1 Department of General Surgery, University Hospital, 72076 Tübingen, Germany; and 2 Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom
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ABSTRACT |
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The concept of functional interaction between
mast cells and intestinal afferents is gaining support. We have
therefore characterized the action of histamine on jejunal afferent
discharge in the anesthetized rat. Whole nerve mesenteric afferent
discharge was recorded in conjunction with intestinal pressure in
response to a range of histamine agonists and antagonists. Histamine at
2, 4, and 8 µmol/kg (iv) evoked a dose-dependent biphasic increase in
afferent discharge together with a biphasic rise in intestinal
pressure. However, these two events were mediated independently, since
nifedipine (1 mg/kg) substantially reduced the intestinal pressure
increase but not the afferent discharge. These responses were
completely inhibited by pyrilamine (5 mg/kg) but unaffected by
ranitidine (5 mg/kg) or thioperamide (2 mg/kg). Neither the
selective H2 receptor agonist
dimaprit nor the selective H3
receptor agonist R--methylhistamine
caused any modulation of afferent discharge. We conclude that histamine
stimulates an H1 receptor-mediated increase in mesenteric afferent discharge that is independent of
intestinal motor events. This suggests that histamine potentially acts
as a mediator in mast cell-to-afferent nerve communication in the small
intestine.
intestine
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INTRODUCTION |
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FEEDING EXPOSES THE gastrointestinal lumen to nutrients that the organism must assimilate to survive and to pathogenic or allergenic materials that it must protect against. The upper gastrointestinal tract contains mechanisms that enable differentiation between nutrients indispensable to the organism and antigenic substances that signify a potential threat. The response to antigenic materials in the gut has been studied in various inflammatory models involving type I hypersensitivity reactions (3, 8, 23). These reactions give rise to intestinal secretory and motor events that are designed to dilute and eventually eliminate the antigen from the gut.
During type I hypersensitivity reactions, histamine is released from
mast cells (27). It acts either directly on the effector, e.g., causing
smooth muscle contraction (5, 23) and electrogenic ion secretion, or
indirectly by the activation of enteric neurons (7). Frieling et al.
(10) demonstrated that histamine reversibly induced hyperexcitability
in submucous neurons in guinea pig colon via
H2 receptors. Similarly,
hyperexcitability was observed in sensitized animals following antigen
challenge, which was also abolished by the
H2 blocker cimetidine. From these
experiments, it was concluded that histamine, released from mucosal
mast cells in response to antigen challenge, activated submucous
neurons (11). Activation of these neurons by histamine mediates
intestinal Cl secretion,
which may play a role in the regulation of transport function (28).
Histamine, therefore, appears to be a paracrine messenger in mast cell
signaling to the enteric nervous system and to other cellular targets
in the gut (24).
Histamine has been shown to stimulate nociceptive afferent fibers in a variety of tissues such as skin (17), joints (13), and muscle (9). It has not been systematically studied with respect to gastrointestinal afferents, although Akoev et al. (1) have demonstrated that histamine activates afferent nerve fibers in the cat small intestine after close arterial injection (1). However, this was a limited study and served only to describe in qualitative terms an apparent afferent sensitivity to histamine. This study, therefore, raises a number of questions related to the actions of histamine on gastrointestinal afferent sensitivity. The aim of the present study is to investigate intestinal afferent nerve sensitivity to histamine and to characterize the response pattern, motility effects, and subtypes of receptors involved.
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METHODS |
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Experiments were performed on adult Hooded-Lister rats (250-350 g), which were housed under standardized conditions (regular rat chow, free access to water, 12:12-h light-dark cycle, lights on at 6 AM). The institutional guidelines for the use and care of animals were followed throughout the study. Animals were withdrawn from food but not water for 12 h before the experiment. Deep anesthesia was induced by an intraperitoneal injection of pentobarbital sodium (60 mg/kg Nembutal; Sanofi Santé Animale, Libourne-Cedex, France). Through a neck incision, the trachea was cannulated to facilitate spontaneous breathing. The right external and internal jugular veins were cannulated separately to enable administration of different drugs and maintenance of anesthesia (~10 mg/kg pentobarbital sodium every 30 min). The left carotid artery was cannulated to monitor arterial blood pressure. Body temperature was maintained at 37°C by a thermostatically controlled heated operating table.
