Central action of somatostatin analog, SMS 201-995, to stimulate gastric acid secretion in rats

The effects of intracisternal and intravenous injections of the somatostatin analog, SMS 201-995, on gastric acid secretion were investigated in rats with pylorus ligation or gastric cannula. Intracisternal injection of SMS 201-995 induced a dose-related (0.1-0.3 microgram) and long-lasting stimulation of gastric acid output with a peak response at 3 h postinjection in conscious, pylorus-ligated rats. Intracisternal SMS 201-995 increased histamine levels in the portal blood, whereas plasma gastrin levels were not modified. Atropine, cimetidine and adrenalectomy abolished the stimulatory effect of intracisternal SMS 201-995 (0.3 microgram). SMS 201-995 (0.03 microgram), microinjected unilaterally into the dorsal vagal complex, increased gastric acid output in urethane anesthetized rats. SMS 201-995, injected intravenously at 0.5 microgram, did not alter gastric secretion, whereas higher doses (5-20 micrograms) resulted in a dose-related inhibition of gastric acid secretion in conscious pylorus-ligated rats. These data indicate that SMS 201-995, a selective ligand for somatostatin-1 receptor subtype, induces a centrally mediated stimulatory effect on gastric acid secretion in rats. The central action involves the parasympathetic system, muscarinic and H2 receptors as well as adrenal-dependent pathways.     

Role of acetylcholine, histamine and gastrin in the acid response to intracisternal injection of TRH analog, RX 77368, in the rat

The role of gastrin, acetylcholine and histamine in the acid response to central vagal activation induced by intracisternal injection of the stable analog, RX 77368, was further investigated in urethane-anesthetized rats with gastric fistula. The gastrin monoclonal antibody 28-2 injected intravenously, at a dose previously shown to prevent gastrin-induced stimulation of acid secretion, did not alter the peak acid response to intracisternal injection of RX 77368 (15 ng). The TRH analog (30 ng) injected into the cisterna magna increased levels of histamine measured in the hepatic portal blood. Cimetidine administered at a dose which completely blocked the stimulation of gastric acid secretion produced by intravenous infusion of histamine, inhibited by 62% the stimulatory effect of intracisternal RX 77368 (30 ng). The M1 muscarinic antagonist, pirenzepine, completely prevented the acid secretion induced by intracisternal RX 77368 (30 ng). These results indicate that the acid response to central vagal activation by the TRH analog in rats involved M1 muscarinic receptors along with histamine release acting on H2 histaminergic receptors whereas gastrin does not appear to play an important role.     

吗啡和纳洛酮对损毁下丘脑诱致的大鼠胃粘膜损伤之影响

本实验观察了静注吗啡和纳洛酮对电解损毁后部下丘脑诱致的大鼠胃粘膜损伤的影响并观察了在静注吗啡、纳洛酮后和侧脑室注射纳洛酮后其胃酸分泌和血清胃泌素水平之变化。实验揭示,吗啡仅略为降低该神经源性胃粘膜损伤程度,而纳洛酮则明显地减少其胃粘膜损伤;静注吗啡能抑制后部下丘脑损毁后大鼠的胃酸分泌,增加其血清胃泌素水平,而静注纳络酮后,这种大鼠的胃酸分泌增加,但血清胃泌素水平无明显变化;侧脑室注射纳洛酮对后部下丘脑损毁后大鼠胃酸分泌和血清胃泌素水平无明显影响。本结果表明,胃酸可能是导致这种消化道损伤的条件之一,而不是最重要因素;静注纳洛酮对后部下丘脑损毀后大鼠胃粘膜变化有保护作用。后者提示,内源性阿片样肽可能参与这种神经源性胃粘膜损伤的形成。     

Intraluminal acid and gastric mucosal integrity: the importance of blood-borne bicarbonate

