1 CURE: Digestive Diseases
Research Center, Corticotropin-releasing factor (CRF)-related
peptides exhibit different affinity for the receptor subtypes 1 and 2 cloned in the rat brain. We investigated, in conscious rats, the
effects of intracisternal (IC) injection of CRF (rat/human) on the 5-h rate of gastric emptying of a solid nutrient meal (Purina chow and
water ad libitum for 3 h) and the CRF receptor subtype involved. CRF,
urotensin I (suckerfish), and sauvagine (frog) injected IC inhibited
gastric emptying in a dose-dependent manner, with
ED50 values of 0.31, 0.13, and
0.08 µg/rat, respectively. Rat CRF-(6
corticotropin-releasing factor; sauvagine; urotensin I; astressin; NBI-27914; CRF-(6 CORTICOTROPIN-RELEASING FACTOR (CRF) is one of the key
mediators involved in stress-related endocrine, immune, visceral, and behavioral responses (9, 26, 38). Substantial evidence shows that brain
CRF receptors play a role in the alterations of gastrointestinal motor
function induced by stress (37). Central injection of CRF inhibits
gastric emptying of a nonnutrient solution through autonomic pathways,
independent of the stimulation of pituitary secretion in conscious rats
and mice (2, 7, 18, 21, 24, 31, 36, 37, 39). In addition, CRF receptor antagonists injected into the cerebrospinal fluid or the
paraventricular nucleus of the hypothalamus prevent the delay in
gastric emptying of a liquid nonnutrient solution induced by
concomitant injection of CRF or exposure to various stressors (surgery,
ether, restraint, immune challenge, forced swimming) in rats (1, 7, 19, 21, 24, 34, 35, 37).
However, existing reports on the inhibitory influence of CRF injected
centrally on gastric transit relate mainly to the gastric emptying of a
small volume of nonnutrient liquid markers delivered intragastrically
in rats or mice (2, 18, 21, 24, 31, 36, 37, 39). A few reports indicate
that CRF injected into the fourth or lateral brain ventricle delays
gastric emptying of a nutrient solution (D-glucose,
peptone) infused intragastrically in non-food-deprived (32) or fasted
rats (7). By contrast, in mice, CRF injected into the lateral brain
ventricle stimulates the gastric emptying of a caloric test meal
(reconstituted milk delivered intragastrically). The central action of
CRF to influence gastric emptying of an ingested physiological meal is
not known in rats.
CRF mediates its actions through interaction with specific,
high-affinity membrane-bound receptors that are coupled to a guanine nucleotide stimulatory factor
(Gs) signaling protein,
resulting in increased intracellular cAMP levels (5, 27, 38). To date,
two distinct CRF receptor subtypes,
CRF1 and
CRF2, have been cloned and
characterized from rat and human brains (5, 20, 27). Receptor subtypes
show an overall 71% identity and differential pharmacological and
anatomic profiles, indicative of distinct functional roles (4, 20).
Binding constants in transfected cells indicate that rat/human CRF
(r/hCRF) exhibits a higher affinity for the
CRF1 receptor compared with the
CRF2 subtype (5, 11, 20). By
contrast, CRF-related peptides sharing 40-50% structure homology
with CRF, namely, sauvagine, a 40-amino acid peptide isolated from
Phyllomedusa sauvagei amphibian skin,
and urotensin I, a 41-residue peptide isolated from teleost fish,
display a higher affinity for the
CRF2 receptor than CRF, while
having a similar affinity for the
CRF1 subtype (5, 11, 20). The
CRF1 receptor is the predominant
form localized in the pituitary, olfactory bulb, and cerebral cortex,
whereas the CRF2 subtype
predominates in the lateral septum, hypothalamus, amygdala, and brain
stem (4, 5, 20).
Recent investigations focused on achieving conformational stability for
CRF antagonists resulted in the development of astressin, cyclo(30 In the present study, we investigated
1) the effect of central injection
of CRF on the gastric emptying of a physiological meal (ingestion of
solid Purina chow) in conscious rats and
2) the CRF receptor subtype
subserving IC CRF-induced inhibition of gastric emptying of a solid
meal. To determine the pharmacological characteristics of the CRF
receptors involved, we compared the potency profiles of r/hCRF with the
nonmammalian CRF-related peptides sauvagine and urotensin I. We also
tested the specificity of the response by using the middle fragment
r/hCRF-(6 Animals.
