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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
JPET 287:952–957, 1998
Vol. 287, No. 3
Printed in U.S.A.
The Role of Histamine H1, H2 and H3 Receptors on Enteric
Ascending Synaptic Transmission in the Guinea Pig Ileum1
ANGELO A. IZZO, MARCELLO COSTA, NICOLA MASCOLO and FRANCESCO CAPASSO
Department of Experimental Pharmacology (A.A.I., N.M., F.C.), University of Naples “Federico II” via D. Montesano 49, 80131 Naples, Italy and
Department of Human Physiology and Centre for Neuroscience (M.C.), School of Medicine, The Flinders University of South Australia, GPO
Box 2100, Adelaide 5001, SA, Australia
Accepted for publication June 24, 1998
This paper is available online at http://www.jpet.org
Histamine is widely distributed within mammalian tissues
in both neural and nonneural compartments and there is
evidence that in the central nervous system, it has a role as
primary transmitter or neuromodulator (Schwartz et al.,
1991). However, histamine is contained in mast cells and
basophils in the wall of the intestine (Burks, 1994) and there
is evidence that when it is released during hypersensitivity
reactions to allergens, it may mediate neural events (Wood,
1992).
Three classes of histamine receptors, H1, H2 and H3 have
been identified in vertebrates (Hill, 1990) and all three are
present in the guinea pig small intestine (Leurs et al., 1991;
Bertaccini and Coruzzi, 1995). Histamine contracts the longitudinal muscle in the guinea pig small intestine. These
contractions are mediated by the H1 receptor subtype, because they can be antagonized by mepyramine (Zavecz and
Yellin, 1982; Trzeciakowski, 1987) and are likely to be due to
a direct action on the smooth muscle.
There is ample evidence that histamine stimulates the
Received for publication March 12, 1998.
1
This work was supported by CNR (Rome, Italy).
mine (1 mM) and tetrodotoxin (0.6 mM). The H2 agonists dimaprit (30 and 100 mM) and amphamine (0.1–300 mM) produced
small contractions of the circular muscle in the oral compartment. These contractile responses were abolished by tetrodotoxin (0.6 mM) and cimetidine (10 mM). The H3 agonist R-amethylhistamine (0.001–1 mM) inhibited (2–58%, P ,.05) the
nerve-mediated contractions. This inhibitory effect was antagonized by the H3 antagonist thioperamide. These results indicate that 1) histamine, acting at H1 receptors, at lower concentrations depresses synaptic transmission, although at higher
concentrations activates the enteric excitatory ascending pathway; 2) activation of H2 receptors by H2 agonists stimulates the
enteric excitatory ascending pathways and 3) activation of H3
receptors inhibits synaptic transmission.
enteric neurons. A tetrodotoxin-sensitive release of acetylcholine via H2 receptors and of tachykinins has been demonstrated (Barker and Ebersole, 1982; Rubinstein and Cohen,
1985). In addition H2 agonists have been shown to increase
the amplitude of electrically evoked contractions of the longitudinal muscle (Zavecz and Yellin, 1982). Thus it is likely
that histamine activates the longitudinal muscle excitatory
motor neurons. Histamine also produces a tetrodotoxin sensitive contraction of the circular muscle in the guinea pig
small intestine indicating that it stimulates excitatory motorneurons to the circular muscle (Harry, 1963). Histamine,
acting via H1- and H2-receptors produces slow depolarization
of guinea pig myenteric neurons that is associated with increase in the input resistance, augmented excitability and
repetitive spike discharge (Nemeth et al., 1984; Tamura and
Wood, 1992).
Histamine also produces inhibitory effects in the guinea
pig small intestine inhibiting atropine-resistant contractions
of the longitudinal muscle elicited by electrical stimulation,
in the presence of H1 and H2 receptor antagonists (Ambache
and Aboo Zar, 1970). Thus receptors other than H1 and H2
appear to be involved in this inhibitory effect. As histamine
ABBREVIATIONS: NO, nitric oxide; L-NMMA, NG-monomethyl-L-arginine; DMSO, dimethyl sulfoxide.
