Vol. 274, Issue 6, R1783-R1788, June 1998
Central action of adrenomedullin to prevent ethanolinduced
gastric injury through vagal pathways in rats
Hiroshi
Kaneko1,
Terunori
Mitsuma1,
Hirofumi
Nagai1,
Shozaburo
Mori1,
Takashi
Iyo1,
Kazuo
Kusugami2, and
Yvette
Taché3
1 Fourth Department of Internal
Medicine, Aichi Medical University, Aichi 480-1195;
2 First Department of Internal
Medicine, Nagoya University School of Medicine, Nagoya 466-8560,
Japan; and 3 Center for Ulcer
Research and Education/Digestive Disease Research Center, West Los
Angeles Veterans Affairs Medical Center, Department of Medicine and
Brain Research Institute, University of California, Los Angeles,
California 90073
 |
ABSTRACT |
Adrenomedullin (AM), belongs to the calcitonin gene-related
peptide (CGRP) family and interacts with AM and
CGRP1 receptors. Specific AM
receptors and immunoreactivity are present in the rat brain. The effect
of intracisternal injection of rat AM on ethanol-induced gastric
lesions was studied in conscious Wistar rats. The peptide was injected
intracisternally or intravenously under short anesthesia 20 min before
intragastric injection of 70% ethanol. Corpus lesions were determined
1 h after ethanol. Intracisternal AM (75, 150, and 300 pmol)
dose-dependently inhibited ethanol-induced gastric lesions by
40-72% and rat 
-CGRP (150 pmol ic) by 76%. Intravenous AM
(300 pmol) had no effect. The CGRP1 receptor antagonist
CGRP-(8
37) (9.6-19.2 nmol ic) dose-dependently inhibited the
protective effect of intracisternal -CGRP but not that of
AM. Subdiaphragmatic vagotomy and peripheral injection of atropine,
indomethacin, or NG-nitro-L-arginine
methyl ester (L-NAME) prevented
AM protective action. L-Arginine
but not D-arginine blocked
L-NAME action. These data
suggest that both AM and CGRP act in the brain to prevent ethanol-induced gastric lesions through interaction with their specific
receptors. AM action may involve vagal cholinergic-dependent modulation
of prostaglandins and nitric oxide protective mechanisms.
calcitonin gene-related peptide antagonist; nitric oxide; prostaglandins; atropine; vagus
| |
INTRODUCTION |
ADRENOMEDULLIN (AM) is a 52-amino acid
peptide recently isolated from a human pheochromocytoma by Kitamura et
al. (14). Subsequent cDNA cloning of the human, rat, and porcine AM
showed high homology across species (14). Rat AM is similar but
distinct from human AM, with two amino acid deletions and six
substitutions (34). The peptide bears homology to calcitonin
gene-related peptide (CGRP), calcitonin, and amylin, which have an
NH2-terminal ring structure of six
to seven amino acids involving a disulfide bridge and an amidated
COOH-terminal end (14, 34). In the COOH-terminal portion (amino acid
residues 16-52), AM shares an ~27% homology with CGRP (34).
Recently, the cDNA for the rat and human AM and
CGRP1 receptors have been cloned
(1, 6, 10, 11). Comparison of the peptide sequence of AM and CGRP seven-transmembrane domain receptors indicates a 30% identity between
them (11). Characterization of these receptors in transfected cells as
well as in binding studies on various membranes indicate that AM
displays a highly specific recognition at the AM receptor over CGRP but
also cross-reacts with the CGRP1
receptor (1, 10, 11, 20, 37). In common with CGRP, AM injected
intravenously was first reported to elicit a strong and long-lasting
hypotensive response in rats (14, 22). Thereafter, there has been
considerable interest in establishing the in vivo and in vitro specific
actions of the peptide in the cardiovascular system (14, 21). In
particular, several studies established that AM vasodilatory properties
in various vascular bed preparations are mediated by selective
interaction with the AM receptor and/or cross talk with the
CGRP1 receptor, as assessed by the
use of the CGRP receptor antagonist CGRP-(837) (7, 14, 21).
