1 Departments of Medicine, This study investigated the role of nitric oxide
(NO) and adrenergic and dopaminergic mechanisms in reflex inhibition of
the migrating myoelectric complex (MMC) after intraperitoneal
administration of acid in rats. Acid instilled immediately after an
activity front inhibited the migrating complex and prolonged the cycle length from 13.0 ± 0.7 to 98.5 ± 17.2 min
(P < 0.001). Administration of
N
acid; calcitonin gene-related peptide; somatostatin
IT IS WELL RECOGNIZED that nociceptive stimulation of
the peritoneum inhibits gastrointestinal motility. In 1922 Arai (2) demonstrated that intraperitoneal injection of iodine or bacteria decreased propulsion of barium through the gastrointestinal tract. In
later studies of small bowel motility in rats, small intestinal transit
of contents was inhibited by stimulation of peritoneal nociceptors by
intraperitoneal injection of chemical irritants, such as iodine (25).
With the use of intraperitoneal acid the migrating myoelectric complex
(MMC) was also inhibited for 1-2 h (14), resulting in paralytic
ileus. The iodine-induced paralysis was slightly ameliorated by
capsaicin treatment but was not affected by Splanchnic nerve resection prevents ileus induced by peritoneal
irritation, suggesting involvement of sympathetic nervous pathways
including a spinal reflex (2). Bueno and co-workers (5) reported that
inhibition of the small bowel myoelectric activity in rats was reduced
by demedullation of the spinal cord and abolished by splanchnicectomy,
whereas vagotomy had no effect. These findings suggest that intestinal
paralysis induced by nociceptive peritoneal stimulation is effected
through sympathetic pathways that relay in the prevertebral ganglia.
Furthermore, stimulation of intra-abdominal nociceptors in cats causes
marked inhibition of gastric motility, mediated through nonadrenergic
noncholinergic (NANC) vagal fibers (1, 18). Because the afferents for
these two reflexes are essentially the same, the activation of
inhibitory NANC reflex mechanisms also in the small intestine may lead
to development of paralytic ileus.
Because nitric oxide (NO) is thought to be involved in NANC transmitter
functions (35) and NO has been implicated in the inhibition of small
bowel motility in rats (6, 23) and dogs (32), we investigated the
possible inhibitory role of NO in paralytic ileus in conjunction with
adrenergic, dopaminergic, and possibly also serotonergic mechanisms.
Because regulatory peptides are also important mediators in the control
of small intestinal motility, we measured the plasma concentrations of neuropeptide Y (NPY), somatostatin (Som), vasoactive intestinal peptide
(VIP), calcitonin gene-related peptide (CGRP), substance P (SP),
neurokinin A (NKA), and neurotensin (NT) after intraperitoneal acid
administration, to clarify possible associations between these
neuropeptides and changes in small bowel motility.
Electromyographic recordings of motility.
Eighty-two male Sprague-Dawley rats (B&K, Sollentuna, Sweden) weighing
300-350 g were used. The animals were anesthetized with pentobarbital (50 mg/kg; Apoteksbolaget, Umeå, Sweden). Then, three bipolar, insulated, stainless steel electrodes (SS-5T, Clark Electromedical Instruments, Reading, UK) were implanted into the
muscular wall in the small intestine 5, 15, and 25 cm distal to the
pylorus. Each animal was implanted with an intraperitoneal catheter for
acid administration and a venous catheter for drug administration in
the jugular vein. The electrodes and catheters were tunneled
subcutaneously and exited at the back of the neck of each rat. A 7-day
recovery period was provided after surgery.
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
-nitro-L-arginine, reserpine, or
guanetidine before acid decreased the prolonged cycle length to 18.1 ± 2.8 (P < 0.001), 19.0 ± 2.0 (P < 0.001), and 27.5 ± 9.3 min (P < 0.001), respectively.
Similarly, haloperidol given before acid shortened the prolonged cycle
length to 46.7 ± 5.2 min (P < 0.05). There was no effect of phentolamine in combination with
propranolol or hexamethonium given alone. After intraperitoneal
instillation of acid there was an increase in the plasma levels of
somatostatin and a decrease of calcitonin gene-related peptide, but
there was no change of neuropeptide Y, vasoactive intestinal peptide,
substance P, neurokinin A, or neurotensin. The results indicate that NO
and adrenergic, dopaminergic, and somatostatinergic mechanisms
cooperate in inhibiting the MMC after nociceptive stimulation of the
peritoneum.