The acid-secreting gastric mucosa resists intraluminal acid better than the nonsecreting. Here we investigated pH at the epithelial cell surface, mucosal permeability, and blood flow during intraluminal administration of acid (100 mM) in acid-stimulated and nonstimulated gastric corpus mucosae. Surface pH (H(+)-selective microelectrodes), permeability (clearance of (51)Cr-EDTA), and mucosal blood flow (laser-Doppler flowmetry) were studied in Inactin-anesthetized rats. Acid secretion was stimulated with pentagastrin (40 microg. kg(-1). h(-1)) or impromidine (500 microg. kg(-1). h(-1)), or HCO(3)(-) (5 mmol. kg(-1). h(-1)) given intravenously. Surface pH was only slightly reduced by intraluminal acid in acid secretion-stimulated or HCO(3)(-)-treated rats but was substantially lowered in nonstimulated rats. Clearance increased threefold and blood flow increased by approximately 75% in nonstimulated rats. During stimulated acid secretion or intravenous infusion of HCO(3)(-), clearance was unchanged and blood flow increased by only approximately 30% during intraluminal acid. Increased epithelial transport of HCO(3)(-) buffering the mucus gel is most probably the explanation for the acid-secreting mucosa being less vulnerable to intraluminal acid than the nonsecreting.     

Gastric secretion and gastrin under progressive doses of somatostatin-14 and -28 administered intraperitoneally to the rat

The actions of progressive doses of intraperitoneally (IP) administered somatostatin-14 (SS-14) and -28 (SS-28) on gastric secretion (acid, pepsin) and mucosal blood flow (MBF) were studied in conscious gastric fistula rats both under basal conditions and under additional administration of pentagastrin. Also, somatostatin-like immunoreactivity was measured in aortal blood in all groups as well as aortal gastrin levels under basal conditions. IP infusion of equimolar doses of SS-14 and SS-28 resulted in an equal and dose-dependent inhibition of basal as well as pentagastrin-stimulated gastric acid secretion. MBF was reduced by either peptide both in the basal and pentagastrin experiments. Under basal conditions pepsin secretion was significantly increased by infusion of SS-14 at the higher doses, by infusion of SS-28 only at the intermediate dose (3.1 nmole kg-1.hr-1). In the pentagastrin experiments, low and intermediate doses of SS-14 tended to lower pepsin outputs but the highest dose of SS-14 stimulated pepsin secretion, whereas SS-28 had no effect on pepsin. Administration of SS-28 inhibited gastrin only at the highest dose (12.3 nmole kg-1.hr-1), and SS-14 had no influence at all on gastrin. After IP infusion of both peptides, plasma SLI rose dose-dependently under basal and stimulated conditions. Gel chromatography indicated an in-vivo conversion of SS-28 to SS-14 or intermediate fragments. It is concluded that SS-14 and SS-28 delivered by IP infusion, inhibit basal and stimulated gastric acid equally in the rat without suppressing gastrin. The mechanism underlying SS-mediated pepsin stimulation is unknown.     

Spinal and peripheral modulation of gastric acid secretion and arterial pressure by neuropeptide Y, peptide YY, and pancreatic polypeptide in rats