Growing evidence also indicates that AM acts in the central nervous
system to influence feeding behavior, sympathetic outflow, and
cardiovascular and gastric motor function in rats (16, 19, 23, 29, 30,
32). A hindbrain site of action for intracisternal injection of
AM-induced increases in blood pressure and heart rate was recently
located in the area postrema, where AM activates a population of
neurons (2, 3). The localization of AM immunoreactivity and binding sites in the brain stem (9, 20, 32) suggests a possible
role of medullary AM. We previously reported that -CGRP injected
intracisternally inhibits experimental models of gastric erosions
[cold restraint, intracisternal injection of
thyrotropin-releasing hormone (TRH), ethanol] induced or
modulated by vagal-dependent mechanisms (25, 27). Whether
intracisternal injection of AM influences the resistance of the gastric
mucosa to injury through vagal-dependent pathways has not yet been
explored. The present study was designed
1) to examine whether AM injected
intracisternally acts in the brain to reduce ethanol-induced gastric
lesions, 2) to establish whether the
protective effects of -CGRP and AM injected intracisternally are
sensitive to blockade by intracisternal injection of the CGRP
antagonist CGRP-(837), and 3) to
define the neurohumoral pathways involved in AM action, in particular
the role of vagal cholinergic pathways previously shown to increase the
resistance of the mucosa to ethanol-induced gastric injury through
prostaglandins and NO-dependent mechanisms (28).
| |
METHODS |
Animals.
Male Wistar rats (specific pathogen free, 200- 300 g;
Japan Shizuoka Laboratory Center, Hamamatsu, Japan) were maintained with a standard diet of laboratory chow and tap water ad libitum under
conditions of controlled temperature (23 ± 2°C), humidity (60 ± 5%), and illumination (12-h light cycle starting 7:30 AM) for at
least 15 days before the experiments. Rats were deprived of food but
not water for 24 h before the beginning of the experiments. Experimental protocols were approved by the animal care and use committee of Aichi Medical University.
Chemicals and treatments.
The following substances were used: rat AM (1-50; no. 4281-s), rat
-CGRP (no. 4163-s), human CGRP-(837) (no. 4232-v; Peptide Institute, Osaka, Japan), BSA, atropine sulfate,
indomethacin, NG-nitro-L-arginine
methyl ester (L-NAME),
L-arginine,
D-arginine, ketamine
hydrochloride (Sigma, St. Louis, MO), ether, and ethanol (Wako
Chemical, Osaka, Japan). Peptides were freshly dissolved in saline
containing 0.1% BSA immediately before the experiment. Atropine,
L-NAME,
L-arginine, and
D-arginine were
dissolved in saline. Indomethacin was dissolved in 1.0%
NaHCO3 solution. Ethanol was
diluted in distilled water. Seventy percent ethanol (5 ml/kg) was given
intragastrically by an oral gavage using a stainless steel cannula.
Atropine was injected subcutaneously and indomethacin was injected
intraperitoneally in 1.0 ml/kg in lightly restrained conscious rats.
Intracisternal injections into the cisterna magna and intravenous
injections into the jugular vein were performed in volumes of 10 µl/rat and 1.0 ml/kg, respectively, in rats under brief ether
anesthesia. Subdiaphragmatic vagotomy or sham operation was performed
in fasted rats under ketamine (100 mg/kg ip) anesthesia 16 h before the
experiment.
Experimental protocols.
In the first experiment, rats under ether anesthesia were injected with
either rat AM (30, 75, 150, or 300 pmol ic or 300 pmol iv) or vehicle
(intracisternal or intravenous saline containing 0.1% BSA). In the
second experiment, the CGRP receptor antagonist human CGRP-(837)
(9.6, 19.2, or 28.8 nmol/10 µl) or vehicle was injected
intracisternally, immediately followed by intracisternal injection with
-CGRP (150 pmol), AM (150 pmol), or vehicle (10 µl). In the third
experiment, rats with sham operation or subdiaphragmatic vagotomy
(
16 h) were injected intracisternally with either AM (150 pmol)
or vehicle (10 µl). In other groups, atropine (0.15 mg/kg sc,
30 min), indomethacin (5 mg/kg ip, 60 min), or
L-NAME (3 mg/kg iv, 1
min) was administered before the intracisternal injection of AM (150 pmol) or vehicle (10 µl). In an additional study,
L-arginine or
D-arginine (300 mg/kg iv) was
injected immediately before
L-NAME (3 mg/kg iv). The regimen
of indomethacin,
L-NAME, and
L-arginine or
D-arginine administration was
based on previous studies that showed the complete blockade of the
vagal-dependent gastric cytoprotection induced by intracisternal
injection of the TRH analog RX-77368 under otherwise similar conditions
(13, 35). In all treated groups, 70% ethanol was administered
intragastrically 20 min after intracisternal injection of peptide or
vehicle. Conscious rats were euthanized by decapitation under ether
anesthesia 1 h after ethanol administration.
Measurement of gastric mucosal lesions.
