1 Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University and 2 Department of Endoscopic Diagnostics and Therapeutics, Kyushu University Hospital, Fukuoka 812-8582, Japan
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Epidermal growth factor
(EGF) has been shown to exert gastric hyperemic and gastroprotective
effects via capsaicin-sensitive afferent neurons, including the release
of calcitonin gene-related peptide (CGRP). We examined the protective
and vasodilatory effects of EGF on the gastric mucosa and its
interaction with sensory nerves, CGRP, and nitric oxide (NO) in
anesthetized rats. Intragastric EGF (10 or 30 µg) significantly
reduced gastric mucosal lesions induced by intragastric 60% ethanol
(50.6% by 10 µg EGF and 70.0% by 30 µg EGF). The protective
effect of EGF was significantly inhibited by pretreatment with
capsaicin desensitization, human CGRP1 antagonist
hCGRP-(8-37), or
N-nitro-L-arginine methyl ester
(L-NAME). Intravital microscopy showed that topically
applied EGF (10-1,000 µg/ml) dilated the gastric mucosal
arterioles dose dependently and that this vasodilatory effect was
significantly inhibited by equivalent pretreatments. These findings
suggest that EGF plays a protective role against ethanol-induced
gastric mucosal injury, possibly by dilating the gastric mucosal
arterioles via capsaicin-sensitive afferent neurons involving CGRP and
NO mechanisms.
vasodilatation; sensory nerves; calcitonin gene-related peptide; nitric oxide
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
EPIDERMAL GROWTH FACTOR (EGF) is a polypeptide of 53 amino acids originally isolated from the rodent submaxillary gland (6). EGF is continuously secreted from the salivary glands and the duodenal Brunner's glands (20, 22). Intragastric EGF has been shown to enhance the healing of gastric mucosal injury (20, 22, 30) and to protect the gastric mucosa against various stimuli such as stress, ethanol, hypertonic saline, and aspirin (12, 16, 21, 24, 26). Recently, much attention has been paid to the mechanisms by which EGF protects the gastric mucosa; a trophic effect (7), inhibition of gastric acid secretion (25), enhanced mucus production (18), and the increase of the gastric mucosal blood flow have been suggested to be the possible mechanisms (12, 16).
Recent studies have shown that capsaicin-sensitive afferent neurons, as
well as prostaglandins, play an important role in the gastric mucosal
defensive mechanisms in rats. The stimulation of these neurons by
intragastric capsaicin alters the gastric mucosal blood flow (27,
28), motility (33), and acid and HCO
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animal preparation. The experiments were reviewed by the Committee on the Ethics of Animal Experiments at the Graduate School of Medical Sciences, Kyushu University and were done according to the Guidelines for Animal Experiments of the Graduate School of Medical Sciences, Kyushu University and the law (no. 105) and notification (no. 6) of the Japanese Government.
Male Wistar rats (conventional, 250 g) were fasted for 24 h. Free access to tap water was allowed before experiments. After anesthetization with intraperitoneal urethane (1.25 g/kg), the rectal temperature was continuously monitored and maintained between 37 and 38°C with a heating lamp. Systemic blood pressure was monitored via a catheter inserted in the left femoral artery. To avoid dehydration, saline was continuously infused at a rate of 1.5 ml/h via a catheter inserted in the left femoral vein.Experiment I. The possible protective effect of intragastric EGF on the gastric mucosa of urethane-anesthetized rats was examined. EGF was dissolved in 0.01 M PBS at the appropriate doses. Gastric mucosal injury was induced by the intragastric application of 60% ethanol (5 ml/kg) through a plastic cannula intubated orally. Sixty minutes after anesthesia, 10 or 30 µg of EGF in 1 ml PBS or vehicle were orally intubated (n = 5/group). Fifteen minutes later, the ethanol was applied topically. The stomach was removed 60 min thereafter and fixed in 0.5% formalin for 30 min. Then the stomach was cut along the greater curvature and photographed. The percentage of injured corpus mucosa was calculated by computerized image analysis (NIH Image, v. 1.61).