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
- and
-adrenoceptor
blockade (25), suggesting that mediators other than adrenergic
transmitters may be involved in this inhibitory response.
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
RIA of regulatory peptides.
Immunochemical measurements of plasma concentrations of NPY, Som, VIP,
CGRP, SP, NKA, and NT were taken after intraperitoneal acid
administration. For this part of the study 16 animals were used to
obtain plasma concentrations of NPY-like immunoreactivity (LI), Som-LI,
VIP-LI, CGRP-LI, SP-LI, NKA-LI, and NT-LI. Through direct heart
puncture blood samples were taken 15 min after acid administration in
all study groups. The samples were centrifuged at 3,000 rpm for 10 min,
and plasma was collected. Plasma samples were then stored frozen at
80°C until extraction procedures and radioimmunoassay (RIA).
Design of studies of paralytic ileus. In the first experimental series, we studied the effect of 0.1 M hydrochloric acid on MMC. After a basal recording period, hydrochloric acid was administered as a 0.5-ml bolus via the intraperitoneal catheter (n = 7). The cycling pattern of MMC before and after administration of hydrochloric acid was compared in the same animal.
In the second series of experiments involving six separate groups, we studied the effect of different drugs that inhibit NO and adrenergic, dopaminergic, serotonergic, as well as preganglionic cholinergic pathways on acid-induced paralytic ileus. Because NO is synthesized from L-arginine by NO synthase (NOS), the NOS inhibitor NDrugs and other chemicals. Hydrochloric acid, 0.1 mol/l (pH 1.2, 290 mosmol/l), was obtained from Chemicon (Sollentuna, Sweden). L-Arginine, L-NNA, and hexamethonium were purchased from Sigma Chemical. Injectable formulations of reserpine (Serpasil), guanethidine (Ismelin), and phentolamine (Regitin) were kindly supplied by Ciba (Basel, Switzerland). Propranolol (Inderal) was obtained from Zeneca (Cheshire, UK) and haloperidol (Haldol) from Janssen Pharmaceutica (Beerse, Belgium). All compounds were dissolved in saline, with the exception of L-NNA, which was dissolved in alkaline saline at pH 8 before use. All drugs were administered intravenously in volumes of 0.1-0.2 ml.
Statistics. Values are expressed as means ± SE in n animals. Statistical significance was evaluated using the Student's t-test for paired data or analysis of variance followed by the Bonferroni multiple comparisons test where appropriate.
Ethical considerations. The study was approved by the Regional Ethics Committee for the Humane Use of Research Animals in Northern Stockholm, Sweden. Surgical procedures and experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health).
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RESULTS |
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MMC under control conditions. Under control conditions, a regular motility pattern with recurring MMCs was recorded in all animals (Fig. 1). The MMC cycle length under basal conditions in the different study groups is shown in Table 1.
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Effects of drug pretreatment on MMC. L-NNA shortened the MMC cycle length (P < 0.001). Reserpine, guanethidine, phentolamine, and propranolol in combination, as well as haloperidol or hexamethonium given alone had no effect on the MMC cycle length (Table 1).
|
Effects of intraperitoneal acid on MMC. Hydrochloric acid instilled intraperitoneally promptly abolished the MMC at all registration levels for a duration of 98.5 ± 17.2 min (P < 0.001, Fig. 1), but there was persistence of slow waves with a frequency of 36.3 ± 1.2 cycles/min (Figs. 2 and 3). After inhibition and reappearance of the MMC, the cycle length was gradually resumed. The cycle length was 37.1 ± 6.3 min between the onset of the first and second activity fronts and 16.2 ± 2.3 min between the second and third activity fronts. Thereafter, the MMC cycle length was completely normalized to 13.2 ± 0.7 min.
|
|
|
Effects of intraperitoneal acid on neuropeptides. Intraperitoneal acid increased the circulating levels of Som increase (P < 0.05), whereas the concentrations of CGRP markedly decreased (P < 0.05) and the concentrations of NPY did not change (Fig. 5). There were no detectable levels of VIP, SP, NKA, and NT in peripheral blood before or after challenge with acid.
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DISCUSSION |
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In this study, nociceptive stimulation of the peritoneum with hydrochloric acid resulted in prompt inhibition of the MMC. Because the basic electrical slow-wave rhythm was preserved, this effect is not likely to be due to a high acidity with an ensuing nonspecific cell damage. Rather, it appeared to be a specific inhibitory action on motility-regulating systems suggested to involve nitrergic, as well as adrenergic, dopaminergic, and somatostatinergic mechanisms.
