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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
Eli Lilly and Company, Lilly Research Laboratories, Neuroscience Research, Lilly Corporate Center, Indianapolis, Indiana
Received July 26, 2002 ; accepted October 18, 2002.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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-nitro-L-arginine methyl ester hydrochloride, and
inhibition of neuronal activation with tetrodotoxin abolished relaxation to
McN-A-343 in tissues from M3 receptor knockout mice, supporting the
neuronal localization of an M1 receptor that activated NO release
to effect relaxation. However, the cyclooxygenase inhibitor indomethacin did
not affect contraction or relaxation to carbamylcholine in stomach fundus from
wild-type or M3 receptor knockout mice, indicating that
cyclooxygenase products played no role in these responses. The neuronal
M1 receptor modulated relaxation induced by carbamylcholine and
McN-A-343 but not relaxation induced by electric field stimulation of the
stomach fundus. These data support the presence of M1
receptor-mediated relaxation in the stomach and suggest that when the
M3 receptor is eliminated or blocked, M1
receptor-mediated gastric relaxation may be enhanced, possibly leading to
alterations in gastric emptying and subsequent effects on body weight.
),
prostanoids (Okada et al.,
2000), and/or NO (Kamata et
al., 1993; Leclere and
Lefebvre, 1998; Lefebvre and
Vandekerckhove, 1998; Ny et
al., 2000; Selemidis and
Cocks, 2000; Baccari and
Calamai, 2001). Activation of NO release by cholinergic agonists
has been reported in guinea pig (Wiklund
et al., 1993) and cat ileum
(Kortezova et al., 1998), rat
jejunum (Olgart and Iversen,
1999), and human pulmonary arteries
(Norel et al., 1996). Using
pharmacological tools, M1 receptor activation has also been linked
to cholinergic relaxant responses in rat duodenum, rabbit vas deferens
(Micheletti and Schiavone,
1990), and rat jejunum (Olgart
and Iversen, 1999) and to NO release
(Iversen et al., 1997).
Preliminary studies in the mouse stomach fundus also suggested the presence of
an M1 receptor-mediated cholinergic relaxant response
(Stengel et al., 2002).
M1 receptors are not the only receptors implicated in
cholinergic relaxant responses in smooth muscle. M3 receptors have
been associated with the relaxant response observed in human pulmonary
arteries (Norel et al., 1996).
M4 receptors were suggested to mediate relaxation in rabbit
anococcygeus muscle (Gross et al.,
1997), and most recently, M5 receptors have been
implicated in the cholinergic dilation of cerebral blood vessels
(Yamada et al., 2001a). Thus,
smooth muscle relaxation has been associated with activation of multiple
cholinergic receptors.
The purpose of the present study was to examine in detail the muscarinic
receptor-mediated relaxant response in the mouse stomach fundus, taking
advantage of the availability of muscarinic receptor knockout mice and the
previous observation (Stengel et al.,
2002) of a pronounced relaxant response to carbamylcholine in the
stomach fundus from M3 receptor knockout mice. Thus, the present
study was designed to 1) explore further the role of M1 receptor
involvement in cholinergic and neuronally induced relaxation of the mouse
stomach fundus, 2) evaluate the role of nitric oxide and/or arachidonic acid
in this response, and 3) compare the stomach fundus from wild-type with
M3 receptor knockout mice with regard to cholinergic
agonist-induced relaxation. For this latter objective, we utilized McN-A-343,
a partial muscarinic agonist
(Brauner-Osborne et al., 1996)
with relative functional selectivity for M1 receptors
(Hammer and Giachetti, 1982;
Eglen et al., 1987).
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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). Male
M3 receptor knockout and wild-type mice of the same genetic
background were obtained from Taconic Farms (Germantown, NY). Animals were
housed in polycarbonate ventilated cages. The animal room was maintained at
22–24°C with a relative humidity of 35 to 70% and daily light/dark
cycle (0600–1800 h light). Dry pellet food (Laboratory Rodent Diet,
5001; PMI Nutrition International, St. Louis, MO) and water were supplied ad
libitum. Mice were killed, and the stomach fundus was quickly excised and
placed in modified Krebs' bicarbonate buffer solution of the following
composition: 4.6 mM KCl, 1.2 mM KH2PO4, 1.2 mM
MgSO4, 118.2 mM NaCl, 10.0 mM glucose, 1.6 mM
CaCl2·2H2O, and 24.8 mM NaHCO3.