Abdominal surgery. After a midline laparotomy, the cecum was removed to augment space in the abdominal cavity. A 10-cm loop of jejunum beginning at the ligament of Treitz was cannulated at both ends with two Portex tubes (5 mm OD). The remaining free ends of the cannula were exteriorized through stab incisions in the right side of the abdominal wall. This setup allowed intestinal pressure recording by a pressure transducer (custom built, G&J Electronics, Toronto, ON, Canada). The abdominal wall at the borders of the laparotomy was sewn to a circular metal ring to create a well. The abdominal cavity was filled with colorless, light liquid paraffin prewarmed to 37°C.
Nerve preparation and recording. A single neurovascular bundle located between 2 and 8 cm distal to the ligament of Treitz was isolated from the surrounding connective tissue and placed on a black plastic platform. With the aid of a viewing microscope (Wild M3Z, Heerburg, Switzerland), a mesenteric nerve was exposed by dissection of the overlying fat and surrounding blood vessels. The nerve was then severed at the proximal end of the bundle ~10-15 mm from the jejunal wall and wrapped around one arm of a bipolar platinum electrode. A sliver of connective tissue was wrapped around the second arm, serving as an indifferent electrode. The electrodes were connected to a differential amplifier (DAM 50, World Precision Instruments, Sarasota, FL) and filtered with a bandwidth of 300 Hz to 1 kHz. The signal was relayed to a spike processor (D-130, Digitimer, Welwyn Garden City, UK) that served to count action potentials per time unit with a variable trigger level. The whole nerve signal was displayed on a digital oscilloscope (TDS 310, Tektronix, Cologne, Germany) and registered by a DAT recorder (DTC 60 ES, Sony, Cologne, Germany). In parallel, spike frequency and arterial blood pressure were continuously recorded with a computer system (1401plus, Cambridge Electronic Design, Cambridge, UK) installed on a personal computer and running software (Spike2, version 4.79, Cambridge Electronic Design).
Compounds.
Histamine, dimaprit, nifedipine, bethanechol, ranitidine, pyrilamine,
and DMSO were purchased from Sigma Chemical (Munich, Germany).
2-Methyl-5-hydroxytryptamine (2m5HT),
R--methylhistamine, and
thioperamide were from Research Biochemicals International (Natick,
MA). Sodium nitroprusside (SNP) was bought from Schwarz Pharma
(Monheim, Germany). Stock solutions were made up to the following
concentrations: 10
5 mol/ml
histamine, dimaprit, and
R-
-methylhistamine; 160 nmol/ml 2m5HT; 0.5 µmol/ml bethanechol; 0.1 mg/ml SNP; 1 mg/ml nifedipine; 2 mg/kg thioperamide; 5 mg/ml ranitidine; and 5 mg/ml pyrilamine. All
solutions were made up in normal saline except nifedipine (in 25%
DMSO). For injection, stock solutions were not diluted except for
2m5HT, which was diluted with normal saline 1:10.
Experimental protocols. All compounds were given intravenously with a minimum interval of 5 min. After a 20-min baseline recording for signal stabilization, a test dose of 2m5HT at 160 nmol/kg was applied to establish the sensitivity of the nerve preparation. Histamine was then administered at 2, 4, and 8 µmol/kg (n = 15). Before the experiment was terminated, nerve sensitivity was again verified by an injection of 2m5HT.
The effects of different histamine receptor antagonists or vehicle on the histamine response were each investigated in six experiments. After consecutive injections of 2, 4, and 8 µmol/kg histamine, either vehicle (for time controls) or one of the following receptor antagonists was administered: the H1 receptor antagonist pyrilamine (5 mg/kg), the H2 receptor antagonist ranitidine (5 mg/kg), or the H3 receptor antagonist thioperamide (2 mg/kg). Ten minutes after administration of vehicle or antagonist, the three histamine doses were repeated. Test doses of 2m5HT were given before and after each experiment, as mentioned previously. In two separate groups of four experiments, the selective H2 receptor agonist dimaprit or the H3 receptor agonist R-Analysis.
