Evaluation of early gastric mucosal permeability induced by central thyrotropin-releasing hormone administration

Takashi Joh,1 Tadayuki Oshima,1 Nobuo Takahashi,1 Hiroshi Kaneko,2 Makoto Sasaki,1 Hiromi Kataoka,1 Katsushi Watanabe,1 Masashi Sobue,1 Hideo Suzuki,1 Tomoyuki Nomura,1 Hirotaka Ohara,1 and Makoto Itoh1

1Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya; and 2Department of Internal Medicine, Division of General Medicine, Aichi Medical University School of Medicine, Aichi, Japan

Submitted 8 March 2004 ; accepted in final form 8 October 2004


    ABSTRACT
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Accumulating evidence suggests that central thyrotropin-releasing hormone (TRH) administration induces gastric erosion 4 h after administration through the vagal nerves. However, early changes in the gastric mucosa during these 4 h have not been described. To assess early changes in the gastric mucosa after intracisternal injection of a stable TRH analog, pGlu-His-(3,3'-dimethyl)-ProNH2 (RX-77368), we measured the blood-to-lumen 51Cr-labeled EDTA clearance and examined the effects of vagotomy, atropine, omeprazole, and hydrochloric acid (HCl) on RX-77368-induced mucosal permeability. A cytoprotective dose of RX-77368 (1.5 ng) did not increase mucosal permeability. However, higher doses significantly increased mucosal permeability. Permeability peaked within 20 min and gradually returned to control levels in response to a 15-ng dose (submaximal dose). Increased mucosal permeability was not recovered after a 150-ng dose (ulcerogenic dose). This increase in permeability was inhibited by vagotomy or atropine. Intragastric perfusion with HCl did not change the RX-77368 (15 ng)-induced increase in permeability, but completely inhibited the recovery of permeability after the peak. Pretreatment with omeprazole did not change the RX-77368 (15 ng)-induced increase in permeability, but quickened the recovery of permeability after the peak. These data indicate that the RX-77368-induced increase in permeability is mediated via the vagal-cholinergic pathway and is not a secondary change in RX-77368-induced acid secretion. Inhibited recovery of permeability on exposure to an ulcerogenic RX-77368 dose or on exposure to HCl plus a submaximal dose of RX-77368 may be crucial for the induction of gastric mucosal lesions by central RX-77368 administration.

intracisternal injection; 51Cr-labeled EDTA clearance


THE ROLE OF THE CENTRAL NERVOUS SYSTEM in the regulation of gastric function has long been recognized. Thyrotropin-releasing hormone (TRH), a stress-related neuropeptide originally isolated from the hypothalamus (1, 10), or its stable analog pGlu-His-(3,3'-dimethyl)-ProNH2 (RX-77368) has been reported to act in the brain to stimulate gastrointestinal secretion, motility, transit, and ulcer formation in conscious or anesthetized rats, rabbits, and cats (14, 15). Many studies (14, 15) indicate that TRH actions on gut function are mediated through activation of the parasympathetic outflow and peripheral muscarinic receptors. TRH or stable TRH analogs injected into the cisterna magna show cytoprotective (19, 25) and ulcerogenic effects (3, 14) on gastric mucosa (17, 18). These stress-related effects on gastric mucosa depend on the balance between vagally activated increases in ulcerogenic agents including acid secretion (16) and cytoprotective factors such as prostaglandins (25) and heat shock proteins (8).

