Bombesin microinjected into the dorsal vagal complex inhibits vagally stimulated gastric acid secretion in the rat

Medullary sites of action for bombesin-induced inhibition of gastric acid secretion were investigated in urethane-anesthetized rats with gastric fistula. Unilateral microinjection of bombesin or vehicle into the dorsal vagal complex was performed using a glass micropipet and pressure ejection of 100 nl volume; gastric acid output was measured every 10 min by flushing the stomach. Microinjection of vehicle into the dorsal vagal complex did not alter gastric acid secretion (1.9 +/- mumol/10) from preinjection levels (2.9 +/- 0.8 mumol/10 min). Microinjection of the stable thyrotropin-releasing hormone (TRH) analog, RX 77368, at a 77 pmol dose into the dorsal vagal complex stimulated gastric acid secretion for 100 min with a peak response at 40 min (24.1 +/- 3.2 mumol/10 min). Concomitant microinjection of RX 77368 (77 pmol) with bombesin (0.6-6.2 pmol) into the dorsal vagal complex dose dependently inhibited by 35-86% the gastric acid response to the TRH analog. Bombesin (6.2 pmol) microinjected into the dorsal vagal complex inhibited by 17% pentagastrin infusion-induced stimulation of gastric acid secretion (13.2 +/- 0.8 mumol/10 min) whereas intracisternal injection induced a 69% inhibition of the pentagastrin response. These results demonstrate that the dorsal motor complex is a sensitive site of action for bombesin-induced inhibition of vagally stimulated gastric secretion. However, other medullary sites must be involved in mediating the inhibitory effect of intracisternal bombesin on pentagastrin-stimulated gastric acid secretion.     

Effects of calcium channel antagonists on the vagally mediated cardiac chronotropic response in dogs

A brief electrical stimulation of the vagus nerve may elicit a triphasic response comprising (i) an initial prolongation of the same or the next cardiac cycle, (ii) a return of the subsequent cardiac cycle to about the level prior to vagal stimulation, and (iii) a secondary prolongation of cardiac cycle length that lasts several beats. We compared the effects of two calcium channel antagonists, verapamil and nifedipine, on this triphasic response to vagal stimulation in chloralose-anesthetized, open-chest dogs. In the absence of vagal stimulation, nifedipine (doses of 10, 40, and 50 micrograms/kg for a total dose of 100 micrograms/kg, i.v.) and verapamil (two doses of 100 micrograms/kg each, i.v.) increased the cardiac cycle length (A-A interval) by 16% (429 +/- 20 to 496 +/- 21 ms) and 29% (470 +/- 33 to 605 +/- 54 ms), respectively. Nifedipine (100 micrograms/kg total) attenuated the initial vagally mediated prolongation of the A-A interval, from 474 +/- 19 to 369 +/- 42 ms above the basal A-A interval. Following the initial prolongation of the vagal effect, other A-A intervals were not affected. In contrast, verapamil potentiated the vagally mediated initial prolongation in cardiac cycle length at the first dose administered (100 micrograms/kg) from 492 +/- 17 to 561 +/- 14 ms, but other increases in dosages had no further effect. Thus these two calcium channel antagonists have different effects on the sinoatrial chronotropic responses caused by brief vagal stimulation.     