The observed acid-induced intestinal paralysis appeared to be a reflex
inhibition of MMC, rather than a peritonitis with an inflammatory
reaction that induced a disturbance of the MMC. In favor of a reflex
mechanism the paralysis occurred immediately after acid administration,
and the slow-wave rhythm persisted throughout the period of intestinal
paralysis. In contrast, however, peritonitis secondary to bowel
perforation has been shown to be associated with a perturbed intestinal
motility that first appears 24 h after induction of peritonitis and
persists 48-72 h (4). Furthermore, our findings point in favor of
a neuronally mediated inhibition of MMC, rather than a humoral
catecholamine-induced effect. Adrenoceptor blockade failed to reduce
intestinal paralysis, whereas reserpine and guanethidine, which both
act at a neuronal site, effectively reduced the inhibitory motility
response to intraperitoneal acid. As an explanation for these apparent
contradictory results between reserpine and guanethidine, and the
adrenergic antagonists, it has been shown that under physiological
conditions blockade of - (by phentolamine or phenoxybenzamine)
or
-adrenoceptors (by propranolol) does not influence the
occurrence of the MMC (13), indicating that the adrenergic nervous
system is not involved in the control of MMC. In addition, under
pathophysiological conditions
- and
-adrenoceptor blockade has
been shown to be ineffective in inhibiting iodine-induced paralysis,
even if a nerve toxin such as capsaicin produces intestinal
disinhibition (25), suggesting that mediators in addition to
norepinephrine may be involved in inhibitory responses of the
gut. In line with this we have previously found that high
doses of
- and
-adrenergic blockers in combination do not produce
as profound an inhibition of motility as seen with guanethidine. In
these studies it was speculated that NPY might be involved in the
inhibitory motility response to sympathetic nerve stimulation of the
colon in cats (21, 24). It was also demonstrated that NPY is released
from sympathetic nerves in the splanchnic area by a
guanethidine-sensitive mechanism in cats (27). These findings indicate
that other mediators apart from norepinephrine acting on
- and
-adrenoceptors may be involved in inhibitory responses of the gut.
Because NPY also has been shown to inhibit the MMC and propulsion of
contents through the small intestine (22), it is a most likely
candidate for additional sympathetic inhibitory mechanisms in the gut.
Furthermore, in this project we tried to measure NPY to verify an
increase of the peptide in plasma after challenge with acid. However,
the high basal levels of NPY found prevented us from detecting any significant increases in the levels of circulating NPY. Hence, a local
inhibitory effect of NPY or some other related transmitter with a
similar inhibitory function, such as Som or VIP, cannot be excluded.
Supportive findings for a neuronal mechanism for the acid-induced inhibition of motility come from Smith and co-workers (34), who reported a transient increase in plasma epinephrine simultaneously with a sustained increase of norepinephrine after laparotomy in the dog. In their study, ileus persisted for a long time after plasma concentrations of epinephrine returned to basal values. Furthermore, studies in the rat have demonstrated that adrenalectomy does not reduce the duration of postoperative ileus (8).
In our study we found that reserpine prevented the acid-induced inhibition of motility. This effect seems to be confined to a reserpine-induced depletion of norepinephrine and dopamine stores, whereas the depletory effect of reserpine on serotonin stores is of limited importance because serotonin is generally considered a motility-stimulating transmitter.
Two different neuronal pathways have been implicated in the intestinal sympathetic inhibitory reflex (16). One pathway has been described to consist of afferent neurons from the gut wall that reach the spinal cord. These neurons connect via short interneurons with efferent preganglionic splanchnic neurons that synapse in the prevertebral ganglia with postganglionic sympathetic neurons innervating the myenteric plexus of the gut. Another pathway consists of short afferents from the gut, which are conveyed to the prevertebral ganglia, where they directly connect with efferent postganglionic sympathetic neurons that finally innervate the myenteric plexus. It has been suggested that the source and intensity of peritoneal irritation determine whether the intestinal inhibitory reflex is restricted to the spinal pathways or whether it also involves sympathetic interconnections via the prevertebral ganglia (16). In our hands, hexamethonium, a ganglionic nicotinic receptor antagonist that inhibits the fast excitatory postsynaptic potential induced by acetylcholine, failed to block the acid-induced intestinal paralysis, suggesting that the activated reflex arc is primarily of the short type with afferent fibers that connect with efferent fibers within the prevertebral ganglia. However, another possible ganglionic transmitter that mediates fast ganglionic transmission is 5-hydroxytryptamine (5-HT, serotonin) by activating 5-HT3 receptors (29). Furthermore, a number of neuropeptides such as SP, VIP, and cholecystokinin have accounted for the mediation of a noncholinergic slow excitatory postsynaptic potential (11, 30). Therefore, the possibility that both long and short reflex arcs are involved in the intestinal inhibitory response to intraperitoneal acid cannot be entirely excluded.