Mucosal permeability plays a key role in regulation of gastric integrity. Although the vagal cholinergic-mediated effects of gastric acid secretion or mucosal blood flow on gut function are well characterized in response to intracisternal injection of TRH (16, 20), little is known about the effects of central RX-77368, a stable TRH analog, on gastric mucosal permeability at cytoprotective (1.5 ng) and ulcerogenic doses (15–150 ng), especially during the first 60 min after intracisternal injection of RX-77368. In the present study, we examined effects of intracisternal injection of RX-77368 on gastric mucosal permeability in vivo by measuring the blood-to-lumen 51Cr-labeled EDTA clearance, which has been developed to assess the mucosal permeability and has been shown to be an extremely sensitive index of mucosal damage (47, 11, 22). We also examined effects of vagotomy, atropine, luminal perfusion with hydrochloric acid (HCl), or omeprazole on RX-77368-induced changes in mucosal permeability.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Drugs

The following substances were used. The stable TRH analog RX-77368 (Reckitt & Colman, Kingston-upon-Hill, UK) in powder form was dissolved in 0.5% bisinchoninic acid (BSA) and 0.1% acetic acid at an initial concentration of 4 mg/ml and kept at –20°C. The required doses were made by dilution of the stock solution with PBS immediately before experiments. Omeprazole, a selective H+-K+-ATPase inhibitor in parietal cells, was kindly provided by AstraZeneca (Molndal, Sweden). Omeprazole was dissolved in 100% DMSO (Sigma, St. Louis, MO), and the stock solution (30 mg/ml) was diluted in bicarbonate buffer (0.56 mg/ml) before experiments. Atropine sulfate was obtained from Sigma.

Animal Preparation

Male Sprague-Dawley rats weighing 250–350 g (Japan SLC, Hamamatsu, Japan) were fasted overnight and anesthetized with intraperitoneal urethane (0.6 g/kg, Tokyo Kasei Kogyo, Tokyo, Japan) and {alpha}-chloralose (0.12 g/kg; Wako Pure Chemical Industries, Tokyo, Japan). The head was placed on an ear bar of a sterotaxic apparatus. The dura mater covering the foramen magnum was exposed. A small pin hole was made into the membrane with a 25-gauge needle 1–1.5 mm distal to the caudal edge of the occipital bone. A polyethylene tube (PE-10) was carefully inserted through the pin hole into the cisterna magna. The tube (10 cm; 7 µl dead space) was filled with saline. Successful cannulation into the cisterna magna was verified by the leakage of cerebrospinal fluid, and the open end of the catheter was then connected to a 50-µl Hamilton syringe. A tracheotomy was performed, and PE-240 tubing was inserted into the trachea to maintain an open airway. The right femoral artery and vein were cannulated (PE-50) for monitoring systemic arterial pressure and for administration of 51Cr-labeled EDTA (PerkinElmer Life & Analytical Sciences), respectively. Body temperature was monitored by a rectal thermometer and maintained at 37°C with a heating pad and lamp throughout the experiment. The studies were approved by the Animal Research Committee of the Nagoya City University Graduate School.

Assessment of Mucosal Integrity (Measurement of 51Cr-Labeled EDTA Clearance)

After an abdominal incision was made, the renal blood vessels were ligated to prevent loss of the low-molecular-weight tracer used to assess gastric mucosal permeability. The stomach was exteriorized, and a ligature was placed around the pylorus. An incision was made in the forestomach, and a double-lumen cannula (outer cannula, 3.25 mm in diameter; inner cannula, 1 mm in diameter) was inserted into the stomach and secured to the forestomach with a ligature. The stomach was perfused with PBS or a solution through the inner cannula at a rate of 1.0 ml/min, and the effluent was collected via the outer cannula. The abdomen was irrigated with saline and covered with plastic wrap to prevent evaporative fluid loss. After surgery was completed, 51Cr-labeled EDTA (3.7 MBq) was administered as a bolus from the right femoral vein. Samples of gastric perfusate were collected at 5-min intervals to monitor 51Cr-labeled EDTA clearance (6). In a series of experiments, the pH of gastric perfusate was measured by using a pH meter (Horiba, Kyoto, Japan). At the end of the experiment, a blood sample (0.3 ml) was taken from the femoral arterial catheter, the animal was killed, and the stomach was removed and weighed. Radioactivity of perfusate and plasma samples was determined in an ALOKA Compu-Gamma spectrometer. The 51Cr-labeled EDTA clearance was calculated by using the following formula: (PR x 51Cr-labeled perfusate x 100)/(51Cr-labeled plasma x stomach weight), where PR is the perfusion rate (milliliters per minute), 51Cr-labeled perfusate is the radioactivity in the perfusate (in counts per minute (cpm) per milliliter), and 51Cr-labeled plasma is the radioactivity in the blood plasma (cpm per milliliter). EDTA clearance was expressed in milliliters per minute per 100 grams and the stomach weight was measured in grams (6).