Calcium, carbonic anhydrase and gastric acid secretion

Previous data concerning the action of calcium (Ca) on gastric acid secretion (GAS) indicated that calcium ions increase GAS elicited by gastrin released through a vagal mechanism, and also by a direct effect on parietal cells. Our research showed that the stimulating effect of calcium on gastric acid secretion can be antagonized by verapamil administration, which reduces gastric acid secretion . In the present study we followed the effect induced by administration of calcium and Ca-chelating agents (disodium EDTA) on gastric acid secretion and on carbonic anhydrase (CA) activity. We selected two groups of healthy volunteers: Group I (n=21) received a single i.v. dose of CaCl2 (15 mg/kg b.w.), whereas Group II (n=22) received a single i.v. dose of disodium EDTA (5 mg/kg b.w.). We determined blood calcium before and after treatment, gastric acid secretion at 2 hours. erythrocyte CA II activity, and CA IV activity in membrane parietal cells, which were isolated from gastric mucosa obtained by endoscopic biopsy. Assessment of carbonic anhydrase activity was achieved by the stopped-flow method. In Group I calcium administration increased blood calcium, HCl output, CA II and CA IV activity as compared to initial values. In Group II, disodium EDTA reduced blood calcium, HCl output, CA II and CA IV activity as compared to initial values. The results demonstrated that increased blood calcium and GAS values after calcium administration correlated with the increase of erythrocyte CA II and parietal cell CA IV activity, while disodium EDTA induced a reversed process. Our results also show that cytosolic CA II and membrane CA IV values are sensitive to calcium changes and they directly depend on these levels. Our data suggest that intra- and extracellular pH changes induced by carbonic anhydrase might account for the modulation of the physiological and pathological secretory processes in the organism.     

Nesfatin-1 inhibits gastric acid secretion via a central vagal mechanism in rats

Nesfatin-1, a novel hypothalamic peptide, inhibits nocturnal feeding behavior and gastrointestinal motility in rodents. The effects of nesfatin-1 on gastrointestinal secretory function, including gastric acid production, have not been evaluated. Nesfatin-1 was injected into the fourth intracerebral ventricle (4V) of chronically cannulated rats to identify a nesfatin dose sufficient to inhibit food intake. Nesfatin-1 (2 μg) inhibited dark-phase food intake, in a dose-dependent fashion, for >3 h. Gastric acid production was evaluated in urethane-anesthetized rats. Nesfatin-1 (2 μg) was introduced via the 4V following endocrine stimulation of gastric acid secretion by pentagastrin (2 μg·kg(-1)·h(-1) iv), vagal stimulation with 2-deoxy-d-glucose (200 mg/kg sc), or no stimulus. Gastric secretions were collected via gastric cannula and neutralized by titration to determine acid content. Nesfatin-1 did not affect basal and pentagastrin-stimulated gastric acid secretion, whereas 2-deoxy-d-glucose-stimulated gastric acid production was inhibited by nesfatin-1 in a dose-dependent manner. c-Fos immunofluorescence in brain sections was used to evaluate in vivo neuronal activation by nesfatin-1 administered via the 4V. Nesfatin-1 caused activation of efferent vagal neurons, as evidenced by a 16-fold increase in the mean number of c-Fos-positive neurons in the dorsal motor nucleus of the vagus (DMNV) in nesfatin-1-treated animals vs. controls (P < 0.01). Finally, nesfatin-induced Ca(2+) signaling was evaluated in primary cultured DMNV neurons from neonatal rats. Nesfatin-1 caused dose-dependent Ca(2+) increments in 95% of cultured DMNV neurons. These studies demonstrate that central administration of nesfatin-1, at doses sufficient to inhibit food intake, results in inhibition of vagally stimulated secretion of gastric acid. Nesfatin-1 activates DMNV efferent vagal neurons in vivo and triggers Ca(2+) signaling in cultured DMNV neurons.     

Peptide histidine valine-42 stimulates gastric acid secretion in man

The effect of peptide histidine valine-42 (PHV-42) on gastric acid secretion was studied in man. PHV-42 was infused into 5 healthy volunteers at a dose of 10 pmol/kg/min. This dose caused a significant stimulation of basal gastric acid and potassium output. there were no significant changes in circulating gastrin throughout the infusion. In 2 subjects with a background of submaximal pentagastrin stimulation, PHV-42 infusion at the same dose did not alter acid secretion in either subject. The previous observation that PHV-42 is found particularly in the stomach and the new finding that it stimulates basal gastric secretion suggest the possibility that PHV-42 could have a role in local control of acid secretion.     

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.     

