Regulation of atrial natriuretic peptide secretion by
cholinergic and PACAP neurons of the gastric antrum
William R.
Gower Jr.1,3,5,6,
John R.
Dietz4,6,
Robert W.
McCuen9,
Peter J.
Fabri2,5,
Ethan A.
Lerner7, and
Mitchell L.
Schubert8,9
1 Laboratory and 2 Surgery Services, James A. Haley
Veterans Administration Hospital; Departments of 3 Biochemistry
and Molecular Biology, 4 Physiology and Biophysics, and
5 Surgery, University of South Florida; and 6 University
of South Florida Cardiac Hormone Center, Tampa, Florida 33612;
7 Department of Dermatology, Harvard Medical School,
Charlestown, Massachusetts 02129; and 8 Department of Medicine,
Medical College of Virginia/Virginia Commonwealth University, and
9 McGuire Veterans Administration Hospital, Richmond, Virginia
23249
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ABSTRACT |
Atrial natriuretic peptide (ANP) released
from enterochromaffin cells helps regulate antral somatostatin
secretion, but the mechanisms regulating ANP secretion are not known.
We superfused rat antral segments with selective neural
agonists/antagonists to identify the neural pathways regulating ANP
secretion. The nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium
(DMPP) stimulated ANP secretion; the effect was abolished by
hexamethonium but doubled by atropine. Atropine's effect implied that
DMPP activated concomitantly cholinergic neurons that inhibit and
noncholinergic neurons that stimulate ANP secretion, the latter effect
predominating. Methacholine inhibited ANP secretion. Neither bombesin
nor vasoactive intestinal polypeptide stimulated ANP secretion, whereas
pituitary adenylate cyclase-activating polypeptide (PACAP)-27,
PACAP-38, and maxadilan [PACAP type 1 (PAC1) agonist] each stimulated
ANP secretion. The PAC1 antagonist M65 1) abolished
PACAP-27/38-stimulated ANP secretion; 2) inhibited basal ANP
secretion by 28 ± 5%, implying that endogenous PACAP stimulates ANP
secretion; and 3) converted the ANP response to DMPP from
109 ± 21% above to 40 ± 5% below basal, unmasking the cholinergic
component and indicating that DMPP activated PACAP neurons that
stimulate ANP secretion. Combined atropine and M65 restored
DMPP-stimulated ANP secretion to basal levels. ANP secretion in the
antrum is thus regulated by intramural cholinergic and PACAP neurons;
cholinergic neurons inhibit and PACAP neurons stimulate ANP secretion.
stomach; methacholine; 1,1-dimethyl-4-phenylpiperazinium; atropine; enterochromaffin; hormone; peptide; enteric nervous system; pituitary
adenylate cyclase-activating peptide
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INTRODUCTION |
ATRIAL NATRIURETIC
PEPTIDE (ANP), a 28-amino acid polypeptide first identified in
cardiac atrial myocytes, is also present in extracardiac tissues,
including the gastrointestinal tract (22). ANP
preferentially binds to two subtypes of natriuretic peptide receptors
(NPR): type A (NPR-A) and type C (NPR-C). NPR-A, a transmembrane cell
surface receptor with ligand-dependent guanylyl cyclase activity,
mediates the biological effects of ANP in kidney, adrenal, and vascular
tissues (9). NPR-C, a transmembrane cell surface receptor
lacking guanylyl cyclase activity, originally thought to act primarily
as a natriuretic peptide clearance receptor, may also inhibit adenylate
cyclase activity (1, 9, 19, 34). Although ANP secreted
from atrial myocytes into the systemic circulation causes natriuresis
and diuresis in the kidney, the fact that ANP and functional ANP
receptors are coexpressed in the same tissues suggests that ANP may
have local physiological roles that are related to the specific organ
system within which it is produced (8, 18, 20, 26, 38).
In the stomach, ANP has been reported to relax smooth muscle cells
(5, 34) and either inhibit or stimulate acid secretion (3, 32). Using molecular biological and
immunohistochemical techniques, we have localized ANP to
enterochromaffin (EC) cells of the gastric antrum (15),
and we and others have demonstrated the presence of NPR-A and NPR-C
receptors in antral mucosa (14, 15, 23, 26). These
findings have led us to postulate that ANP may regulate gastric
function, perhaps via a paracrine and/or autocrine pathway. In support
of this notion, ANP stimulates cGMP production in rat pyloric glands
(15, 26) and somatostatin secretion in superfused rat and
human antral segments (14). The precise pathways that
regulate ANP secretion from this region of the stomach, however, are
not known.