Experimental Protocols

In all experiments, gastric mucosal permeability was continuously monitored by measuring 51Cr-labeled EDTA clearance. Once steady-state clearances were obtained (20–30 min), an additional 30-min perfusion served as a control. Changes in mucosal permeability were assessed by measurement of 51Cr-labeled EDTA clearance 60–90 min after intracisternal injection of RX-77368. In each of the studies, the treatments were administered in a randomized fashion. Randomization of the treatments was performed by an assistant who did not know the results of the studies.

Effect of intracisternal injection of RX-77368 on gastric mucosal permeability. A 10-µl aliquot containing 1.5, 15, or 150 ng/300 g rat of RX-77368 was injected intracisternally.

Effect of vagotomy and atropine. In another series of experiments, subdiaphragmatic vagotomy was performed by transection of the esophagus between two ligatures immediately below the diaphragm before positioning the gastric cannula. Vagotomy or sham operation was performed 1 h before RX-77368 (15 ng) injection. Thirty minutes after subcutaneous (sc) vehicle or atropine (2 mg/kg) injection. Thirty minutes after subcutaneous (sc) vehicle or atropine (2 mg/kg) injection, RX-77368 (15 ng) was injected intracisternally.

Effect of omeprazole. Vehicle or omeprazole (40 mg/kg) was injected subcutaneously. At 60 min after omeprazole, RX-77368 (15 ng) was injected intracisternally.

Effect of luminal perfusion with 0.05 N HCl. The stomach was perfused with PBS or a solution containing PBS and 0.05 N HCl through the inner cannula at a rate of 1.0 ml/min throughout the experiment. After being stabilized for 30 min, the rats were injected intracisternally with RX-77368 (15 ng).

Statistical Analysis

All values are expressed as means ± SE. Unpaired t-tests were used to compare mean values between groups. ANOVA and Duncan’s test were employed for comparison of mean values among three or four groups. Significance was accepted at P < 0.05.


    RESULTS
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Effect of Intracisternal Injection of RX-77368 on Gastric Mucosal Permeability

A cytoprotective dose (1.5 ng) (25) of RX-77368 did not increase gastric mucosal permeability. However, a dose of 15 ng (submaximal dose) consistently increased mucosal permeability immediately after intracisternal injection of RX-77368 (P < 0.05). The permeability peaked within 20 min and gradually returned to control levels within 60 min. A dose of 150 ng (ulcerogenic dose) increased mucosal permeability (P < 0.01). However, levels did not return to normal during the 60 min of monitoring (Fig. 1). Gross erosion was not observed at 60 min under any condition.



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Fig. 1. Effect of intracisternal injection of thyrotropin-releasing hormone (TRH) on gastric mucosal permeability. The TRH-induced changes in mucosal permeability were assessed by measurement of 51Cr-labeled EDTA clearance 60 min after intracisternal injection of TRH. At a 1.5-ng TRH dose ({circ}), the mucosal permeability was not significantly increased. However, mucosal permeability consistently increased after intracisternal injection of 15 ({blacklozenge}) and 150 ng ({square}) TRH. Permeability was still significantly elevated 60 min after intracisternal injection of TRH (90 min on the figure) at the highest dose (150 ng). Each value represents the mean ± SE of each group (n = 5). *P < 0.01, #P < 0.05 vs. baseline (the stabilization period before injection).

