 1987). This effect was blocked by atropine,
indicating that it was mediated by activation of muscarinic receptors.
Administration of the muscarinic agonist, bethanechol, to the brain of
anesthetized dogs via a vascular cross-perfusion technique from a donor
dog, reduced bladder capacity and increased maximal voiding pressure
(O'Donnell, 1990). In rats anesthetized with pentobarbital, the
bladder hyperactivity induced by L-DOPA seems to be
mediated in part by activation of central muscarinic receptors, because
it was reduced by atropine, which acts at both central and peripheral
muscarinic receptors, but not by methylscopolamine, a quaternary
muscarinic antagonist that does not penetrate the blood-brain barrier
(BBB) (Sillen et al., 1982). Intravenous administration of
oxotremorine, a muscarinic agonist that enters the brain, facilitated
the L-DOPA-induced bladder hyperactivity. This effect was
not blocked by methylscopolamine, indicating a central site of action.
Thus studies in several species indicate that voiding can be
facilitated by central muscarinic mechanisms.
Other studies identified central inhibitory mechanisms. Injections of
carbachol into brain stem sites ventral to the pontine micturition
center (Matsuzaki, 1990) or into the locus coeruleus (Roppolo et al.,
1987) suppressed bladder activity and increased bladder capacity in the
decerebrate cat. These effects were blocked by microinjections of
atropine into the pons. However, administration of atropine alone did
not alter bladder activity, suggesting that muscarinic mechanisms in
the pons do not have a tonic influence on voiding function in the
decerebrate animal (Roppolo et al., 1987). Evidence for muscarinic
inhibitory receptors has also been obtained in the rat (Thor et al.,
2000). Intravenous administration of oxotremorine, a muscarinic
agonist, or physostigmine, an anticholinesterase agent, suppressed
reflex contractions of the anal sphincter induced by nociceptive
stimulation of the urinary bladder of anesthetized rats. The effects
were blocked by atropine but not by a peripherally acting
antimuscarinic agent. These studies raise the possibility that
inhibitory muscarinic mechanisms control the central processing of
afferent input from the bladder.
The contribution of cholinergic transmission to the central regulation
of micturition was evaluated further in the present study. We examined
the changes in voiding function in awake normal rats following i.c.v.,
i.t. or i.v. administration of a muscarinic agonist (oxotremorine
methiodide, OXO-M) or antagonist (atropine). A preliminary account of
this work has been presented in an abstract (Ishiura et al., 1999).
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Animal Preparation. Female Sprague-Dawley rats weighing 250 to 300 g were anesthetized with halothane (2% in oxygen) for surgical insertion of either an i.c.v., i.t., or i.v. catheter and an intravesical catheter. To implant an i.c.v. catheter, the rats were positioned in a stereotaxic frame, a scalp incision was made over the sagittal suture, and a hole (diameter approximately 1.0 mm) was drilled in the right parietal bone to expose the dural surface 1.0 mm lateral and 0.3 mm anterior to the bregma. A sterile stainless steel catheter (o.d. 0.6 mm, i.d. 0.3 mm, length 10.5 mm) was lowered 5.3 mm from the bregma with a micromanipulator. With the aid of a small screw placed in the skull as an anchor, the catheter was fixed to the skull with dental acrylic. Solutions were injected via an infusion catheter (o.d. 0.3 mm, i.d. 0.1 mm) inserted into the larger catheter. Single doses of drugs were administered in a volume of 1 µl and the infusion catheter was left in place for 1 min after infusion to allow for diffusion of the drug solution. At the end of the experiment, Blue Food Color (McCormick, Hunt Valley, MD) was injected to verify the location of the cannula tip.
An i.t. catheter was inserted with a technique developed by Yaksh and Rudy (1976). The occipital crest of the skull was exposed and the
atlanto-occipital membrane was incised at the midline with the tip of
an 18-gauge needle. A catheter (PE-10) was inserted through the slit
and passed caudally to the L6 level of the spinal cord. The volume of
fluid within the cannula was kept constant at 9 µl in all animals.
Single 1-µl volumes of drug solutions were administered followed by a
10-µl flush of artificial cerebrospinal fluid (Feldberg and
Fleischhauer, 1960). At the end of the experiment, a laminectomy was
performed to verify the location of the cannula tip. For i.v. drug
administration, a catheter (PE-50) was placed in the left jugular vein.
Single 100-µl volumes of drug solutions were administered in sterile
physiological saline (0.9% sodium chloride solution) followed by a
100-µl flush of sterile physiological saline.
