1 First Department of Surgery and 2 Department of Physiology II, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
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ABSTRACT |
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The aim of the present study was to analyze the neuromodulation of rectoanal reflex activity by lumbar sympathetic nerves in guinea pigs. The mechanical activities of the rectum were recorded with a balloon connected to a pressure transducer, and those of the internal anal sphincter (IAS) were recorded with a custom-made strain gauge force transducer. Gradual and sustained rectal distension evoked the rectoanal reflex, causing cholinergic contractions of the rectum and synchronous nitrergic relaxations of the IAS. Section of the lumbar colonic nerves enhanced both rectal contractions and IAS relaxations. Section of the 13th thoracic cord abolished both rectal contractions and IAS relaxations, but section of the lumbar colonic nerves restored them. Lumbar sympathectomy and pithing sacral cords greatly diminished these rectal contractions and IAS relaxations, but the intrinsic reflex component remained. NG-nitro-L-arginine methyl ester enhanced the intrinsic reflex-mediated contraction of the rectum and abolished reflex-mediated relaxation of the IAS and converted into cholinergic contractions. The present results indicate that the extrinsic lumbar inhibitory outflow causes marked inhibition of the rectoanal reflex via the lumbar colonic nerves.
extrinsic reflex; internal anal sphincter; intrinsic reflex; pelvic nerves; rectum
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INTRODUCTION |
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WE HAVE PREVIOUSLY REPORTED (22) that a rectorectal reflex is induced by prompt rectal distension in the guinea pig. This rectorectal reflex is composed of the extrinsic excitatory reflex via sacral cords (S1-3), the extrinsic inhibitory reflex via lumbar cords (L1-4), and the intrinsic cholinergic excitatory reflex via the enteric nervous system (22). The afferent and efferent limbs of the extrinsic excitatory reflex travel in the pelvic nerves, whereas the limbs of the extrinsic inhibitory reflex pass in the lumbar colonic nerves (LCNs) (22). Furthermore, we have found that the inhibitory reflex is suppressed by descending input from the pontine defecation center, leading to a disinhibition of the sacral excitatory reflex and intrinsic excitatory reflex (22-24). In view of these findings, we have proposed that the lumbar colonic inhibitory reflex contributes to the rectorectal reflex, one important component of the defecation reflex (22-25).
To clarify the integrative control of the defecation reflex by the lumbar sympathetic nerves, the goal of the present study was to elucidate the rectoanal reflex [especially the rectointernal anal sphincter (recto-IAS) reflex], because the act of defecation is a consequence of successive phenomena occurring in both the colon and anorectum (9). There is considerable evidence to support the view that the descending inhibitory reflex involving inhibitory motor neurons occurs along the entire large intestine (1, 2, 6, 7). In the current study, the rectoanal reflex (especially the recto-IAS reflex) was analyzed, and the role of the lumbar sympathetic nerves in integrative control of the distension-induced rectoanal reflex was evaluated.
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METHODS AND MATERIALS |
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Experimental procedures followed the guidelines of the local animal ethics committee. Experiments were performed on 50 male guinea pigs (315-450 g body wt) anesthetized with ethyl carbamate (0.7-1.0 g/kg ip), artificially ventilated via a trachea cannula, and immobilized with gallamine (0.1 mg/kg iv). The level of anesthesia was intermittently tested after the immobilization was stopped. The postganglionic axons from the inferior mesenteric ganglia travel to the colon, the rectum, and the IAS via the LCNs and hypogastric nerves (HGNs) (2, 10-12). These nerves were viewed with a binocular stereomicroscope and cut extraperitoneally.
Figure 1 shows the protocols used in the
present study. Protocols 1 and 2 were performed
to analyze the extrinsic rectoanal reflex. Lumbar sympathectomy (LS),
composed of section of the LCNs and section of HGNs, was performed with
simultaneous section of the intermesenteric nerve fibers to prevent the
influence of the superior mesenteric ganglia (8), although
the majority of inferior mesenteric ganglion cells project into the
LCNs (and HGNs) (10). After laminectomy, spinal
transection at the 13th thoracic cord (TH 13) was performed with a
blunt knife to exclude influence from the supraspinal pathway. Pithing
the first to the third sacral cords [PITH (S1-3)] was performed
by inserting the needle into the vertebral canal to exclude the
center of the extrinsic excitatory reflex through the pelvic nerves,
leaving behind the intrinsic (enteric) neural pathway.
Hemostasis was obtained by inserting cotton wool into the
vertebral canal. The difference between protocols 1 and
2 was only in the order of LS and TH 13.