Experimental protocols and procedures were approved by the Eli Lilly and
Company Animal Care and Use Committee. The investigation fully conformed to
the Institute for Laboratory Animal Research Guide for Care and Use of
Laboratory Animals.
Stomach Fundus Preparation. A longitudinal section of stomach fundus
was prepared for in vitro examination. One end of the stomach fundus was
attached with thread to a stationary glass rod while the other end was tied
with thread to the transducer. Tissues were placed in organ baths containing
10 ml of Krebs' bicarbonate buffer (see above for composition). The organ bath
solution was maintained at 37°C and aerated with a 95:5% mixture of
O2/CO2, respectively. The mouse stomach fundus was
placed under an initial optimal force of 4.0 g as determined in preliminary
length-tension optimizing studies (Stengel
et al., 2000) and equilibrated for 1 h, during which time the
tissues were washed at 15-min intervals. Isometric force in g was measured
with Sensotec transducers (model MBL55140-02; Columbus, OH) that were coupled
to a Deskpro-compatible data-acquisition system (Biopac Systems Inc., Goleta,
CA). The stomach fundus was initially challenged with KCl (67 mM) to confirm
viability of the preparation. Cumulative contractile concentration-response
curves to carbamylcholine (10—8–3.0 x
10—5 M) or McN-A-343
(10—6–10—3 M)
were generated and expressed as a percentage of the KCl (67 mM)-induced
contraction determined for each tissue. For experiments examining relaxation
to McN-A-343, tissues were precontracted with
PGF2
(10—6 M). On
each day, tissues from M3 receptor knockout and wild-type mice were
used to avoid the possibility of any daily systematic effect. Experiments were
performed over multiple days.
In some experiments, stomach fundus from wild-type and/or M3
receptor knockout mice were incubated with indomethacin
(10—6 M), L-NAME (10—4
M), pirenzepine (3.0 x 10—7 M), tetrodotoxin
(200 ng/ml), or vehicle for 20 min, and concentration-response curves to
carbamylcholine (10—8–3.0 x
10—4 M) or McN-A-343
(10—6–10—3 M)
were generated. Only one agonist with one antagonist or vehicle was examined
in each tissue. Relaxation to electric field stimulation (40.0 V, 0.7 ms,
1–32 Hz) after precontraction with PGF2
(10—6 M) was also examined in stomach fundus from
wild-type and M3 receptor knockout mice in the presence of vehicle,
pirenzepine (3 x 10—7 M), or L-NAME
(10—4 M).
The antagonist equilibrium dissociation constant (KB)
for pirenzepine versus carbamylcholine was determined according to the
following equation (Furchgott,
1972): KB = [B]/[dose ratio — 1], where
[B] is the concentration of the antagonist and the dose ratio is the
EC50 of the agonist in the presence of the antagonist divided by
the control EC50. EC50 was the concentration of agonist
required to elicit 50% of the maximal response. The antagonist equilibrium
dissociation constant for pirenzepine was expressed as the negative logarithm
of the KB (i.e., pKB).
Statistical Analyses. Results were expressed as the mean ±
S.E.M. of 3 to 12 isolated tissues obtained from 3 to 12 animals. Agonist
concentration-response curves were analyzed by a three-parameter logistic
nonlinear model (De Lean et al.,
1978). The three modeled parameters included the maximal response
(Emax) of the tissue, the EC50, and the slope
of the curves. Each curve was fitted using SAS software (SAS Institute Inc.,
Cary, NC). Two-way repeated-measures analysis of variance was used to compare
agonist responses in stomach fundus between wild-type and M3
receptor knockout mice and to examine the effect of antagonists on
carbamylcholine, McN-A-343, or electric field stimulation-induced relaxation
in stomach fundus from wild-type and/or M3 receptor knockout mice.
Bonferroni correction was performed to control for multiple comparisons.
Comparisons were conducted between vehicle and treated tissues examined in
each study and were considered significant for P values of 0.05 or
less.