 
Effect of Vagotomy and Atropine on RX-77368-Induced Changes in Mucosal Permeability

Vagotomy or sham operation was performed 1 h before RX-77368 injection. Vehicle or atropine sulfate (2 mg/kg sc) was administered 30 min before RX-77368 injection. Changes in mucosal permeability in response to vagotomy or atropine pretreatment were assessed by measurement of 51Cr-labeled EDTA clearance 90 min after intracisternal injection of RX-77368. The RX-77368 (15 ng)-induced increase in permeability was completely blocked by vagotomy (P < 0.05) and was significantly blocked by atropine (P < 0.05) (Fig. 2).



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Fig. 2. Effect of vagotomy and atropine on TRH (15 ng)-induced changes in mucosal permeability. A: increase in permeability after intracisternal injection of TRH was completely attenuated by vagotomy ({square}). Each value represents the mean ± SE of each group (n = 5). *P < 0.05 vs. sham + TRH ({blacklozenge}). B: increase in permeability was significantly blocked by atropine (2 mg/kg sc) ({blacktriangleup}). Each value represents the mean ± SE of each group (n = 5). *P < 0.05 vs. vehicle + TRH ({blacklozenge}).

 
Effect of Luminal Perfusion with 0.05 N HCl on RX-77368-Induced Changes in Mucosal Permeability

Effects of RX-77368 (15 ng) on perfusion with 0.05 N HCl were tested. After luminal perfusion with 0.05 N HCl or PBS, RX-77368 (15 ng) was intracisternally injected into the rats after a 30-min stabilization period. Intragastric perfusion with 0.05 N HCl did not change either the initial 51Cr-labeled EDTA clearance before RX-77368 injection or clearance during the initial phase, which included the peak value 20 min after RX-77368 administration. However, intragastric perfusion with 0.05 N HCl completely inhibited the recovery of permeability after the peak (P < 0.05) (Fig. 3).



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Fig. 3. Effect of luminal perfusion with 0.05 N hydrochloric acid (HCl) on TRH (15 ng)-induced changes in mucosal permeability. PBS ({blacklozenge}) or 0.05 N HCl ({triangleup}) was perfused throughout the experiment. Intragastric perfusion with 0.05 N HCl did not change the clearance during the initial phase, including the peak value 20 min after TRH injection, but completely inhibited recovery of permeability after peak. Permeability was still significantly elevated 90 min after intracisternal injection of TRH (120 min on the figure) during perfusion with 0.05 N HCl. Each value represents the mean ± SE of each group (n = 5). *P < 0.05 vs. control.

 
Effect of Omeprazole on 15 ng RX-77368-Induced Changes in Mucosal Permeability

Omeprazole (40 mg/kg sc) was injected subcutaneously 60 min before RX-77368 injection. Pretreatment with omeprazole did not change the basal pH before RX-77368 injection, and no changes in pH were observed after intracisternal RX-77368 (15 ng) injection in omeprazole-treated rats. However, pH decreased from 7 to 3 after RX-77368 (15 ng) injection in rats receiving PBS-only luminal perfusion (P < 0.05) (Fig. 4).



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Fig. 4. Effect of omeprazole on TRH-induced changes in pH. Omeprazole (40 mg/kg sc) was injected 60 min before TRH injection. Pretreatment with omeprazole ({bullet}) prevented a change in pH before or after TRH injection. However, pH changed from 7 to 3 during luminal perfusion with PBS alone after intracisternal TRH (15 ng) injection ({circ}). Each value represents the mean ± SE of each group (n = 5). *P < 0.05 vs. baseline (the stabilization period before injection).

 
Pretreatment with omeprazole did not change the initial 51Cr-labeled EDTA clearance before RX-77368 injection. Intragastric perfusion with PBS and pretreatment with omeprazole (subcutaneously) did not change the permeability during the initial phase, including the peak value 20 min after RX-77368 injection, but pretreatment with omeprazole quickened the recovery of permeability after the peak (P < 0.05) (Fig. 5).