Vagus-mediated activation of mucosal mast cells in the stomach: effect of ketotifen on gastric mucosal lesion formation and acid secretion induced by a high dose of intracisternal TRH analogue.

TRH analogue, RX 77368, injected intracisternally (i.c.) at high dose (3 microg/rat) produces gastric mucosal lesion formation through vagal-dependent pathway. The gastric mucosal hyperemia induced by i.c. RX 77368 was shown to be mediated by muscarinic vagal efferent fibres and mast cells. Furthermore, electrical vagal stimulation was observed to induce gastric mucosal mast cell degranulation. The aim of the study was to assess the influence of ketotifen, a mast cell stabilizer, on RX 77368-induced gastric lesion formation and gastric acid secretion. RX 77368 (3 microg, i.c.) or vehicle (10 microL, i.c.) was delivered 240 min prior to the sacrifice of the animals. Ketotifen or vehicle (0.9% NaCl, 0.5 mL) was injected intraperitoneally (i.p.) at a dose of 10 mg x kg(-1) 30 min before RX 77368 injection. The extent of mucosal damage was planimetrically measured by a video image analyzer (ASK Ltd., Budapest) device. In the gastric acid secretion studies, the rats were pretreated with ketotifen (10 mg x kg(-1), i.p.) or vehicle (0.9% NaCl, 0.5 mL, i.p.), 30 min later pylorus-ligation was performed and RX 77368 (3 microg, i.c.) or vehicle (0.9% NaCl, 10 microL, i.c.) was injected. The rats were killed 240 min after i.c. injection, and the gastric acid secretion was measured through the titration of gastric contents with 0.1 N NaOH to pH 7.0. RX 77368 (3 microg, i.c.) resulted in a gastric mucosal lesion formation involving 8.2% of the corpus mucosa (n = 7). Ketotifen elicited an 85% inhibition on the development of mucosal lesions (n = 7, P < 0.001) whereas ketotifen alone had no effect on the lesion formation in the mucosa (n = 7). The RX 77368 induced increase of gastric acid secretion was not influenced by ketotifen pretreatment in 4-h pylorus-ligated animals. Central vagal activation induced mucosal lesion formation is mediated by the activation of mucosal mast cells in the stomach. Mast cell inhibition by ketotifen does not influence gastric acid secretion induced by i.c. TRH analogue in 4-h pylorus-ligated rats.     

Somatostatin release induced by gastrin-releasing peptide in man. Effect of proximal gastric vagotomy and cholinergic blockade

The influence of intragastric pH on the basal release of somatostatin has been studied in healthy controls and in duodenal ulcer patients. In addition the somatostatin response to gastrin-releasing peptide infusion has been evaluated both regarding the effect of intragastric pH and the influence of vagal innervation and muscarinic blockade. No difference was found in basal blood levels, when changing the intraluminal pH, although a slightly higher basal somatostatin concentration was noticed in patients with duodenal ulcer disease. Neither proximal gastric vagotomy nor cholinergic blockade had any effect on basal somatostatin concentrations. GRP infused in stepwise increasing doses from 20 pmol/kg/h to 400 pmol/kg/h induced a small but significant response. This effect of GRP was most evident, when the stomach was perfused with 0.1 M HCl. The small, somatostatin response to GRP infusion was not influenced by vagal denervation of the parietal cell area, neither by cholinergic blockade. Despite the previously observed effects of vagotomy and cholinergic blockade on gastrin release induced by GRP, a corresponding inverse effect on somatostatin is not apparent.     