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Protocol 3 was performed to analyze the intrinsic rectoanal reflex. LS and PITH (S1-3) were performed at first to exclude the extrinsic reflexes, and guanethidine sulfate (3 mg/kg iv) was administered to block sympathetic adrenergic nerve terminals, leaving only the intrinsic reflex pathways. To evaluate the contribution of enteric cholinergic and nitrergic nerve pathways to the intrinsic reflex, a nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester hydrochloride (L-NAME; 10 mg/kg iv), NG-nitro-L-arginine (L-NNA; 10 mg/kg iv), tetrodotoxin (2 µg/kg iv), L-arginine (L-ARG; 50 mg/kg iv), or atropine sulfate (0.5 mg/kg iv), was administered. Apart from protocol 3, we investigated the effect of atropine sulfate (0.5 mg/kg iv) on the reflex-mediated rectal contraction and that of L-NAME (10 mg/kg iv) on reflex-mediated IAS relaxation in each of three different intact guinea pigs.
Rectal motility was recorded with a warm water-filled balloon that was
attached to flexible polyethylene tubing connected to a pressure
transducer. The 1.5-cm-long balloon was introduced into the rectum 4 cm
oral to the anus (Fig. 2), and the tubing was loosely fixed to a metal rod to prevent evacuation of the balloon
through the anus. To record the basal rectal motility, 0.05 ml of water
had been infused into the balloon. We confirmed that the balloon itself
did not generate any pressure due to the elastic properties of the
balloon when <2.0 ml of water was infused. Gradual and sustained
rectal distension at each interval of 20 min was performed by
continuously infusing 0.6 ml of warm water into the balloon at the rate
of 1.5 ml/min for 24 s and by clamping the infusion tube for 4 min
36 s (total 5 min; Figs. 2 and 3). This rectal distension method simulated the rectal distension by
transported and reserved feces. The rectal distension did not affect
the systemic blood pressure, indicating that the stimulus was
nonnociceptive. During infusion of water into the balloon up to 0.6 ml
for 24 s, no reflex response was evoked. Subsequent sustained
rectal distension evoked reflex responses superimposed on a sustained,
passively generated pressure of 55-75 mmHg. This volume is the
same as the previous one (22) and corresponds to two
pieces of fresh feces.
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The motility of the IAS was recorded with a custom-made strain gauge
force transducer (Fig. 2) composed of a pair of needles and a base. The
needles were horizontally fixed and inserted into the anus 0.5 cm oral
to the anal margin. The needles were fixed on the base where two strain
gauges (120 ± 0.5 each) forming a half-bridge were mounted
(see Fig. 2, inset). The needles moved from the left to the
right according to the IAS motility, and this moved the strain gauges.
At calibration, this transducer was vertically fixed at the base so
that the needle on either side was upward, and 1-g weights were
suspended on it. The transducer was similar to that used by Mizutani
and Nakayama (11) to measure the motility of the canine
IAS but was modified for use in guinea pigs. Force generated by strain
in this transducer was linear, between 0 and 1.0 mm. The mean
frequencies of the spontaneous motility of the rectum and the IAS
without any interventions were 6.14 ± 2.54 and 10.14 ± 3.13 cycles/min, respectively, and there were significant differences
(P < 0.001) between them in seven guinea pigs. The
rhythm of the present IAS spontaneous motility overlapped with that in
opossum IAS (20). After L-NAME, IAS relaxations were converted into contractions, whereas the rectal contractions remained, as shown in Fig. 8, A, c
and B, c. We therefore judged that the motility
of the IAS detected with this transducer was independent of rectal motility.
The trial for control rectoanal reflex response was repeated three times in each experiment. A constant reflex response was repeatedly produced in normal animals throughout the experiments by the present protocol without any interventions. After the control reflex response became constant, each guinea pig underwent various surgical operations. After each surgical operation or drug application, two or three trials of rectal distension for 5 min at 20-min intervals were performed and the best reflex response in two or three trials was evaluated. Mean systemic arterial blood pressure (SAP) was maintained between 100 and 150 mmHg (physiological range) throughout the experiment, and PO2, PCO2, and pH were maintained within the physiological range by changing the tidal volume and rate of artificial ventilation. The body temperature was also maintained within the physiological range at 36-37°C with a heating pad.