Adult male Sprague-Dawley rats (Harlan, San Diego, CA) weighing
280-320 g were maintained on a 12:12-h light-dark cycle with controlled temperature (21-23°C). Animals were housed in group cages with free access to food (Purina rat chow) and tap water. All
experiments were performed in rats fasted 18-20 h, with free access to water.
Drugs and treatments.
The following peptides were synthesized and purified as previously
described (12): r/hCRF, amphibian sauvagine, suckerfish urotensin I,
r/hCRF-(6
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
33) (0.1-10 µg ic) had
no effect. The nonselective CRF1
and CRF2 receptor antagonist,
astressin, injected IC completely blocked the inhibitory effect of IC CRF, urotensin I, and sauvagine with antagonist-to-agonist ratios of 3:1, 10:1, and 16:1, respectively. The
CRF1-selective receptor antagonist
NBI-27914 injected IC at a ratio of 170:1 had no effect. These data
show that central CRF and CRF-related peptides are potent inhibitors of
gastric emptying of a solid meal with a rank order of potency
characteristic of the CRF2
receptor subtype affinity (sauvagine > urotensin I > CRF). In
addition, the reversal by astressin but not by the
CRF1-selective receptor antagonist
further supports the view that the
CRF2 receptor subtype is primarily
involved in central CRF-induced delayed gastric emptying.
33); CRF antagonists; brain
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
33)-[D-Phe12,Nle21,38,
Glu30,Lys33]r/hCRF-(12
41)
(12, 23), which has low intrinsic activity, high solubility in aqueous
solutions, and high affinity for both CRF1 and
CRF2 receptor subtypes, although
it is devoid of affinity for the CRF binding protein (12). Astressin
displays ~32- and ~100-fold higher potency than
[D-Phe12,Nle21,38]r/hCRF-(12
41)
and
-helical CRF-(12
41), respectively, to inhibit ACTH secretion
from pituitary cells in culture (12, 23). Moreover, after peripheral
administration in rats, astressin is 10-fold more potent than any other
CRF antagonists reported to date to inhibit stress-induced increases in
ACTH plasma levels (12). Astressin injected intracisternally
(IC) is also more potent to antagonize central CRF-induced delayed
gastric emptying of a nonnutrient solution in rats (21). Several lines
of evidence indicate that CRF-induced pituitary ACTH secretion and
anxiogenic behavior are mediated by the activation of the
CRF1 receptor (6, 30, 38). However, the CRF receptor subtype that underlies the autonomic nervous
system-mediated changes in gastric emptying is not known.
33), which is devoid of intrinsic activity at both CRF
receptor subtypes (11, 33). In addition, we examined the antagonist
action of astressin, the potent
CRF1/CRF2
receptor antagonist (12), and NBI-27914, a nonpeptide
CRF1-selective receptor antagonist
(6), against inhibition of gastric emptying induced by CRF-related
peptides.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
33)-OH, and
cyclo(30
33)-[D-Phe12,Nle21,38,Glu30,Lys33]r/hCRF-(12
41)
(astressin) (Salk Institute, Clayton Foundation Laboratories for
Peptide Biology, La Jolla, CA). Peptides were kept in powder form at
70°C, and, immediately before use, CRF and its related
peptides were dissolved in sterile saline, and astressin was dissolved
in double-distilled water (adjusted to pH 7.0, warmed to 37°C). The
nonpeptide CRF1-selective receptor antagonist NBI-27914 (Neurocrine Biosciences, San Diego, CA) was synthesized as a tosylate salt as previously described (6). Before use,
NBI-27914 was dissolved in 100% DMSO, and 100% DMSO served as the
control vehicle.
Gastric emptying of a nutrient solid meal.
The gastric emptying of a nutrient solid meal was measured with
modifications of the method originally described by Robert et al. (29).
Fasted rats had free access to water and preweighed Purina chow for a
3-h period. Food and water were then removed, and gastric emptying of
the ingested meal was assessed 5 h later. Animals were euthanized by
CO2 inhalation followed by
thoracotomy. The abdominal cavity was opened, the pylorus and cardias
were clamped, and the stomach was removed. The stomach was weighed and
then opened, and the gastric contents were washed out with tap water.