铃蟾肽(Bombesin)对离体灌流大鼠胃的胃泌素、生长抑素、胰升糖素及胃酸释放的影响

本研究用离体大鼠胃灌流技术来观察铃蟾肽对胃-肠激素及胃酸分泌的影响。2×10~(?)mol/L铃蟾肽以0.3ml/min速度作动脉内输注,可刺激胃酸的分泌,自2.50±0.05×10~(-1)增至5.50±1.50×10~(-1)mEq/min,但与外源性五肽胃泌素无协同作用。铃蟾肽引起两次性的门脉中胃泌索及生长抑素的释放,但抑制胰升糖素释放。这三种激素的基础释放率分别为:胃泌素62±8pg,生长抑素5.9±1.1ng,胰升糖素0.40±0.03ng/min;2×10~(-8)mol/L铃蟾肽以0.3ml/min作动脉内输注,胃泌素及生长抑素的峰值分别为1,000±20pg及12.2±2.0ng/min,胰升糖素的最低值为0.17±0.05ng/min,三种激素的反应均与铃蟾肽的浓度成正比。在胃腔流出液中也可测到上述三种激素,但量要少得多。     

Gastric acid and vagus nerve response to GABA agonist baclofen

Baclofen [beta-(p-chlorophenyl)-gamma-aminobutyric acid], a lipophilic derivative of GABA, was studied for its effect upon the efferent activity of the left cervical vagus in urethane-anesthetized rats. Baclofen (4 mg/kg, s.c.) produces neural discharges in the multifiber vagus preparation. The time course of vagal activation is well correlated with the profile of stimulation of gastric acid secretion recorded every 2 min. Atropine pretreatment (1 mg/kg) did not modify baclofen stimulation of vagal activity. These results demonstrated that a GABAB receptor agonist stimulates the parasympathetic outflow through mechanisms independent of interaction with muscarinic receptors leading to stimulation of gastric acid secretion.     

Intracisternal injection of TRH precursor, TRH-glycine, stimulates gastric acid secretion in rats

Intracisternal injection of thyrotropin-releasing hormone (TRH)-Gly (pGlu-His-Pro-Gly) produced a dose-dependent (1-100 micrograms) stimulation of gastric acid secretion in urethane-anesthetized rats implanted acutely with a gastric fistula. The peak response occurred 20-30 min after intracisternal injection and lasted for more than 2 h. Intravenous injection of TRH-Gly (100 micrograms) did not modify gastric acid secretion. Following intracisternal injection of TRH-Gly, a peak elevation of both TRH-Gly and TRH levels is observed in the cerebrospinal fluid (CSF) within 15 min. Thereafter, TRH values are returned to basal levels at 75 min after the injection, whereas TRH-Gly concentrations remain significantly elevated throughout the 2-h period of measurement. Compartmental analysis revealed that CSF conversion of TRH-Gly to TRH was only 0.0072%/min. Medullary coronal sections containing the dorsal vagal complex and the raphé nucleus revealed increased content of TRH-Gly, but not TRH, 40 min after administration of TRH-Gly at an intracisternal dose effective in stimulating gastric acid secretion (100 micrograms). In addition, TRH but not TRH-Gly (10(-7)-10(-5) M) displaced [3H]MeTRH binding from rat medullary blocks containing the dorsal vagal complex. These data suggest that the intracisternal TRH-Gly-induced stimulation of gastric acid secretion is not related to its conversion to TRH in the CSF, or direct activation of TRH receptors in the medulla. The acid secretory response of TRH-Gly may be due to the formation of TRH at the active brain sites, or alternatively to activation of its own specific receptors.     

Intracisternal TRH analog induces Fos expression in gastric myenteric neurons and glia in conscious rats

Activation of gastric myenteric cells by intracisternal injection of the stable thyrotropin-releasing hormone (TRH) analog RX-77368, at a dose inducing near maximal vagal cholinergic stimulation of gastric functions, was investigated in conscious rats. Fos immunoreactivity was assessed in gastric longitudinal muscle-myenteric plexus whole mount preparations 90 min after intracisternal injection. Fos-immunoreactive cells were rare in controls (~1 cell/ganglion), whereas intracisternal RX-77368 (50 ng) increased the number to 24.8 +/- 1.8 and 26.8 +/- 2.2 cells/ganglion in the corpus and antrum, respectively. Hexamethonium (20 mg/kg sc) prevented Fos expression by 90%, whereas atropine (2 mg/kg sc) had no effect. The neuronal marker protein gene product 9.5 and the glial markers S-100 and glial fibrillary acidic proteins showed that RX-77368 induced Fos in both myenteric neurons and glia. Vesicular ACh transporter and calretinin were detected around the activated myenteric neurons. These results indicated that central vagal efferent stimulation by intracisternal RX-77368 activates gastric myenteric neurons as well as glial cells mainly through nicotinic ACh receptors in conscious rats.     