After ligation of the pylorus and the esophagus at the gastric
junction, stomachs were removed, inflated with 10 ml of 0.5% Formalin
solution, and lightly fixed by immersion in 0.5% Formalin solution for
10 min. The gastric mucosa was exposed by cutting the stomach along the
greater curvature, washed with saline-wetted gauzes, laid on a flat
surface, and photographed. The outline of the gastric corpus and the
localization of the lesions characterized by dark bands on the pictures
were traced onto a transparent film using a felt-tip marker by a
trained person unaware of the treatment regimen. The percentage of the
gastric corpus containing lesions was determined by a computed image
analyzer device (Macintosh LC 630; Apple Japan, Tokyo, Japan;
application with National Institutes of Health Image 1.55 and Adobe
Photoshop 3.0J) equipped with an imaging scanner (GT-8000; Epson,
Tokyo, Japan).
Statistics.
Results are expressed as means ± SE. Multiple group comparisons
were performed by a one-way ANOVA followed by a Dunnett's contrast.
Comparisons between two groups were performed by Student's t-test. A probability level of
P < 0.05 was considered significant.
| |
RESULTS |
Oral administration of 70% ethanol (5 ml/kg) produced macroscopic
gastric lesions visualized as long dark red bands linearly oriented
along a cranial to caudal axis and primarily confined to the proximal
corpus mucosa. Gastric mucosal lesions covered 10.4 ± 2.0 and 12.1 ± 1.5% of the corpus mucosa in rats injected with vehicle into the
cisterna magna or jugular vein, respectively (Fig.
1). Intracisternal injection of AM at 75, 150, and 300 pmol significantly inhibited ethanol-induced lesions to
6.2 ± 0.8, 3.1 ± 0.5, and 2.9 ± 0.4% of the
gastric mucosa, respectively, whereas at 30 pmol, intracisternal AM had
no effect (11.4 ± 0.9%) compared with the vehicle-treated group
(Fig. 1). In contrast to the intracisternal injection of AM
(75-150 pmol), which dose-dependently inhibited ethanol-induced
gastric injury by 42-70%, the peptide injected intravenously at
300 pmol had no effect (Fig. 1).
View larger version (19K):
[in this window]
[in a new window]
|
Fig. 1.
Effect of adrenomedullin injected intracisternally or intravenously on
70% ethanol-induced gastric mucosal lesions in conscious rats. Under
short ether anesthesia, rats were injected intracisternally or
intravenously with vehicle or adrenomedullin, and, 20 min later, 70%
ethanol was administered orogastrically (5 ml/kg). Gastric lesions were
monitored 60 min after ethanol. Each bar represents mean ± SE of
number of rats indicated at top of
each column. * P < 0.05, ** P < 0.01 compared with
intracisternal vehicle.
|
|
Intracisternal injection of -CGRP at 150 pmol inhibited
ethanol-induced gastric mucosal lesions by 76% (Fig.
2). -CGRP-induced gastric protection was
partly prevented by the CGRP receptor antagonist CGRP-(837) injected
intracisternally at 9.6 nmol (30 µg) immediately before -CGRP and
was completely blocked when CGRP-(837) was injected at 19.2 nmol (60 µg) (Fig. 2). By contrast, CGRP-(837) (19.2 nmol ic) did not modify
the gastric protective effect of AM (150 pmol) injected into the
cisterna magna under the same conditions (Fig. 2). Intracisternal
injection of CGRP-(837) alone at 9.6 or 19.2 nmol did not influence
ethanol-induced gastric lesions, whereas a higher dose (28.8 nmol) had
a significant 36% inhibitory effect (Fig. 2).
View larger version (26K):
[in this window]
[in a new window]
|
Fig. 2.
Effect of intracisternal injection of calcitonin gene-related peptide
antagonist [CGRP-(837)] on rat -CGRP and rat
adrenomedullin injected intracisternally induced gastric cytoprotection
in conscious rats. Under short ether anesthesia, rats were injected
intracisternally with vehicle or human -CGRP-(837) immediately
after with vehicle, -CGRP, or adrenomedullin, and, 20 min later,
70% ethanol was administered orogastrically (5 ml/kg). Gastric lesions
were monitored 60 min after ethanol. Each bar represents mean ± SE
of number of rats indicated at top of
each column. * P < 0.05, ** P < 0.01 compared with
respective intracisternal vehicle;
## P < 0.01 compared with
intracisternal vehicle + -CGRP; + P < 0.05 compared with
intracisternal vehicle + intracisternal vehicle.
|
|
In sham-operated rats, orogastric administration of 70% ethanol
resulted in 18.8 ± 1.4% lesions of the corpus mucosa that were
reduced by 74% in rats injected intracisternally with AM (150 pmol)
(Fig. 3). Subdiaphragmatic vagotomy
completely abolished AM (150 pmol ic)-induced gastric protection
(P < 0.01) (Fig. 3). Vagotomy itself
did not influence ethanol-induced gastric injury (Fig. 3). Pretreatment
with atropine (0.15 mg/kg sc) and indomethacin (5 mg/kg ip) prevented
the protective effect of AM (150 pmol ic) on ethanol-induced gastric
injury by 82 and 100%, respectively (P < 0.01) (Fig.