In the present study, we have used the nicotinic agonist
1,1-dimethyl-4-phenylpiperazinium (DMPP), alone and in combination with
various selective antagonists, to identify the neural pathways that
regulate ANP secretion in rat antrum. The results indicate that ANP
secretion is regulated by intramural cholinergic and pituitary
adenylate cyclase-activating polypeptide (PACAP) neurons. Activation of
cholinergic neurons inhibits and activation of PACAP neurons stimulates
ANP secretion.
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MATERIALS AND METHODS |
Materials.
The nicotinic agonist DMPP, the muscarinic agonist methacholine, the
nicotinic antagonist hexamethonium bromide, the muscarinic antagonist
atropine sulfate, and the axonal blocker tetrodotoxin were purchased
from Sigma (St. Louis, MO). PACAP-27, PACAP-38, and antiserum to rat
ANP were purchased from Peninsula Labs (Belmont, CA). Bombesin and
vasoactive intestinal polypeptide (VIP) were purchased from Bachem
(Torrance, CA). Recombinant maxadilan [PACAP type I (PAC1) receptor
agonist] and its deleted peptide M65 (PAC1 receptor antagonist) were
produced in Escherichia coli and purified to homogeneity
using reverse-phase high performance liquid chromatography by E. Lerner
(25, 36). 125I-ANP and Amprep-mini C18 columns
were purchased from Amersham (Arlington Heights, IL).
Superfusion of rat antral segments.
Male Sprague-Dawley rats, weighing 250-350 g, were deprived of
solid food overnight but allowed free access to water containing 5%
dextrose. The animals were anesthetized with 20% urethane (5 ml/kg
body wt ip). The serosal and muscle layers were partly removed from the
antrum to improve drug diffusion, and a segment, ~1 cm2,
was cut into six to eight segments, washed with saline, and placed on a
porous grid separating the two halves of a minichamber (Swinnex 25, 1.4 ml volume; Millipore, Bedford, MA) as previously described
(31). Krebs-bicarbonate solution containing 0.2% bovine serum albumin, 4% dextran, and 4.5 mM glucose was perfused into the
bottom of the chamber at a rate of 1 ml/min, and the effluent was
collected via a catheter leading from a small aperture at the top of
the chamber. The perfusate was gassed with 95% O2 and 5%
CO2. Drugs were delivered at the rate of 0.1 ml/min via a
side arm close to the inlet. The entire preparation was contained
within a chamber maintained at 37°C. The protocol was approved by the Virginia Commonwealth University Institutional Animal Care and Use
Committee
Experimental design.
A 30-min equilibration period was followed by an 80- to 100-min
sampling period. The sampling period consisted of a 30-min control
basal period, a 20-min period during which DMPP (10 pM-10 µM),
methacholine (10 pM-1 mM), PACAP-27 (10 pM-0.1 µM),
PACAP-38 (10 pM-0.1 µM), maxadilan (10 pM-0.1 µM), M65
(10 nM), bombesin (10 pM-0.1 µM), or VIP (10 pM-0.1 µM)
was superfused, and a final 30-min control period. In some experiments,
atropine (0.1 µM or 0.1 mM), hexamethonium (1 mM), M65 (10 nM), or
tetrodotoxin (5 µM) was superfused for 20 min before as well as
during superfusion with DMPP, methacholine, PACAP-27, PACAP-38, or
maxadilan. Five-milliliter samples of the effluent were obtained at
5-min intervals and stored at
20°C for subsequent measurement of
ANP concentration by radioimmunoassay.
Radioimmunoassay.
ANP was extracted from pooled aliquots of effluent collected for 5 min,
and its concentration was measured in duplicate by radioimmunoassay as
described in detail previously (6, 12). ANP-containing
superfusates were applied to Amprep-mini C18 columns equilibrated with
0.1 N acetic acid and eluted with a mixture of acetonitrile and 0.1 M
trifluoracetic acid (60:40). The eluate was dried under nitrogen,
resuspended in a minimal volume of radioimmunoassay buffer, and then
assayed for immunoreactive ANP. The recovery of added rat ANP was
82 ± 3%. The limit of detection was 0.6 pg/tube, and the
IC50 was 12.2 pg/tube. Interassay and intra-assay
coefficients of variability were 7.0% and 9.4%, respectively.
