Gastrointestinal Diseases Research Unit, Departments of Biology, Medicine, and Physiology, Queen's University, Kingston, Ontario, Canada K7L 5G2
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ABSTRACT |
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This study examined whether myenteric neurons activate submucosal vasodilator pathways in in vitro combined submucosal-myenteric plexus preparations from guinea pig ileum. Exposed myenteric ganglia were electrically stimulated, and changes in the outside diameter of submucosal arterioles were monitored in adjoining tissue by videomicroscopy. Stimulation up to 18 mm from the recording site evoked large TTX-sensitive vasodilations in both orad and aborad directions. In double-chamber baths, which isolated the stimulating myenteric chamber from the recording submucosal chamber, hexamethonium or the muscarinic antagonist 4-diphenylacetoxy-N-(2-chloroethyl)-piperdine hydrochloride (4-DAMP) almost completely blocked dilations when superfused in the submucosal chamber. When hexamethonium was placed in the myenteric chamber ~50% of responses were hexamethonium sensitive in both orad and aborad orientations. The addition of 4-DAMP or substitution of Ca2+-free, 12 mM Mg2+ solution did not cause further inhibition. These results demonstrate that polysynaptic pathways in the myenteric plexus projecting orad and aborad can activate submucosal vasodilator neurons. These pathways could coordinate intestinal blood flow and motility.
vasodilator reflexes; intestinal blood flow; enteric reflexes; submucosal arterioles
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INTRODUCTION |
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THE DEMANDS FOR MUCOSAL BLOOD flow in the gastrointestinal microcirculation are significantly greater than in other peripheral vascular beds (14, 17). Mucosal oxygen and transcapillary fluid and solute transport needs vary significantly, depending on the physiological state of the intestine. For example, vascular perfusion to intestinal mucosa increases by up to 100% during digestion (9, 15). The rate of vascular perfusion to the mucosa is directly controlled by the contractile state of submucosal arterioles, the major resistance vessels in the gastrointestinal tract (14). Although multiple regulatory systems are important in modulating this tone (14, 17, 32), neural regulatory mechanisms are poised to rapidly respond to the widely fluctuating demands as stimuli are constantly changing within the lumen of the intestine.
Although extrinsic neural reflexes have been implicated in the regulation of intestinal blood flow, functional studies (4, 5, 14, 17, 19) have demonstrated that important neural vasodilator reflexes exist within the intestine. These studies suggest that enteric neural reflexes can respond to increased mucosal requirements for blood flow as chyme moves through the lumen. For example, in in vivo studies (14, 17) both local mechanical and chemical stimulation of the mucosa have been shown to initiate neurally mediated reflex vasodilation. This action is mediated by enteric nerves because these responses were not blocked by extrinsic denervation (3, 19). The neuronal pathways mediating these enteric neural reflexes could not, however, be deduced from these in vivo studies. More recently, in vitro studies (24) of guinea pig ileum have demonstrated that submucosal cholinergic vasodilator neurons innervating submucosal arterioles appear to be the major "final common pathway" mediating enteric vasodilator reflexes. In vitro studies (32) have also shown that mechanical stimulation of the mucosa can activate these neurons. This reflex, however, was mediated entirely by submucosal neurons because the myenteric plexus had been dissected from this preparation. Nonetheless, there is evidence that implies that vasodilator reflexes are also mediated by the myenteric plexus. For example, in vivo studies show a close relationship between intestinal motility and blood flow (10); such actions may well be coordinated by neural connections between the myenteric and submucosal plexus. The existence of multiple enteric neural pathways is consistent with the parallel and overlapping nature of other effector systems within the intestine that regulate blood flow (14, 17, 32). Which of these systems predominates appears to depend on the physiological and pathophysiological state of the intestine.