Spinal and peripheral modulation of pentagastrin-stimulated gastric acid secretion by the pancreatic polypeptide-fold (PP-fold) peptides, neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP), in urethane-anesthetized rats was evaluated. Neuropeptide Y, PYY, and PP (400 pmol) were administered via intravenous (IV) and intrathecal (IT) injections. The ₂ antagonist, yohimbine, was used to evaluate the role of the ₂ adrenergic receptors in the modulation of pentagastrin-stimulated gastric acid secretion by NPY, PYY, and PP. Peptide YY and PP (IV) rapidly increased pentagastrin-stimulated gastric acid secretion. Peptide YY and PP (IT) increased pentagastrin-stimulated gastric acid secretion following administration into the thoracic (T8–T10) region of the spinal cord. The ₂ adrenergic receptor antagonist, yohimbine, did not modify the increases in pentagastrin-stimulated gastric acid secretion following PYY and PP (IV or IT) administration. Neuropeptide Y (IT) decreased pentagastrin-stimulated gastric acid secretion. However, in the presence of ₂ adrenergic receptor blockade, pentagastrin-stimulated gastric acid secretion was potentiated by NPY (IT) administration. Therefore, the inhibitory effect of NPY (IT) on pentagastrin-stimulated gastric acid secretion required the activation of ₂ adrenergic receptors in the spinal cord of rats. Mean arterial blood pressure (MAP) was increased immediately following NPY and PYY (IV) administration. During the same time period, PP (IV) decreased MAP in anesthetized rats. Mean arterial blood pressure was rapidly increased by NPY and PYY (IT) in anesthetized rats. The increase in MAP following PYY (IT) was partially attenuated in the presence of yohimbine. The modulation of MAP and gastric acid secretion by the PP-fold peptides occurred by independent mechanisms at spinal and peripheral sites in the rat. The modulation of pentagastrin-stimulated gastric acid secretion by PYY and PP in rats differed from that of the third member of the PP-fold family, NPY, following spinal and peripheral administration.     

Effect of gastrin monoclonal antibody 28.2 on acid response to chemical vagal stimulation in rats

The role of gastrin in mediating the acid response to chemical vagal stimulation was evaluated by intravenous injection of the gastrin monoclonal antibody 28.2 (2.6 mg/rat). The antibody was injected 30 min prior to the administration of vagal stimulants in urethane-anesthetized rats equipped with a double lumen gastric cannula. The gastrin monoclonal antibody 28.2 prevented gastrin-17- but not carbachol-stimulated gastric acid secretion. The gastric acid response to vagal stimulation produced by thyrotrophin-releasing hormone (TRH) injected into the cisterna magna or the dorsal vagal complex and by the GABAB agonist, baclofen, infused intravenously was reduced by 33, 22 and 33% respectively in rats administered with gastrin monoclonal antibody 28.2. These immunoneutralization studies provide evidence that approximately 75% of the acid response to vagal stimulation is not mediated by gastrin in urethane-anesthetized rats.     

Central catecholaminergic control of ACTH secretion

Plasma adrenocorticotropic hormone (ACTH) has been measured after an intra-third ventricular administration of noradrenaline, an adrenergic agonist or an adrenergic antagonist. Centrally administered noradrenaline caused a significant increase in ACTH secretion. The alpha-agonist phenylephrine also increased the ACTH level. However, neither the alpha-antagonist phentolamine nor beta-agonist isoproterenol affected the ACTH level. The beta-antagonist propranolol evoked a significant elevation in ACTH. Passive immunoneutralization was examined with anti-rat corticotropin-releasing factor (CRF) rabbit serum, anti-arginine vasopressin (AVP) rabbit serum and normal rabbit serum (NRS) on the intra-third ventricular noradrenaline-induced ACTH secretion to study the involvement of endogenous CRF. An intra-third ventricular administration of noradrenaline caused a significant increase of ACTH levels in NRS-injected rats and anti-AVP-injected rats, whereas an i.v. anti-rat CRF injection significantly reduced the intra-third ventricular noradrenaline-induced ACTH secretion. These results suggest that central catecholamine stimulated ACTH secretion via the alpha-adrenergic mechanism and that endogenous CRF is at least partly involved in the noradrenaline-induced ACTH secretion.     