Data analysis.
ANP secretion was expressed as the mean increase or decrease as
picograms per minute or as percentage of basal level during the 10 min
immediately preceding the experimental period. Data are presented as
means ± SE of n experiments on different animals. Changes in secretion were tested for significance using Student's t-test for unpaired values. Differences were considered
significant at P < 0.05.
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RESULTS |
Effect of DMPP alone and in combination with various antagonists on
ANP secretion from antrum.
Basal secretion of ANP from rat antral segments was uniform from one
experimental series to another and reverted to control basal levels at
the end of the experimental period (start, 10 ± 3; end, 12 ± 4 pg/min).
Superfusion for 20 min with the nicotinic agonist DMPP, in the range of
10 pM-10 µM, caused a prompt, reversible, and
concentration-dependent increase in ANP secretion (Figs.
1 and 2).
The EC50 was 3 nM, and maximal stimulation of ANP
secretion, expressed as the integrated 20-min response, was 109 ± 29% at 1 µM (P < 0.01; n = 6).

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Fig. 1.
Effect of the nicotinic agonist
1,1-dimethyl-4-phenylpiperazinium (DMPP; 10 pM-10 µM) on basal
atrial natriuretic peptide (ANP) secretion from rat antral segments.
Results are expressed as integrated response during 20 min of
superfusion with DMPP. Data are means ± SE of 5-8
experiments with each dose. *P < 0.05 vs. basal.
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Fig. 2.
Time course for the effect of
the nicotinic agonist DMPP (1 µM) alone ( ) and in
combination with the nicotinic antagonist hexamethonium (HEX; 0.1 mM;
) on basal ANP secretion. Data are means ± SE of
6 experiments each.
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Addition of the nicotinic antagonist hexamethonium (0.1 mM;
n = 8), although having no significant effect on basal
ANP secretion, abolished the increase in ANP secretion induced by DMPP
(1 µM), indicating that DMPP acted specifically at nicotinic sites in this preparation (Fig. 2).
To determine whether cholinergic neurons are involved in the regulation
of ANP secretion, experiments were performed in the presence of the
muscarinic antagonist atropine. Addition of atropine (10 µM) to the
superfusate, although having no significant effect on basal ANP
secretion, augmented the stimulatory effect of DMPP (1 µM) on ANP
secretion by twofold, from 109 ± 29% above basal level with DMPP
alone to 210 ± 21% above basal level with DMPP plus atropine
(P < 0.01 for the difference; Figs.
3 and 10). The results imply that DMPP
activated cholinergic neurons that inhibit ANP secretion and
noncholinergic neurons that stimulate ANP secretion, the effect of the
latter predominating.

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Fig. 3.
Time course for the effect of the nicotinic agonist DMPP
(1 µM) alone ( ) and in combination with the
muscarinic antagonist atropine (10 µM; ), the
pituitary adenylate cyclase-activating polypeptide (PACAP) type I
antagonist M65 (10 nM; ), or atropine plus M65
( ). Data are means ± SE of 6-8 experiments
each.
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Consistent with this notion, superfusion of antral segments for 20 min
with the muscarinic agonist methacholine, in the range of 10 pM-1
mM, caused a concentration-dependent decrease in ANP secretion (Fig.
4). The EC50 was 5 nM, and
maximal inhibition of ANP secretion, expressed as the integrated 20-min
response, was 79 ± 4% below basal level (P < 0.001;
n = 4). Addition of atropine (10 µM) to the
superfusate, although having no significant effect on basal ANP
secretion, abolished the decrease in ANP secretion induced by 0.1 µM
methacholine (Fig. 5). Tetrodotoxin (5 µM) had no significant effect on the ANP response to 0.1 µM
methacholine (62 ± 6% below above basal level with
methacholine alone vs. 48 ± 6% below basal level with
methacholine plus tetrodotoxin; no significant difference; Fig. 5).

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Fig. 4.
Effect of the muscarinic agonist methacholine (10 pM-1 mM) on basal ANP secretion from rat antral segments. Results
are expressed as integrated response during 20 min of superfusion with
methacholine. Data are means ± SE of 5-8 experiments with
each dose. *P < 0.05 vs. basal.