Multiple neural projections from neurons in the myenteric plexus with axons terminating in the submucosal plexus have been described in immunohistochemical studies (20, 26). Our (22) recent in vitro electrophysiological studies have demonstrated that most submucosal neurons receive synaptic inputs after stimulation of the myenteric plexus, but the functional role of these neurons was not known. In the current study, we examined whether these inputs activated submucosal vasodilator pathways and if so, what was the organization of these myenteric reflexes.
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METHODS |
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Experimental protocols were approved by the Queen's University
Animal Care Committee. Guinea pigs (150-225 g) were rendered unconscious by isoflurane inhalation and immediately killed by cervical
transection. Segments of small intestine were removed from the distal
ileum, and dissection of conventional submucosal in vitro preparations
(33) was modified to expose the submucosal plexus on one
half and the myenteric plexus on the other (Fig. 1). Briefly, the intestine was opened
along the mesenteric border and pinned out flat with the mucosa facing
upward. One half of the mucosa was stripped off, exposing the
submucosa, and the mucosa, submucosa, and circular muscle were removed
from the other half, exposing the myenteric plexus. The exposed
myenteric plexus was intact with the myenteric plexus lying beneath the
exposed submucosa on the other half. The orientation of the preparation
was carefully recorded by placing a small hole in the orad end.
Preparations (~7.5 mm wide and 15-30 mm long ) were pinned in a
small organ bath, and a double chamber was created by placing a small
Plexiglas divider over the tissue at the junction of the exposed
submucosa and myenteric plexus. Silicone gel was placed between the
divider and tissue to prevent communication of solutions between the
chambers. Each chamber was superfused separately with a physiological
saline solution containing (in mM) 126 NaCl, 25 NaH2PO4, 1.2 MgCl2, 2.5 CaCl2, 5 KCl, 25 NaHCO3, and 11 glucose gassed
with 95% O2-5% CO2 at 35-36°C (pH
7.4). Nifedipine (1 µM) was added to prevent muscle movement. Drugs
were added to the bath by superfusion. In a few experiments,
CaCl2 was omitted and MgCl2 was increased to 12 mM. This modified saline solution has been shown previously to block
synaptic transmission (18, 30). The integrity
of the "seal" between the chambers was checked after each
experiment by determining whether there was leakage of trypan blue dye
between the chambers.
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The outside diameter of individual submucosal arterioles was monitored
using a computer-assisted videomicroscopy system (Diamtrak), as
previously described (21). Briefly, this system uses an
Imaging Technology PCVision frame-grabber board in an IBM PC/AT
computer to digitize television images of the arteriole. This is
converted to an analog signal and stored on a chart recorder. The
resolution of the system is <1 µm, and the sampling rate was 15 Hz.
Vasodilator responses were monitored by first preconstricting
arterioles 80-95% (maximum) with
9,11-dideoxy-11,9
-epoxy-methanoprostaglandin F2
(PGF2
). The magnitude of the dilations was quantified by
measuring the amplitude and duration at one-half the amplitude of the
response and expressing the product of the two in millimeters per second.
Myenteric ganglia were stimulated (at 20 Hz for 6 s) using a Grass S88 stimulator and stimulus isolation unit with a bipolar tungsten electrode modified to stimulate several myenteric ganglia simultaneously (22). Electrodes were fashioned from insulted tungsten wire (75 µm) by bending a 3-mm distal portion parallel with the preparation and removing the insulation from this segment.
Drugs.
The following drugs were used: 5-hydroxytryptamine (5-HT), TTX,
hexamethonium, nifedipine, and PGF2 were from Sigma
(Oakville, ON, Canada); and
4-diphenylacetoxy-N-(2-chloroethyl)-piperdine hydrochloride
(4-DAMP) was from Research Biochemicals (Oakville, ON, Canada).