The effect of pretreatment with sensory desensitization by capsaicin, human calcitonin gene-related peptide (CGRP)1 antagonist hCGRP-(8-37), or nitric oxide (NO) synthase inhibitor NIntravital microscopy. Intravital microscopy was applied by the method reported by Ohono et al. (29), with a slight modification. Briefly, the stomach was exposed through a ventral midline abdominal incision and cut along the greater curvature. After the anterior wall was recected with an electric cautery scalpel (B-3396; Summit Medical, Tokyo, Japan), the posterior wall of the glandular stomach was fixed in a plastic chamber with the mucosal surface facing the bottom and superfused with modified Krebs buffer (3) (in g/l: 8.0 NaCl, 0.20 KCl, 0.265 CaCl2 · 2H2O, and 2.25 Tris; pH adjusted to 7.40 with HCl) warmed at 37°C. A small window (3 mm diameter) was made by a partial removal of the serosa, the smooth muscle, and the submucosa using microsurgical scissors. Minimal bleeding during the procedure was controlled with bipolar coagulator (MICRO-3E; Mizuho Ikakogyo, Tokyo, Japan). Microvasculature in the basal part of the gastric mucosa was observed through the window by transillumination under a stereomicroscope with a long working-distance objective lens (BX50-33; Olympus, Tokyo, Japan). The images were displayed on a video monitor (PVM-20550M; Sony, Tokyo, Japan) via a charge-coupled device (CCD) camera (DXC-108; Sony) connected to the microscope.
Experiment II. The peripheral effect of EGF on gastric mucosal microcirculation was investigated in urethan-anesthetized rats. The diameter of gastric mucosal microvessels was measured using the intravital microscopic technique. After surgery, a resting period of at least 15 min was allowed to achieve stability of the preparation. Arterioles with inner diameters of 25-50 µm and 30- to 60-µm venules in the basal part of the gastric mucosa were examined. A series of increasing concentrations of EGF (0, 10, 20, 40, 100, and 1,000 µg/ml) was topically applied on the gastric wall (20 µl) through the window every 9 min (n = 6/group). Changes in the diameter of the arteriole and the venule were recorded on videotape for 3 min. The videotape was played back, and then the maximal diameter of the vessel was directly measured on the video monitor. The superfusion of the buffer was stopped 15 s before the topical application of EGF and then was resumed for 6 min until the next application to wash out the preceding compound.
The effect of pretreatment with sensory desensitization by capsaicin, hCGRP-(8-37), or L-NAME was tested (n = 6/group). For sensory desensitization, capsaicin at 5 mM was superfused for 10 min after the confirmation of arteriolar dilatation by topical capsaicin at a concentration of 160 µM and then by modified Krebs solution for 60 min. The arteriolar dilatation reached a maximum within 1 min after initiation and then remained at that level for at least 10 min. The arteriolar diameter gradually returned to the basal value within 60 min after the removal of capsaicin. In a preliminary experiment, capsaicin desensitization was confirmed by the second topical capsaicin application 70 min later at a concentration of 160 µM, which has been demonstrated to induce a maximal response (40). Arteriolar dilatation by the second application of capsaicin was <10%, and therefore the capsaicin-sensitive afferent neurons were considered to be desensitized. Either hCGRP-(8-37) (100 nmol/kg) or L-NAME (10 mg/kg) was bolus injected intravenously 10 min before the topical EGF application (100 µg/ml). L-NAME was given either alone or in combination with L-arginine (300 mg/kg iv).Chemicals and treatments. The following chemicals were used: EGF (kindly provided by Dr. B. Nakajima, Hitachi Chemical, Japan), capsaicin (Wako Chemical, Osaka, Japan), hCGRP-(8-37), L-NAME, L-arginine (Sigma, St. Louis, MO), and ethanol (Wako Chemical, Osaka, Japan). EGF was dissolved in 0.01 M PBS (Sigma) in experiment I and in modified Krebs buffer in experiment II. Capsaicin was dissolved in a solvent composed of 10% ethanol, 10% Tween 80 (Sigma), and 80% vol/vol normal saline (0.15 N NaCl). hCGRP-(8-37), L-NAME, and L-arginine were dissolved in saline containing 0.1% BSA. Ethanol was diluted in distilled water. All chemicals were freshly prepared just before the experiments.