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Fig. 5.
Time course for the effect of the muscarinic agonist
methacholine (0.1 µM) alone ( ) and in combination
with the muscarinic antagonist atropine (10 µM; ) or
the axonal blocker TTX (5 µM; ) on basal ANP
secretion. Data are means ± SE of 4-6 experiments each.
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Prime candidates for noncholinergic transmitter responsible for
stimulation of ANP secretion include bombesin, VIP, and PACAP. All are
present in gastric antral mucosal nerve fibers and capable of
stimulating secretion from neuroendocrine cells (2, 7, 21, 33,
35, 40). Superfusion for 20 min with bombesin or VIP, in the
range of 10 pM-0.1 µM, however, had no significant effect on ANP
secretion (n = 4-6 each). In contrast, PACAP-27 (10 pM-0.1 µM), PACAP-38 (10 pM-0.1 µM), and the PAC1
receptor agonist maxadilan (10 pM-0.1 µM) each stimulated ANP
secretion in a concentration-dependent manner, with threshold
concentrations <10 pM (Fig. 6). Both the
ANP response to 1 nM PACAP-27 and 1 nM PACAP-38 were abolished by the
PAC1 receptor antagonist M65 (10 nM; Figs.
7 and 8).
Tetrodotoxin (5 µM), on the other hand, inhibited the ANP response to
1 nM PACAP-27, 1 nM PACAP-38, and 1 nM maxadilan by 38-62%
[PACAP-27, 165 ± 21% (P < 0.001) above basal
level with PACAP-27 alone vs. 63 ± 6% (P < 0.001) above basal level with PACAP-27 plus tetrodotoxin
(P < 0.01 for the difference); PACAP-38, 130 ± 20% (P < 0.01) above basal level with PACAP-38 alone
vs. 80 ± 15% (P < 0.01) above basal level with
PACAP-38 plus tetrodotoxin (P < 0.05 for the
difference); and maxadilan, 116 ± 6% (P < 0.001) above basal level with maxadilan alone vs. 59 ± 8%
(P < 0.001) above basal level with maxadilan plus
tetrodotoxin (P < 0.01 for the difference); Figs. 7
and 8]. The results suggest that PACAP stimulates ANP secretion
directly as well as indirectly by activating noncholinergic neurons.

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Fig. 6.
Effect of PACAP-27 ( ), PACAP-38
( ), and the PACAP type 1 agonist maxadilan
( ; 10 pM-0.1 µM) on basal ANP secretion from rat
antral segments. Results are expressed as integrated response during 20 min of superfusion with each peptide. Data are means ± SE of
5-8 experiments with each dose. *P < 0.05 vs.
basal.
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Fig. 7.
Time course for the effect of PACAP-27 (1 nM) alone
( ) and in combination with the PACAP type 1 antagonist
M65 (10 nM; ) or the axonal blocker TTX (5 µM;
) on basal ANP secretion. Data are means ± SE of
6 experiments each.
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Fig. 8.
Time course for the effect of PACAP-38 (1 nM) alone
( ) and in combination with the PACAP type 1 antagonist
M65 (10 nM; ) or the axonal blocker tetrodotoxin (5 µM; ) on basal ANP secretion. Data are means ± SE of 6 experiments each.
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It should be noted that superfusion of antral segments for 20 min with
M65 (10 nM) alone caused a prompt and reversible decrease in ANP
secretion (mean integrated response, 28 ± 5% below basal level;
P < 0.001; n = 12), implying that
endogenous PACAP, acting via the PAC1 receptor, stimulates ANP
secretion (Fig. 9).

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Fig. 9.
Time course for the effect of the PACAP type 1 antagonist
M65 (10 nM) on basal ANP secretion. Data are means ± SE of 6 experiments.
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To determine the participation of PACAP neurons in DMPP-stimulated ANP
secretion, experiments were performed in the presence of M65 (Figs. 3
and 10). Addition of M65 (10 nM) to the
superfusate converted the increase in ANP secretion induced by DMPP (1 µM) from a 109 ± 29% increase above basal level to a 40 ± 5% (P < 0.001; n = 6) decrease
below basal level, unmasking the cholinergic component and implying
that DMPP activated PACAP neurons that stimulate ANP secretion. A
combination of atropine (0.1 mM) and M65 (10 nM) had the same effect as
hexamethonium, restoring DMPP-stimulated ANP secretion to control basal
levels (Figs. 3 and 10).

