Central neurotensin protects the mucosa by a prostaglandin-mediated mechanism and inhibits gastric acid secretion in the rat.
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Animals↗
Biomedical subjects
G L Kauffman
Publications and source records attributed to G L Kauffman.
Intrahypothalamic corticotropin-releasing factor elevates gastric bicarbonate and inhibits stress ulcers in rats.
The effects of intrahyopthalamic microinfusions of corticotropin-releasing factor (CRF) on gastric bicarbonate, acid, and pepsin content and on cold restraint-induced gastric lesion formation were tested in three experiments. Bilateral microinfusions of CRF into the hypothalamic ventromedial nucleus (0.86 nmol/rat) significantly increased both gastric bicarbonate concentration and total bicarbonate output. These effects were observed irrespective of whether rats were pretreated with the acid antisecretory drug omeprazole. In nonomeprazole-pretreated rats, CRF microinfusions also significantly reduced acid secretion and raised pH. The increase in bicarbonate content accounted for half of the observed decrease in acid output, suggesting that CRF microinfusions activated separable bicarbonate-stimulating and acid-inhibiting hypothalamic systems. In non-omeprazole-pretreated rats, CRF microinfusions significantly increased serum gastrin, whereas pepsin output was unchanged. Gastric mucosal damage produced by 4 h of cold restraint was significantly diminished by CRF microinfusion into the ventromedial hypothalamus. These data demonstrate that ventromedial hypothalamic microinfusions of CRF increase bicarbonate content, decrease gastric acid content, and confer protection against cold restraint-induced gastric mucosal damage. Hypothalamic CRF neuronal terminals and receptors may be involved in the central regulation of gastric bicarbonate secretion as well as acid secretion.
Animals↗
Effect of neurotensin on regional cerebral glucose utilization in cold water-restrained rats.
Neurotensin (NT), given intracerebroventricularly (icv), attenuates cold water restraint (CWR)-induced gastric mucosal injury; however, it is not clear which brain nuclear group or groups are involved. These studies tested the hypothesis that neuronal function, as measured by regional cerebral metabolic rate for glucose (rCMRGlc), is altered by icv NT with or without CWR. CWR resulted in a reduced global glucose utilization of 72 and 65% in control and NT-treated rats, respectively. NT, given icv, protected against ulcer formation induced by CWR. In those rats given NT icv, rCMRGlc was elevated significantly in amygdala, nucleus accumbens, substantia nigra, tuberculum olfactrium, hypothalamus, and cerebellum compared with CWR rats without NT pretreatment. This rCMRGlc increase was observed in both unstressed and stressed rats given NT icv in the nucleus accumbens and amygdala. These observations suggest that the nucleus accumbens and amygdala, both components of the mesolimbic dopamine system, are involved in the central action of NT on the gastric mucosa.
Animals↗
Central neurotensin inhibits gastric acid secretion: an adrenergic mechanism in rats.
Although parenteral neurotensin (NT) inhibits stimulated gastric acid secretion, published reports on the effect of centrally administered NT on gastric acid secretion are conflicting. This study provides evidence suggesting that, in chronic gastric fistula rats, intracerebroventricularly administered NT (15-60 micrograms) significantly reduces both basal and pentagastrin-, 2-deoxy-D-glucose-, and carbachol-but not histamine-stimulated gastric acid secretion. Using radioimmunoassay, the concentration of plasma immunoreactive NT increased from 30 to 200 pg/ml at 30 and 60 min, respectively after a single intracerebroventricular (i.c.v.) administration of NT at a dose of 60 micrograms. These serum NT concentrations can be reproduced by a constant NT i.v. infusion at 2 micrograms/kg.h. This parenteral infusion dose does not inhibit acid secretion as does i.c.v. NT. Pretreatment with the i.c.v. dopamine-2 receptor antagonists haloperidol or domperidone totally abolishes the inhibitory effect of i.c.v. NT on pentagastrin-stimulated gastric acid secretion. In contrast, pretreatment with the specific dopamine-1 receptor antagonist SCH 23900 or the specific dopamine-2 receptor antagonist sulpiride does not affect i.c.v. NT-induced inhibition of pentagastrin-stimulated gastric acid secretion. Pretreatment (intracerebroventricularly) with the alpha-adrenergic antagonist phentolamine blocks the antisecretory effect of i.c.v. NT. Administration of 3.0 micrograms NT per side directly into nucleus accumbens (NACB), using a stereotaxic technique, significantly reduces basal gastric acid secretion. This effect of central NT is blocked by pretreatment with intra-NACB haloperidol (0.5 microgram per side). These findings suggest that NT acts centrally to inhibit gastric acid secretion, an effect that may occur within NACB and be mediated by central nervous system alpha-adrenergic receptor activation.