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Fig. 5. Effect of omeprazole on TRH (15 ng)-induced changes in mucosal permeability. Pretreatment with omeprazole ({bullet}) did not change the initial 51Cr-labeled EDTA clearance before TRH injection or the increased clearance after TRH injection, but quickened the recovery of permeability after the peak. Each value represents the mean ± SE of each group (n = 7). *P < 0.05 vs. control ({circ}).

 

    DISCUSSION
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
TRH has been convincingly established by several groups of investigators as a central vagal stimulator of acid secretion in rats and cats (15). TRH or TRH analogs injected into the cisterna magna increase efferent activity in the gastric branch of the vagus nerve (8a) and increases vagal muscarinic-dependent stimulation of gastric acid, pepsin, histamine, and serotonin secretion, mucosal blood flow (MBF), emptying, and contractility (2, 12, 13, 15, 23, 24). Gastric acid secretion peaks within 20–30 min after TRH injection and returns to the preinjection level in 90–120 min (13, 20). Four hours after TRH or RX-77368 injection into the cisterna magna, erosion appeared on the gastric mucosa but was mitigated by cimetidine or omeprazole (3). These data indicate that gastric acid is an import factor contributing to the ulcerogenic effect of TRH. However, little is known about the early phase (within 60 min) of gastric mucosal change after intracisternal injection of RX-77368, because macroscopic changes are not observed in that period. We report herein the first observations of gastric mucosal damage within 60 min of RX-77368 injection as measured by gastric mucosal permeability using the blood-to-lumen 51Cr-labeled EDTA clearance technique, which has been shown to be an extremely sensitive index of mucosal damage (47, 11, 22).

In the present study, RX-77368 increased mucosal permeability in a dose-dependent manner after intracisternal injection (Fig. 1). A cytoprotective dose (1.5 ng) of RX-77368 (25) did not increase mucosal permeability. It has been also reported that such a low dose of TRH analog (1.5 ng) does not increase gastric acid secretion (25). On the other hand, permeability increased and peaked within 20 min of dosing with 15 and 150 ng RX-77368. Permeability gradually returned to control levels within 60 min of administration of the 15-ng dose. However, at the highest dose (150 ng), permeability did not return to baseline levels within 60 min. Previous reports indicated that enhancement of both gastric acid secretion and MBF by intracisternal TRH or RX-77368 injection was abolished by subdiaphragmatic vagotomy (20) or blockade of cholinergic receptors by atropine (25). Even in our present study, the RX-77368-induced increase in permeability was completely abolished by vagotomy and was significantly blocked by atropine (Fig. 2). These data indicate that the effect of RX-77368 was mediated via the vagal-cholinergic pathway. In our experimental protocol, the luminal concentration of HCl actually decreased, because PBS was continuously perfused intragastrically. We then performed experiments in the presence of intragastric perfusion with 0.05 N HCl, a concentration that is similar to physiological conditions. Intragastric perfusion with 0.05 N HCl did not change the clearance during the initial phase, including peak value 20 min after RX-77368 injection, but completely inhibited the recovery of permeability after peak (Fig. 3). These data indicate that intracisternal RX-77368 injection induces first, an increase in gastric mucosal permeability and second, macroscopic lesions in the presence of acid (3).

Although omeprazole had no effect on the increase in clearance during the first 20 min, acid secretion was completely inhibited (Fig. 4) and RX-77368-induced permeability was significantly attenuated in the later period, beginning 30 min after RX-77368 treatment (Fig. 5). We measured the pH of perfusate every 5 min (Fig. 4), and these data were consistent with previous reports (16) on gastric acid secretion. These data strongly suggest that the mechanism responsible for RX-77368-induced increases in permeability is composed of at least two phases: 1) an initial phase, which includes the peak value 20 min after RX-77368 intracisternal injection and which is independent of acid secretion; and 2) the recovery, which is dependent on acid secretion. Sustained increases in acid secretion induced by RX-77368 are important for ulcerogenic effects of the peptide. Although pepsin or histamine secretion, mast cell, or contractility may be related to the initial increase in RX-77368-induced gastric mucosal permeability (2, 9, 23, 24), the specific factors that are related to the initial increase in permeability remain to be investigated in detail.