As indicated by our findings that guanethidine and reserpine blocked
the inhibition of MMC after intraperitoneal acid, an increased
sympathetic activity prevails in this type of paralytic ileus. Our
results are in agreement with previous pharmacological data (34). In
addition, chemical destruction of sympathetic nerves by pretreatment
with 6-hydroxydopamine prevents inhibition of gastric emptying and
intestinal transit after abdominal surgery in the rat (10). Increased
synthesis and release of norepinephrine from the intestinal wall in the
rat have been reported (9, 10). In rats, impaired gastrointestinal
motility was restored by - but not by
-adrenoceptor blockade
(31). Furthermore, blockade of adrenoceptors prevented inhibition of
gastric activity fronts in the dog but had no effect on gastric
emptying or small intestinal myoelectric activity and transit of
contents (34). Thus it seems that the adrenergic pathway is not the
only mechanism responsible for the reflex inhibition evoked by
peritoneal irritation.
An important mechanism for the inhibition of motility is dopamine acting at neural D2 receptors. Previous studies have shown that stimulation of D2 receptors decreases acetylcholine release from cholinergic motoneurons innervating the gastrointestinal tract (26). In our study, haloperidol was used as an antagonist on inhibitory D2 neural receptors. Presumably, haloperidol removed dopamine-mediated inhibition and facilitated acetylcholine release, resulting in increased acetylcholine levels (36), which should counteract acid-induced intestinal paralysis.
During intestinal paralysis we observed an increase in plasma concentrations of Som-LI and a decrease in CGRP-LI. In the rat, cell bodies reactive to Som are located mainly in the myenteric plexus (33) and are considered to participate in abolishing peristalsis. Nerve cell bodies reactive to CGRP are found within the myenteric plexus as well, but also in nerve fibers around ganglia, in the mucosa, and around arterioles as peripheral endings of sensory neurons (17). Speculative reasoning would infer that the observed increase in Som may contribute to the inhibition of motility, as Som inhibits the firing rate of myenteric neurons (15) and decreases acetylcholine release (20). The decrease in CGRP is interesting because this peptide has been demonstrated to disrupt MMC and stimulate irregular spiking in the rat small intestine (28). Even if speculative, the observed changes in plasma concentrations of these peptides from the gastrointestinal tract and nervous system may have an association with inhibition of motility as seen after intraperitoneal acid.
L-NNA diminished the period of acid-induced inhibition of the gut. In agreement with this a high density of NOS-positive neurons has been demonstrated mainly confined to the myenteric plexus in the mammalian gastrointestinal tract (12). From immunohistochemical studies of autonomic ganglia, NO appears to be a mediator both in parasympathetic postganglionic neurons as well as in preganglionic sympathetic neurons (7). NO can inhibit gastrointestinal motility either through actions in the autonomic nervous system or within the myenteric plexus to exert a local inhibitory action on the smooth muscle itself. The latter mechanism would be more consistent with the profound inhibition of motility as seen in our acid-induced paralysis. Because L-NNA by itself stimulated the MMC with a shortening of the cycle length, we cannot exclude the possibility that the effect of L-NNA in conjunction with intraperitoneal acid is also related to an alteration of the regulation of the MMC rather than a block of the nociceptive inhibitory response of the gut.
In conclusion, our results indicate that intraperitoneal administration of hydrochloric acid activates an intestinal inhibitory reflex mechanism. Of the different mediators involved, NO in addition to adrenergic and dopaminergic, and possibly also peptidergic mechanisms cooperate in the acid-induced inhibition of the MMC after nociceptive stimulation of the peritoneum.
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ACKNOWLEDGEMENTS |
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The study was supported by the Swedish Medical Research Council (Grant 7916), the Magnus Bergvall Foundation, the Åke Wiberg Fund, and the Prof. Nanna Svartz Fund.
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FOOTNOTES |
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Address for reprint requests: P. M. Hellström, Gastroenterology Section, Dept. of Medicine, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
Received 26 March 1997; accepted in final form 24 November 1997.
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