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Fig. 10.
Mean ANP responses during 20-min period of superfusion
with methacholine (MTH; 0.1 µM), PACAP-27 (PAC-27; 1 nM), PACAP-38
(PAC-38; 1 nM), the PAC1 receptor agonist maxadilan (MAX; 1 nM), as
well as the nicotinic agonist DMPP (1 µM) alone and in combination
with atropine (ATR; 10 µM), the PAC1 receptor antagonist M65 (10 nM),
atropine (10 µM) plus M65 (10 nM), or the nicotinic antagonist
hexamethonium (HEX; 0.1 mM). Mean data are derived from Figs. 1-6.
*P < 0.01 vs. control basal levels.
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DISCUSSION |
Although quantitatively the most important source of ANP may be
cardiac atrial myocytes, ANP is present in a variety of tissues, including the gastrointestinal tract (11). In the stomach,
transcripts for ANP as well as its receptors, NPR-A and NPR-C, have
been detected in antral mucosa (14, 15, 26). In this
region, ANP has been localized to EC cells by in situ hybridization and
immunohistochemistry (15). The presence of ANP and its
receptor in antral mucosa suggests that ANP may regulate gastric
function in a paracrine manner. In support of this notion, the NPR-A
receptor antagonist, anantin, inhibits somatostatin secretion in rat
antral segments (13). The results of the antagonist imply
that endogenous ANP, acting via the NPR-A receptor, stimulates antral
somatostatin secretion. The mechanisms, however, that regulate the
secretion of ANP from this region of the stomach have not been examined.
Previous studies using superfused antral segments (28),
antral sheets mounted in Ussing chambers (30), and
vascularly perfused rat stomach (29), preparations that
retain intact intramural neural pathways, have shown that peptide
(i.e., gastrin and somatostatin) secretion from this region of the
stomach is regulated by cholinergic and noncholinergic (i.e., bombesin
and VIP) neurons. More recently, the release of gastric serotonin,
which is colocalized with ANP in EC cells (15), has been
shown to be regulated by cholinergic neurons in the vascularly perfused
rat stomach preparation (39).
In the present study, we have demonstrated, for the first time, by
using rat superfused antral segments, that ANP secretion from EC cells
can also be regulated by intramural cholinergic and noncholinergic
(i.e., PACAP) neurons. The evidence for this is based on the fact that
pharmacological activation of intramural neurons by the ganglionic
nicotinic agonist DMPP caused a concentration-dependent increase in ANP
secretion. The ANP response to DMPP was completely inhibited by the
ganglionic nicotinic antagonist hexamethonium but was augmented twofold
by atropine. The effect of atropine implies that DMPP activated
cholinergic neurons that inhibit ANP secretion and concomitantly
noncholinergic neurons that stimulate ANP secretion; the effect of the
latter appears to predominate, resulting in a net increase in ANP
secretion. Consistent with this notion, the muscarinic agonist
methacholine caused a concentration-dependent and atropine-sensitive
decrease in ANP secretion.
The regulation of ANP secretion by cholinergic and noncholinergic
intramural neurons parallels closely that of other gastric neuroendocrine cells as discussed above, in particular
somatostatin-containing D cells. In both instances, activation of
cholinergic neurons inhibits and activation of noncholinergic neurons
(e.g., VIP) stimulates peptide secretion. We hypothesized that VIP
and/or bombesin might be the noncholinergic transmitter responsible for stimulation of ANP secretion; both are present in antral mucosal nerve
fibers and are capable of stimulating peptide secretion (VIP stimulates
somatostatin and bombesin stimulates gastrin) in response to
physiological stimuli such as mechanical distension and luminal protein
(4, 7, 21, 27, 28, 30). Neither peptide, however, had any
significant effect on ANP secretion in our preparation when
superfused at concentrations ranging from 10 pM to 0.1 µM.
PACAP has recently been localized to efferent and afferent nerve fibers
innervating gastric antral mucosa (10, 16, 35). PACAP,
which shows 68% sequence homology with VIP, has two bioactive forms,
with 38 (PACAP-38) and 27 (PACAP-27) amino acid residues. In rat,
PACAP-38 and the COOH-terminally truncated PACAP-27 are derived from a
common 175-amino acid precursor (24). PACAP exerts its
actions through at least three distinct receptors: the PAC1 receptor,
which binds PACAP with 1,000 times higher affinity than VIP, and the
VPAC1 and VPAC2 receptors, which bind PACAP and VIP with equal
affinities (17).