The gastric wall was dried and weighed. The amount (g) of food
contained in the stomach was estimated as the difference between the
total weight of the stomach plus the content and the weight of the
stomach after the content was removed. The solid food ingested by the
animals was determined by the difference between the weight of the
Purina chow before feeding and the weight of the pellet and spill at
the end of the 3-h feeding period. The rate of gastric emptying during
the 5-h experimental time was calculated according to the following
equation: gastric emptying (% in 5 h) = (1 gastric
content/food intake) × 100.
Experimental protocols.
All experiments were started between 7:30 AM and 8:00 AM in rats fasted
for 18-20 h. Rats were given preweighed Purina chow and water ad
libitum for a 3-h period. Then food and water were removed, and under
short enflurane anesthesia, rats were injected IC with either saline
(10 µl), CRF (0.1, 0.3, and 1 µg/rat in 10 µl), sauvagine (0.03, 0.1, 0.3, or 1 µg/rat in 10 µl), urotensin I (0.03, 0.1, 0.3, or 1 µg/rat in 10 µl), or CRF-(633) (0.3, 1, or 10 µg/rat in 10 µl). In a second experiment, rats were injected IC with either
vehicle (water or DMSO, 5 µl/rat), astressin (1, 1.5, 3, or 5 µg/rat in 5 µl), or NBI-27914 (50 µg/rat in 5 µl). Immediately
afterward, the rats were injected with either vehicle (5 µl saline),
CRF (0.3 or 1 µg/rat in 5 µl), sauvagine (0.3 or 1 µg/rat in 5 µl), or urotensin I (0.3 µg/rat in 5 µl). In each daily
experiment, a control and several doses of peptides were included and
repeated on multiple days. The doses of astressin were based on the
previous antagonistic action of the peptide injected IC against CRF- or
stress-induced inhibition of gastric emptying of a nonnutrient solution
(21). The dose of NBI-27914 used corresponds to the highest effective
dose tested using other peptide CRF antagonists, to prevent CRF- or
abdominal surgery-induced delay of gastric emptying (35).
Statistical Analysis
Results are expressed as means ± SE. Comparisons between groups were performed using one-way analysis of variance (ANOVA) followed by a Student-Newman-Keuls multiple-comparisons test. P values <0.05 were considered statistically significant. ED50, defined as the dose of peptide that induced 50% inhibition of gastric emptying compared with the rate of emptying in vehicle-treated rats (taken as 0% inhibition), was determined by nonlinear regression to a sigmoidal equation with variable slope (Prism, version 2.0; GraphPad, San Diego, CA). ![]() |
RESULTS |
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During the 3-h feeding period after an 18-h fast, rats ate 6.46 ± 0.10 g of Purina chow. The rate of gastric emptying of the food ingested was 61.8 ± 3.8% (n = 8) as measured at 5 h after the end of the feeding period in control rats (nontreated group). Saline, injected IC under short enflurane anesthesia at the end of the feeding period, did not significantly modify gastric emptying of food ingested (53.1 ± 4.6%, n = 12, P > 0.05).
Effect of Intracisternal CRF and CRF-Related Peptides on Gastric Emptying of a Solid Nutrient Meal
r/hCRF injected IC (0.1, 0.3, and 1 µg) dose dependently inhibited gastric emptying of the solid nutrient meal to 49.8 ± 6.1%, (n = 5, P > 0.05), 26.2 ± 8.8% (n = 6, P < 0.05), and 6.7 ± 5.5% (n = 6, P < 0.05), respectively (F4,32 = 14.686, P < 0.05; Fig. 1).
|
The CRF-related peptides, suckerfish urotensin I and amphibian sauvagine, also inhibited gastric emptying of the solid nutrient meal in a dose-dependent manner. Urotensin I injected IC had no significant effect at 0.03 µg (49.5 ± 5.5%), whereas at 0.1 and 0.3 µg urotensin I decreased gastric emptying to 33.1 ± 7.5% and 8.5 ± 4.2%, respectively (F5,36 = 15.44, P < 0.05, n = 5 for each dose; Fig. 1). There was no additional inhibitory effect at a higher dose (1 µg) of urotensin I (Fig. 1). Sauvagine, injected IC at 0.03, 0.1, and 0.3 µg/rat, decreased the 5-h rate of gastric emptying to 42.1 ± 8.3% (P > 0.05), 20.4 ± 7.7% (P < 0.05), and 11.6 ± 5.3% (P < 0.05), respectively (n = 4-5 for each dose, Fig. 1). At a dose of 1 µg, sauvagine completely suppressed gastric emptying for the 5-h experimental period (Fig. 1). Based on ED50 values calculated from nonlinear regression analysis of the dose-response curves, the rank order of potency to inhibit gastric emptying of the solid meal was sauvagine > urotensin I > CRF (Table 1).