Statistics. Values are expressed as means ± SE. Student's t-test was used for comparisons of two groups. Significance of differences was determined with a one-way ANOVA followed by Fischer's protected least significant difference (PLSD) for the comparison of multiple groups. A two-factor repeated-measures ANOVA followed by Fisher's PLSD was used for the data of serial measurements. P values <0.05 were considered statistically significant.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Experiment I.
Gastric mucosal lesions 60 min after ethanol injection occupied
24.3 ± 2.6% of the glandular area in vehicle-treated rats. The
intragastric application of EGF (10 or 30 µg) significantly reduced
the gastric mucosal lesions (12.0 ± 3.5% in the 10 µg group,
P < 0.01, and 7.3 ± 1.3% in the 30 µg group,
P < 0.001, Fig. 1).
|
|
Experiment II.
The basal diameters of the arterioles and venules were 34.5 ± 2.5 µm and 42.5 ± 2.4 µm, respectively. When EGF was applied topically, the arterioles were rapidly dilated, but the venules remained unchanged (Fig. 3A).
Dilatation of the arterioles reached a maximum at 60 s after the
application of the peptides and then remained at a maximum level for
~20 s. The topical application of the vehicle showed little
dilatation of the arterioles (5.4 ± 2.2% , Fig. 3B).
As shown in Fig. 3B, topically applied EGF (10, 20, 40, 100, and 1,000 µg/ml, 20 µl) dilated the arterioles dose dependently
(10.4 ± 1.5%, 13.7 ± 2.0%, 19.4 ± 2.4%, 24.4 ± 3.1%, and 33.7 ± 3.6%, respectively).
|
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Our results showed that in urethan-anesthetized rats 1) intragastric EGF prevents ethanol-induced gastric mucosal injury and topically applied EGF dilates the arterioles but not the venules in the basal part of gastric mucosa dose dependently and 2) these effects of EGF are mediated through the capsaicin-sensitive afferent neurons via CGRP- and NO-dependent mechanisms. Because EGF was applied to the serosal side of the glandular stomach in the second experiment, the effect of EGF on the arteriole observed in the experiment may be slightly different from that under physiological conditions. However, our observations suggest that EGF does dilate arterioles in damaged gastric mucosa that lacks an epithelial layer (i.e., gastric ulcer and erosion).
The EGF receptor (EGF-R) has been shown to belong to the type 1 tyrosine kinase receptor family and to be located in the gastric tissue of both rodents and humans (31, 34). At the acute and healing stage of gastric mucosal damage, EGF-R has been shown to be overexpressed in the epithelia (19, 35). It has also been confirmed in rats that the main source of EGF in the gastric contents is the submandibular glands (20, 22), and that growth factor exists at a concentration of 19.6 µg/l in the rat (14). Furthermore, EGF in the salivary glands (9) and in the gastric juice (23) increases by severalfold that of the basal value under conditions of gastric mucosal damage induced by various stimuli. Whereas we applied EGF to rats at extremely high concentrations compared with those in physiological conditions, a similar preventive effect of large amounts of EGF against mucosal injury has been shown in other experiments (12, 16).