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RESULTS |
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General observations. The outside diameter of vasodilator responses examined in this study ranged from 62 to 87 µm (n = 97). Cursors employed by the videomicroscopy system to monitor changes in the outside diameter of the blood vessels were typically positioned proximally on a first- or second-order branch (see Fig. 1). Preliminary experiments demonstrated that when the preparation was oriented with stimulating electrode placed orad to the recording site, vasodilator responses could be consistently elicited at distances of 5-10 mm. Optimum electrical stimuli were determined by varying the frequency and duration of stimuli in control experiments (Fig. 1). Vasodilator responses were evoked by 2-30 Hz, and maximal responses were evoked at 10-20 Hz (n = 3). Train durations were studied at 20 Hz, and large, reproducible responses were evoked with durations of 6-9 s (n = 3). Based on these findings, all subsequent electrical stimuli were delivered at 20 Hz for 6 s.
Several experiments were conducted to confirm that nerve-evoked vasodilator responses resulted from activation of myenteric neurons. First, to establish that responses evoked by electrical stimulation were neurally mediated, the effects of TTX (1 µM) were examined. TTX blocked all vasodilator responses evoked by electrical stimulation (Fig. 1, n = 12). The possibility that current spread from the stimulating electrode could have activated neurons in the submucosal ganglia in the adjacent bath (see Fig. 1) was examined by cutting the preparation between the exposed myenteric plexus and submucosal plexus borders and then repinning the edges together. Nerve stimulation in these preparations had no effect (n = 3).Effects of 4-DAMP and hexamethonium in the recording chamber.
The effect of cholinergic blockade was examined by stimulating
myenteric neurons orad to the recording site and superfusion antagonists into the recording "submucosal chamber" (see Fig. 1).
When the muscarinic antagonist 4-DAMP (1 µM) was applied
(n = 5), the nerve-evoked vasodilator responses in the
submucosa were completely blocked in three preparations and only small
residual vasodilator responses remained in the other two (10.8 and 13.2 mm · s; Fig. 2). The ganglionic
nicotinic receptor antagonist hexamethonium (500 µM) blocked
nerve-evoked vasodilator responses by >80% in all preparations
(n = 5, Fig. 2).
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Orientation and distances of myenteric synaptic inputs.
The vasodilator responses elicited by stimulating at sites 5-20 mm
from the recording site in the orad and aborad direction were examined.
The proportion of preparations responding were grouped into three
distances: 5-10, >10-15, and >15-20 mm. Nerve-evoked vasodilator responses were elicited up to 18 mm from the recording site
in both directions (Fig. 3) but not at 20 mm. At each of the three distances, there was no significant difference
in the proportion of preparations that responded, regardless of whether the preparation was oriented in the orad-aborad or aborad-orad orientation (Fig. 3).
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Effects of hexamethonium, 4-DAMP, and 0 Ca2+ and 12 mM
Mg2+ in the stimulating myenteric chamber.
The possibility that nerve-evoked vasodilator responses were elicited
by nicotinic receptor-mediated pathways in the myenteric plexus was
examined by studying the effects of hexamethonium (500 µM) superfused
into the stimulating myenteric chamber (see Fig. 1) ( n = 16). Two types of effects were observed. In ~50% of preparations, nerve stimulation evoked vasodilator responses that were completely or
partially blocked by hexamethonium. In the other preparations, hexamethonium-insensitive responses were elicited (Fig.
4). No significant difference in the
relative proportion of hexamethonium-sensitive to -insensitive
responses was observed when stimulating orad or aborad to the recording
site (Fig. 4).
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Effects of 5-HT superfusion in the stimulating myenteric chamber.
Superfusion of 5-HT (5-10 µM; n = 30) in the
stimulating myenteric chamber evoked vasodilator responses in the
submucosal chamber (Fig. 6). This
stimulus, however, was much less robust than electrical stimulation. In
some series, 5-HT superfusion failed to elicit any detectable
vasodilator response in up to 40% of preparations. In addition, in
those preparations where 5-HT had an effect, the vasodilator responses
were typically smaller or absent when 5-HT was reapplied after a 15-min
washout period. The effects of TTX on these vasodilator responses was
studied by first examining the effects of 5-HT (5 µM) in the presence of TTX (1 µM) and then 5-HT alone, after a 10-min washout of TTX. In
all preparations (n = 5) in which a vasodilator
response to 5-HT was obtained after the washout of TTX, the initial
application of 5-HT combined with TTX failed to elicit any response in
the same preparation (Fig. 6).