|
The midsequence CRF analog, r/hCRF-(633) (0.3-10 µg ic), did
not significantly influence the 5-h percentage of gastric emptying (0.3 µg, 44.1 ± 3.0%, n = 4; 1 µg,
59.9 ± 4.1%, n = 5; 10 µg, 66.3 ± 4.0%, n = 5) compared with the
vehicle-treated group (53.1 ± 4.6%,
n = 12;
F4,22 = 2.94, P = 0.05681).
Effect of Intracisternal Astressin on Inhibition of Gastric Emptying of a Solid Nutrient Meal Induced by Intracisternal CRF and CRF-Related Peptide
In animals injected with vehicle (5 µl ic distilled water + 5 µl ic saline), 53.5 ± 4.0% (n = 8) of the meal had emptied from the stomach after 5 h. The basal rate of emptying was not significantly modified by astressin (3 or 5 µg) followed by the injection of saline (44.5 ± 3.5%, n = 6; and 53.3 ± 4.3%, n = 5, respectively). The antagonist-to-agonist ratios required for IC injection of astressin to completely block IC CRF-, urotensin I-, and sauvagine-induced inhibition of gastric emptying of a solid meal were 3:1, 10:1, and 16:1, respectively (Fig. 2). The inhibition of emptying of a solid meal induced by 0.3 µg CRF injected IC (23.5 ± 7.3%, n = 4) was completely prevented by astressin at 1 and 3 µg as values reached 40.2 ± 5.7% and 47.7 ± 4.7%, respectively (n = 4-5 per group, P > 0.05 compared with astressin alone or vehicle) (Fig. 2). A similar antagonist-to-agonist ratio of 3:1 was observed when CRF was injected IC at 1 µg, which reduced the rate of emptying to 12.9 ± 6.6% (n = 6). IC injection of astressin completely prevented the CRF (1 µg) inhibitory effect when injected at a dose of 3 µg (gastric emptying, 51.5 ± 10.5%, n = 5) but had no effect when injected at a dose of 1 µg (ratio 1:1) (17.4 ± 6.0%, n = 4) (Fig. 2).
|
Inhibition of gastric emptying induced by urotensin I injected IC at 0.3 µg (14.2 ± 5.7%, n = 6) was partially blocked by 1.5 µg astressin (ratio 5:1; 23.4 ± 7.4%, n = 5) and completely prevented by 3 µg astressin (ratio 10:1, 52.0 ± 5.5%, n = 4, Fig. 2). Sauvagine (0.3 µg ic) inhibited gastric emptying to 18.6 ± 6.1% (n = 5). Astressin at 3 µg (ratio 10:1) partly blocked the sauvagine effect (30.7 ± 15.9%, n = 4) and completely prevented it when injected at 5 µg (ratio 16:1) (49.4 ± 4.3%, n = 5, Fig. 2).
Effect of Intracisternal NBI-27914 on Inhibition of Gastric Emptying of a Solid Nutrient Meal Induced by Intracisternal CRF and CRF-Related Peptide
In animals injected with vehicle (5 µl DMSO + 5 µl saline, ic), the 5-h rate of gastric emptying was 52.0 ± 3.8% (n = 6). The basal rate of emptying was not significantly modified by NBI-27914 (50 µg), followed by the injection of vehicle (Table 2). Injection of NBI-27914 (50 µg/rat ic) immediately before peptide administration at a low dose (0.3 µg/rat) did not modify CRF-, sauvagine-, or urotensin I-induced inhibition of gastric emptying of a solid meal (Table 2).