Drugs. Carbamylcholine chloride, indomethacin, L-NAME, pirenzepine
dihydrochloride, tetrodotoxin, and PGF2 were
purchased from Sigma-Aldrich (St. Louis, MO). McN-A-343 was purchased from
Sigma/RBI (Natick, MA).
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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),
carbamylcholine produced a concentration-dependent contractile response in
stomach fundus from wild-type and M3 receptor knockout mice
(Fig. 1). The maximal
contraction to carbamylcholine was approximately 2-fold greater in the stomach
fundus from wild-type than from M3 receptor knockout mice
(Fig. 1). Although maximal
contraction to carbamylcholine was reduced in stomach fundus from
M3 receptor knockout mice, contraction to KCl (67 mM) was not
statistically different (P = 0.21) between stomach fundus from
M3 receptor knockout (1.73 ± 0.14 g, n = 28) and
wild-type (1.53 ± 0.08 g, n = 51) mice. In addition, as the
concentration of carbamylcholine increased
(>10—6 M), a marked relaxant response was
observed in stomach fundus from the M3 receptor knockout mice
(Figs. 1 and
2). In contrast, in wild-type
mice, relaxation of stomach fundus was not readily apparent at low
carbamylcholine concentrations but was transiently observed at a concentration
of 3.0 x 10—5 M carbamylcholine
(Fig. 2). The contraction
observed in wild-type mice to carbamylcholine is a composite of the activation
of both M2 and M3 receptors, whereas the contractile
response of stomach fundus from M3 receptor knockout mice appears
to result exclusively from activation of M2 receptors
(Stengel et al., 2002).
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Effect of Pirenzepine on Carbamylcholine-Induced Response in the Stomach
Fundus. Pirenzepine (3.0 x 10—7 M), a
selective M1 receptor antagonist, produced a small dextral shift in
carbamylcholine-induced contraction in the stomach fundus from wild-type mice
(Fig. 3, top). The antagonist
dissociation constant for pirenzepine (pKB = 6.85 ±
0.06) in blocking carbamylcholine-induced contraction in tissue from wild-type
mice was consistent with the affinity of pirenzepine at M3
(pKi = 6.9; from Table 1 of
Stengel and Cohen, 2002)
receptors but not at M1 receptors.
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In contrast, pirenzepine (3.0 x 10—7 M)
had little inhibitory effect on the contractile response of the stomach fundus
to carbamylcholine in tissues from M3 receptor knockout mice
(Fig. 3, bottom), consistent
with its low affinity for M2 receptors. However, pirenzepine
produced a marked dextral shift of the relaxant response to carbamylcholine in
stomach fundus from the M3 receptor knockout mice. In fact, the
antagonist dissociation constant for pirenzepine-induced antagonism of
carbamylcholine-induced relaxation (pKB = 7.89 ±
0.04) was consistent with its affinity at M1 receptors
(pKi = 7.96; from Table 1 of
Stengel and Cohen, 2002).
Effect of Indomethacin on Carbamylcholine-Induced Response in the Stomach Fundus. Indomethacin (10—6 M) was studied to explore a possible role of cyclooxygenase products in the relaxant response to carbamylcholine. Indomethacin (10—6 M) had no effect on either the contraction or relaxation produced by carbamylcholine in tissues from wild-type or M3 receptor knockout mice (data not shown).
Effect of NO Synthase Inhibition with L-NAME on Carbamylcholine-Induced Response in Stomach Fundus. L-NAME (10—4 M), an inhibitor of NO synthase, had no effect on the contraction to carbamylcholine in stomach fundus from wild-type mice or M3 receptor knockout mice (Fig. 4). However, L-NAME (10—4 M) dramatically inhibited the relaxation produced by carbamylcholine in stomach fundus from M3 receptor knockout mice (Fig. 4), indicating that the relaxation to carbamylcholine was mediated by formation and release of NO.