In the present study, PACAP-38 and PACAP-27 each stimulated ANP
secretion in a concentration-dependent manner. The fact that VIP had no
significant effect on ANP secretion led us to postulate that the effect
of PACAP was mediated via the PAC1 receptor. Consistent with this
notion, the PAC1 receptor agonist maxadilan caused a concentration-dependent increase in ANP secretion. The pattern of
response led us to postulate that PACAP may be the noncholinergic transmitter responsible for ANP secretion.
To evaluate the role of endogenously released PACAP in neurally
mediated ANP secretion, studies were performed in the presence of the
PAC1 receptor antagonist M65. First, M65 abolished PACAP-38- and
PACAP-27-stimulated ANP secretion, establishing its function as a
specific PAC1 receptor antagonist in this preparation. Secondly, M65
inhibited basal ANP secretion, implying that endogenous PACAP tonically
stimulates ANP secretion. Thirdly, M65 converted the ANP response to
DMPP from an increase above to a significant decrease below basal
levels, thus unmasking the cholinergic component and indicating that
DMPP activated PACAP neurons that stimulate ANP secretion. The
combination of atropine and M65, like hexamethonium, restored the ANP
response to DMPP to control basal levels, implying that activation of
cholinergic and PACAP neurons accounted for the entire response to DMPP.
The fact that the axonal blocker tetrodotoxin attenuated PACAP-38-,
PACAP-27-, and maxadilan-stimulated ANP secretion by ~50% suggests
that PACAP stimulates ANP secretion directly as well as indirectly by
releasing a noncholinergic stimulatory neurotransmitter, the identity
of which is not known. Although gastric EC cells have yet to be
isolated, the fact that histamine-containing EC-like cells isolated
from rat stomach express functional PAC1 receptors lends support to the
notion that PAC1 receptors might also be present on EC cells (2,
40). In support of an indirect neurally mediated effect, PAC1
mRNA has been demonstrated in the muscle, but not mucosal, layers of
the antrum (16, 35, 37). The fact that tetrodotoxin had no
significant effect on the inhibition in ANP secretion induced by
methacholine suggests that acetylcholine may directly inhibit ANP
secretion, analogous to its effect on antral somatostatin secretion
(28-31).
In summary, the present study demonstrates that ANP secretion from
antral EC cells is regulated by at least two intramural neural pathways
(i.e., postganglionic neurons): a cholinergic pathway that inhibits ANP
secretion directly and a noncholinergic pathway involving the release
of the neurotransmitter PACAP, which, acting via PAC1 receptors,
stimulates ANP secretion directly as well as indirectly via activation
of an additional noncholinergic neuron. The fact that ANP secretion can
be regulated by intramural neurons suggests that ANP may participate
physiologically in the regulation of gastric endocrine and/or exocrine
secretion. In support of this notion, we have shown, in preliminary
experiments, that endogenous ANP, acting via the NPR-A receptor,
stimulates somatostatin and thus inhibits gastrin secretion
(13). Because feeding stimulates and fasting inhibits ANP
mRNA in rat antrum (15), we speculate that ANP may
function, in this region of the stomach, in a paracrine feedback
pathway that modulates somatostatin, and hence gastrin secretion; i.e.,
a decrease in somatostatin, as occurs during ingestion of a meal,
stimulates ANP secretion, which, in turn, attenuates somatostatin secretion.
 |
ACKNOWLEDGEMENTS |
This work was supported in part by the Veterans Administration
Medical Research Fund (M. L. Schubert and W. R. Gower, Jr.), a Grant-In-Aid from the American Heart Association, Florida Affiliate (W. R. Gower, Jr. and J. R. Dietz), and the Eleanor Schultze
Memorial Fund (W. R. Gower, Jr.).
 |
FOOTNOTES |
Address for reprint requests and other correspondence: M. Schubert, McGuire VAMC, 111N, 1201 Broad Rock Blvd., Richmond, VA 23249 (E-mail: mitchell.schubert{at}med.va.gov).
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. Section 1734 solely to indicate this fact.
10.1152/ajpgi.00113.2002
Received 25 March 2002; accepted in final form 1 October 2002.
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