4). Neither atropine nor indomethacin
influenced ethanol-induced lesions in intracisternal vehicle-injected
rats (Fig. 4). L-NAME (3 mg/kg
iv) also suppressed the gastric protective effect of intracisternal AM
(150 pmol) by 91% (P < 0.01) (Fig. 5).
L-Arginine, but not
D-arginine, injected
intravenously at 300 mg/kg before
L-NAME (3 mg/kg iv) restored the
cytoprotective action of AM injected intracisternally (Fig. 5).
View larger version (17K):
[in this window]
[in a new window]
|
Fig. 3.
Effect of subdiaphragmatic vagotomy on gastric protection induced by
adrenomedullin injected intracisternally in conscious rats. Vagotomy or
sham operation was performed 16 h before intracisternal injection of
vehicle or adrenomedullin, and, 20 min later, 70% ethanol was
administered orogastrically (5 ml/kg). Gastric lesions were monitored
60 min after ethanol. Each bar represents mean ± SE of number of
rats indicated at top of each column.
** P < 0.01 compared with
respective intracisternal vehicle group,
## P < 0.01 compared with sham
operation + intracisternal adrenomedullin.
|
|
View larger version (23K):
[in this window]
[in a new window]
|
Fig. 4.
Effect of peripheral atropine or indomethacin on gastric protection
induced by adrenomedullin injected intracisternally in conscious rats.
Rats were pretreated with indomethacin or vehicle for 60 min or
atropine or vehicle for 30 min before intracisternal injection of
vehicle or adrenomedullin under short ether anesthesia, and, 20 min
later, 70% ethanol was administered orogastrically (5 ml/kg). Gastric
lesions were monitored 60 min after ethanol. Each bar represents mean ± SE of number of rats indicated at
top of each column.
** P < 0.01 compared with
respective intracisternal vehicle group,
## P < 0.01 compared with
vehicle + intracisternal adrenomedullin.
|
|
View larger version (21K):
[in this window]
[in a new window]
|
Fig. 5.
Effect of NG-nitro-L-arginine methyl
ester (L-NAME) on gastric
protection induced by adrenomedullin injected intracisternally in rats.
Rats under short ether anesthesia were injected into the jugular vein
with vehicle, L-NAME,
L-NAME + L-arginine
(L-Arg), or
L-NAME + D-arginine
(D-Arg) immediately after with
intracisternal injection vehicle or adrenomedullin; 20 min later, 70%
ethanol was administered orogastrically (5 ml/kg). Gastric lesions were
monitored 60 min after ethanol. Each bar represents mean ± SE of
number of rats indicated at top of
each column. ** P < 0.01 compared with intravenous vehicle + intracisternal vehicle;
# P < 0.05, ## P < 0.01 compared with
intravenous vehicle + intracisternal adrenomedullin;
++ P < 0.01 compared with
intravenous L-NAME + intracisternal adrenomedullin.
|
|
| |
DISCUSSION |
AM (75-150 pmol) injected into the cisterna magna dose-dependently
inhibited gastric injury induced by orogastric administration of 70%
ethanol by 42-70% in conscious, fasted rats. At 150 pmol injected
intracisternally, AM induced a maximal protective effect, because 300 pmol resulted in a similar 72% inhibition of ethanol lesions. In
contrast to the intracisternal route of administration, AM injected
intravenously at two times the maximal effective dose given
intracisternally had no effect. These results indicate that the gastric
protection induced by AM injected into the cisterna magna is mediated
through the central nervous system and does not represent a leakage of
the peptide into the periphery (4). Other studies showed that
intracerebroventricular injection of AM or the truncated form,
AM-(1352) at higher doses (0.3-5 nmol) increases blood pressure
and abdominal sympathetic activity and decreases food intake (29, 30,
32), whereas similar or lower doses injected intracerebroventricularly
were reported to inhibit salt appetite and experimentally induced
drinking behavior and, given intracisternally, to delay gastric
emptying (16, 19, 23).