952
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ABSTRACT
The role of histamine H1-, H2- and H3-receptors was studied on
neural transmission in ascending excitatory pathways of the
guinea pig ileum. A two-compartment (oral and anal compartments) bath was used: ascending neural pathways were activated by electrical stimulation in the anal compartment and the
resulting contraction of the circular muscle in the oral compartment was recorded. Drugs were applied in the anal compartment and each agonist was evaluated in the presence of the
antagonists of the other two receptors. In the presence of
cimetidine (10 mM) and thioperamide (1 mM), histamine (0.03–3
mM) depressed the nerve-mediated contractions (5–70% inhibition, P ,.05–.01). The inhibitory effect of histamine was antagonized by mepyramine. At the higher concentrations (10 and
30 mM), histamine elicited contractions of the circular muscle in
the oral compartment, and these were abolished by mepyra-
1998
Histamine and Enteric Ascending Synaptic Transmission
Materials and Methods
Male guinea pigs weighing between 250 and 350 g were used. The
animals were killed by being stunned and bled via the carotid arteries. Segments (4 – 6 cm) of ileum were removed and the content of
intestine flushed. The segments were placed horizontally in a bath
filled with warm (37°C) oxygenated Krebs’ solution (composition in
mM: NaCl 119, KCl 4.7, KH2PO4 1.2, NaHCO3 25, MgSO4 1.5, CaCl2
2.5 and glucose 11) and set up as described previously (Izzo et al.,
1997b). The mechanical activity of the circular muscle at the oral end
was recorded isotonically (load 0.5 g) with a transducer connected to
a “Gemini” recording apparatus (Ugo Basile, Comerio VA, Italy). The
enteric nerve pathways were activated by electrical field stimulation
(10 Hz for 2 sec, 45 mA, 0.5-msec pulse duration) via a pair of
platinum electrodes placed around the intestine in the anal compartment, 30 mm from the partition. The distance between the stimulating electrodes and the recording of the circular muscle was 35 mm.
To study neural transmission, drugs were applied in the anal compartment. Stable and reproducible contractions were obtained with
stimulation every 2.5 min and expressed as percentage of lumen
occlusive contraction produced by 10 mM carbachol applied to the
recording site. Previous studies have shown that responses evoked
by electrical stimulation are abolished by either tetrodotoxin or
hexamethonium (Izzo et al., 1997b), added in the anal compartment.
The effect of H1, H2 and H3 histamine agonists (histamine for H1
receptors, dimaprit and amthamine for H2 receptors and R-a-methylhistamine for H3 receptors) on neural transmission was evaluated
by adding the drugs to the anal compartment. Cumulative concentration-effects curves (0.03–3 mM histamine, 0.1–300 mM dimaprit,
0.1–300 mM amthamine and 0.001–1 mM R-a-methylhistamine, contact time 5 min for each concentration) were constructed. To determinate antagonistic activity (pA2), histamine and R-a-methylhistamine were tested 20 min after mepyramine (3, 10, 30 and 100 nM)
and thiopheramine (30, 100 and 300 nM) respectively. To ensure that
histamine only acted on H1 receptors, the H2 receptor antagonist
cimetidine (10 mM) and the H3 antagonist thioperamide (1 mM) were
present in the anal bath; the effect of dimaprit and amthamine was
observed in the presence of mepyramine (1 mM) and thioperamide (1
mM) and the effect of R-a-methylhistamine was observed in the
presence of mepyramine (1 mM) and cimetidine (10 mM). The concentration of antagonists used were selected from previous work
(Trzeciakwski, 1987; Hew et al., 1990; Poli et al., 1994). In some
experiments the effect of histamine was observed 20 min after LNMMA (100 mM), naloxone (1 mM) or phentolamine (1 mM) although
the contractile effect of histamine and dimaprit (or anthamine) was
studied 20 min after hexamethonium (100 mM). These concentrations were shown effective in previous papers (Waterman et al.,
1992; Yuan et al., 1995; Izzo et al., 1997b). In another set of experiments, to block all synaptic transmission without blocking the action
potentials in neurons, the anal compartment was perfused with
Krebs with no Ca11 which was replaced by 12 mM Mg11 (Tonini and
Costa, 1990).