Animals↗
Central neurotensin affects rat gastric integrity, prostaglandin E2, and blood flow.
The aim of this study is to define the effect(s) of centrally administered neurotensin (NT) on gastric mucosal integrity, prostaglandin E2 (PGE2) generation, and blood flow during stress induced by cold-water restraint (CWR) in rats. Intracerebroventricular (icv) NT reduced macroscopic and microscopic damage. The former effect was dose dependent and was totally blocked by indomethacin pretreatment. Gastric mucosal PGE2 increased 27 and 30% at 30 and 60 min, respectively, in nonrestrained rats given icv NT. PGE2 generation was reduced in control rats during CWR but was maintained in CWR rats treated with icv NT. Gastric mucosal blood flow (GMBF) was significantly reduced in control rats during CWR. Mucosal blood flow was maintained at nonrestraint levels in the presence of icv NT during CWR; however, this effect was abolished by parenteral indomethacin pretreatment. Similarly, intravenous 16,16-dimethyl-PGE2 (200 micrograms.kg-1.h-1) maintained GMBF of non-CWR levels as well as preventing the macroscopic damage normally associated with CWR. These data suggest a protective role for central NT on the gastric mucosa, mediated, at least in part, by PGE2 generation and gastric mucosal blood flow.
16,16-Dimethylprostaglandin E2↗
Thermal resistance of human malignant melanoma modulated by prostaglandin E2.
The inhibition of DNA synthesis in a human malignant melanoma cell line as measured by tritiated thymidine (3H-TdR) incorporation was both time- and temperature dependent. Two components of cell damage were identified: a cytostatic, temporary component from which cells recovered within 2-6 days, and a cytotoxic, permanent component from which no recovery was observed. Thermotolerance was induced in M14 cells by sublethal heat treatment at 41 degrees C for 1 hr. However, induction of thermotolerance was blocked by indomethacin, a prostaglandin synthetase inhibitor. Exogenous PGE2 at concentrations up to 10 micrograms/ml also protected cells from heat damage. These data suggest that prostaglandin synthesis increases during heat stress and may play a role in protecting cells from thermal damage.
Dinoprostone↗
Role of prostanoids in experimental duodenal ulcer in rat.