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DISCUSSION |
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This study demonstrated that stimulation of myenteric neurons activated submucosal neural pathways, causing vasodilation of submucosal arterioles. These vessels are the major resistance within the intestine, controlling blood flow to the mucosa (19). Our previous electrophysiological studies (22) and others (6) identified synaptic connections between the myenteric and submucosal plexus, but the functional identity of these neurons was unknown. The present study provides direct functional evidence that the myenteric plexus can play a major role in regulating mucosal function through the modulation of vasodilator reflexes in the submucosal plexus. In addition, there is evidence that some vasodilator neurons may have a dual secretomotor function (16), raising the possibility that these pathways might also coordinate secretion.
A fundamental requirement in these studies was to ensure that the nerve-evoked vasodilator responses could be activated by stimulating myenteric neurons without any direct stimulation of submucosal neural or nonneural pathways. The neural origin of the vasodilator response was confirmed by demonstrating that TTX blocked all electrically evoked vasodilator responses. The possibility that current spread from the stimulating electrode directly activated submucosal vasodilator neurons (24) was excluded by several methods. The most direct method was to demonstrate that responses were completely ablated when the preparation was severed between the edges of the exposed myenteric and submucosal halves (see Fig. 1). In these studies, the stimulating electrode was positioned within 500 µm of the cut edge. The lack of vasodilator responses in the adjacent recording site would suggest that current spread from the electrode tips did not carry for significant distances beyond this point. Additional evidence for the myenteric origin of the vasodilator responses was obtained in the studies examining the effects of antagonists in the myenteric stimulating chamber because the antagonists inhibited the responses. An additional pathway that might have been implicated in these results consisted of capsaicin-sensitive nerves. However, submucosal arterioles with their perivascular nerves were completely excised from the stimulating chamber and therefore very few capsaicin-sensitive nerves projecting from the submucosa were present in the preparation. Furthermore, all responses were blocked by TTX, whereas our previous studies (31) have shown that capsaicin-sensitive vasodilator responses are not TTX-sensitive in this preparation.
A number of conclusions can be drawn about the connections of myenteric neurons in the submucosal plexus based on the findings of this study and those of previous investigators. Several studies (1, 24) have provided strong evidence that intrinsic cholinergic submucosal vasodilator neurons are the major final common pathway mediating enteric vasodilator reflexes in this preparation. The most direct evidence was obtained in electrophysiological studies (24) in which intracellular recordings were made from single submucosal neurons. These studies (24) showed that activation of single submucosal neurons evoked a nerve-mediated dilation of adjacent submucosal arterioles. In these (24) and subsequent studies (1), it was shown that these neurons released acetylcholine from perivascular nerve terminals that in turn activated M3 receptors on the blood vessels. The ensuing vasodilation resulted from release of nitric oxide, presumably from endothelial cells. These studies failed to find any evidence that the myenteric plexus directly innervated submucosal arterioles in normal physiological settings (24), although myenteric pathways may emerge under at least some pathophysiological settings (12, 13). In the current study, the responses were almost completely blocked by hexamethonium or 4-DAMP when placed in the submucosal recording chamber (see Fig. 2). Given the findings of the previous studies described above, this suggests that myenteric neurons activate submucosal vasodilator neurons through stimulation of nicotinic receptors within the submucosal plexus. These findings are also consistent with our recent electrophysiological studies (22) that demonstrate that most submucosal neurons receive fast EPSPs from myenteric neurons. The possibility that nicotinic synapses in the myenteric plexus, located in close proximity to the recording site (i.e., located in the recording chamber directly above the recording site), also play a role cannot, however, be excluded. Taken together, these data suggest that myenteric neurons activate nicotinic receptors on submucosal vasodilator neurons either directly, or through stimulation of interneurons, and that the vasodilator neurons in turn release acetylcholine, which binds to muscarinic receptors on submucosal arterioles.