Figure 3 shows how we obtained the net area of each rectoanal reflex-mediated contraction of the rectum and relaxation of the IAS. The baseline was drawn on the basal pressure (Fig. 3A) or basal force level (Fig. 3B). Gradual distension for 24 s by continuously infusing 0.6 ml of warm water into the balloon and sustained rectal distension was performed after clamping the infusion tube for 4 min 36 s. We digitized the observed curves of each rectal contraction and IAS relaxation and contraction and calculated the area under the intraluminal pressure-time curve (AUC) of rectal contraction (Fig. 3A), the area over the force-time curve (AOC) of IAS relaxation, and the AUC of IAS contraction (Fig. 3B) with a computer-operated scanner-digitizer (Macintosh and Flexi-Trace; Three's Company, Tokyo, Japan). We also digitized and calculated each nonreflex area (see Fig. 3) with the same computer-operated scanner-digitizer. In each rectal contraction and IAS relaxation and contraction, the area of the tetrodotoxin-insensitive first phasic response was excluded from reflex area, since it is not a neural reflex response. We finally obtained the shaded area, which was considered the reflex area, by subtracting nonreflex area from the AUC (Fig. 3A) and by subtracting the nonreflex area from the AOC or AUC (Fig. 3B). The reflex area is expressed as positive values for rectal contractions and IAS relaxations and as a negative value for IAS contractions. The reflex area sensitively reflects any changes in amplitude, duration, or frequency of the reflex-mediated response. The reflex index is expressed as a relative ratio to the control reflex area (equal to 1.0).
The following drugs were used: atropine sulfate, L-ARG, gallamine triethiodide, L-NAME, and L-NNA (Sigma, St. Louis, MO); ethyl carbamate (Wako Pure Chemical Industries, Osaka, Japan); guanethidine sulfate (Tokyo Chemical Industry, Tokyo, Japan); and tetrodotoxin (Sankyo, Tokyo, Japan). Statistical significance of differences between means was estimated by one-way ANOVA and followed by multiple comparisons by means of Bonferroni t-tests. A P value of < 0.01 was considered statistically significant.
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RESULTS |
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Activation of the recto-IAS reflex by rectal distension. Gradual and sustained rectal distension for 5 min at 20-min intervals constantly elicited the rectoanal reflex, causing rectal contractions and IAS relaxations in each guinea pig. Initial experiments were conducted to evaluate the extent of variability of the distension-induced responses among different animals under control conditions. Control reflex index absolute values (arbitrary units) for rectal contractions and IAS relaxations calculated in 20 control rectoanal reflexes of 20 guinea pigs were 4,874 ± 672.1 (coefficient of variance = 0.14) and 49,822 ± 8,368.7 (coefficient of variance = 0.17), respectively. These findings suggested that variations among control studies were rather small.
The rectal contractions were abolished by atropine or tetrodotoxin in all three intact guinea pigs tested. In three other animals, L-NAME converted the IAS relaxations into contractions, whereas the rectal contractions were unaffected (data not shown). These results indicate that the rectal contractions were elicited by the cholinergic nerve pathway and that the IAS relaxations were elicited by the nitrergic nerve pathway.Effects of LCNs and PITH (S1-3) on extrinsic rectoanal reflex.
The representative sets of tracings of the reflex-mediated rectal
contractions and the IAS relaxations in control (Fig.
4A), after LCNs (Fig.
4B), and after PITH (S1-3) (Fig. 4C)
(protocol 1) are shown. The initial transient increase in
rectal intraluminal pressure induced by gradual distension did not
elicit the reflex response and was tetrodotoxin insensitive. This phase
is excluded from the reflex area (see Fig. 3). The subsequent,
sustained rectal distension evoked reflex responses superimposed on a
sustained, passively generated pressure of 55-75 mmHg. The
rectoanal reflex caused six phasic contractions in the rectum and
simultaneous phasic relaxations in the IAS. LCNs noticeably increased
amplitude in rectal contractions (reflex index from 1.0 to 1.78) and
IAS relaxations (reflex index from 1.0 to 1.36) (Fig. 4B).
Subsequent HGNs did not result in a further change in the reflex
responses (not shown), but PITH (S1-3) markedly decreased both the
rectal contractions and IAS relaxations without any effect on basal
motility (Fig. 4C). The basal motility was greatly
attenuated by papaverine (5 mg/kg iv).
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Effects of LCNs, TH 13, and PITH (S1-3) on extrinsic rectoanal
reflex.
The summarized data on the effects of successive surgical operations on
reflex-mediated rectal contractions and IAS relaxations evaluated by
the reflex index in the same guinea pigs (n = 6; protocol 1) are shown in Fig.
5. The reflex index in the control was
expressed as 1.0. LCNs significantly increased both rectal (P < 0.005) and IAS reflex indexes (P < 0.001) by approximately twofold to 2.18 ± 0.96 and 2.34 ± 0.46, but subsequent HGNs did not lead to further alteration of
these indexes. TH 13 caused slight reductions in rectal and IAS reflex
indexes to 1.57 ± 0.48 and 1.96 ± 0.20, but these changes
were not significant. PITH (S1-3) significantly decreased rectal
(P < 0.005) and IAS reflex indexes (P < 0.001) to 0.34 ± 0.24 and 0.51 ± 0.08, respectively (Fig. 5A).