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Relaxant Effect of McN-A-343 in the Stomach Fundus from Wild-Type and
M3 Receptor Knockout Mice. Based on the ability of pirenzepine
to block carbamylcholine-induced relaxation in the stomach fundus, we further
explored the relaxant effect of McN-A-343, a functionally selective
M1 receptor agonist (Hammer and
Giachetti, 1982; Eglen et al.,
1987). McN-A-343-induced relaxation was highly variable in stomach
fundus from wild-type mice. McN-A-343 produced a small but nonsignificant
relaxation of PGF2
(10—6 M)-induced tone in the stomach fundus from
seven of nine wild-type mice, which was followed by a contractile response as
the concentration of McN-A-343 increased (>10—4
M) (Fig. 5). Relaxation to
McN-A-343 was not observed in the stomach fundus from two of nine wild-type
mice. McN-A-343 produced a consistent and greater maximal relaxation in
stomach fundus from five of five M3 receptor knockout mice than was
observed in tissues from wild-type mice. However, McN-A-343 did not completely
relax PGF2-contracted tissues, suggesting that it
was a partial relaxant agonist in the stomach fundus. PGF2a-induced
contraction was similar (P = 0.13) in stomach fundus from wild-type
and M3 receptor knockout mice [112.71 ± 9.47 (n =
39) and 89.30 ± 9.87% (n = 19), respectively, of the 67 mM KCl
maximal contraction].
|
Effect of Pirenzepine on McN-A-343-Induced Relaxation in the Stomach Fundus. Pirenzepine (3.0 x 10—7 M) completely blocked the relaxation produced by McN-A-343 (Fig. 6) in tissues from wild-type and M3 receptor knockout mice. In the presence of pirenzepine, McN-A-343 markedly contracted (in concentrations of 10—5 M and greater) the stomach fundus from wild-type but not from M3 receptor knockout mice. Thus, pirenzepine dramatically inhibited the relaxation to McN-A-343 and exacerbated a contractile response to this agonist only in the stomach fundus from wild-type mice that possessed M3 contractile receptors.
|
Effect of L-NAME on McN-A-343-Induced Relaxation in the Stomach Fundus. Since relaxation to carbamylcholine was mediated by NO (i.e., inhibited by L-NAME), we also examined the effect of L-NAME on McN-A-343-induced relaxation (Fig. 7). In the presence of L-NAME (10—4 M), the relaxant response to McN-A-343 was converted to a marked contractile response in stomach fundus from wild-type mice.
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L-NAME (10—4 M) also blocked the relaxation to McN-A-343 in tissues from M3 receptor knockout mice. However, in the stomach, fundus from the M3 receptor knockout mice, contraction did not occur to McN-A-343 even in the presence of L-NAME, suggesting that the contractile response to McN-A-343 observed in the stomach fundus from wild-type mice resulted from activation of M3 receptors by McN-A-343.
Effect of Tetrodotoxin on McN-A-343-Induced Relaxation in the Stomach Fundus. To determine whether the relaxant response to McN-A-343 was a direct effect of this agonist on smooth muscle or resulted from the neuronal release of NO, we evaluated the effect of tetrodotoxin (200 ng/ml) on McN-A-343-induced relaxation in the stomach fundus (Fig. 8). In the presence of tetrodotoxin, the relaxant response to McN-A-343 was blocked in stomach fundus from wild-type and M3 receptor knockout mice and converted to a contractile response in stomach fundus from wild-type mice.
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Effect of Pirenzepine and L-NAME on Field Stimulation-Induced Relaxation
in the Mouse Stomach Fundus from Wild-Type and M3 Receptor Knockout
Mice. Carbamylcholine- and McN-A-343-induced relaxation was antagonized by
pirenzepine and tetrodotoxin, suggesting the presence of a neuronal
M1 relaxant response in the mouse stomach fundus. Based on this, we
asked whether relaxation to field stimulation in the stomach fundus could be
modulated by M1 receptor activation. Relaxation to field
stimulation (1–32 Hz) was similar in stomach fundus from wild-type and
M3 receptor knockout mice (Figs.
9 and
10), in contrast to the
greater relaxation observed to carbamylcholine
(Fig. 1) and McN-A-343
(Fig. 5) in tissues from
M3 receptor knockout mice. Furthermore, pirenzepine (3 x
10—7 M) did not alter the relaxant response
produced by field stimulation in stomach fundus from wild-type or
M3 receptor knockout mice (Fig.
9). These data suggest that the relaxant response mediated by
field stimulation was not modulated by activation of M1 receptors.