AM shares some similar spectrum of activity with CGRP (14, 21, 34). In
the present study, intracisternal injection of -CGRP at an equimolar
dose as AM (150 pmol) resulted in a similar 70% protection against
70% ethanol-induced gastric injury in conscious rats. These results
are in agreement with our previous report in which -CGRP injected
intracisternally in doses ranging from 8 to 80 pmol prevented 40%
ethanol-induced gastric lesions by 76-97%, respectively (25). In
addition, -CGRP injected intravenously had no effect on
ethanol-induced gastric lesions (15) as observed for intravenous
injection of AM. AM displays a slight (25-30%) sequence homology
with CGRP at both the peptide (14) and receptor levels (10, 11). In
addition, binding studies in several tissues including rat brain
membranes and in transfected cells indicate that AM activates the AM
receptor as well as interacts with the CGRP1 receptor, whereas CGRP is
devoid of agonist action on AM receptors (1, 10, 11, 20, 37). However,
several sets of evidence indicate that intracisternal AM-induced
gastric protection does not involve an interaction with the
CGRP1 receptor. First, the
intracisternal injection of CGRP-(837) immediately before that of AM
did not modify the gastric protective effect of intracisternal AM when
tested at a high CGRP antagonist/AM molar ratio (128:1). Second,
intracisternal CGRP-(837) completely abolished the cytoprotective effect of intracisternal -CGRP at a similar 128:1 ratio. Such conditions seem to be optimal to assess the CGRP receptor involvement in AM action, because at a higher dose, CGRP-(837) injected
intracisternally displays an agonist action in agreement with
neurobehavioral effects observed after intracerebroventricular
injection of CGRP-(837) at doses reaching 80 µg (25.6 nmol) (8). In
addition, previous studies showed that intracerebroventricular
injection of CGRP-(837) reversed intracerebroventricular AM-induced
inhibition of food intake and increase in blood pressure at
CGRP-(837)/AM molar ratios of 17:1 and 0.7:1, respectively (29, 30).
Taken together, these results suggest that intracisternal injection of
-CGRP and AM to induce gastric cytoprotection against ethanol are
mediated by specific interactions with their respective receptors.
Gastric protection elicited by AM injected intracisternally does not
seem to be secondary to enhanced emptying of ethanol from the stomach.
A recent study using AM injected intracisternally at a similar dose as
in the present protocol (150 pmol) inhibited gastric emptying of a
liquid meal in conscious rats (16). Therefore, changes in gastric
transit cannot account for the gastric protection against ethanol
injury under the present experimental conditions. It is also unlikely
that the central action of AM is secondary to changes in blood
pressure, because the hypertensive response was reported to occur at
intracerebroventricular or intracisternal doses in the 300-800
pmol range (29), whereas lower doses (88-176 pmol icv) did not
alter mean arterial blood pressure in rats (19). In addition, central
injection of CGRP-(837) reversed the hypertensive response induced by
intracisternal or intracerebroventricular injection of AM (29) while
not altering the cytoprotective effect induced by intracisternal AM
(present observation).
Previous studies indicate that the peripheral mechanisms through which
peptides injected centrally protect the gastric mucosa against ethanol
lesions relate to the autonomic nervous system-dependent changes in the
release of gastric protective factors (12, 13, 33, 35). The protective
role of prostaglandins and endogenous NO against ethanol-induced
gastric injury has been well established (17, 33). There is also
evidence that gastric prostaglandins and NO release are under a
stimulatory vagal cholinergic control (12, 24, 36). In the present
study, subdiaphragmatic vagotomy, blockade of muscarinic receptors by
peripheral injection of atropine, and gastric prostaglandin synthesis
by intraperitoneal injection of indomethacin abolished the protective
effect of intracisternal AM. The observation that
indomethacin blocked the gastric protection induced by intracisternal
AM whereas it did not influence that of intracisternal -CGRP (25)
further supports the contention that peptide actions are initiated by
different receptors. In addition,
L-NAME, injected intravenously
at a dose that inhibits NO synthesis from
L-arginine (18) completely
abolished the cytoprotective effect of AM. The action of
L-NAME was reversed in an
enantiomerically specific manner by
L-arginine, a substratum for NO
synthase, whereas D-arginine was
inactive. In intracisternal vehicle-treated rats, no significant
changes in ethanol-induced gastric injuries were observed after
atropine, indomethacin, or
L-NAME pretreatment as
previously reported in conscious rats (13, 35). Taken together, these
results suggest that intracisternal injection of AM induces vagal
cholinergic activation of the
L-arginine-NO synthase and prostaglandin-dependent protective mechanisms. Other studies showed that intracisternal or intracerebroventricular injection of AM-induced delayed gastric emptying, increased sympathetic outflow, and
hypertensive response are mediated by CGRP receptor-dependent
activation of sympathetic adrenal pathways (16, 29, 30).
The present findings represent the first demonstration of a central
action of AM mediated through AM receptors and vagal-dependent
cholinergic pathways.