Intragastric EGF protects the gastric mucosa against various stimuli such as stress, ethanol, hypertonic saline, and aspirin (12, 16, 21, 24, 26). Although parenteral EGF has been shown to decrease gastric acid secretion (25), intragastric EGF revealed a protective effect against aspirin- and stress-induced mucosal damage without reducing acid secretion (24). It thus seems likely that acid suppression alone is not the significant mechanism of the protective effect of EGF in our experiments. The trophic action to the gastric mucosa characterized by increase in DNA, RNA, protein, and mucus secretion (15, 18) has been confirmed, but this effect seems to be unrelated to the preventive effect of intragastric EGF. Cytoprotection through the stimulation of prostaglandin production by EGF (5, 8) has been suggested to be another mechanism for the preventive effect. However, the role of prostaglandin synthesis in the protective effect of EGF still remains controversial because intragastric EGF exhibited a preventive effect even against aspirin-induced mucosal injury of the rat stomach without affecting prostaglandin production (26).
It has been shown in several experiments that intragastric EGF increases the mucosal blood flow of the stomach. Hui et al. (12) demonstrated that intragastric EGF increased the blood flow of the rat gastric mucosa after topical ethanol treatment, and it also dose-dependently reduced the degree of mucosal damage. Although Hui et al. (12) measured the mucosal blood flow by laser-Doppler flowmetry, we directly observed the arterioles in the gastric mucosa induced by intragastric EGF by using intravital microscopy. Whereas an increase in the gastric mucosal blood flow has been shown in rats treated by subcutaneous EGF (16), the vasodilatory action of EGF seems to be attributed to an extremely topical response, because the arterioles dilated even after the removal of submucosal tissue in our experiment.
Recently, the interaction of EGF and NO in the gastric protection has been investigated in animal experiments (1, 36, 37). Tripp and Tepperman (37) reported in sialoadenectomized rats that subcutaneous EGF did not influence NO synthase activity in ethanol-treated gastric lesions, whereas EGF reduced ethanol-induced mucosal lesions. However, Brzozowski et al. (1) reported that in stress-induced mucosal lesions an increase in the mucosal blood flow induced by subcutaneous EGF was inhibited by either capsaicin desensitization or NO synthase inhibitor. Our results also indicated a close interaction between EGF and NO in unsialoadenectomized rats. The discrepancy in the role of NO in EGF-treated animals may relate to sialoadenectomy or differences in the route of EGF administration. On the basis of these previous data and our results, it seems obvious that EGF induces hyperemia through a NO-dependent mechanism, although the protective effect of EGF may not be explained by an increase of gastric mucosal blood flow alone.
It has been established in both rodents and humans that capsaicin plays a protective role against gastric mucosal injury and that the capsaicin-sensitive afferent neurons play a major role in the regulation of the gastric mucosal blood flow (10, 27, 28). The release of CGRP from stimulated capsaicin-sensitive neurons and subsequent increase in endothelial NO have been shown to result in vasodilatation and increase in blood flow (4, 10, 13, 40). Our results strongly suggested that EGF, as well as capsaicin, dilated the arteriole through capsaicin-sensitive afferent neurons. Kang et al. (16) have also reported that the EGF-induced increase in the blood flow of the rat gastric mucosa was inhibited by either capsaicin desensitization or hCGRP-(8-37). These findings suggest that the protective effect of EGF against gastric mucosal injury is due partly to mucosal hyperemia through the stimulation of capsaicin-sensitive afferent neurons.
The precise mechanism of stimulation of capsaicin-sensitive neurons by EGF remains unclear. On the sensory afferent neuron, a receptor, which is sensitive to capsaicin, protons, and noxious heat, has recently been cloned and referred to as vanilloid receptor subtype 1 (2). EGF may directly stimulate the vanilloid receptor subtype 1. The stimulation of a capsaicin-sensitive afferent neuron through mast cells may be another explanation, because substances released from these cells have been shown to stimulate the sensory neurons in the rat gastric mucosa (39). However, the EGF receptors on mast cells remain to be determined.