Partial sleep deprivation compromises gastric mucosal integrity in rats

The gastric mucosa is most susceptible to stress that has been shown to induce mucosal damage in humans and animals. This study aims to explore the underlying mechanisms of partial sleep deprivation, as a source of psychophysiological stress, on gastric functions and its effect on mucosal integrity. Sprague-Dawley rats were partially sleep deprived (PSD) for 7 or 14 days by housing inside slowly rotating drums. Gastric tissues and plasma were sampled at the end of the sleep deprivation periods and mucosal lesion scores were evaluated. Morphological examination was performed after Hematoxylin and Eosin staining. Plasma levels of noradrenaline, adrenaline, gastrin, histamine and somatostatin were determined with enzyme immunoassays. Gastric acidity was measured with acid-base titration in pylorus ligated rats. Gastric mucosal blood flow was evaluated with Laser Doppler Flowmetry. It was found that gastric lesions were induced in about 30%-50% of the PSD rats. Gastric acidity as well as plasma levels of noradrenaline, gastrin and histamine were elevated. Gastric mucosal blood flow and plasma somatostatin level were on the contrary reduced, especially in rats with PSD for 14 days. It is concluded that partial sleep deprivation compromises gastric mucosal integrity by increasing gastric acidity, plasma levels of noradrenaline, gastrin, histamine, and decreasing gastric mucosal blood flow. These results provided experimental evidence on the gastric damaging effects of PSD and it could be one of the risk factors contributing to gastric ulcer formation.     

Exogenous and endogenous ghrelin in gastroprotection against stress-induced gastric damage

Ghrelin, identified in the gastric mucosa has been involved in control of food intake and growth hormone (GH) release but little is known about its influence on gastric secretion and mucosal integrity. The effects of ghrelin on gastric secretion, plasma gastrin and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) were determined. Exogenous ghrelin (5, 10, 20, 40 and 80 microg/kg i.p.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS and this was accompanied by the significant rise in plasma ghrelin level, gastric mucosal blood flow (GBF) and luminal NO concentrations. Ghrelin-induced protection was abolished by vagotomy and attenuated by suppression of COX, deactivation of afferent nerves with neurotoxic dose of capsaicin or CGRP(8-37) and by inhibition of NOS with L-NNA but not influenced by medullectomy and administration of 6-hydroxydopamine. We conclude that ghrelin exerts a potent protective action on the stomach of rats exposed to ethanol and WRS, and these effects depend upon vagal activity, sensory nerves and hyperemia mediated by NOS-NO and COX-PG systems.     

The role of food intake on gastric mucosal growth and gastrin receptors during pregnancy and lactation

We examined the effects of pregnancy and lactation on mucosal growth and the numbers and affinity of gastrin receptors in the oxyntic gland mucosa in rats and compared these with changes in serum gastrin levels and food consumption. Gastric mucosal DNA, RNA, and protein contents were significantly increased during lactation. These changes were not observed in either pregnant or nonlactating rats which had given birth at the same time as the lactating animals. The gastrin-binding capacity of a membrane fraction of the oxyntic mucosa was also increased at the corresponding periods in lactating rats (Days 7, 15, 20). Scatchard plot analysis revealed that the number of gastrin receptors was significantly increased without any change in affinity. Food consumption and levels of serum gastrin remained unaltered in pregnant and non-lactating rats compared to virgin controls, but were significantly increased in lactating rats. Increased serum gastrin levels and gastrin binding capacities in lactating rats (Day 15) were abolished by preventing increased food consumption by means of pair feeding. The results demonstrate that the number of gastrin receptors in the oxyntic mucosa increases during lactation in rats. This increase is probably due to hypergastrinemia caused by increased food intake. The increased number of gastrin receptors may be involved in the mechanism of hypertrophic responses of the gastric mucosa in lactating rats.     

The influence of prolonged cimetidine administration on serum gastrin levels and gastric acid secretion in rats.

The correlation between serum gastrin levels and gastric acid secretion during 4 weeks of cimetidine administration (once daily) was investigated. Serum gastrin levels and gastric acid secretion were estimated on the 7th, 14th, 21st and 28th day after cimetidine administration (25 mg.kg-1, intragastrically). At the mentioned time intervals gastric acid secretion stimulated by histamine and pentagastrin was also studied. It was found that on the 14th and 21st day after cimetidine administration serum gastrin levels were significantly elevated. Basal gastric acid secretion after cimetidine administration was significantly decreased at all the observed time intervals. Histamine-stimulated gastric acid secretion was increased on the 14th, 21st and 28th day after cimetidine administration. Hypoacidity was not followed at all time intervals by hypergastrinaemia (only on day 14 and 21 after cimetidine).     