Statistical analysis. Results are given as mean 6 S.E.M. Competitive antagonism was quantified as the ratio of equi-active molar
concentrations. These values were estimated at the level of the
half-maximal response. Antagonist activity (pA2 value) was estimated with the Schild analysis of these data (Aranlakshana and
Schild, 1959). Statistical analysis was carried out with analysis of
variance or Student’s t test for paired data. P ,.05 was considered
significant.
Drugs. Drugs used were: histamine hydrochloride, dimaprit hydrochloride, R-a-methylhistamine hydrochloride, mepyramine hydrochloride, cimetidine, thiopheramide hydrochloride, tetrodotoxin
(all purchased from RBI, Milan, Italy), carbachol chloride, hexamethonium bromide, naloxone hydrochloride and L-NMMA acetate,
phentolamine hydrochloride (Sigma, Milan, Italy) and amphamine
dihydrobromide (Tocris Cookson, Bristol, UK). The drugs were dissolved in distilled water with the exception of cimetidine which was
dissolved in DMSO. All drugs were added in volumes less than 0.1%
of the bath volume. DMSO had no effect on the responses studied.
Results
Contractile effect of H1, H2 and H3 agonists. Histamine (10 and 30 mM, but not lower), applied to the anal
compartment, with cimetidine and thioperamide in the bath,
produced contractions of the circular smooth muscle in the
oral compartment with a latency of 15 to 20 sec; the contractile effect of histamine consisted of a series of 5 to 10 phasic
contractions superimposed to a small tonic component (fig.
1). The amplitude of the contraction produced by 30 mM
histamine was greater than that of 10 mM (table 1). Mepyramine (1 mM) and tetrodotoxin (0.6 mM) or hexamethonium
(100 mM) applied to the anal compartment, abolished the
histamine-induced contractions (fig. 1; table 1). Replacing the
Krebs’ solution in the anal compartment with a Ca11 free (12
mM Mg11 Krebs’ solution) almost abolished the contractile
effect of histamine 30 mM (fig. 1).
The H2 agonist dimaprit (30 mM), applied to the anal
compartment, in the presence of mepyramine and thioperamide, evoked a small multiphasic contractile response (fig.
1). The initial phasic contraction reached maximum in 15 to
30 sec. The latter phasic contractions were variable and
consisted of a series of three to six phasic contractions. A
greater concentration of dimaprit (100 mM), produced
smaller contractions and 300 mM dimaprit did not produce
any contraction. Amphamine, another H2 agonist, also produced a contractile response but at lower concentrations
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in these conditions does not inhibit the contraction produced
by exogenous bradykinin (Ambache and Aboo Zar, 1970) is
unlikely to inhibit directly the muscle. Thus the inhibitory
action is likely to be via enteric neurons. A third class of
histamine receptors has been identified. Histamine H3 receptors were originally identified as inhibitory autoreceptors on
histamine-containing nerve terminals in rat cerebral cortex
(Arrang et al., 1983), but have since been shown to inhibit the
release of a variety of neurotransmitters in both central
(Schilicker et al., 1988) and peripheral tissues (Ishikawa and
Sperelakis, 1987). Hew et al. (1990) have demonstrated the
presence of binding sites for H3 ligands in the guinea pig
small intestine. In this preparation the H3 receptor agonists
act presynaptically or prejunctionally to inhibit cholinergic
and non-cholinergic excitatory transmission (Trzeciakowski,
1987; Tamura et al., 1988; Taylor and Kilpatrick, 1992; Bertaccini and Coruzzi, 1995). In addition histamine has a presynaptic inhibitory action on nicotinic synaptic transmission
in the myenteric plexus (Tamura et al., 1988).