However, L-NAME (10—4 M) inhibited field
stimulation-induced relaxation of PGF2-contracted
stomach fundus from wild-type and M3 receptor knockout mice,
indicating that the relaxation caused by field stimulation, although not
modulated by M1 receptors, was due to NO release
(Fig. 10).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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,
2002) established that
M3 and, to a lesser extent, M2 receptors mediate the
contractile response to carbamylcholine in the mouse stomach fundus. Although
M2 receptors may account for 70 to 80% of the receptor population
in smooth muscle based on radioligand binding studies
(Eglen et al., 1996),
contraction of smooth muscle (Ehlert et
al., 1997), and in particular, the stomach fundus (Stengel et al.,
2000,
2002) appears to be
predominantly mediated by activation of M3 receptors. Compensatory
changes in cholinergic receptors have not been apparent when cholinergic
receptors have been abolished, since immunoprecipitation studies in brain and
heart of muscarinic receptor knockout mice have not shown alteration or
compensatory changes in receptor numbers or distribution
(Hamilton et al., 1997; Gomeza
et al.,
1999a,b;
Nadler et al., 1999; Yamada et
al.,
2001a,b).
Previous studies (Stengel et al.,
2002) using the stomach fundus from M3 receptor
knockout mice revealed a marked relaxant response to high concentrations
(>10—6 M) of carbamylcholine. The present
studies expanded on this initial observation by demonstrating that 1) modest
cholinergic relaxation could also be detected in stomach fundus from wild-type
mice and 2) muscarinic-induced relaxation in the mouse stomach fundus was
unequivocally mediated by neuronal M1 receptor activation of NO
release. This latter conclusion was supported by the observations that 1) the
functionally selective M1 receptor agonist, McN-A-343, like
carbamylcholine, also relaxed the mouse stomach fundus, 2) the selective
M1 receptor antagonist pirenzepine inhibited relaxation to both
carbamylcholine and to the M1 receptor agonist McN-A-343, and 3)
the antagonist dissociation constant estimated for pirenzepine
(pKB = 7.89) was similar to the pKi
determined in radioligand binding studies for the interaction of pirenzepine
with M1 receptors (pKi for M1
receptors 
7.96 as summarized in
Stengel and Cohen, 2002).
Thus, in the mouse stomach fundus, like several other gastrointestinal
preparations (Barocelli et al.,
1994; Iversen et al.,
1997; Olgart and Iversen,
1999), M1 receptors appear to be the predominant
muscarinic receptor subtype associated with inhibitory (relaxant) responses.
In contrast, muscarinic relaxant responses in vascular tissue may be mediated
via other cholinergic receptors (Norel et
al., 1996; Liu and Lee,
1999; Yamada et al., 2001).
Although prostanoids have been involved in the carbamylcholine-induced
responses of some smooth muscles (Armstead
et al., 1988; Norel et al.,
1996; Stengel and Cohen,
2002) and have been associated with both contraction and
relaxation of the mouse stomach fundus
(Okada et al., 2000), we were
unable to demonstrate a role for arachidonic acid metabolites in the relaxant
response observed to carbamylcholine in the stomach fundus from M3
receptor knockout mice. Indomethacin did not potentiate or antagonize
carbamylcholine-induced relaxation in the stomach fundus.
Clearly, however, as observed with other smooth muscle relaxant responses,
relaxation in response to both carbamylcholine and McN-A-343 was mediated by
NO release, as indicated by the ability of L-NAME
(10—4 M) to inhibit the relaxation to both
agonists in the M3 receptor knockout mice. The involvement of NO in
the relaxant response observed in stomach fundus from M3 receptor
knockout mice was similar to the involvement of this signaling mechanism in
other smooth muscle preparations (Kamata
et al., 1993; Leclere and
Lefebvre, 1998; Lefebvre and
Vandekerckhove, 1998; Ny et
al., 2000; Selemidis and
Cocks, 2000; Baccari and
Calamai, 2001).