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![]() |
DISCUSSION |
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Rats fasted for 18-20 h and given access to Purina chow and water
ad libitum ingested 6.46 ± 0.10 g of food within the 3-h period, of
which 62% was emptied from the stomach after 5 h. r/hCRF and the
CRF-related peptides, amphibian sauvagine and suckerfish urotensin I,
injected into the cisterna magna in picomolar amounts, dose dependently
inhibited the gastric emptying of the solid nutrient meal. By contrast,
the CRF analogs, r/hCRF-(633) or
cyclo(30
33)-[D-Phe12,Nle21,38,Glu30,Lys33]r/hCRF-(12
41)
(astressin) injected IC at similar or higher doses, as well as IC
injection of vehicle, did not influence the rate of gastric emptying
compared with the nontreated control group. These results show the
specificity of the inhibitory action induced by r/hCRF and the
nonmammalian CRF-related peptides, urotensin I and sauvagine. Previous
studies showed that r/hCRF injected into the cerebrospinal fluid
inhibited gastric emptying of an intragastrically delivered noncaloric
(2, 15, 18, 21, 36, 37, 39) or caloric solution (7, 32) in rats.
Broccardo and Improta (2) and Improta (15) also reported that sauvagine and urotensin I injected into the lateral brain ventricle delayed gastric emptying of a nonnutrient solution. These data, together with
the present results, establish CRF and nonmammalian CRF-related peptides as potent inhibitors of gastric emptying in rats, irrespective of the nature of the meal (caloric liquid or solid, or noncaloric liquid or viscous). Likewise, in the dog, intracerebroventricular injection of CRF delayed the total gastric emptying time of a solid
meal (17).
A recent study indicates that there is an active carrier-mediated brain-to-blood transport of CRF (22). However, several control experiments established that the inhibition of gastric emptying of a liquid meal induced by IC injection of CRF reflects a central nervous system-mediated action (37). Therefore it is likely that the long-lasting inhibition of gastric emptying of a solid meal induced by CRF, sauvagine, and urotensin I injected into the cisterna magna at picomolar amounts reflects an action initiated in the central nervous system. The site of action of CRF injected into the cisterna magna may involve the dorsal vagal complex. Microinjection of CRF at this site, as opposed to nearby nuclei, mimicked the effect of IC injection by suppressing central vagal stimulation of gastric motility in anesthetized rats (10, 14). In addition, the inhibitory effect of central CRF and sauvagine on gastric emptying is dependent on the vagus (2, 36).
CRF mediates its effects in the brain through interaction with
high-affinity CRF1 and
CRF2 receptor subtypes. Convergent
sets of evidence are consistent with the involvement of the
CRF2 receptor subtype in IC
CRF-induced delay in gastric emptying of a solid meal. The potency
order of IC CRF and the nonmammalian CRF-related peptides to inhibit
gastric emptying of a solid meal exhibits a characteristic profile
similar to that defined for the
CRF2 subtype (sauvagine > urotensin I > r/hCRF), unlike that expected for
CRF1 receptor (r/hCRF urotensin
I
sauvagine) (5). The ED50
values, defined as the molar dose necessary to inhibit the 5-h rate of
gastric emptying by 50%, were ~17 pmol for sauvagine and 26 pmol for
urotensin I, values ~3.8-fold and ~2.5-fold lower, respectively,
than the r/hCRF ED50 (65 pmol).
Consistent with these observations, the 20-min rate of gastric emptying
of a nonnutrient liquid meal was inhibited with a similar rank
order of potency (sauvagine > urotensin I > CRF) when peptides were
injected into the lateral brain ventricle in rats (2, 15).
Recently, several novel molecules with antagonist activity to CRF
receptors have been described (6, 12, 30). Astressin, a CRF-derived
antagonist, exhibits equally high affinity at both the
CRF1 and
CRF2 receptor subtypes and greater
in vitro and in vivo potency than the previously developed antagonists,
-helical CRF-(9
41) and
[D-Phe12,Nle21,38]r/hCRF-(12
41)
(12). In addition, nonpeptide CRF receptor antagonists have also been
developed (6, 30); among them, NBI-27914 exhibits high
CRF1-selective antagonist action
(6). IC injection of astressin at doses of 3-5 µg/rat, which by
themselves had no effect on the basal rate of gastric emptying,
completely blocked CRF, sauvagine, and urotensin I inhibitory action at
antagonist-to-agonist ratios (µg) of 3:1, 10:1, and 16:1
respectively. The higher IC antagonist-to-agonist ratio needed to block
sauvagine compared with CRF is in line with the higher affinity of
sauvagine on CRF2 receptors
compared with CRF (5). We previously reported that similar doses of
astressin injected IC antagonized IC CRF-induced delay of gastric
emptying of a noncaloric viscous solution at an antagonist-to-agonist
ratio of 5:1 in rats (21). By contrast, NBI-27914 injected IC at 50 µg, the higher effective dose determined for other CRF antagonists
(35), did not modify CRF- or CRF-related peptide-induced inhibition of
gastric emptying. It is unlikely that the lack of action of the
NBI-27914 is related to the use of a subeffective treatment. In cells
stably transfected with the CRF1
receptor, astressin and NBI-27914 shared similar affinity (Ki in the 2 nM
range) to inhibit CRF binding (6, 12). In the present study, NBI-27914
was injected IC at an antagonist-to-agonist ratio (µg) of 167:1,
which is 330-fold higher on a molar basis than the effective ratio for
astressin and CRF. Because NBI-27914 is devoid of activity in cells
transfected with the CRF2 receptor subtype, whereas astressin displays a similar affinity for both receptor subtypes (6, 12), these results further support the view that
peptide interaction with the CRF2
receptor subtype is likely to mediate the central CRF action to inhibit
gastric motor function.