Mechanisms underlying intracisternal TRH-induced stimulation of gastric acid secretion in rats

The neurohumoral pathways mediating intracisternal TRH-induced stimulation of gastric acid secretion were investigated. In urethane-anesthetized rats, with gastric and intrajugular cannulas, TRH or the analog [N-Val2]-TRH (1 microgram) injected intracisternally increased gastric acid output for 90 min. Serum gastrin levels were not elevated significantly. Under these conditions the TRH analog, unlike TRH, was devoid of thyrotropin-releasing activity as measured by serum TSH levels. In pylorus-ligated rats, gastrin values were not modified 2 h after peptide injection whereas gastric acid output was enhanced. TRH (0.1-1 micrograms) stimulated vagal efferent discharge, recorded from a multifiber preparation of the cervical vagus in urethane-anesthetized rats and the response was dose-dependent. The time course of vagal activation was well correlated with the time profile of gastric stimulation measured every 2 min. These results demonstrated that gastric acid secretory stimulation elicited by intracisternal TRH is not related to changes in circulating levels of gastrin or TSH but is mediated by the activation of efferent vagal pathways that stimulated parietal cell secretion.     

Effect of atropine on plasma gastrin and somatostatin concentrations during sham feeding in man

The purpose of these studies was to measure circulating gastrin and somatostatin concentrations during sham feeding in humans and to evaluate the effect of two doses of intravenous atropine on circulating concentrations of these peptides. Gastric acid and bicarbonate secretion and pulse rate were also measured. Sham feeding increased plasma gastrin concentrations by approximately 15 pg/ml but had no effect on plasma somatostatin-like immunoreactivity (SLI). A small dose of atropine (5 micrograms/kg) augmented plasma gastrin concentrations during sham feeding significantly (P less than 0.01), but did not affect plasma SLI. Atropine also significantly inhibited gastric acid secretion and gastric bicarbonate secretion (by 62% and 52%, respectively), but pulse rate was not affected. A larger dose of atropine (15 micrograms/kg intravenously) suppressed plasma gastrin concentrations significantly compared to the smaller 5 micrograms/kg atropine dose (P less than 0.02), so that plasma gastrin concentrations when 15 micrograms/kg atropine was given were not significantly different from those during the control study. 15 micrograms/kg atropine reduced gastric acid and bicarbonate secretion by 81% and 66%, respectively, and also increased pulse rate by 15 min-1. These studies indicate that small doses of atropine enhance vagally mediated gastrin release in humans, probably by blocking a cholinergic inhibitory pathway for gastrin release. Although the nature of this cholinergic inhibitory mechanism is unclear, we found no evidence to incriminate somatostatin. Our finding that the larger dose of atropine reduced serum gastrin concentrations compared with the smaller dose suggests that certain vagal-cholinergic pathways may facilitate gastrin release.     

Physiological responses to low dose infusions of atrial peptide in conscious dogs