Thus there is ample evidence that histamine has multiple
sites of action on enteric neurons. To establish the action of
histamine on specific enteric neural pathways and the nature
of the receptors involved, we have used a preparation of
guinea pig small intestine in which ascending nerve pathways can be stimulated electrically to activate synaptically
excitatory motor neurons to the circular muscle and the
action of drugs on enteric nerve pathway can be studied
without interfering with the recording of the smooth muscle
contractions (Izzo et al., 1997b). A preliminary account of this
work was presented at the XXVIII National Congress of the
Italian Pharmacological Society (Izzo et al., 1997a).
953
954
Izzo et al.
Vol. 287
Fig. 1. Representative tracings of the contractile responses to histamine 30 mM or dimaprit 30 mM added
to the anal compartment. The effect of both histamine
and dimaprit was also evaluated in the presence of
tetrodotoxin (0.6 mM), mepyramine (1 mM) (or cimetidine, 10 mM) or in a Krebs solution without Ca11 (12
mM Mg11).
Drugs (mM)
Histamine
Histamine
Histamine
Histamine
Histamine
Dimaprit
Dimaprit
Dimaprit
Dimaprit
10
30
30 1 mepyramine 1
30 1 tetrodotoxin 0.6
30 1 hexamethonium 100
30
30 1 cimetidine 10
30 1 tetrodotoxin 0.6
30 1 hexamethonium 100
Amthamine
Amthamine
Amthamine
Amthamine
Amthamine
Amthamine
Amthamine
10
30
100
300
300 1 cimetidine 10
300 1 tetrodotoxin 0.6
300 1 hexamethonium 100
Contraction (%)
na
13 6 4
17 6 3
0
0
263
12
11
6
4
4
562
0
0
0
16
6
4
4
564
563
864
863
0
0
0
6
6
6
6
6
4
4
The effect of histamine was evaluated in the presence of cimetidine (10 mM) and
thioperamide (1 mM), while the effect of the H2 agonists dimaprit and amthamine
was evaluated in the presence of mepyramine (1 mM) and thioperamide (1 mM).
a
Indicates the number of experiments.
(starting from 10 mM) (table 1). The contractile effect of
dimaprit (30 mM) or amthamine (300 mM) was abolished by
cimetidine (10 mM), tetrodotoxin (0.6 mM) or hexamethonium
applied to the anal compartment (fig. 1; table 1). Removal of
Ca11 from the anal compartment (replacing it with 12 mM
Mg11) also blocked the contractile effect of both dimaprit
(fig. 1) and amphamine (data not shown). The H3 agonist
R-a-methylhistamine, applied to the anal compartment, did
not produce any contraction.
Effect of H1, H2 and H3 agonists and antagonists on the
ascending excitatory pathways activated by electrical
stimulation. Electrical field stimulation in the anal compartment elicited a single phasic contraction of the circular smooth
muscle in the oral compartment that lasted about 2 to 3 sec.
These contractions were 28 6 4% of the contraction produced by
10 mM carbachol (n 5 92).