The physiological role of CGRP-related peptides in the regulation of
the resistance of the gastric mucosa to injury is still to be
established. The CGRP1 receptor
antagonist injected intracisternally at a dose that blocked exogenous
injection of -CGRP did not influence the development of gastric
lesions induced by 70% ethanol. These results suggest that endogenous
CGRP does not exert a tonic modulation of gastric mucosal resistance
under these conditions of ethanol injury in conscious rats. The lack of
specific AM receptor antagonist precludes the assessment of the role of
brain AM. However, the demonstration of specific binding sites for AM
in rat brain stem by binding and autoradiography studies (20) along
with the presence of AM immunoreactivity in the rat medulla, including
the midline raphe and the dorsal vagal complex (9, 32), support a role at these sites. AM injected intracerebroventricularly at low doses (80-160 pmol) similar to those in the present study inhibits salt appetite, and such biological action of AM was established to have
physiological significance in the central regulation of sodium homeostasis during hypovolemia, as assessed by intracerebroventricular injection of AM antibody (23). Whether AM may increase the resistance of the gastric mucosa through autonomic modulation of defensive mechanisms under pathophysiological conditions associated with the
central release of this peptide (31) remains to be established.
In summary, the present data indicate that intracisternal AM and
-CGRP injected at picomole doses act in the brain to protect the
gastric mucosa against ethanol injury in conscious rats. Results obtained with the CGRP1 receptor
antagonist CGRP-(837) injected intracisternally indicate that the
central action of -CGRP is mediated by an interaction with
CGRP receptors, whereas that of AM is unrelated to the cross talk of AM
with the CGRP1 receptor. The
central action of AM appears to be mediated through modulation of vagal
cholinergic-dependent protective mechanisms involving prostaglandins
and NO. This represents the first demonstration of a central action of
AM mediated through autonomic vagal pathways and unrelated to
interaction with central CGRP receptors.
Perspectives
The present results indicate that low doses of AM injected
intracisternally act through central AM receptors to elicit a vagal cholinergic activation of prostaglandins and NO-dependent protective mechanisms against ethanol-induced gastric injury in conscious rats.
Medullary TRH was previously established to protect the gastric mucosa
against ethanol injury through similar vagal cholinergic activation of
prostaglandin E2 and NO protective
mechanisms (12, 27, 28, 35, 36). Whether AM action is mediated by
modulating the release of TRH contained in nerve terminals synapsing on
neurons of the dorsal motor nucleus of the vagus (26) needs to be
investigated further. In vitro single-unit recording demonstrated a
direct excitatory effect of AM on area postrema neurons (2), which are
known to project to the caudal dorsal vagal complex (5). Mapping
studies will be required to localize the brain stem site(s) at which AM
acts to induce vagal cholinergic-dependent gastric cytoprotection.
| |
ACKNOWLEDGEMENTS |
P. Kirsch is acknowledged for helping in the preparation of the
manuscript.
| |
FOOTNOTES |
This study was supported by the Grant-in-Aid for Encouragement of Young
Scientists 07770402 (H. Kaneko); a Grant-in Aid for Scientific Research
(C) 09670586 (H. Kaneko, T. Mitsuma, and S. Mori) from the Ministry of
Education, Science, Sports and Culture, Japan; the National Institute
of Mental Health, Grant MH-00663 (Y. Taché); and the National
Institute of Diabetes and Digestive and Kidney Diseases, Grant DK-30110
(Y. Taché).
Address for reprint requests: H. Kaneko, Fourth Dept. of Internal
Medicine, Aichi Medical Univ., 21 Karimata, Yazako, Nagakute, Aichi-gun
480-1195, Japan.
Received 17 November 1997; accepted in final form 18 February
1998.
| |
REFERENCES |
1.
Aiyar, N.,
K. Rand,
N. A. Elshourbagy,
Z. Zeng,
J. E. Adamou,
D. J. Bergsma,
and
Y. Li.
A cDNA encoding the calcitonin gene-related peptide type 1 receptor.
J. Biol. Chem.
271:
11325-11329,
1996[Abstract/Free Full Text].
2.
Allen, M. A.,
and
A. V. Ferguson.
In vitro recordings from area postrema neurons demonstrate responsiveness to adrenomedullin.
Am. J. Physiol.
270 (Regulatory Integrative Comp. Physiol. 39):
R920-R925,
1996[Abstract/Free Full Text].
3.
Allen, M. A.,
P. M. Smith,
and
A. V. Ferguson.
Adrenomedullin microinjected into the area postrema increases blood pressure.
Am. J. Physiol.
272 (Regulatory Integrative Comp. Physiol. 41):
R1698-R1703,
1997[Abstract/Free Full Text].
4.
Banks, W. A.,
and
A. J. Kastin.
Passage of peptides across the blood-brain barrier: pathophysiological perspectives.
Life Sci.
59:
1923-1943,
1996[Medline].
5.