Mongrel dogs prepared with chronic catheters in their femoral artery and vein and urinary bladder received 60 minute infusions of atrial peptide ranging from 5 to 100 ng/kg/min. Infusion of atrial peptides caused dose dependent increases in plasma atrial peptide concentration with doses of 25 ng/kg/min or less increasing plasma concentrations to levels observed in normal animals during stimulation of endogenous atrial peptide secretion. Atrial peptide infusion at doses of 10 ng/kg/min and above caused significant decreases in mean arterial pressure which were not accompanied by statistically significant changes in heart rate. Atrial peptide infusion at doses of 25 ng/kg/min and above increased urinary sodium excretion and urine flow rate. Atrial peptide infusion was without effect on plasma vasopressin, ACTH and corticosterone concentrations. However, atrial peptide infusion resulted in dose dependent decreases in plasma aldosterone concentration and plasma renin activity, but the decreases were only significant with the high physiologic (25 ng/kg/min) and pharmacologic doses (50 & 100 ng/kg/min). These data show that atrial peptide infusions in conscious dogs have minimal effects when infused in small doses that mimic endogenous atrial peptide release. At higher doses, significant effects on the cardiovascular, renal and endocrine systems can be observed but their physiological significance is unclear.     

Comparison of enkephalin and atropine in the inhibition of vagally stimulated gastric and pancreatic secretion and gastrin and pancreatic polypeptide release in dogs

Enkephalins have been detected in vagal nerves and myenteric plexus neurons but no study has been performed to determine their action on vagally stimulated gastric and pancreatic secretion. In this study we infused IV methionine-enkephalin (Met-enk) alone, naloxone (a pure opiate antagonist) alone, or their combination before, during and after vagal stimulation in 4 dogs with esophageal, gastric and pancreatic fistulas. For the comparison, atropine was given before, during and after vagal stimulation in the same animals. Vagal stimulation was obtained by 15 min sham-feeding, which produced an increase in gastric H⁺ output to a peak of about 75% of the maximal response to pentagastrin and pancreatic protein secretion amounting to about 71% of the maximal response to caerulein. It was accompanied by a significant rise in serum gastrin and pancreatic polypeptide (PP) levels. Met-enk inhibited significantly both gastric H⁺ and pancreatic protein secretion and reduced plasma PP but not gastrin levels. Similar effects were obtained after the administration of atropine. The effects of Met-enk were partly reversed by the addition of naloxone. We conclude that (1) enkephalin suppresses vagally stimulated gastric and pancreatic secretion and plasma PP release; (2) these secretory effects of enkephalin seem to be mediated by opiate receptors and could be explained by its inhibitory action on acetylcholine release (“anticholinergic” action) in the stomach and the pancreas.     

Peripheral PYY inhibits intracisternal TRH-induced gastric acid secretion by acting in the brain

The site of action of peripheral peptide YY (PYY)-induced inhibition of vagally stimulated gastric acid secretion was studied using immunoneutralization with PYY antibody in urethan-anesthetized rats. Gastric acid secretion (59+/-7 micromol/90 min) stimulated by intracisternal injection of the stable thyrotropin-releasing hormone (TRH) analog RX-77368 (14 pmol/rat) was dose-dependently inhibited by 52%, 69%, and 83% by intravenous infusion of 0.25, 0.5, and 1.0 nmol. kg(-1) x h(-1) PYY, respectively. PYY or PYY(3-36) (2.4 pmol/rat) injected intracisternally also inhibited the acid response to intracisternal RX-77368 by 73% and 80%, respectively. Intravenous pretreatment with PYY antibody (4.5 mg/rat), which shows a 35% cross-reaction with PYY(3-36) by RIA, completely prevented the inhibitory effect of intravenously infused PYY (1 nmol x kg(-1) x h(-1)). When injected intracisternally, the PYY antibody (280 microg/rat) reversed intracisternal PYY (2.4 pmol)- and intravenous PYY (1 nmol x kg(-1) x h(-1))-induced inhibition of acid response to intracisternal RX-77368 by 64% and 93.5%, respectively. These results provide supporting evidence that peripheral PYY inhibits central vagal stimulation of gastric acid secretion through an action in the brain.     