The urinary bladder was catheterized using the method of Yaksh et al.
(1986). The bladder was exposed via a midline abdominal incision. A
catheter (PE-50), the bladder end of which was heated to create a
collar, was inserted through a small incision at the bladder dome, and
a suture was tightened around the collar. The other end of the catheter
was passed through subcutaneous tissue and exited through the skin.
After closing the abdominal incision by suturing the muscle and skin,
the rats were placed in a restraining cage that was large enough to
permit them to adopt a normal crouching posture, but narrow enough to
prevent them from turning around. The rats were subsequently allowed to
recover from halothane anesthesia.
The bladder catheter was connected via a T-stopcock to a pump for
continuous infusion of physiological saline and to a pressure transducer. Physiological saline was infused at room temperature into
the bladder at a constant rate of 0.1 ml/min to elicit repeated voiding
responses. The volume-evoked micturition reflexes were studied in
conscious, restrained rats after allowing at least 2 h for
recovery from halothane anesthesia. All experiments were carried out on
the same day that the operative procedures were performed.
Evaluation.
In all experiments, control cystometrograms
(CMG) were recorded for 1 to 2 h prior to i.c.v., i.t., and i.v.
administration of vehicle or drug solutions. Cumulative dose-response
curves were constructed by administering drugs at increasing doses
(OXO-M, 0.01-1 µg/rat and atropine, 0.1-30 µg/rat) at 1- to 2-h
intervals. In some experiments OXO-M was also tested after atropine
pretreatment (15-30 min). Saline voided from the urethral meatus was
collected and measured to determine the voided volume (VV). Residual
volume (RV) was measured by evacuating the bladder catheter after
voiding. RV was measured at least two times during each 30-min period. Bladder capacity (BC) was then calculated as the sum of VV and RV; and
voiding efficiency (VE) calculated as BC RV/BC × 100. The
intravesical pressure to induce micturition (i.e., pressure threshold,
PT) and maximal voiding pressure (MVP) were also measured (Yoshiyama et
al., 1999). The pressure immediately after voiding was termed
postvoiding intravesical pressure (PVIP; Fig.
1). Bladder compliance was calculated as
the amount of infused saline/PT. The presence of nonvoiding
contractions, which occurred at a pressure greater than 10 cm of
H2O during bladder filling after OXO-M injection, was also noted. These parameters were measured for each CMG.
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Drugs. Drugs used in this study included halothane (Wyeth-Ayerst Laboratories, Philadelphia, PA), oxotremorine methiodide (a nonselective muscarinic acethylcholine receptor agonist; Research Biochemicals International, Natick, MA), atropine sulfate (Sigma Chemical Co., St. Louis, MO). Oxotremorine-M and atropine sulfate were dissolved in artificial CSF for i.c.v. or i.t. administration and in sterile saline for i.v. administration.
Statistical Analysis. Data are expressed as mean ± S.E.M. The changes in the evoked responses after treatment with the drugs were evaluated statistically by means of repeated measures of analysis of variance (ANOVA) followed by Fisher's Protected Least Significant Difference test as a post hoc multiple comparison procedure. The differences among groups were evaluated statistically with the Mann-Whitney U test. A level of p < 0.05 or p < 0.01 was considered statistically significant.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Effects of Intracerebroventricular Administration of
Oxotremorine-M.
Under control conditions, mean BC was 0.37 ± 0.04 ml, mean MVP was 38 ± 3 cm of H2O,
mean PT was 13 ± 1 cm of H2O, mean PVIP was
11.40 ± 0.6 cm of H2O, and mean VE was
94 ± 2%. Intracerebroventricular, i.t., or i.v. administration
of vehicles did not elicit detectable changes in any CMG parameter. The
low dose of the drug was ineffective, but higher doses (0.1 and 1 µg)
caused a dose-dependent increase in BC (range 100-200%), PT
(160-300%), and MVP (45-100%) and a decrease in VE (17-68%)
(Figs. 2A and
3). The effect of OXO-M was apparent
within 5 min after administration, and the effects were evaluated
within the first 30 min. The largest dose (1 µg) of OXO-M also
significantly increased PVIP. Bladder compliance after OXO-M injection
was significantly smaller (0.01 µg: 0.14 ± 0.03 ml/cm of
H2O; 0.1 µg: 0.07 ± 0.02 ml/cm of
H2O; 1 µg: 0.03 ± 0.06 ml/cm of
H2O) than control values (0.26 ± 0.05 ml/cm
of H2O). Nonvoiding contractions were not seen
before OXO-M injection but were detected in three of nine animals after
0.1 µg of OXO-M and in all animals after 1 µg of OXO-M. The effects
of 0.1 µg of OXO-M disappeared in 30 to 60 min (Figs. 2A and
4A); whereas the effects of the largest
dose of the drug (1 µg) on BC and VE persisted for the duration of
the experiment (approximately 2 h; Fig. 4A). The effects of OXO-M
(0.1 and 1 µg) were blocked by pretreatment (15-30 min) with
atropine in a dose (1 µg i.c.v.) that did not cause significant
changes in CMG parameters (Figs. 5A and
6A).