Histamine (0.03–3 mM), in the presence of cimetidine and
thioperamide, produced a concentration-dependent inhibition
of the nerve mediated contraction when applied to the anal
compartment (fig. 2). Significant inhibition was achieved with
the 1 to 3 mM concentrations (P ,.05 at 1 mM and P ,.01 at 3
Fig. 2. Ascending excitatory response elicited by electrical stimulation:
graph showing the effect of increasing concentration of histamine added
to the anal compartment alone or in the presence of mepyramine (3–100
nM). The electrodes were placed on the intestine in the anal compartment
about 30 mm from the partition. The experiments were performed in the
presence of cimetidine (10 mM) and thioperamide (1 mM). Each point
represents the mean 6 S.E.M. of five to seven experiments.
mM). The effect of histamine was competivively prevented by
mepyramine (fig. 2) with a pA2 of 9.14 6 0.10 (Schild slope:
0.60 6 0.03). The inhibitory effect of histamine was not modified
by L-NMMA (100 mM), naloxone (1 mM) or phentolamine (1 mM)
added in the anal compartment before histamine (fig. 3). LNMMA, naloxone or phentolamine did not modify the nervemediated contractions (% variation of control response: 112 6
10%, 17 6 10%, 15 6 4, n 5 6 for each drug tested, P ..2).
The H2 agonist dimaprit (0.1–300 mM), in the presence of
mepyramine and thioperamide, produced a significant (P
,.01) inhibition of the nerve mediated contraction only at
higher concentration (300 mM, fig. 4). This effect was not
modified by the H2 antagonist cimetidine (10 mM, fig. 4). By
contrast, amthamine (0.1–300 mM), another H2 agonist, was
without effect on the nerve mediated contractions (fig. 4).
The potent H3 receptor agonist R-a-methylhistamine
(0.001–1 mM) reduced, in a concentration-dependent manner,
the nerve mediated contraction when applied to the anal
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TABLE 1
Contractile effect of histamine, dimaprit and amthamine added to the
anal compartment
1998
Fig. 4. Ascending excitatory response elicited by electrical stimulation:
graph showing the effect of increasing concentration of amthamine and
dimaprit (alone or in presence of cimetidine 10 mM) added to the anal
compartment. The electrodes were placed on the intestine in the anal
compartment about 30 mm from the partition. The experiments were
performed in the presence of mepyramine (1 mM) and thioperamide (1
mM). Each point represents the mean 6 S.E.M. of seven experiments. *P
,.05 vs. control.
compartment (fig. 5). Significant inhibition (P ,.05) was
achieved with the 0.1 to 1 mM concentrations. The inhibitory
effect of R-a-methylhistamine was competitively inhibited by
thioperamide, with a pA2 of 8.12 6 0.23 (Schild slope: 0.96 6
0.19).
When the stimulating electrode was placed 2 mm just anal
to the partition, thus bypassing synaptic transmission along
the chain of ascending interneurons (Izzo et al., 1997b), histamine, dimaprit or R-a-methylhistamine had no significant
effect, even at the highest concentrations used (fig. 6).
Addition to the anal compartment of any of the receptor
955
Fig. 5. Ascending excitatory response elicited by electrical stimulation:
graph showing the effect of increasing concentration of R-a-methylhistamine added to the anal compartment alone or in the presence of thioperamide (30 –300 nM). The electrodes were placed on the intestine in the
anal compartment about 30 mm from the partition. The experiments
were performed in the presence of mepyramine (1 mM) and cimetidine (10
mM). Each point represents the mean 6 S.E.M. of five to seven experiments.
Fig. 6. Graph showing the lack of effect of histamine (0.1-3 mM), dimaprit
(0.1-300 mM) and R-a-methylhistamine (0.001-1 mM), applied to the anal
compartment, on the ascending excitatory response elicited by electrical
stimulation just anal to the partition to bypass any synaptic transmission
within the anal compartment. Each point represents the mean 6 S.E.M.
of seven experiments. No statistical differences with control were observed.
antagonists mepyramine (1 mM) cimetidine (10 mM) or thioperamide (1 mM), failed to modify the ascending nerve mediated contractions (% inhibition: mepyramine 0 6 7, cimetidine 9 6 8, thioperamide 1 6 7).