A somewhat unexpected finding in this study was the lack of polarity to the myenteric-submucosal vasodilator pathway. Our previous electrophysiological studies (22) have shown a clear predominance of aborad-oriented synaptic inputs from myenteric neurons. These findings correlate with a number of immunohistochemical studies (8, 9, 20, 26, 28, 29) that demonstrate several descending pathways [choline acetyltransferase (ChAT)/5-HT, ChAT/somatostatin, and ChAT/nitric oxide synthase/vasoactive intestinal polypeptide (VIP) immunoreactive fibers] from the myenteric to the submucosal plexus. An ascending myenteric interneuron pathway (ChAT/tachykinin/enkephalin immunoreactive fibers) has also been identified (7), making it a likely candidate for the ascending myenteric-evoked vasodilator responses described in the current study. There are several possible explanations that might explain the lack of polarity observed in the present study. First, it is probable that the majority of, or possibly all, neurons recorded from in our electrophysiological study (22) were nonvasodilator motoneurons, because these neurons appear to comprise only one or two neurons in each ganglia (24). Alternatively, the few ascending synaptic inputs defined in these electrophysiological studies were those that predominantly innervated vasodilator submucosal motoneurons. Differences in innervation of submucosal vasodilator and secretomotor neurons would suggest they can be activated under in different settings, reflecting their separate functions in the intestine.
The results of this study demonstrate that acetylcholine is the major excitatory neurotransmitter mediating synaptic connections in myenteric plexus-evoked vasodilator reflexes. Hexamethonium caused significant inhibition of >50% of the responses when stimulating either orad or aborad to the recording site (see Fig. 4), but the addition of the muscarinic antagonist 4-DAMP did not cause further inhibition. Consequently, these pathways appear to be mediated by acetylcholine acting at nicotinic receptors on postsynaptic myenteric neurons. A significant role for a noncholinergic component of neurogenic vasodilation by the peptide VIP has been suggested by a large body of previous in vivo and in vitro work (4, 5, 15, 27) performed on cat blood vessels. Nonetheless, the in vitro studies (1, 24) of the innervation of submucosal arterioles in guinea pig ileum did not detect a significant noncholinergic component (however, see Ref. 33). These differences were not resolved in the current study as noncholinergic components were not observed within the pathways mediating the myenteric-evoked vasodilator responses.
In summary, this study has demonstrated that long neural pathways in the myenteric plexus can activate submucosal vasodilator neurons. These findings highlight the importance of myenteric projections modulating submucosal neural activity and describe pathways that may be important for coordinating motor and mucosal blood flow in the intestine. For example, this pathway could explain the finding that hyperemia accompanies every migrating motor complex in conscious dogs (10). The mechanism by which the pathways described in the current study may be activated remains to be determined, but in the in vivo dog studies hyperemia was not observed if luminal contents were drained out in the cephalad direction, suggesting that reflexes are initiated by luminal stimulation of mucosal factors. 5-HT release from enterochromaffin cells (5, 19), with ensuing activation of sensory submucosal and/or myenteric neurons projecting within the myenteric plexus (2), appears to be a likely candidate for such a role. Similar pathways may activate the reflexes described in the current study.
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ACKNOWLEDGEMENTS |
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The excellent technical assistance of Margaret O'Reilly is greatly appreciated.
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FOOTNOTES |
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This study was supported by an operating grant from the Medical Research Council of Canada.
Address for reprint requests and other correspondence: S. Vanner, 166 Brock St., Hotel Dieu Hospital, Kingston, Ontario, Canada K7L 5G2 (E-mail: vanners{at}hdh.kari.net).
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. §1734 solely to indicate this fact.
Received 14 October 1999; accepted in final form 7 March 2000.
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