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Effects of Intrathecal Administration of Oxotremorine-M.
The
lowest dose of OXO-M (0.01 µg) was ineffective, but a 0.1-µg dose
selectively increased BC (85 ± 17%) without altering other
parameters. This effect of 0.1 µg of OXO-M persisted for 30 to 60 min
(Fig. 4B) but disappeared between 1 and 2 h. OXO-M at a dose of 1 µg increased BC (179 ± 21%), MVP (48 ± 20%), and PT
(215 ± 55%) in a dose-dependent fashion (Figs. 2B and 3). The largest dose (1 µg) of OXO-M also caused a significant increase in
PVIP from 9.9 ± 0.4 cm of H2O to 16.7 ± 1.2 cm of H2O, and a significant decrease in
VE (11.6 ± 2%), but this effect was significantly smaller than
that after i.c.v. administration of OXO-M (Fig. 3). Bladder compliance
after injection of 1 µg of OXO-M was significantly smaller (0.05 ± 0.01 ml/cm of H2O) than the preinjection value
(0.30 ± 0.06 ml/cm of H2O), whereas smaller doses had no effect. Nonvoiding contractions were noted in only a few
animals (one of seven after either 0.1 µg or 1 µg of OXO-M). Following 1 µg of OXO-M, complete recovery of BC and PT occurred 60 to 90 min after administration (Fig. 4B). Pretreatment with atropine at
a dose of 1 µg, which had no effect on the CMG, blocked the effects
of OXO-M (0.1 and 1 µg) (Figs. 5B and 6B).
Effects of Intravenous Administration of Oxotremorine-M. Although low doses of OXO-M (0.01 and 0.1 µg) did not significantly change CMG parameters, the highest dose (1 µg) caused small but significant increases in MVP (65 ± 21%), PT (111 ± 29%) (Figs. 1C and 2), and PVIP from 9.4 ± 0.4 cm of H2O to 14.6 ± 1.3 cm of H2O. BC did not change significantly (Fig. 2C). Bladder compliance after injection of 1 µg of OXO-M was significantly smaller (0.04 ± 0.02 ml/cm of H2O) than the preinjection value (0.30 ± 0.04 ml/cm of H2O) whereas smaller doses were ineffective. Nonvoiding contractions was noted in two of five animals after 1 µg of OXO-M. All parameters returned to normal 60 min after i.v. administration.
Effects of Atropine.
Small doses of atropine (0.1-1 µg,
i.c.v., i.t., and i.v.) did not cause any significant change in CMG
parameters. High doses (10-30 µg, i.c.v., i.t., and i.v.) reduced
MVP by 31 to 34% and VE by 18 to 25% (Figs.
7 and 8).
It is noteworthy that even the highest doses of atropine (i.t. and
i.v.) did not cause significant changes in BC. PT and PVIP also were
not changed significantly by i.c.v., i.t., or i.v. administration of
atropine (data not shown). The effects of atropine (i.v.) on MVP were
reversed within 90 min (41.3 ± 3.3 cm of
H2O, 7 ± 3% change from pretreatment control) whereas the effects on MVP elicited by i.c.v. or i.t. atropine
persisted for 2 h (i.c.v., 27.7 ± 4 cm of
H2O, 30 ± 5%; and i.t., 24.7 ± 1.6 cm of H2O, 35 ± 5.6%).
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The present study demonstrated that activation of muscarinic receptors in the brain and the spinal cord can induce prominent changes in voiding function in the awake rat. Intracerebroventricular or i.t. administration of a muscarinic agonist (OXO-M) had primarily a depressant effect on voiding, although some facilitatory effects were also noted. Atropine in low doses blocked these effects. Higher doses of atropine alone also had a depressant effect. These observations indicate that inhibitory and excitatory muscarinic mechanisms coexist in the central micturition pathways. Muscarinic inhibitory receptors do not appear to be tonically active (i.e. silent receptors) but can be stimulated by administration of muscarinic agonists. On the other hand, the depressant effect of atropine on voiding indicates that muscarinic excitatory mechanisms are tonically active.