Central regulation of gastric acid secretion: The role of neuropeptides

A variety of stimuli can act through the central nervous system to alter gastric acid secretion. Lesioning and stimulation experiments have established roles for the lateral and ventromedial hypothalamus and the limbic system in the central regulation of gastric acid secretion. Recently a number of neuropeptides have been demonstrated to alter gastric acid secretion after central administration. Thyrotropin-releasing hormone (TRH) and gastrin both increase gastric acid secretion, whereas bombesin, calcitonin, the endogenous opioid peptides and neurotensin decrease gastric acid secretion. With the exception of bombesin, all the other neuropeptides appear to produce their effects through a vagally mediated mechanism. In addition, a number of these neuropeptides, when centrally administered, have been demonstrated to exert a potent cytoprotective effect against stress ulcer development. This review develops a peptidergic hypothesis of gastric acid secretion, suggesting that the final integration of the cephalic phase of gastric acid secretion is brought about by maintaining a delicate balance in the concentration of a number of interacting peptides and monoamines.     

Gastrin and interleukin-1beta stimulate growth factor secretion from cultured rabbit gastric parietal cells

The hormone gastrin stimulates proliferation of the gastric mucosa. Inflammation of the stomach is also associated with increased proliferation. The proliferative response is important in the reparative response to injury but can be deleterious by predisposing to the development of cancer. Parietal cells, but not the cells in the proliferative zone of the gastric glands, express the appropriate gastrin receptor. Parietal cells may mediate the trophic effects of gastrin by secreting other growth factors. The role of parietal cells in the proliferative responses has been examined in this study. Rabbit parietal cells were cultured with gastrin or the cytokine interleukin-1beta for 18 hours. The conditioned medium from gastrin or IL-1beta stimulated parietal cells increased proliferation of HeLa cells in an epidermal growth factor-receptor dependant manner. Gastrin and IL-1beta stimulated the secretion of heparin-binding epidermal growth factor and amphiregulin but not transforming growth factor-alpha from parietal cells. Combinations of gastrin and IL-1beta on growth factor secretion were synergistic. The protein kinase C inhibitor staurosporine abolished these stimulatory effects of gastrin and IL-1beta. Divergent effects on histamine-stimulated acid secretion were observed; 18 hours pre-treatment with gastrin enhanced acid secretion by 50% but IL-1beta inhibited acid secretion in both control and gastrin pre-treated parietal cells. The acid-secreting parietal cell plays a central role in the regulation of mucosal proliferation in gastric inflammation. Secretion of paracrine growth factors by parietal cells may be an important point of integration between the endocrine and inflammatory stimuli in determining mucosal responses to injury and inflammation.     

Inhibition of gastric acid secretion by intracerebral injection of calcitonin gene related peptide in rats

Calcitonin gene related peptide (CGRP), a 37 amino acid peptide recently characterized from the rat brain, injected into the cisterna magna or the lateral hypothalamus, inhibited gastric acid secretion and increased serum gastrin levels in conscious pylorus-ligated rats. CGRP suppressed pentagastrin- and histamine-induced stimulation of gastric secretion in urethane-anesthetized gastric fistula rats. Peptide action was dose-dependent, not modified by adrenalectomy and peripheral sympathectomy induced by guanethidine pretreatment and reversed by vagotomy. These results demonstrate that intracisternal or intralateral hypothalamic injection of CGRP inhibits stimulated gastric acid secretion. The mechanism of action is vagal dependent and unrelated to modification of gastrin secretion or activation of sympathetic outflow.     

Effect of sialoadenectomy on stomach lesions induced by indomethacin and ethanol in relation to gastric vascular permeability, the gastrin level and HCl secretion in rats.