In conclusion, RX-77368 at ulcerogenic doses increased gastric mucosal permeability, which is mediated via the vagal-cholinergic pathway and is not a secondary change to RX-77368-induced acid secretion. Inhibited recovery of permeability on exposure to ulcerogenic doses of RX-77368 or exposure to HCl plus the submaximal dose of RX-77368 may be crucial for the induction of gastric mucosal lesions by intracisternal injection of a TRH analog.


    FOOTNOTES
 

Address for reprint requests and other correspondence: T. Joh, Dept. of Internal Medicine and Bioregulation, Nagoya City Univ. Graduate School of Medical Sciences, 1 Kawasumi, Mizuho, Nagoya, 467-8601, Japan (E-mail: tjoh{at}med.nagoya-cu.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.


    REFERENCES
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Burgus R, Dunn TF, Desiderio D, Ward DN, Vale W, and Guillemin R. Characterization of ovine hypothalamic hypophysiotropic TSH-releasing factor. Nature 226: 321–325, 1970.[ISI][Medline]
  2. Garrick T, Buack S, Veiseh A, and Tache Y. Thyrotropin-releasing hormone (TRH) acts centrally to stimulate gastric contractility in rats. Life Sci 40: 649–657, 1987.[CrossRef][ISI][Medline]
  3. Goto Y and Tache Y. Gastric erosions induced by intracisternal thyrotropin-releasing hormone (TRH) in rats. Peptides 6: 153–156, 1985.[ISI][Medline]
  4. Ikai M, Itoh M, Joh T, Yokoyama Y, Okada N, and Okada H. Complement plays an essential role in shock following intestinal ischaemia in rats. Clin Exp Immunol 106: 156–159, 1996.[CrossRef][ISI][Medline]
  5. Iwata F, Joh T, Ueda F, Yokoyama Y, and Itoh M. Role of gap junctions in inhibiting ischemia-reperfusion injury of rat gastric mucosa. Am J Physiol Gastrointest Liver Physiol 275: G883–G888, 1998.[Abstract/Free Full Text]
  6. Kawai T, Joh T, Iwata F, and Itoh M. Gastric epithelial damage induced by local ischemia-reperfusion with or without exogenous acid. Am J Physiol Gastrointest Liver Physiol 266: G263–G270, 1994.[Abstract/Free Full Text]
  7. Kurokawa T, Joh T, Ikai M, Seno K, Yokoyama Y, and Itoh M. Rebamipide protects against oxygen radical-mediated gastric mucosal injury in rats. Dig Dis Sci 43, Suppl: 113S–117S, 1998.[ISI][Medline]
  8. Nagahashi S, Suzuki H, Miyazawa M, Nagata H, Suzuki M, Miura S, and Ishii H. Ammonia aggravates stress-induced gastric mucosal oxidative injury through the cancellation of cytoprotective heat shock protein 70. Free Radic Biol Med 33: 1073–1081, 2002.[CrossRef][ISI][Medline]
  9. O-Lee TJ, Wei JY, and Tache Y. Intracisternal TRH and RX-77368 potently activate gastric vagal efferent discharge in rats. Peptides 18: 213–219, 1997.[CrossRef][ISI][Medline]
  10. Santos J, Saperas E, Mourelle M, Antolin M, and Malagelada JR. Regulation of intestinal mast cells and luminal protein release by cerebral thyrotropin-releasing hormone in rats. Gastroenterology 111: 1465–1473, 1996.[ISI][Medline]
  11. Schally AV, Bowers CY, Redding TW, and Barrett JF. Isolation of thyrotropin releasing factor (TRF) from porcine hypothalamus. Biochem Biophys Res Commun 25: 165–169, 1966.[CrossRef][ISI][Medline]