Because muscarinic receptors are present in the bladder; one potential
concern in the present study was the possibility that drugs
administrated into the central nervous system could enter the
bloodstream and have effects directly on the bladder. OXO-M was used to
reduce this problem because it is a hydrophilic quaternary amine that
does not penetrate the BBB as readily as the tertiary amine,
oxotremorine, which was used in previous studies (Sillen et al., 1982;
O'Donnell, 1990). We believe that only local effects on the brain and
the spinal cord were elicited in our experiments because the effects of
i.c.v. and i.t. administration of OXO-M were not duplicated by i.v.
administration of the same or higher doses of the drug. A larger dose
of OXO-M i.v. did alter bladder activity, but even this dose produced
effects that were of shorter duration than those resulting from central
administration. A previous study reported that doses of OXO-M such as
those administered in this study produced effects including
hypothermia, tremors, and salivation when administered i.c.v. but not
when administered peripherally, indicating a localized effect on the
brain (Sanchez and Meier, 1993).
Another potential problem is the spread of drugs within the central nervous system between the spinal and the supraspinal sites. This does not appear to have been a factor in our study, because the onset of the effects of OXO-M was too rapid after both i.c.v. and i.t. administration to be explained by diffusion to other areas. In addition, a moderate dose of OXO-M (0.1 µg, i.c.v.) elicited qualitatively different responses (i.e., increases in BC, PT, and MVP and a decrease in VE) than the response to i.t. administration (a selective increase in BC).
On the other hand, atropine and its quaternary analog both penetrate
the BBB (Sanchez and Meier, 1993), so that the potential for systemic
effects resulting from muscarinic antagonists after i.c.v. or i.t.
administration is greater. Indeed, the time for onset of action and the
dose-response curves for effects on MVP and VE were similar for
atropine i.c.v., i.t., and i.v. administration. Only BC was selectively
increased by i.c.v. administration, indicating a selective action on
the brain. This selectivity is also supported by differences in the
duration of action; i.e., the effects of i.v. atropine disappeared
after 90 min, but those produced by i.c.v. or i.t. administration were
still apparent after 2 h. Sanchez and Meier (1993) also reported
that the effects of i.c.v. administration of atropine on
oxotremorine-induced hypothermia, tremors, or salivation were more than
10 times stronger than those of atropine administered peripherally.
Another study found that doses of atropine equivalent to those
administered in this study were effective in inhibiting the presser
responses induced by muscarinic agonists when administered i.c.v. but
not when administered i.v. (Brezenoff et al., 1988). Thus, it seems
reasonable to conclude that atropine administered by the three routes
in our experiments inhibits voiding function by acting at different
sites. It is well known that atropine can act on peripheral muscarinic
receptors in the bladder muscle to reduce the amplitude of bladder
contractions as well as reducing voiding efficiency. Our findings
indicate that atropine produces similar effects by acting on the
central nervous system. It also increases bladder capacity by blocking
muscarinic receptors in the brain.
Our observations regarding the central effects of OXO-M are somewhat
different from those reported by other investigators who administered
oxotremorine i.v. or i.a. (Sillen et al., 1982; O'Donnell, 1990). A
decrease in BC and an increase in MVP was detected after i.v. injection
in the rat and in vascular cross-perfusion studies in the dog brain. It
seems likely that these studies reflected in large part the peripheral
excitatory effects of the muscarinic agonist; whereas our experiments
revealed a central inhibitory effect. The most prominent effect of the
drug after i.c.v. or i.t. administration was an increase in BC,
indicating that the drug increases the central threshold for triggering
voluntary voiding. This implies that inhibitory muscarinic receptors
can modulate the processing of sensory input from the bladder and suppress the detection of bladder filling. These findings are compatible with those of a previous study (Roppolo et al., 1987), which
revealed that injections of carbachol in the region of the locus
coeruleus increased BC and suppressed rhythmic bladder
contractions in decerebrate cats. Another study (Thor et al., 2000)
showed that after blocking peripheral muscarinic receptors, i.v.
injection of oxotremorine suppressed reflexes induced by nociceptive
stimulation of the bladder. This effect could be elicited by an
inhibition of the central processing of afferent input from the bladder
and is consistent with other reports of antinociceptive effects of muscarinic agonists administered i.c.v. (Bartolini et al., 1992) or
i.t. (Yaksh et al., 1985; Zhou and Gebhart, 1991; Iwamoto and Marion,
1993).