19-hydroxyandrostenedione and 6 beta-hydroxyandrostenedione: new steroids regulated by the renin-angiotensin system in man

The changes of plasma 19-hydroxyandrostenedione (19-OH-A-dione) and 6 beta-hydroxyandrostenedione (6 beta-OH-A-dione) during the infusion of angiotensin II were evaluated and were compared with those of plasma aldosterone in man. Angiotensin II was infused into 5 normal subjects with an infusion pump at rates of 0.5, 1.0, 2.0 and 4.0 ng/kg per min. Each dose was infused for 20 min. Plasma 19-OH-A-dione rose significantly following the infusion of angiotensin II at a rate of 0.5 ng/kg per min and plasma 6 beta-OH-A-dione rose significantly following the infusion of angiotensin II at a rate of 1.0 ng/kg per min. In contrast, plasma aldosterone did not change significantly until the infusion rate reached 4.0 ng/kg per min. These results indicate that the secretion of 19-OH-A-dione and 6 beta-OH-A-dione is under the control of angiotensin II and the release of 19-OH-A-dione and 6 beta-OH-A-dione is induced earlier by the smaller doses of angiotensin II prior to the secretion of aldosterone. As 19-OH-A-dione and 6 beta-OH-A-dione amplify the action of aldosterone in bioassays using adrenalectomized rats and work as sodium-retaining and hypertensinogenic agents in intact rats, they are newly recognized biologically active steroids which are regulated by the renin-angiotensin system in man.     

Central noradrenergic inhibition of gastric mucosal blood flow and acid secretion in rats

To investigate the role of central noradrenaline (NA) in gastric functions, changes in mucosal blood flow (MBF) and acid secretion following electrical stimulation of the lateral hypothalamic area (LHA) and the effects of NA on these parameters were examined in rats anesthetized with urethane. NA 10 μg/animal injected into the lateral ventricle decreased the basal value of both the gastric MBF and acid output, while the same dose of acetycholine or dopamine was without effect. Repetitive electrical stimulation of LHA at 10 cycles/sec, 0.5 mA, 2 msec for 10 min elicited a significant, reproducible increase in both gastric MBF and acid output. NA 10 μg/animal injected into the lateral ventricle completely blocked these increases induced by the electrical stimulation. These data suggest that a central noradrenergic inhibitory mechanism is involved in regulation of the gastric MBF and acid secretion.     

Chronic Helicobacter pylori infection results in gastric hypoacidity and hypergastrinemia in wild-type mice but vagally induced hypersecretion in gastrin-deficient mice

Helicobacter pylori infection is a causal factor of gastric cancer (which is associated with low gastric acid secretion) or duodenal ulcer (high acid secretion). Parietal cells and ECL cells in the stomach are controlled by gastrin, which plays a crucial role in the regulation of acid secretion. The present study was undertaken to identify a possible role of gastrin in determining the different responses of the parietal cells and ECL cells to chronic H. pylori infection. Wild-type (C57BL/6J) gastrin(+/+) mice and gastrin(-/-) knockout mice, generated through targeted gene disruption and backcrossed eight times to C57BL/6J, were infected with H. pylori for 9 months. The acid output was measured 4 h after pylorus ligation (known to cause vagal excitation). The gastric mucosa was examined by immunocytochemistry with antisera to alpha-subunit of H+/K(+)-ATPase for the parietal cells, and to histamine and vesicle monoamine transporter-2 for the ECL cells, and by quantitative electron microscopy. In infected gastrin(+/+) mice, the acid output and the percentage of secreting parietal cells (freely fed state) were 20-30% of the values in uninfected controls, while the density and ultrastructure of parietal cells were normal. The infected mice had hypergastrinemia and displayed hypertrophy and hyperplasia of ECL cells. Although uninfected gastrin(-/-) mice had lower the acid output than uninfected gastrin(+/+) mice, there was a higher acid output (approximately 3 times) in infected gastrin(-/-) mice than their uninfected homologues. The numbers of parietal cells and ECL cells remained unchanged in infected gastrin(-/-) mice. In conclusion, chronic H. pylori infection results to impaired parietal-cell function (acid hyposecretion), hypergastrinemia and hyperplasia of ECL cells in wild-type mice but leads to vagally induced hypersecretion in gastrin-deficient mice.