Discussion
Our study shows that activation of histamine receptors
modifies transmission in the ascending excitatory pathways
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Fig. 3. Ascending excitatory response elicited by electrical stimulation:
graph showing the effect of increasing concentration of histamine added
to the anal compartment alone or in the presence of L-NMMA (100 mM),
naloxone (1 mM) or phentolamine (1 mM). The electrodes were placed on
the intestine in the anal compartment about 30 mm from the partition.
The experiments were performed in the presence of cimetidine (10 mM)
and thioperamide (1 mM). Each point represents the mean 6 S.E.M. of
five to seven experiments.
Histamine and Enteric Ascending Synaptic Transmission
956
Izzo et al.
sis (Waterman et al., 1992). NO is synthetised in inhibitory
motor neurons and descending interneurons in the guinea
pig small intestine (Costa et al., 1992). NO inhibits synaptic
transmission in myenteric ganglia in the guinea pig ileum
(Yuan et al., 1995) and histamine has been shown to release
NO in several tissues (Garrison, 1990). Noradrenaline, released from postganglionic sympatetic neurons, acts presynaptically to inhibit acetylcholine release (Wood, 1987). However it is unlikely that histamine inhibits synaptic
transmission in the ascending excitatory pathways by releasing NO, opioids or noradrenaline as the NO synthase inhibitor L-NMMA, the opioid antagonist naloxone or the alphaadrenoceptor antagonist phentolamine failed to modify the
inhibitory effect of histamine.
The inhibitory action of dimaprit does not appear to be
mediated by H2 receptors as it was not antagonized by cimetidine. Bertaccini and Zappia (1981) showed that dimapritinduced relaxation of guinea pig duodenum that was not
counteracted by cimetidine and other H2 antagonists. In the
same way, Leurs et al. (1991) also showed that the dimapritinduced relaxation of the guinea pig ileum, jejunum and
colon was unaffected by a number of H2 antagonists, such as
famotidine, mifentidine and tioxidine.
The potent and selective H3 receptor agonist R-a-methylhistamine produced a concentration-dependent inhibition of
the neural contraction when applied in the anal compartment. This effect was competitively antagonized by the H3
antagonist thioperamide, indicating that was mediated by H3
histamine receptors. The pA2 value for thioperamide is in
keeping with previous studies on guinea pig intestine (Leurs
et al., 1991; Taylor and Kilpatric, 1992). The most likely site
and mechanism of action of H3 agonists is by presynaptic
inhibition along the chain of ascending excitatory interneurons. Presynaptic inhibition mediated by H3-receptors is
widespread in central and peripheral nervous system
(Schwartz et al., 1991). There is ample evidence for H3 receptors on longitudinal muscle enteric motorneurons to mediate
inhibition of transmitter release (Bertaccini and Coruzzi,
1995; Leurs et al., 1991; Taylor and Kilpatrick, 1992; Trzeciakowski, 1987). Poli et al. (1994) showed that histamine
acts on these neurons in the duodenum by decreasing Ca11
entry via the N-type Ca11 channels in the nerve terminals. It
is possible that the inhibitory effect of R-a-methylhistamine
on synaptic transmission demonstrated in our work is due to
a similar mechanism as N-type Ca11 channels are involved
in the ascending excitatory pathways (Izzo et al., 1997b). The
discrepancy with the findings of Poli and Pozzoli (1997) who
have shown that R-a-methylhistamine did not modify either
the ascending excitatory reflex elicited by caudal distention
or peristaltic movements in the isolated guinea pig ileum
remains to be explained.
The failure of the histamine receptor antagonist, mepyramine, cimetidine and thioperamide, to affect transmission
along the intestine indicates that endogenous histamine is
not involved in neural transmission along the ascending excitatory pathways activated by electrical stimulation. There
is no evidence for the presence of histamine in enteric neurons in the guinea pig intestine although histidine decarboxylase, the enzyme involved in the synthesis of histamine and
its mRNA are present in enteric neurons (Ekblad et al.,
1985). If histamine plays a functional role in intestinal mo-
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to the circular muscle in the guinea pig small intestine.