In past experiments, capsaicin desensitization for sensory neurons was completed by systemic administration of high dose capsaicin (42), as in our first experiment. The procedure of desensitization seems to induce a systemic functional depletion of capsaicin-sensitive neurons. In experiment II, however, we intentionally applied a high dose of capsaicin directly on the gastric wall, and a substantial desensitization could thus be achieved. The method of desensitization coupled with intravital microscopy may be a model for investigating the role of capsaicin-sensitive afferent neurons in the regulation of mucosal blood flow.
In conclusion, intragastric EGF plays a protective role against gastric mucosal injury induced by ethanol, and the effect may be attributable to hyperemia through stimulation of capsaicin-sensitive afferent neurons and subsequent CGRP- and NO-dependent mechanisms. It is presumed that the dilatation of the arterioles may thus be an essential event in the protective effect of EGF against gastric mucosal injury.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: Y. Matsumoto, Dept. of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu Univ., Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan (E-mail: yoji{at}intmed2.med.kyushu-u.ac.jp).
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.
Received 21 August 2000; accepted in final form 28 November 2000.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Brzozowski, T,
Konturek PC,
Sliwowski Z,
Drozdowicz D,
Hahn EG,
and
Konturek SJ.
Importance of nitric oxide and capsaicin-sensitive afferent nerves in healing of stress lesions induced by epidermal growth factor.
J Clin Gastroenterol
25:
S28-S38,
1997[ISI][Medline].
2.
Caterina, MJ,
Schumacher MA,
Tominaga M,
Rosen TA,
Levine JD,
and
Julius D.
The capsaicin receptor: a heat-activated ion channel in the pain pathway.
Nature
389:
816-824,
1997[ISI][Medline].
3.
Chen, RYZ,
and
Guth PH.
Interaction of endogenous nitric oxide and CGRP in sensory neuron-induced gastric vasodilation.
Am J Physiol Gastrointest Liver Physiol
268:
G791-G796,
1995
4.
Chen, RYZ,
Li DS,
and
Guth PH.
Role of calcitonin gene-related peptide in capsaicin-induced gastric submucosal arteriolar dilation.
Am J Physiol Heart Circ Physiol
262:
H1350-H1355,
1992
5.
Chiba, T,
Hirata Y,
Taminato T,
Kadowaki S,
Matsukura S,
and
Fujita T.
Epidermal growth factor stimulates prostaglandin E release from isolated perfused rat stomach.
Biochem Biophys Res Commun
105:
370-374,
1982[ISI][Medline].
6.
Cohen, S.
Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the newborn animal.
J Biol Chem
237:
1555-1562,
1962
7.
Dembinski, A,
Gergory H,
Konturek SJ,
and
Polanski M.
Trophic action of epidermal growth factor on the pancreas and gastroduodenal mucosa in rats.
J Physiol
325:
35-42,
1982[Abstract].
8.
DiJoseph, JF,
and
Wells CL.
Effect of epidermal growth factor on non-steroidal anti-inflammatory drug-induced intestinal damage.
Agents Actions
27:
294-296,
1989[ISI][Medline].
9.
Gysin, B,
Muller RKM,
Otten U,
and
Fischli AE.
Epidermal growth factor content of submandibular glands is increased in rats with experimentally induced gastric lesions.
Scand J Gastroenterol
23:
665-671,
1988[ISI][Medline].
10.
Holzer, P.
Neural emergency system in the stomach.
Gastroenterology
114:
823-839,
1998[ISI][Medline].
11.
Holzer, P,
and
Lippe IT.
Stimulation of afferent nerve endings by intragastric capsaicin protects against ethanol-induced damage of gastric mucosa.
Neuroscience
27:
981-987,
1988[ISI][Medline].
12.
Hui, WM,
Chen BW,
Kung AWC,
Cho CH,
Luk CT,
and
Lam SK.
Effect of epidermal growth factor on gastric blood flow in rats: possible role in mucosal protection.
Gastroenterology
104:
1605-1610,
1993[ISI][Medline].
13.
Li, DS,
Raybould HE,
Quintero E,
and
Guth PH.
Role of calcitonin gene-related peptide in gastric hyperemic response to intragastric capsaicin.