The purposes of this study were to determine whether inhibition of cyclooxygenase is a mechanism by which cysteamine and mepirizole produce duodenal ulcers, identify qualitative or quantitative differences in prostanoid production between gastric mucosa and duodenum, and determine whether differences in cyclooxygenase sensitivity to inhibition by aspirin exist between these two tissues. In fed female rats, gastric mucosal prostaglandin E2 (PGE2) and prostacyclin (PGI2) generation was 235 +/- 25 and 832 +/- 40 ng/g/min, respectively, whereas full-thickness duodenal PGE2 and PGI2 generation was 665 +/- 46 and 662 +/- 49 ng/g/min, respectively. Over an intraperitoneal dose range of 0-25 mg/kg, aspirin-induced cyclooxygenase inhibition was dose-dependent and similar for the two tissues. Duodenal ulceration (16.7 mm2) produced by cysteamine, 425 mg/kg, was associated with a 46% reduction in duodenal PGE2 generation, while having no effect on PGI2 generation; however, cysteamine, 213 mg/kg, produced no visible duodenal mucosa injury yet reduced duodenal PGE2 generation 39% compared to control values. In fed male rats, gastric mucosal PGE2 and PGI2 generation was 179 +/- 18 and 813 +/- 61 ng/g/min, respectively, whereas duodenal PGE2 and PGI2 generation was 321 +/- 27 and 454 +/- 38 ng/g/min, respectively. Duodenal ulceration (7.7 +/- 2.3 mm2) produced by oral mepirizole was associated with a 63% reduction in duodenal PGE2 generation compared to control values, while having no effect on PGI2 generation. Subcutaneous aspirin, 100 mg/kg, which reduced duodenal PGE2 generation to a greater degree than either ulcerogen, given in conjunction with pentagastrin, did not produce visible duodenal ulceration.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Central nervous system action of calcitonin to alter experimental gastric ulcers in rats.
The central nervous system action of calcitonin to influence various experimental models of gastric ulcers and gastric function was studied in rats fasted for 24 h. Intracisternal injection of salmon calcitonin (5 micrograms) completely suppressed gastric ulcerations induced by exposure to cold restraint stress, intracisternal injection of a stable thyrotropin-releasing hormone analogue, or peroral administration of aspirin. By contrast, intracisternal calcitonin enhanced gastric lesions elicited by peroral administration of 40% ethanol or 0.6 N HCl. Calcitonin action was dose-dependent (0.01-1 microgram) and central nervous system mediated inasmuch as intravenous calcitonin, given at a dose 50-fold higher than that effective intracisternally, did not significantly modify gastric mucosal injuries elicited by aspirin or ethanol. Intracisternal injection of calcitonin at 0.01 microgram inhibited gastric acid output by 90% in pylorus-ligated rats and suppressed gastric emptying of a liquid meal by 63%-94% in doses ranging from 0.01 to 5 micrograms. Prostaglandin generation in the gastric mucosa was not modified by intracisternal injection of calcitonin. These results demonstrate that intracisternal calcitonin acts within the brain to potently prevent ulcer formation elicited by stress, thyrotropin-releasing hormone analogue, or aspirin, but is not cytoprotective against necrotizing agents. Calcitonin action is not related to modification of gastric prostaglandin generation but it may involve the inhibition of gastric secretory and motor function.
Animals↗
Gastric vascular and mucosal damaging actions of platelet activating factor in the canine stomach.
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Animals↗
Prostaglandin requirements are greater for protection in cold restraint-induced than alcohol-induced gastric mucosal injury.
Exogenous prostaglandins inhibit visible gastric mucosal lesions produced by both absolute ethanol and cold restraint in the rat. Pretreatment with "mild irritants" significantly reduces the magnitude of ethanol-induced lesions presumably by stimulating endogenous prostanoid production. The effect of mild irritant pretreatment on cold restraint-induced lesion formation has not been previously reported. This study was designed to compare the protective effect of pretreatment with two "mild irritants," 4% NaCl and 0.35 M HCl, and the synthetic prostanoid, 16,16 dimethyl PGE2(16,16-dm PGE2), on lesions produced by cold restraint or absolute ethanol. Pretreatment with both mild irritants produced complete visible protection against ethanol-induced injury but had variable effects against cold restraint-induced injury. Whereas 5 micrograms/kg 16,16-dmPGE2 provided complete visible protection against ethanol-induced injury, 20 micrograms/kg 16,16-dmPGE2 was required for complete visible protection against cold restraint-induced injury. We conclude that prostaglandin requirements for protection against cold restraint injury are greater than for protection against ethanol-induced gastric mucosal injury.
16,16-Dimethylprostaglandin E2↗
Endoscopic measurement of gastric corpus mucosal blood flow in conscious dogs.