The pituitary response to CRF involved an interaction with the CRF1 receptor subtype, as shown by the equal potency of CRF, sauvagine, and urotensin I to stimulate in vitro and in vivo pituitary ACTH release, which are blocked by both NBI-27914 and astressin (6, 28, 38). The lack of influence of the specific CRF1 receptor antagonist on gastric stasis is consistent with previous reports indicating that the inhibition of gastric emptying induced by central CRF administration is mediated through autonomic vagal pathways and is independent from its pituitary action in rats and dogs (2, 7, 17, 37). Interestingly, sauvagine injected into the lateral ventricle was reported to be 5- to 10-fold more potent than CRF to induce an autonomic nervous system-mediated increase in plasma catecholamine and glucose levels, elevation of mean arterial pressure and thermogenesis from brown adipose tissue, and a decrease in gastric vagal efferent discharges in rats (3, 16, Kosoyan and Taché, unpublished observations). These data suggest that autonomic-dependent gastrointestinal, cardiovascular, and thermogenic responses to central CRF and CRF-related peptides may be primarily mediated by the activation of brain CRF2 receptors. This is also supported by the presence of CRF2 receptors in the hypothalamus, amygdala, lateral septum, and brain stem (4, 20), which contain autonomic regulatory centers (i.e., paraventricular nucleus of the hypothalamus and dorsal vagal complex) that are target sites of action of CRF-induced inhibition of gastric motor function (24, 25, 37).
Central injection of the CRF receptor antagonists -helical
CRF-(9
41),
[D-Phe12,Nle21,38]r/hCRF-(12
41),
or astressin (12, 13) prevented gastric stasis induced by various
stressors (7, 19, 21, 34, 37). By contrast, the CRF receptor
antagonists did not influence the basal rate of gastric emptying of a
liquid meal (37). Likewise, astressin injected IC at doses sufficient
to antagonize central CRF did not alter gastric emptying of a solid
nutrient meal. These data suggest that brain stem CRF receptors are not
involved in postprandial regulation of gastric emptying, at least under
nonstress conditions.
In conclusion, IC CRF and its related nonmammalian peptides, amphibian sauvagine and suckerfish urotensin I, dose dependently inhibit gastric emptying of a physiological meal in rats. The rank order of potency of the peptides (sauvagine > urotensin I > r/hCRF) to inhibit gastric emptying of a solid nutrient meal is consistent with the profile characterized in vitro for activation of the CRF2 receptor subtype, rather than the CRF1 receptor subtype. This assumption is further supported by the complete blockade of IC CRF-, sauvagine-, and urotensin I-induced delay of gastric emptying by the CRF1/CRF2 receptor antagonist, astressin, whereas the CRF1-selective receptor antagonist, NBI-27914, had no effect.
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ACKNOWLEDGEMENTS |
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We thank Dr. E. B. De Souza and Dr. J. R. McCarthy (Neurocrine Biosciences, San Diego, CA) for the generous donation of NBI-27914. P. Kirsch is acknowledged for help in the preparation of the manuscript.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-33061 (Y. Taché) and DK-26741 (J. Rivier) and by National Institute of Mental Health Grant MH-00663 (Y. Taché).
Address for reprint requests: Y. Taché, CURE: Digestive Diseases Research Ctr., West Los Angeles Veterans Affairs Medical Ctr., Bldg. 115, Rm. 203, 11301 Wilshire Blvd., Los Angeles, CA 90073.
Received 20 August 1997; accepted in final form 29 January 1998.
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