Am J Physiol Gastrointest Liver Physiol
261:
G657-G661,
1991
14.
Joh, T,
Itoh M,
Yasue N,
Miyamoto T,
Iwai A,
Matsusako K,
Endoh K,
Takeuchi T,
Moriyama A,
and
Kato T.
A sensitive enzyme immunoassay system of rat epidermal growth factor in biological fluids and tissue extracts.
Acta Endocrinol (Copenh)
120:
616-623,
1989[Medline].
15.
Johnson, LR,
and
Guthrie PD.
Stimulation rat oxyntic gland mucosal growth by epidermal growth factor.
Am J Physiol Gastrointest Liver Physiol
238:
G45-G49,
1980
16.
Kang, JY,
Teng CH,
Chen FC,
and
Wee A.
Role of capsaicin sensitive nerves in epidermal growth factor effects on gastric mucosal injury and blood flow.
Gut
42:
344-350,
1998
17.
Kang, JY,
Teng CH,
Wee A,
and
Chen FC.
Effect of capsaicin and chili on ethanol-induced gastric mucosal injury in the rat.
Gut
36:
664-669,
1995[Abstract].
18.
Kelly, SM,
and
Hunter JO.
Epidermal growth factor stimulates synthesis and secretion of mucus glycoproteins in human gastric mucosa.
Clin Sci
79:
425-427,
1990[ISI][Medline].
19.
Konturek, PC,
Ernst H,
Brzozowski T,
Ihlm A,
Hahn EG,
and
Konturek SJ.
Expression of epidermal growth factor and transforming growth factor- after exposure of rat gastric mucosa to stress.
Scand J Gastroenterol
31:
209-216,
1996[ISI][Medline].
20.
Konturek, PC,
Konturek SJ,
Brzozowski T,
and
Ernst H.
Epidermal growth factor and transforming growth factor-: role in protection and healing of gastric mucosal lesions.
Eur J Gastroenterol Hepatol
7:
933-938,
1995[ISI][Medline].
21.
Konturek, SJ.
Role of epidermal growth factor in gastroprotection and ulcer healing.
Scand J Gastroenterol
23:
129-133,
1988[ISI][Medline].
22.
Konturek, SJ.
Role of growth factors in gastroduodenal protection and healing of peptic ulcer.
Gastroenterol Clin North Am
19:
41-65,
1990[ISI][Medline].
23.
Konturek, SJ,
Brzozowski T,
Konturek PK,
and
Majka J.
Role of salivary glands and epidermal growth factor (EGF) in gastric secretion and mucosal integrity in rats exposed to stress.
Regul Pept
32:
203-215,
1991[ISI][Medline].
24.
Konturek, SJ,
Brzozowski T,
Piastucki I,
Dembinski A,
Radeck T,
Dembinska-kiec A,
Zmnda A,
Gryglewski H,
and
Gregory H.
Role of mucosal prostaglandins and DNA synthesis in gastric protection by luminal epidermal growth factor.
Gut
22:
927-932,
1981[Abstract].
25.
Konturek, SJ,
Cieszkowski M,
Jaworek J,
Konturek J,
Brzozowski T,
and
Gergory H.
Effects of epidermal growth factor on gastrointestinal secretions.
Am J Physiol Gastrointest Liver Physiol
246:
G580-G586,
1984
26.
Konturek, SJ,
Radeck T,
Brzozowski T,
Piastucki I,
Dembinski A,
Dembinska-kiec A,
Zmnda A,
Gryglewski H,
and
Gregory H.
Gastric cytoprotection by epidermal growth factor. Role of endogenous prostaglandins and DNA synthesis.
Gastroenterology
81:
438-443,
1981[ISI][Medline].
27.
Lippe, IT,
Pabst MA,
and
Holzer P.
Intragastric capsaicin enhances rat gastric acid elimination and mucosal blood flow by afferent nerve stimulation.