Cunningham, E. T.,
R. R. Miselis,
and
P. E. Sawchenko.
The relationship of efferent projections from the area postrema to vagal motor and brain stem catecholamine-containing cell groups: an axonal transport and immunohistochemical study in the rat.
Neuroscience
58:
635-648,
1994[Medline].
6.
Hanze, J.,
K. Dittrich,
J. Dotsch,
and
W. Rascher.
Molecular cloning of a novel human receptor with homology to the rat adrenomedullin receptor and high expression in heart and immune system.
Biochem. Biophys. Res. Commun.
240:
183-188,
1997[Medline].
7.
Haynes, J. M.,
and
M. E. Cooper.
Adrenomedullin and calcitonin gene-related peptide in the rat isolated kidney and in the anaesthetized rat: in vitro and in vivo effects.
Eur. J. Pharmacol.
280:
91-94,
1995[Medline].
8.
Jolicoeur, F. B.,
D. Menard,
A. Fournier,
and
S. St-Pierre.
Structure-activity analysis of CGRP's neurobehavioral effects.
Ann. NY Acad. Sci.
657:
155-163,
1992[Medline].
9.
Kaneko, H.,
N. Rhue,
S. Nagai,
K. Mori,
C. Yamagushi,
Y. Taché,
and
T. Mitsuma.
Central distribution and action of adrenomedullin (AD) to induce gastric protection against ethanol in rats (Abstract).
Gastroenterology
110:
A1087,
1996.
10.
Kapas, S.,
K. J. Catt,
and
A. J. L. Clark.
Cloning and expression of cDNA encoding a rat adrenomedullin receptor.
J. Biol. Chem.
270:
25344-25347,
1995[Abstract/Free Full Text].
11.
Kapas, S.,
and
A. J. L. Clark.
Identification of an orphan receptor gene as a type 1 calcitonin gene-related peptide receptor.
Biochem. Biophys. Res. Commun.
217:
832-838,
1995[Medline].
12.
Kato, K.,
H. Yang,
and
Y. Taché.
Low doses of TRH analogue act in the dorsal motor nucleus to induce gastric protection in rats.
Am. J. Physiol.
269 (Regulatory Integrative Comp. Physiol. 38):
R1301-R1307,
1995[Abstract/Free Full Text].
13.
Király, A.,
G. Sütö,
and
Y. Taché.
Role of nitric oxide in the gastric cytoprotection induced by central vagal stimulation.
Eur. J. Pharmacol.
240:
299-301,
1993[Medline].
14.
Kitamura, K.,
K. Kangawa,
H. Matsuo,
and
T. Eto.
Adrenomedullin implication for hypertension research.
Drugs
49:
485-495,
1995[Medline].
15.
Maggi, C. A.,
S. Evangelista,
S. Giuliani,
and
A. Meli.
Antiulcer activity of calcitonin gene-related peptide in rats.
Gen. Pharmacol.
18:
33-34,
1987[Medline].
16.
Martinez, V.,
F. Cuttitta,
and
Y. Taché.
Central action of adrenomedullin to inhibit gastric emptying in rats.
Endocrinology
138:
3749-3755,
1997[Abstract/Free Full Text].
17.
Masuda, E.,
S. Kawano,
K. Nagano,
S. Tsuji,
Y. Takei,
M. Tsujii,
M. Oshita,
T. Michida,
I. Kobayashi,
A. Nakama,
H. Fusamoto,
and
T. Kamada.
Endogenous nitric oxide modulates ethanol-induced gastric mucosal injury in rats.
Gastroenterology
108:
58-64,
1995[Medline].
18.
Moncada, S.,
R. M. J. Palmer,
and
E. A. Higgs.
Nitric oxide: physiology, pathophysiology, and pharmacology.
Pharmacol. Rev.
43:
109-142,
1991[Medline].
19.
Murphy, T. C.,
and
W. K. Samson.
The novel vasoactive hormone, adrenomedullin, inhibits water drinking in the rat.
Endocrinology
136:
2459-2463,
1995[Abstract].
20.
Owji, A. A.,
D. M. Smith,
H. A. Coppock,
D. G. A. Morgan,
R. Bhogal,
M. A. Ghatei,
and
S. R. Bloom.
An abundant and specific binding site for the novel vasodilator adrenomedullin in the rat.
Endocrinology
136:
2127-2134,
1995[Abstract].
21.
Richards, A. M.,
M. G. Nicholls,
L. Lewis,
and
J. G. Lainchbury.
Adrenomedullin.
Clin. Sci. (Colch.)
91:
3-16,
1996[Medline].
22.
Sakata, J.,
T. Shimokubo,
K. Kitamura,
S. Nakamura,
K. Kangawa,
H. Matsuo,
and
T. Eto.
Molecular cloning and biological activities of rat adrenomedullin, a hypotensive peptide.