These pathways involve at least three neurons (Izzo et al.,
1997b). A final excitatory motor neuron to the circular muscle is located in myenteric ganglia in the oral compartment.
The motor neurons receive excitatory nicotinic synaptic inputs from the only class of ascending interneurons that form
an excitatory chain of neurons (Tonini and Costa, 1990;
Brookes et al., 1991a, 1991b; Izzo et al., 1997b). These neurons and their projections have been identified by tracing
experiments (Brookes et al., 1990, 1991b). The electrical
stimulation in the anal compartment activates this chain of
ascending interneurons thus involving at least two neural
synapses in the pathway. Both stimulatory or inhibitory effects of histamine agonists were observed, depending of the
concentrations used and the type of receptor involved.
Activation of H1 and H2 receptors, by high concentrations
of histamine, dimaprit or amthamine, added to the anal
compartment, produced a contractile response of the circular
muscle in the oral compartment. Blockade of nerve activity
by tetrodotoxin abolished these contractile responses indicating that they are nerve mediated. Blockade of all synaptic
transmission in the anal compartment, by replacing calcium
with magnesium, significantly reduced the contractile responses to both agonists. Histamine has been shown to depolarize myenteric neurons via both H1 and H2 receptors
(Nemeth et al., 1984; Tamura and Wood, 1992) with consequent release of acetylcholine (Rubinstein and Cohen, 1985)
and to elicit synaptic potentials in myenteric neurons (Nemeth et al., 1984; Tamura and Wood, 1992). H2-receptor agonists have been shown to enhance the release of acetylcholine
from the enteric nerves (Barker and Erbesole, 1982). We
have shown that hexamethonium, a nicotinic receptor antagonist, strongly reduced the contractile effect of both H2 agonists, suggesting that these drugs may act mainly by releasing acetylcholine from the presynaptic nerve terminals of
ascending interneurons in the chain.
Histamine acting on H1 receptors, dimaprit and R-a-methylhistamine depressed, in a concentration-dependent manner, the ascending excitatory synaptic transmission. Histamine is unlikely to inhibit directly the myenteric neurons as
no postsynaptic hyperpolarizing effects have been observed
on myenteric neurons (Tamura et al., 1988). In addition in
our experiments when the axons of ascending interneurons
were stimulated just anal to the partition, thus bypassing
synaptic transmission (Izzo et al., 1997b), histamine, dimaprit or R-a-methylhistamine had no effect on the contractile
response. Thus, the inhibitory effects of histamine are most
likely to be due to inhibition of synaptic transmission along
the ascending chain of interneurons.
The inhibitory action of histamine was competitively antagonized by mepyramine and thus is mediated by H1 receptors. The pA2 value for mepyramine correlates well with
previous findings (Barker, 1985). There is no evidence in
intestinal preparations for presynaptic inhibition mediated
by H1 receptors. Thus it is more likely that activation of these
receptors releases endogenous substances from presynaptic
nerve endings within the myenteric ganglia, which in turn
inhibit synaptic transmission. A number of endogenous substances released by histamine may be involved in this inhibition. Opioids are known to inhibit ascending synaptic
transmission (Tonini et al., 1992), are contained in enteric
neurons (Costa et al., 1996) and are released during peristal-
Vol. 287
1998
tility is more likely to originate from nonneural cells in
pathophysiological conditions (Wood, 1992).
The presence of inhibitory and excitatory histamine receptors on different populations of enteric neurons acting at
different sites suggests that caution must be exerted in the
interpretation of the net effects of pharmacological studies on
enteric motor functions, using histamine receptors agonists.
Acknowledgments
The authors thank Bao Nan Chen for her help in the references.
This work was supported by CNR, Murst and Enrico and Enrica
Sovena Foundation (Roma).
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Histamine and Enteric Ascending Synaptic Transmission