This study reports the feasibility of applying the hydrogen gas clearance technique with 3% hydrogen in air and platinum contact electrode to measure corpus mucosal blood flow in conscious dogs. Three percent hydrogen in air is safe and does not produce hypoxia during inhalation. A specially prepared, six-inch polyvinyl chloride pipe was used as a bite-block. The platinum contact electrode, attached to (but not within) a soft rubber suction cup, was passed into the stomach with the aid of a gastroscope. Because of gastric contractions, low, continuous suction was required to maintain the electrode in contact with the corpus mucosa. Stable baseline corpus mucosal blood flow measurements were obtained on control and experimental days in five of 10 dogs. In these five dogs during 2 micrograms/kg/hr pentagastrin infusion, which induced submaximal acid secretion, corpus mucosal blood flow and gastric acid output were increased significantly (P less than 0.05) by 26 +/- 4% and 238 +/- 79%, respectively. These increases were similar to those previously observed in anesthetized rats, cats, rabbits, and dogs. In an anesthetized rat study, the measurement of corpus mucosal blood flow was found to be unaffected by the low continuous suction. Since the use of 3% hydrogen in air is safe, the technique deserves to be further evaluated in human studies.
Animals↗
Gastric mucus: lubricant or more?
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Animals↗
Carbamylcholine, but not somatostatin or neurotensin, stimulates prostaglandin E2 release from the isolated perfused rat stomach.
Prostaglandin E2 release by carbamylcholine (10(-6) M), somatostatin (10(-10)-10(-8) M) and neurotensin (10(-10) - 10(-8) M) has been evaluated in the isolated perfused rat stomach. Carbamylcholine significantly stimulated gastric PGE2 release and increased the perfusion pressure, whereas somatostatin and neurotensin had no effect. Combination of carbamylcholine with somatostatin or neurotensin produced no increase over that found with carbamylcholine alone. The relationship between perfusion-pressure and PGE2 release was not causal. The present findings do not support a role for prostaglandins in the mechanism of somatostatin or neurotensin action in the stomach.
Animals↗
Hemostatic mechanisms, independent of platelet aggregation, arrest gastric mucosal bleeding.
Platelet adhesion, aggregation, and subsequent plug formation play a major role in the control of cutaneous and vascular hemostasis. Little is known, however, about the hemostatic processes in gastric mucosal tissue. A method for evaluating bleeding from a standard incision in the gastric mucosa of the rat, rabbit, and dog has therefore been developed. By using pharmacological agents that interfere with platelet aggregation and blood coagulation, the mechanism of gastric hemostasis has been compared to that in the vasculature, using the rat mesenteric artery. Intravenous infusion of prostacyclin (0.5 micrograms X kg-1 X min-1), which inhibits platelet aggregation directly, or administration of the thromboxane synthase inhibitor 1-benzylimidazole (50 mg X kg-1) significantly prolonged bleeding in the mesenteric artery yet failed to alter gastric mucosal bleeding. In contrast, a low dose of heparin (100 units X kg-1), which interferes with the clotting process, had no effect on mesenteric bleeding but substantially prolonged bleeding from the gastric mucosa. These findings suggest that, unlike in the skin or vasculature, platelet aggregation plays a minimal role in the initial hemostatic events in the gastric mucosa and that the arrest of gastric hemorrhage is brought about largely by processes primarily involving the coagulation system.
Animals↗
Blood flow limitation of stimulated gastric acid secretion in the rat.
Secretagogue-stimulated gastric acid output is reduced when gastric mucosal blood flow is below normal. We tested the hypothesis that the reduction in acid secretion associated with reduced mucosal blood flow was due to a decrease in the delivery of the secretagogue. Gastric acid output was determined by continuous gastric lavage with 0.15 M NaCl, and gastric corpus mucosal blood flow was measured by hydrogen gas clearance in anesthetized, pylorus-ligated rats before and during a period of hypovolemia-induced reduction in mucosal blood flow. A linear correlation between pentagastrin- and histamine-stimulated gastric acid output and gastric corpus mucosal blood flow during hypotension over a range of mucosal blood flow rates was found, and each was expressed as a percentage of the plateau values before hemorrhage. When the dose of pentagastrin was doubled or tripled, or when the stimulation of gastric acid secretion was vagus nerve stimulation, a stimulant of acid secretion that is independent of blood flow for secretatogue delivery, the reduction in gastric acid output by hypotension was not reversed. We conclude that stimulated gastric acid secretion during hemorrhagic hypotension is blood flow-limited and not related to inadequate delivery of secretagogue to parietal cells.