The cholinergic-induced relaxant response in the stomach fundus resulted
from neuronal release of NO, since tetrodotoxin inhibited the NO-mediated
relaxation induced by McN-A-343. Thus, as postulated in other smooth muscle
preparations (Iversen et al.,
1997; Olgart and Iversen,
1999), M1 receptor-mediated presynaptic release of NO
was responsible for the relaxant response observed. Having established the
presence of a presynaptic M1 receptor that can modulate NO release,
we asked whether this mechanism was activated endogenously upon neuronal
activation by field stimulation in the mouse stomach fundus. If field
stimulation activated release of acetylcholine, which in turn could modulate
M1 receptors mediating NO release, we hypothesized that the
relaxation produced by field stimulation would be enhanced in the stomach
fundus from M3 receptor knockout mice. However, this did not occur
(Fig. 10). Furthermore,
pirenzepine had no effect on the relaxation produced by field stimulation in
tissues from either the wild-type or M3 receptor knockout mice.
Although field stimulation-induced relaxation was inhibited by L-NAME and
involved NO release, NO released by field stimulation was independent of the
M1 receptor, since it was not blocked by pirenzepine. Thus, the
M1 receptor-induced relaxant mechanism appears operative only when
M1 receptors are activated by exogenous agents, such as
carbamylcholine or McN-A-343.
McN-A-343 is an agonist that shows functional selectivity for M1
receptors (Heldman et al.,
1996) but displays nonselective affinity for all muscarinic
receptors (Richards and van Giersbergen,
1995; Ensinger et al.,
1997). In the present study, McN-A-343 produced a partial agonist
relaxant response, with higher concentrations producing a frank contraction in
tissues from wild-type mice and a return to baseline force in tissues from
M3 receptor knockout mice. It was interesting to note that after
L-NAME, pirenzepine, and tetrodotoxin, the relaxant response in the mouse
stomach fundus to McN-A-343 was eliminated and instead, a marked contraction
of the stomach fundus occurred in tissues from wild-type but not from
M3 receptor knockout mice. These data are consistent with the
conclusion that when the relaxant response to McN-A-343 was eliminated,
McN-A-343 contracted the stomach fundus via activation of M3
receptors, an effect that did not occur in the tissues from M3
receptor knockout mice. The ability of McN-A-343 to activate M3
receptors has not been widely appreciated, although it has been shown to
contract rat colon (Börjesson et al.,
2000) and guinea pig ileum
(Barocelli et al., 1994),
stimulate gastric acid and salivary secretions
(Black and Shankley, 1985;
Schiavone et al., 1988), and
stimulate mitogen-activated protein kinase in Chinese hamster ovary cells
expressing the M3 receptor
(Wotta et al., 1998), all
effects thought to be mediated by activation of M3 receptors. The
ability of McN-A-343 to contract the stomach fundus from wild-type mice via
M3 receptor activation might provide an explanation for the
variable and modest relaxant response observed to McN-A-343 in the stomach
fundus from wild-type mice. The ability of McN-A-343 to activate M3
receptors was also consistent with the ability of this agent to contract the
urinary bladder (Poli et al.,
1992), a tissue shown to contract via activation of M3
receptors (Poli et al., 1992;
Stengel et al., 2002).
The present studies demonstrated that deletion of the M3
receptor will magnify M1 receptor-mediated relaxation. Like-wise,
pharmacological block of M3 receptors also magnified
M1-receptor mediated relaxation in rat jejunum
(Olgart and Iversen, 1999).
Clearly, the presence of M3 receptors in stomach fundus from
wild-type mice is sufficient to mask M1 receptor-mediated
relaxation. These data support the contention that blockade of M3
receptors with pharmacological agents or pathology would serve to unmask
M1 receptor-mediated relaxation of gastrointestinal tissue.
Although the direct implications of this action are unknown, such an effect is
likely to alter gastric emptying and may be important in the proposed utility
of M3 receptor antagonists in obesity
(Teff et al., 1999).
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: NO, nitric oxide; M1 to M5
receptors, muscarinic acetylcholine receptors; L-NAME,
N-nitro-L-arginine methyl ester hydrochloride;
McN-A-343, (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate
chloride; PGF2, prostaglandin F2a.
1 Current address: Creative Pharmacology Solutions LLC, 10532 Copper-gate,
Carmel, IN 46032. 
Address correspondence to: Peter W. Stengel, Eli Lilly and Company, Lilly Research Laboratories, Neuroscience Research, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: stengel_peter_w{at}lilly.com
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