Neural and hormonal control of Brunner's gland secretion

For many years it has been speculated that the physiological function of Brunner's glands was to secrete mucus to protect the proximal duodenum from the corrosive effects of acidified gastric juice. However the control of Brunner's gland secretion remains an enigma. Some evidence exists which indicates both cholinergic and adrenergic innervation of these glands, but current consensus weighs heavily in favor of a hormonal stimulus for glandular secretion. This is based in part on evidence obtained from denervated Brunner's gland pouches following a feeding stimulus. A number of hormones and hormone-like substances have been investigated as possible mediators in this secretory response, however, no specificity was ever demonstrated. The inability to pinpoint a given substance as a common mediator can be attributed to the fact that most active agents employed also affect duodenal motility. We present evidence that Brunner's gland secretion can be observed to be a diphasic response. The initial, transient response is always observed in the presence of increased duodenal motility. The sustained response does not require duodenal motility and is probably hormonally mediated.     

Stomach-brain communication by vagal afferents in response to luminal acid backdiffusion, gastrin, and gastric acid secretion

Vagal afferents play a role in gut-brain signaling of physiological and pathological stimuli. Here, we investigated how backdiffusion of luminal HCl or NH(4)OH and pentagastrin-stimulated acid secretion interact in the communication between rat stomach and brain stem. Rats were pretreated intraperitoneally with vehicle or appropriate doses of cimetidine, omeprazole, pentagastrin, dexloxiglumide (CCK(1) receptor antagonist), and itriglumide (CCK(2) receptor antagonist) before intragastric administration of saline or backdiffusing concentrations of HCl or NH(4)OH. Two hours later, neuronal activation in the nucleus of the solitary tract (NTS) and area postrema was visualized by c-Fos immunohistochemistry. Exposure of the rat gastric mucosa to HCl (0.15-0.5 M) or NH(4)OH (0.1-0.3 M) led to a concentration-dependent expression of c-Fos in the NTS, which was not related to gender, gastric mucosal injury, or gastropyloric motor alterations. The c-Fos response to HCl was diminished by cimetidine and omeprazole, enhanced by pentagastrin, and left unchanged by dexloxiglumide and itriglumide. Pentagastrin alone caused an omeprazole-resistant expression of c-fos, which in the NTS was attenuated by itriglumide and prevented by dexloxiglumide but in the area postrema was reduced by dexloxiglumide and abolished by itriglumide. We conclude that vagal afferents transmit physiological stimuli (gastrin) and pathological events (backdiffusion of luminal HCl or NH(4)OH) from the stomach to the brain stem. These communication modalities interact because, firstly, acid secretion enhances afferent signaling of gastric acid backdiffusion and, secondly, gastrin activates NTS neurons through stimulation of CCK(1) receptors on vagal afferents and of CCK(2) receptors on area postrema neurons projecting to the NTS.     

Effect of bombesin-stimulated gastrin on gastric acid secretion in man

The effect of bombesin on gastrin release and gastric acid secretion was investigated in 10 healthy volunteers. Bombesin (0.6 μg · Kg^?1 · hr^?1) produced a significantly higher $\text{(}\text{p}\text{<}\text{0.001)}$ increase in plasma gastrin levels (86.7 11.1 pmo/1 than after a protein meal (39.6 ± 5.6 pmol1/1). The gastric acid secretory response to bombesin (12.1 ± 2.9 mEq · hr^?1) was however significantly lower $\text{(}\text{p}\text{<}\text{0.005)}$ than the maximal response produced by pentagostrin (20.9 ± 3.5 mEq · hr^?1) at the dose of 6 μg · Kg^?1. Atropine did not modify gastrin release induced by bombesin but significantly reduced gastric acid secretion $\text{(}\text{p}\text{<}\text{0.01)}$. From the data presented it may be hypothesized that less biologically active forms of gastrin and/or other peptides inhibiting the gastrin effect upon gastric acid secretion may be released by bombesin.     