Whole nerve discharge frequencies in response to intravenous substances
were determined by the CED computer system off-line from the digitized
raw nerve signal. All impulses were counted as they matched templates
previously defined by the Spike2 software (see Ref. 14 for details).
Thus erroneous discharge frequencies due to baseline shifts were
avoided. Nerve discharge responses to compounds were characterized in
terms of peak discharge frequency (impulses1) minus
baseline discharge frequency, response duration, and latency between
injection and response onset. The area under the response curve (AUC;
total number of impulses) was determined after subtraction of baseline
discharge.
Statistics. Paired t-tests were used to statistically compare data within single experimental groups. The unpaired t-test was used when data from groups of animals treated with either histamine receptor antagonists or nifedipine were compared with their respective vehicle-treated group. P < 0.05 was taken to indicate statistical significance. Data are presented as means ± SE. In Fig. 4, in which data was normalized to the time-matched controls, statistical comparisons were performed on the raw data.
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RESULTS |
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Afferent nerve discharge following histamine. Histamine evoked a powerful and, in the majority of cases, a biphasic increase in afferent nerve discharge frequency. It was apparent from the multiunit raw nerve signal that the majority of afferents, recognized by their variable spike amplitudes, responded to histamine. In addition to the discharge frequency of spontaneously active fibers being augmented by histamine, nonspontaneously active fibers were also recruited, and they contributed to the overall response observed. The afferent nerve response to histamine was accompanied by a decrease in arterial blood pressure and was generally followed by a biphasic increase in intestinal pressure (Fig. 1).
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Intestinal motor events. Increases in intestinal pressure induced by 8 µmol/kg histamine were analyzed in 12 experiments when a biphasic response was obtained. The first peak was 1.3 ± 0.5 cmH2O above baseline pressure and occurred 9.8 ± 0.7 s after the histamine injection, whereas the second pressure peak was 1.7 ± 0.3 cmH2O and occurred after 48.7 ± 6.0 s. Thus the pressure peaks always followed the peaks in afferent nerve discharge (both P < 0.001).
The first peak in intestinal pressure following histamine was reduced after nifedipine (n = 6) but not after vehicle (n = 6) administration. The reduction of the second peak following nifedipine pretreatment was not significant compared with the time-controlled vehicle administration. In contrast, afferent nerve discharge to histamine was similar after either nifedipine or vehicle. 2m5HT and bethanechol were administered as a comparison, and both agents caused an increase in intestinal pressure of 1.1 ± 0.3 and 3.8 ± 0.8 cmH2O, respectively, with a peak discharge frequency of 62 ± 9.1 and 48 ± 4.0 impulses/s. Nifedipine did not alter the afferent nerve response to 2m5HT. In contrast, the afferent nerve response following bethanechol was reduced after nifedipine as was the concomitant increase in intestinal pressure (Fig. 4).
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Effect of histamine receptor antagonists. The effects of selective histamine receptor antagonists on the responses to 2-, 4-, and 8-µmol/kg doses of histamine were compared with time-matched control experiments (Fig. 5). The H1 receptor antagonist pyrilamine (5 mg/kg) completely abolished both the afferent and intrajejunal pressure responses to all three doses of histamine compared with the time controls (P < 0.001). In contrast, the responses to histamine were unchanged after administration of the H2 and the H3 receptor antagonists ranitidine (5 mg/kg, not significant) and thioperamide (2 mg/kg, not significant).
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Effects of selective histamine receptor agonists.
The afferent and intrajejunal pressure responses to 2, 4 and 8 µmol/kg of the selective H2
receptor agonist dimaprit and the selective
H3 receptor agonist
R--methylhistamine were evaluated in four experiments each (Fig. 2). No change in afferent nerve discharge or intrajejunal pressure was observed after either dimaprit or R-
-methylhistamine
administration. However, decreases in mean blood pressures of 26 ± 3.5 and 25 ± 4.0 mmHg were observed after doses of 8 µmol/kg
dimaprit and 8 µmol/kg
R-
-methylhistamine. In all
experiments, sensitivity of the afferent nerve bundle was confirmed by
administration of 2m5HT (160 nmol/kg) and histamine (8 µmol/kg) after agonist injection.