Br J Pharmacol
96:
91-100,
1989[Abstract].
28.
Matsumoto, J,
Takeuchi K,
and
Okabe S.
Characterization of gastric mucosal blood flow response induced by intragastric capsaicin in rats.
Jpn J Pharmacol
57:
205-213,
1991[ISI][Medline].
29.
Ohono, T,
Katori M,
Nishiyama K,
and
Saigenji K.
Direct observation of microcirculation of the basal region of rat gastric mucosa.
J Gastroenterol
30:
557-564,
1995[ISI][Medline].
30.
Olsen, PS,
Poulsen SS,
Therkelsen K,
and
Nexo E.
Oral administration of synthetic human urogastrone promotes healing of chronic duodenal ulcer in rats.
Gastroenterology
90:
911-917,
1986[ISI][Medline].
31.
Sottili, M,
Sternini C,
Brecha NC,
Lezoche E,
and
Walsh JH.
Transforming growth factor alpha receptor binding sites in the canine gastrointestinal tract.
Gastroenterology
103:
1427-1436,
1992[ISI][Medline].
32.
Takeuchi, K,
Matsumoto J,
Ueshima K,
and
Okabe S.
Role of capsaicin-sensitive afferent neurons in alkaline secretory response to luminal acid in the rat duodenum.
Gastroenterology
101:
951-961,
1991.
33.
Takeuchi, K,
Niida H,
Matsumoto J,
Ueshima K,
and
Okabe S.
Gastric motility changes in capsaicin-induced cytoprotection in the rat stomach.
Jpn J Pharmacol
55:
147-155,
1991[ISI][Medline].
34.
Tarnawski, A,
Lu SY,
Stachura J,
and
Sarfeh IJ.
Adaptation of gastric mucosa to chronic alcohol administration is associated with increased mucosal expression of growth factors and their receptor.
Scand J Gastroenterol
193:
S59-S63,
1992.
35.
Tarnawski, A,
Stachura J,
Durbin T,
Sarfeh IJ,
and
Gergely H.
Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats.
Gastroenterology
102:
695-698,
1992[ISI][Medline].
36.
Tepperman, BL,
and
Soper BD.
Interaction of nitric oxide and salivary gland epidermal growth factor in the modulation of rat gastric mucosal integrity.
Br J Pharmacol
110:
229-234,
1993[Abstract].
37.
Tripp, MA,
and
Tepperman BL.
Effect of nitric oxide on integrity, blood flow and cyclic GMP levels in the rat gastric mucosa: modulation by sialoadenectomy.
Br J Pharmacol
115:
344-348,
1995[Abstract].
38.
Uchida, M,
Yano S,
and
Watanabe K.
The role of capsaicin-sensitive afferent nerves in protective effect of capsaicin against absolute ethanol-induced gastric lesions in rats.
Jpn J Pharmacol
55:
279-282,
1991[ISI][Medline].
39.
Wallace, JL,
McKnight GW,
and
Befus AD.
Capsaicin-induced hyperemia in the stomach: possible contribution of mast cells.
Am J Physiol Gastrointest Liver Physiol
263:
G209-G214,
1992
40.
Whittle, BJR,
Lopez-Belmonte J,
and
Moncada S.
Nitric oxide mediates rat mucosal vasodilatation induced by intragastric capsaicin.
Eur J Pharmacol
281:
339-341,
1992.
41.
Yeoh, KG,
Kang JY,
Yap I,
Guan R,
Tan CC,
Wee A,
and
Teng CH.
Chili protects against aspirin-induced gastroduodenal mucosal injury in humans.
Dig Dis Sci
40:
580-583,
1995[ISI][Medline].
42.
Yonei, Y,
Holtzer G,
and
Guth PH.
Laparotomy-induced gastric protection against ethanol injury is mediated by capsaicin-sensitive sensory neurons.
Gastroenterology
99:
3-9,
1990[ISI][Medline].
HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Visit Other APS Journals Online |