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Effects of TH 13, LCNs, and PITH (S1-3) on extrinsic rectoanal
reflex.
Each representative set of tracings of reflex-mediated rectal
contractions and IAS relaxations in control (Fig.
6A), after TH 13 (Fig.
6B), after HGNs (Fig. 6C), and after LCNs (Fig.
6D) (protocol 2) is shown in Fig. 6. The
rectoanal reflex was composed of four phasic contractions in the rectum
and four phasic relaxations in the IAS (Fig. 6A). TH 13 abolished both rectal contractions and IAS relaxations (Fig.
6B) without a decrease in the SAP (data not shown). HGNs did
not alter the previously abolished contractions and relaxations (Fig.
6C), but LCNs restored the amplitude and frequencies of
rectal contractions and IAS relaxations to near control levels (Fig.
6D). The final PITH (S1-3) decreased both rectal
contractions and IAS relaxations (data not shown).
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Effects of L-NAME or L-NNA and atropine,
tetrodotoxin, or L-ARG on intrinsic rectoanal reflex.
PITH and guanethidine treatment abolished typical reflex-mediated
rectal contractions and IAS relaxations without any effect on basal
motility (protocol 3; n = 4) (Fig.
8A, b). Only the
intrinsic (enteric) inhibitory nerve pathways would be expected to
remain under these conditions. L-NAME administration led to
intrinsic rectal and IAS contractions (Fig. 8A,
c), and these contractions were abolished by tetrodotoxin
(Fig. 8A, d) without any effect on basal
motility. These data indicate that the intrinsic excitatory and
inhibitory nerves remain intact in the intrinsic rectoanal reflex
pathway after PITH (S1-3) and guanethidine.
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DISCUSSION |
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The most important finding in the present study was that the
lumbar inhibitory outflow through the LCNs markedly suppressed rectoanal reflexes, causing both contractions (cholinergic) of the
rectum and relaxations (nitrergic) of the IAS. Consistent with this,
rectal balloon distension-mediated IAS relaxation is significantly
suppressed by the 2-adrenoceptor agonist clonidine (28) and by lumbar sympathetic nerve stimulation
(14) in the opossum. Although HGN stimulation suppressed
the rectal balloon distension-induced fall in IAS pressure, rectal
balloon distension caused a fall in IAS pressure without any
significant change in HGN efferent activity (20). It was
suggested that HGNs may not play a significant role in rectoanal
reflex-induced IAS relaxation (20). Together, these data
suggest the contribution of lumbar sympathetic nerves excluding HGNs,
i.e., LCNs, to the rectoanal reflex in opossum. Moreover, we suggest
that the inhibitory outflow from the lumbar spinal cord by way of the
LCNs plays an important role in integrative control of the rectoanal
reflex in the guinea pig.
The recto-IAS reflex by rectal distension. Rectal distension is a more physiological stimulus than electrical field stimulation, which is commonly used in in vitro studies (4, 5). Distension stimulates afferent stretch receptors in the rectum, whereas electrical field stimulation directly activates enteric nerve pathways. Gradual, sustained rectal distension, as used in the current study, simulating the rectal distension by transported and then reserved two pieces of feces was a more physiological stimulus than those in our previous studies (22-24), in which prompt, sustained rectal distension was used. In the present study, we were able to induce constant rectal contractions and simultaneous IAS relaxations by means of the rectal distension, although the possibility that the rectal contraction evoked by rectal distension secondarily causes IAS relaxation cannot be excluded. Furthermore, spontaneous slowly migrating motor activity involving both excitatory and inhibitory enteric neurons has recently been observed in guinea pigs (3). We have tested this possibility by simultaneous recording of the motility in the colon (7-9 cm oral to the anus) and rectum (4 cm oral to the anus) (our unpublished observations). Several phasic rectal contractions were elicited by the balloon distension in the rectum, whereas the colonic motility was unchanged. It seems likely that spontaneous slowly migrating motor activity never occurred during the rectal distension without any intervention. Although further studies are needed to determine whether this motor activity could be involved in reflex-mediated contractions and relaxations, it is conceivable that major parts of rectal contractions and IAS relaxations elicited by rectal distension are nerve-mediated reflex responses.