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DISCUSSION |
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We studied the effects of the mast cell mediator histamine on
mesenteric afferent nerve fibers in the rat proximal jejunum in vivo.
Histamine evoked a dose-dependent increase in afferent nerve discharge
that was typically biphasic at a dose of 8 µmol/kg. After one series
of histamine applications, the second series tended to induce lower
responses, indicating that desensitization of the response occurred.
This observation necessitated the use of time-matched control
experiments. The H1 receptor
antagonist pyrilamine completely abolished the afferent nerve response
to histamine, whereas the H2
receptor antagonist ranitidine and the H3 receptor antagonist
thioperamide did not. Correspondingly, neither the selective
H2 receptor agonist dimaprit nor
the selective H3 receptor agonist
R--methylhistamine caused any
modulation of afferent nerve discharge. These observations indicate
that the afferent nerve response following systemic histamine is
selectively mediated via the H1
receptor. However, this is at variance with the study by Akoev and
colleagues (1) in which both H1
and H2 receptors were implicated
in the response to histamine in the cat. This discrepancy could reflect
a species difference; however, in their study (1), the decreased
response to histamine in the presence of antagonists was not quantified
and the potential for desensitization of the response following
repeated administration of histamine was not assessed.
H1 receptors have previously been described in rat nervous tissue (22) and dorsal root ganglion neurons of other species (2, 21). We are, however, unaware of any study that characterized histamine receptor subclasses on intestinal nerve fibers in rat. Consequently, there is no evidence for H1 receptors on intestinal afferent nerve terminals. Without this evidence, it is uncertain whether the increase in afferent nerve discharge following histamine is due to a direct histamine effect on afferent nerve terminals or an indirect effect. However, the rapidness of the response corresponding to the circulating delay from injection site and intestine is consistent with a direct action. Despite this uncertainty, our data demonstrate that the receptor that mediates the afferent nerve response is the H1 receptor. Notably, in the guinea pig, histamine stimulates enteric neurons via H2 receptors (10). H2 or H3 receptors may simply not be present in the rat enteric nervous system or on afferent intestinal nerve terminals as a result of species differences. However, an alternative explanation may relate to the differential expression of receptors on enteric neurons compared with extrinsic afferents. In the case of serotonin (5-HT) sensitivity, it has been recently demonstrated that, whereas extrinsic afferents are stimulated by 5-HT3 receptors (14), enteric sensory neurons may respond to 5-HT via 5-HT1p receptors (15). It may be that extrinsic and enteric reflex circuits are equipped with different subsets of receptors to the same mediator.
We further explored the hypothesis that the histamine-induced increase in afferent nerve discharge may be secondary to other histamine in vivo. Histamine caused a fall in systemic blood pressure. Therefore, we investigated whether this decrease in blood pressure gave rise to a subsequent increase in afferent nerve discharge, potentially by inducing ischemia in the gut, which has been shown to stimulate intestinal afferents via prostaglandin synthesis (18). This possibility, however, was ruled out because a comparable blood pressure fall in the absence of histamine only caused a minimal increase in afferent nerve discharge. In addition, this minimal response was delayed compared with the histamine response.