Stomach lesions induced by indomethacin (20 mg.kg-1 i.p.) and ethanol (1 ml 95% intragastrically) were studied after a 24 hour fast in rats which had undergone sialoadenectomy. The size of the lesions was correlated with gastric HCl secretion, with gastric vascular permeability (determined from the Evans blue concentration in the stomach tissue after its i.v. administration) and with the serum gastrin level. These parameters were also studied in sialoadenectomized rats and in animals given epidermal growth factor (EGF) (50 lg.kg-1). It was found that sialoadenectomy significantly (p < 0.01) raised the incidence of stomach lesions after the administration of indomethacin and also after ethanol (p < 0.05). A significant increase in both basal and stimulated HCl secretion was found after sialoadenectomy. Both indomethacin and ethanol also increased gastric vascular permeability in rats not subjected to sialoadenectomy, but sialoadenectomy raised it significantly compared with the non-sialoadenectomized group. The serum gastrin levels fell after sialoadenectomy and the decrease was significant after the subsequent administration of indomethacin or ethanol. The administration of EGF to sialoadenectomized rats lowered the incidence of stomach lesions, inhibited HCl secretion and reduced vascular permeability. The lowered susceptibility of the gastric mucosa to the formation of lesions in sialoadenectomized rats given indomethacin or ethanol can be regarded as the outcome of the uptake of EGF.     

血清胃泌素变化与急性胃粘膜病变关系的研究

对大白鼠血清中胃泌素水平的变化与急性胃粘膜病变的关系进行了初步的研究,结果表明以消炎痛为诱因引起的急性胃粘膜病变大白鼠血清胃泌素水平明显增高。而维酶素可以抑制因消炎痛引起的急性胃粘膜病变时血清胃泌素的释放,对胃粘膜具有保护作用。     

Urethane-induced somatostatin mediated inhibition of gastric acid: reversal by the somatostatin 2 receptor antagonist, PRL-2903.

Urethane increases the release of somatostatin (SRIF) which inhibits gastric acid secretion. The SRIF monoclonal antibody, CURE.S6 and the novel sst2 antagonist, PRL-2903 injected intravenously at maximal effective doses increased gastric acid secretion by 2 and 10 fold respectively from basal values within 30 min in urethane-anesthetized rats. Plasma gastrin levels were elevated 2.5 fold within 15 min by PRL-2903 (1.3 micromol/kg, i.v.). These data indicate that the low gastrin and acid secretion levels induced by urethane result from endogenous SRIF acting on sst2 and that PRL-2903 is a valuable SRIF antagonist to assess sst2 mediated events.     

Synergistic action of gastrin and ghrelin on gastric acid secretion in rats

Gastrin and ghrelin are secreted from G cells and X/A-like cells in the stomach, respectively, and respective hormones stimulate gastric acid secretion by acting through histamine and the vagus nerve. In this study, we examined the relationship between gastrin, ghrelin and gastric acid secretion in rats. Intravenous (iv) administration of 3 and 10 nmol of gastrin induced transient increases of ghrelin levels within 10 min in a dose-dependent manner. Double immunostaining for ghrelin and gastrin receptor revealed that a proportion of ghrelin cells possess gastrin receptors. Although (iv) administration of gastrin or ghrelin induced significant gastric acid secretion, simultaneous treatment with both hormones resulted in a synergistic, rather than additive, increase of gastric acid secretion. This synergistic increase was not observed in vagotomized rats.These results suggest that gastrin may directly stimulate ghrelin release from the stomach, and that both hormones may increase gastric acid secretion synergistically.     

Calcitonin and secretin inhibit bombesin-stimulated serum gastrin and gastric acid secretion in man

The effect of intravenously administered calcitonin and secretin on bombesin-stimulated serum gastrin and gastric acid secretion was studied in 7 volunteers. Secretin G.I.H. (1 C.U./kg per h) and calcitonin (0.5 I.U./kg per h) significantly ($\text{P < 0.05}$) inhibited the serum gastrin and gastric acid responses to bombesin-14 (90 pmol/kg per h). Inhibition of gastrin release could not fully account for the inhibition of gastric acid secretion.