Rationality of the reflex index. In the present study, we adopted a reflex index to quantitatively evaluate reflex-mediated rectal contractions and IAS relaxations and contractions. There are many studies, including our own (21), that evaluate gut motility quantitatively, but the reflex responses are composed of various wave patterns, so that the simple evaluation of the amplitude and frequency of each wave is not appropriate in evaluating the rectoanal reflex. The present reflex index is a relevant assessment because it corresponds to the power evacuating fecal contents, and it would be appropriate for quantitative evaluation of the reflex response composed of various wave patterns.
Extrinsic lumbar inhibitory reflexes through LCNs. The rectoanal reflex causing both rectal contractions and IAS relaxations were doubly enhanced after LCNs (not HGNs), indicating that the lumbar outflow through the LCNs halved the rectoanal reflex in the guinea pig. This finding is novel and somewhat different from that in our previous reports (22-24). It seems likely that the inhibition from the pons to lumbar nerve efferent activity was less potent in the present study than in our previous studies (22-24). The difference between our previous result and the present one may involve the different methods of rectal distension that were employed (prompt distension vs. gradual, sustained distension) as discussed below.
Extrinsic sacral excitatory reflexes. Final PITH (S1-3) in protocols 1 and 2 largely attenuated the rectal contraction and IAS relaxation, indicating that the sacral excitatory reflex through the pelvic nerves causes the rectal contraction and IAS relaxation. This is partly supported by previous findings indicating that synaptic inputs to myenteric neurons in the guinea pig rectum from pelvic nerves have been identified (27). The enhanced rectal contraction and IAS relaxation after LCNs (see Fig. 5) were only slightly decreased after TH 13, indicating that the supraspinal facilitation on the pelvic nerve outflow does not play an important role in the present reflex mechanism. This is consistent with our previous results on the rectorectal reflex in the guinea pig (22).
Supraspinal inhibition on lumbar inhibitory outflow. The reflex-mediated rectal contraction and IAS relaxation appeared to be abolished without any fall in SAP after TH 13. As mentioned above, the supraspinal facilitation on the pelvic nerve outflow does not greatly contribute to the present reflex mechanism. The restoration of both rectal contractions and IAS relaxations after the following LCNs indicates that the descending nerve pathway, possibly from the pons (23), contributes to suppress the lumbar inhibitory outflow in the rectoanal reflex. This descending nerve pathway from the pons is activated by pelvic afferent nerve activation (23). The pelvic afferent nerve is activated by rectal distension (22). The intensity of the descending inhibition seems to depend on the method of rectal distension. It seems likely that the present gradual and sustained rectal distension activates pelvic afferents less potently than the prompt rectal distension does (22).
Role of the enteric nitrergic nerve pathway in the intrinsic reflexes. A recent study suggested the possibility that nitrergic neurotransmission is involved in electrical field stimulation-induced nonadrenergic, noncholinergic relaxation of the rat rectal circular muscle (26) and IAS (4). In the human distal rectum, nitrergic axons enter shunt fascicles that descend into the anal canal, where they ramify into and throughout the IAS (15). It is reasonable, therefore, that the nitrergic nerve pathways in the rectum and IAS are activated by the rectal distension. The extrinsic sacral excitatory and lumbar inhibitory nerve pathways (adrenergic nerve fibers) in the rectum and IAS were impaired after PITH (S1-3) and guanethidine (9), and only intrinsic (enteric) excitatory and inhibitory nerve pathways remained. Consequently, both rectal and IAS reflex indexes were greatly decreased (see Figs. 5 and 7) but were not 0. L-NAME or L-NNA enhanced the intrinsic rectal contractions and converted IAS relaxations into contractions or evoked IAS contractions. These intrinsic reflex-mediated rectal and IAS contractions were abolished by tetrodotoxin or atropine or were greatly decreased by L-ARG. Moreover, these findings indicate that enteric cholinergic excitatory and nitrergic inhibitory nerve pathways contribute to the intrinsic rectoanal reflex, although it is unknown whether intrinsic reflex-mediated IAS relaxations are evoked by rectal distension or are secondarily evoked by rectal distension-induced rectal contraction.
L-NNA has been reported to convert the relaxations in the isolated human rectum into cholinergic contractions and to convert the relaxations in the isolated human IAS into ![]() |
ACKNOWLEDGEMENTS |
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We thank G. Mawe in the Department of Anatomy and Neurobiology in the University of Vermont for critical reading of this manuscript.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Takaki, Dept. of Physiology II, Nara Medical Univ., 840 Shijo-cho, Kashihara, Nara 634-8521, Japan (E-mail: mtakaki{at}naramed-u.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published March 6, 2002;10.1152/ajpgi.00497.2001
Received 19 November 2001; accepted in final form 7 February 2002.
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