Smooth muscle contraction is another well-known histamine effect that may have affected afferent nerve discharge indirectly (25). In our study, histamine administration typically caused a biphasic increase in afferent nerve discharge, which was followed by a biphasic pressure increase. Although the time course of the events suggests that stimulation of afferent nerves occurred before the intestinal motor response, this delay in the intraluminal pressure recording may also be related to a delay in pressure signal transduction. Therefore, we studied afferent nerve discharge following histamine before and after nifedipine administration. Nifedipine as an L-type Ca2+ channel antagonist and smooth muscle relaxant substantially reduces intestinal motor responses (19). However, the afferent response to histamine after nifedipine remained comparable to the time-matched control despite a reduction in the contractile response, which was significant for the first pressure peak only. This is largely because of the variable extent to which the second component of the contractile response was attenuated. Nevertheless, there were occasions after nifedipine administration when a robust afferent response occurred with only a minimal rise in pressure. This suggests that afferent nerve discharge following histamine is independent of intestinal motor events. The muscarinic agonist bethanechol was administered as a positive control, which caused an increase in afferent nerve discharge that is entirely secondary to smooth muscle contraction (6, 14) and a subsequent intraluminal pressure increase. The indirect action of bethanechol on afferent discharge was evident because the afferent response was reduced after nifedipine together with a decrease in intraluminal pressure. The effect of nifedipine on pressure, however, exceeded that on afferent discharge. This may be explained by a predominance of low-threshold mechanosensitive afferents in the mesenteric bundles and a nonlinear relationship between pressure and afferent discharge. In contrast to bethanechol, 2m5HT had mainly a direct effect on afferent nerve terminals via the 5-HT3 receptor (14) and was used as a second control. Although the pressure response to 2m5HT was attenuated, the afferent discharge was maintained. The lack of sensitivity of the afferent histamine response to nifedipine resembled the 2m5HT sensitivity. This is consistent with a direct effect on the afferent discharge. The contractile responses to bethanechol, 2m5HT, and histamine were not equally influenced by nifedipine with the second component of the histamine response being least susceptible. The H1 receptor-mediated contraction may have a greater dependence on Ca2+ released from intracellular stores than from external sources (16).
These experiments suggest that the afferent nerve response and the intestinal motor responses to histamine are coincidental. Nevertheless, the associated intestinal pressure increase is likely to also stimulate some mechanosensitive afferent nerve fibers. However, the contribution of these relatively weak contractions to the overall increase in afferent nerve discharge seems to be rather small. With our experimental setup, we were unable to determine whether the intestinal pressure increase following histamine was a direct effect on gut smooth muscle or a reflex-induced contraction due to the stimulation of afferent nerve fibers. This question was addressed by Sakai (25) who studied intraluminal pressure increase following close arterial histamine injection in a segment of isolated rat small intestine (25). With this preparation, a biphasic pressure increase was described that corresponded to the motor pattern observed in our study. This similarly suggested that the intestinal pressure increase after histamine injection was a direct effect by intestinal structures rather than a reflex contraction via the central nervous system (CNS), which would be elicited by stimulation of extrinsic afferent nerve fibers.
Our study demonstrates that histamine stimulates afferent mesenteric nerve fibers in rat proximal jejunum. Histamine is one of an array of mediators that are released during mast cell activation, e.g., during type I hypersensitivity reactions (12). We have previously shown that the mast cell mediator 5-HT stimulates vagal afferent nerve fibers originating in the mucosa of the gastrointestinal tract (14). In addition, some limited data show that other mast cell mediators such as prostaglandin E2 may also modulate intestinal afferents (1). Consequently, data are accumulating that suggest that mast cells may sensitize afferent nerve fibers by the release of various mediators. Such a signal transduction pathway from mast cell to nerve may be pivotal in the capability of the organism to detect potentially hazardous materials in the gut lumen. Subsequent central processing of this information, which is transmitted by intestinal afferents, may trigger not only protective reflexes but also an efferent modulation of immune cells (26).
The small intestine is supplied by two types of afferent nerve fibers that project to the CNS in either vagal or splanchnic nerves. In addition, mesenteric nerves contain intestinal afferent fibers projecting to the prevertebral ganglia (20). In the present study, we did not determine in which of these afferent populations the sensitivity to histamine resides. It remains to be determined which type of fiber is stimulated by systemic histamine and where in the gut wall the endings of these fibers are located. The presented data, however, allow us to conclude that histamine stimulates afferent intestinal nerve fibers exclusively via H1 receptors. The response in afferent nerve discharge does not appear to be secondary to the concomitant intestinal motor response or the fall in blood pressure. Thus histamine has the potential to participate in signal transduction from mucosal mast cells to the CNS in the small intestine.
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ACKNOWLEDGEMENTS |
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This study was funded by a grant from the University Hospital Tübingen (Fortüne) and with support from the Dept. of General Surgery, University Hospital Tübingen, made available by Prof. H. D. Becker.
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FOOTNOTES |
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A. J. Kirkup is a Glaxo Wellcome research fellow.
Address for reprint requests: D. Grundy, Univ. of Sheffield, Dept. of Biomedical Science, Western Bank, Sheffield, S10 2TN, UK.
Received 7 November 1997; accepted in final form 21 May 1998.
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