Other effects of OXO-M suggest excitatory actions. For example, the drug stimulated nonvoiding contractions, decreased bladder compliance, and increased MVP. The first two effects could be mediated by stimulation of the parasympathetic excitatory outflow to the bladder during filling. Thus, OXO-M might elicit two opposing actions on the afferent and efferent limbs of the supraspinal micturition reflex, suppression of the afferent limb to increase the volume threshold for voiding and stimulation of the efferent limb to reduce storage capability of the bladder.
The increase in MVP, coupled with an increase in PVIP and a decrease in
VE after OXO-M administration to the brain, is most reasonably
explained by a dysfunction of the urethral outlet to increase outlet
resistance and reduce the flow of fluid from the bladder. In the rat,
rhythmic contractions of the external urethral sphincter are necessary
for efficient voiding (Yoshiyama et al., 2000). A previous study found
that microinjection of carbachol to locus coeruleus alpha suppressed
urethral sphincter activity (Sugaya et al., 1987). Our findings that
MVP, PVIP, and nonvoiding contractions were increased and VE reduced by
OXO-M suggest that coordinated sphincter activity was reduced by the drug.
The effects of atropine are important for identifying the role of
endogenous acetylcholine in the central control of the lower urinary
tract. It would be expected that if muscarinic inhibitory mechanisms
are tonically active in controlling voiding function, then atropine
would decrease BC and induce bladder hyperactivity. On the contrary,
atropine administered i.c.v. increased BC and reduced MVP and VE. This
indicates that tonic muscarinic excitatory mechanisms in the brain
regulate the afferent and efferent limbs of the micturition reflex
pathway, whereas inhibitory mechanisms seem to be inactive. The
excitation may occur at sites distant to the pontine micturition center
because previous studies (Roppolo et al., 1987) in decerebrate cats did
not detect any effect of atropine injected directly into the pons.
The physiological role of muscarinic receptors in the spinal cord is different from in the brain. Administration of atropine to the spinal cord reduced VE and MVP but did not increase BC significantly. This indicates that activation of muscarinic receptors facilitates the efferent rather than the afferent limb of the micturition reflex pathway in the spinal cord and that acetylcholine may play an active role during voiding but not during urine storage.
In summary, our findings indicate that activation of muscarinic receptors in the central nervous system can inhibit as well as facilitate voiding function in the awake rat. Excitatory muscarinic mechanisms appear to be tonically active to control both the afferent and efferent pathways involved in voiding. On the other hand, the physiological functions of inhibitory muscarinic mechanisms that can be activated by exogenously administered agonists are uncertain because these mechanisms seem to be inactive under normal conditions.
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Footnotes |
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Accepted for publication February 4, 2001.
Received for publication November 14, 2000.
Send reprint requests to: Yoshiyuki Ishiura, Department of Urology, Kanazawa University School of Medicine, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan. E-mail: yoship{at}p2332.nsk.ne.jp
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Abbreviations |
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OXO-M, oxotremorine methiodide; CMG, cystometrogram; BC, bladder capacity; VV, voided volume; RV, residual volume; MVP, maximal voiding pressure; PT, pressure threshold; PVIP, postvoiding intravesical pressure; VE, voiding efficiency; CNS, central nervous system; PMC, pontine micturition center; PLSD, protected least significant difference; BBB, blood-brain barrier; ANOVA, analysis of variance.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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, i.c.v., n = 9; 
, i.t., n = 7; 
, i.v.,
n = 5). Abscissa, the dose of oxotremorine-M
(µg/rat); C, control (prior to drug administration); Veh., vehicle;
ordinates, BC (ml) (A), MVP (cm of H2O) (B), PT (cm of
H2O) (C), and VE (%) (D). Each data point represents
mean ± S.E. Individual doses are compared with control using
repeated measures ANOVA followed by Fisher's PLSD test as a post hoc
multiple comparison procedure (*p < 0.05, **p < 0.01). Comparisons among i.c.v., i.t., and
i.v. administration were evaluated by the Mann-Whitney U
test (#p < 0.05, ##p < 0.01).
,
5 to 30 min after OXO-M injection; 
, 30 to 60 min after 0.1-µg
injection of OXO-M; 
, 60 to 120 min after 1-µg OXO-M injection.