Animals↗
Neurotensin-like immunoreactivity released into the portal vein by duodenal acidification in the dog.
The present study in the dog evaluates neurotensin as a potential hormone, mediating the inhibition of gastric acid secretion by duodenal acidification. Histamine-stimulated acid output was determined before and during duodenal acidification. Portal vein blood was obtained and assayed for carboxy-terminal neurotensin-like immunoreactivity (NTLI). Duodenal perfusion with 15 mmol HCL for 30 min significantly inhibited histamine-stimulated acid output to 67% of control output. This inhibition was not associated with any change in the peripheral plasma NTLI, but the portal plasma NTLI was significantly elevated from 27 to 78 pM. The effect of duodenal acidification on liver extract meal-stimulated acid secretion was determined in a second group of dogs without portal vein catheter. Duodenal perfusion with 15 mmol HCl for 30 min significantly inhibited meal-stimulated acid secretion to 37% of control output. Intravenous infusion of synthetic neurotensin to a plasma level of 130 pM was required to inhibit meal-stimulated acid output significantly. In summary, NTLI is elevated in portal, but not peripheral, plasma after duodenal acidification. The associated inhibition of acid secretion is not due to hormonal action of neurotensin.
Animals↗
The gastric mucosal barrier. Component control.
The 'gastric mucosal barrier' is a descriptive term for the ability of the gastric epithelium to hold a large (10(5)) H+ concentration gradient from lumen to mucosa under physiological conditions. Compounds which classically have been used to describe the functional integrity of the 'barrier', in addition to very low H+ diffusion from lumen to mucosa, include low diffusion of Na+ and K+ from mucosa to lumen and maintenance of a lumen-negative transmucosal potential difference (PD). Na+ appearance in the luminal fluid is a function of active transport and diffusion. Fixed charges within diffusion channels with pK values greater than or equal to 9, may contribute to maintenance of H+ gradients. Luminal application of aspirin, bile salts, and ethanol increases net cationic flux and reduces PD. When acidified, these luminal agents produce histological and visible damage, yet damage can be produced by parenteral agents without concomitant change in these components. Although no anatomical 'barrier' has been described, it has been suggested that the gel mucus and epithelial phospholipids are constituents. Exogenous administration of a variety of prostanoids attenuate the change in cationic flux and PD produced by those agents in both animals and humans. The role of endogenous prostaglandins in barrier integrity has been questioned since it has been shown that salicylic acid produces permeability changes which are equal to aspirin, yet the former does not inhibit cyclooxygenase while the latter does. The gastric mucosal barrier is physiologically important because, by whatever mechanism, H+ back-diffusion is kept to a minimum under physiological conditions.
16,16-Dimethylprostaglandin E2↗
Prostaglandins may not mediate inhibition of gastric acid secretion by somatostatin in the rat.
The role of prostaglandins as mediators of the inhibitory effect of somatostatin on gastric acid secretion has been evaluated in conscious and anesthetized rats. The effect of somatostatin on bethanechol-stimulated gastric acid secretion was determined with or without indomethacin pretreatment. Prostaglandin synthesis inhibition (less than 90%) by indomethacin was verified with PGE2-generation assay on gastric mucosal tissue. In both conscious and anesthetized rats somatostatin significantly inhibited the stimulated acid output in the control and indomethacin pretreated groups. The present findings do not support a role for prostaglandins in the inhibition of gastric acid secretion by somatostatin in the rat.
Anesthesia↗