Biochem. Biophys. Res. Commun.
195:
921-927,
1993[Medline].
23.
Samson, W. K.,
and
T. C. Murphy.
Adrenomedullin inhibits salt appetite.
Endocrinology
138:
613-616,
1997[Abstract/Free Full Text].
24.
Saperas, E.,
M. Mourelle,
J. Santos,
S. Moncada,
and
J. R. Malagelada.
Central vagal activation by an analogue of TRH stimulates gastric nitric oxide release in rats.
Am. J. Physiol.
268 (Gastrointest. Liver Physiol. 31):
G895-G899,
1995[Abstract/Free Full Text].
25.
Taché, Y.
Intracisternal injection of calcitonin-gene related peptide inhibits experimental gastric ulcers.
In: Mechanisms of Injury, Protection and Repair of the Upper Gastrointestinal Tract, edited by A. Garner,
and P. E. O'Brien. Chichester, UK: Wiley, 1991, p. 383-393.
26.
Taché, Y.,
H. Yang,
and
H. Kaneko.
Caudal raphe-dorsal vagal complex peptidergic projections: role in gastric vagal control.
Peptides
16:
431-435,
1995[Medline].
27.
Taché, Y., and M. Yoneda. Central action of TRH to
induce vagally mediated gastric cytoprotection and ulcer formation in
rats. J. Clin. Gastroenterol. 17, Suppl. 1: S58-S63, 1993.
28.
Taché, Y., M. Yoneda, K. Kato, A. Király, G. Sütö, and H. Kaneko. Intracisternal
thyrotropin-releasing hormone-induced vagally mediated gastric
protection against ethanol lesions: central and peripheral mechanisms.
J. Gastroenterol. Hepatol. 9, Suppl. 1:
S29-S35, 1994.
29.
Takahashi, H.,
T. X. Watanabe,
M. Nishimura,
T. Nakanishi,
M. Sakamoto,
M. Yoshimura,
Y. Komiyama,
M. Masuda,
and
T. Murakami.
Centrally induced vasopressor and sympathetic responses to a novel endogenous peptide, adrenomedullin, in anesthetized rats.
Am. J. Hypertens.
7:
478-482,
1994[Medline].
30.
Taylor, G. M.,
K. Meeran,
D. O'Shea,
D. M. Smith,
M. A. Ghatei,
and
S. R. Bloom.
Adrenomedullin inhibits feeding in the rat by a mechanism involving calcitonin gene-related peptide receptors.
Endocrinology
137:
3260-3264,
1996[Abstract].
31.
Wang, X.,
T. L. Yue,
F. C. Barone,
R. F. White,
R. K. Clark,
R. N. Willette,
A. C. Sulpizio,
N. V. Aiyar,
R. R. Ruffolo,
and
G. Z. Feuerstein.
Discovery of adrenomedullin in rat ischemic cortex and evidence for its role in exacerbating focal brain ischemic damage.
Proc. Natl. Acad. Sci. USA
92:
11480-11484,
1995[Abstract/Free Full Text].
32.
Wei, Y. J.,
Q. H. Li,
D. Zhao,
Z. Zhang,
R. He,
and
J. Tang.
The central distribution of adrenomedullin and its effects on blood pressure and heart rate in rats.
Chin. Med. Sci. J.
11:
1-7,
1996[Medline].
33.
Whittle, B. J. R.,
J. Lopez-Belmonte,
and
S. Moncada.
Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with prostanoids and sensory neuropeptides in the rat.
Br. J. Pharmacol.
99:
607-611,
1990[Medline].
34.
Wimalawansa, S. J.
Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily.
Crit. Rev. Neurobiol.
11:
167-239,
1997[Medline].
35.
Yoneda, M.,
and
Y. Taché.
Central thyrotropin-releasing factor analog prevents ethanol-induced gastric damage through prostaglandins in rats.
Gastroenterology
102:
1568-1574,
1992[Medline].
36.
Yoneda, M.,
and
Y. Taché.
Vagal regulation of gastric prostaglandin E2 release by central TRH in rats.
Am. J. Physiol.
264 (Gastrointest. Liver Physiol. 27):
G231-G236,
1993[Abstract/Free Full Text].
37.
Zimmermann, U.,
J. A. Fischer,
and
R. Muff.
Adrenomedullin and calcitonin gene-related peptide interact with the same receptor in cultured human neuroblastoma SK-N-MC cells.
Peptides
16:
421-424,
1995[Medline].
Am J Physiol Regul Integr Compar Physiol 274(6):R1783-R1788
0002-9513/98 $5.00
Copyright © 1998 the American Physiological Society
Top
Abstract
Introduction