  12. Sobue M, Joh T, Oshima T, Suzuki H, Seno K, Kasugai K, Nomura T, Ohara H, Yokoyama Y, and Itoh M. Contribution of capsaicin-sensitive afferent nerves to rapid recovery from ethanol-induced gastric epithelial damage in rats. J Gastroenterol Hepatol 18: 1188–1195, 2003.[CrossRef][ISI][Medline]
  13. Stephens RL and Tache Y. Intracisternal injection of a TRH analogue stimulates gastric luminal serotonin release in rats. Am J Physiol Gastrointest Liver Physiol 256: G377–G383, 1989.[Abstract/Free Full Text]
  14. Tache Y, Goto Y, Lauffenburger M, and Lesiege D. Potent central nervous system action of p-Glu-His-(3,3'-dimethyl)-Pro NH2, a stabilized analog of TRH, to stimulate gastric secretion in rats. Regul Pept 8: 71–78, 1984.[CrossRef][ISI][Medline]
  15. Tache Y, Maeda-Hagiwara M, Goto Y, and Garrick T. Central nervous system action of TRH to stimulate gastric function and ulceration. Peptides 9, Suppl 1: 9–13, 1988.[CrossRef]
  16. Tache Y, Stephens RL Jr, and Ishikawa T. Central nervous system action of TRH to influence gastrointestinal function and ulceration. Ann NY Acad Sci 553: 269–285, 1989.[Abstract]
  17. Tache Y, Vale W, and Brown M. Thyrotropin-releasing hormone: central nervous system action to stimulate gastric acid secretion. Nature 287: 149–151, 1980.[CrossRef][ISI][Medline]
  18. Tache Y, Yang H, and Yoneda M. Vagal regulation of gastric function involves thyrotropin-releasing hormone in the medullary raphe nuclei and dorsal vagal complex. Digestion 54: 65–72, 1993.[ISI][Medline]
  19. Tache Y and Yoneda M. Central action of TRH to induce vagally mediated gastric cytoprotection and ulcer formation in rats. J Clin Gastroenterol 17, Suppl 1: S58–S63, 1993.
  20. Tache Y, Yoneda M, Kato K, Kiraly A, Suto G, and Kaneko H. 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.
  21. Thiefin G, Tache Y, Leung FW, and Guth PH. Central nervous system action of thyrotropin-releasing hormone to increase gastric mucosal blood flow in the rat. Gastroenterology 97: 405–411, 1989.[ISI][Medline]
  22. Watanabe K, Joh T, Seno K, Takahashi N, Ohara H, Nomura T, Tochikubo K, and Itoh M. Injurious effect of Helicobacter pylori culture fluid to gastroduodenal mucosa, and its detoxification by sucralfate in the rat. Aliment Pharmacol Ther 13: 1363–1371, 1999.[CrossRef][ISI][Medline]
  23. White RL Jr, Rossiter CD, Hornby PJ, Harmon JW, Kasbekar DK, and Gillis RA. Excitation of neurons in the medullary raphe increases gastric acid and pepsin production in cats. Am J Physiol Gastrointest Liver Physiol 260: G91–G96, 1991.[Abstract/Free Full Text]
  24. Yanagisawa K and Tache Y. Intracisternal TRH analogue RX-77368 stimulates gastric histamine release in rats. Am J Physiol Gastrointest Liver Physiol 259: G599–G604, 1990.[Abstract/Free Full Text]
  25. Yoneda M and Tache Y. Central thyrotropin-releasing factor analog prevents ethanol-induced gastric damage through prostaglandins in rats. Gastroenterology 102: 1568–1574, 1992.[ISI][Medline]




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