胃酸分泌的外周调节

肠神经节后神经纤维支配了胃粘膜壁细胞、ＥＣＬ细胞、Ｇ细胞和Ｄ细胞,某些体液因子也可影响后三种内分泌细胞的分泌功能,它们相互作用最终调节组织胺的释放,从而组织胺、胃泌素、乙酰胆碱、生长抑素共同调节壁细胞的泌酸功能,以控制胃内适当的酸度。这些中调节机制涉及神经、体液、内分泌、旁分泌、自然分泌和神经一一内分泌等的过程。     

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.     

Phenylethylamide derivatives of the C-terminal tetrapeptide of gastrin. Potent inhibitors of gastrin-stimulated acid secretion

Peptide analogues of the C-terminal tetrapeptide of gastrin in which the phenylalanine had been replaced were synthesized and their biological activity on acid secretion evaluated. Compounds Boc-Trp-Leu-Asp phenylethylamide 6, Boc-beta-Ala-Trp-Leu-Asp phenylethylamide 9, Boc-Trp-Leu-Asp p-fluorophenylethylamide 19, Boc-Trp-psi(CH2NH)-Leu-Asp phenylethylamide 23, Boc-Trp-Leu-Asp 2,2-diphenylethylamide 15, and Boc-D Trp-Leu-Asp 2,2-diphenylethylamide 21, in which the phenylalanine had been replaced by phenylethylamine, p-fluorophenylethylamine or 2,2-diphenylethylamine were synthesized. None of these derivatives showed activity on acid secretion in the anaesthetized rat at doses as high as 5 mg/kg. However, they were potent inhibitors of gastrin-induced acid secretion, with ED50 varying from 0.1 to 0.6 mg/kg.     

Neural regulation of renal tubular sodium reabsorption and renin secretion

The entire mammalian nephron, including the juxtaglomerular apparatus, receives an exclusive noradrenergic innervation. Renal tubular alpha 1 adrenoceptors mediate the alterations in tubular segmental sodium, chloride, and water reabsorption that occur in response to direct or reflex changes in efferent renal sympathetic nerve activity. Specific tubular segments so identified are the proximal convoluted tubule, the loop of Henle (thick ascending limb), and the collecting duct. Alterations in efferent renal sympathetic nerve activity represent an important physiological contribution to the overall role of the kidney in the regulation of external sodium balance in conscious animals during both dietary sodium restriction and acute and chronic increases in total-body sodium. Progressively more intense activation of the renal nerves recruits a series of adrenergically mediated influences on renin secretion that are additive, ranging from subtle (modulation of nonneural mechanisms without directly causing renin secretion) to marked (renal vasoconstriction, antinatriuresis, high renin secretion rates). Juxtaglomerular granular cell beta 1 adrenoceptors mediate renin secretion responses to frequencies of renal nerve stimulation that do not cause renal vasoconstriction; at higher frequencies of renal nerve stimulation where renal vasoconstriction is present, renal vascular alpha 1 adrenoceptors mediate a portion of the renin secretion response.     

Neural regulation of glucagon-like peptide-1 secretion in pigs

Glucagon-like peptide (GLP)-1 is secreted rapidly from the intestine postprandially. We therefore investigated its possible neural regulation. With the use of isolated perfused porcine ileum, GLP-1 secretion was measured in response to electrical stimulation of the mixed, perivascular nerve supply and infusions of neuroactive agents alone and in combination with different blocking agents. Electrical nerve stimulation inhibited GLP-1 secretion, an effect abolished by phentolamine. Norepinephrine inhibited secretion, and phentolamine abolished this effect. GLP-1 secretion was stimulated by isoproterenol (abolished by propranolol). Acetylcholine stimulated GLP-1 secretion, and atropine blocked this effect. Dimethylphenylpiperazine stimulated GLP-1 secretion. In chloralose-anesthetized pigs, however, electrical stimulation of the vagal trunks at the level of the diaphragm had no effect on GLP-1 or GLP-2 and weak effects on glucose-dependent insulinotropic peptide and somatostatin secretion, although this elicited a marked atropine-resistant release of the neuropeptide vasoactive intestinal polypeptide to the portal circulation. Thus GLP-1 secretion is inhibited by the sympathetic nerves to the gut and may be stimulated by intrinsic cholinergic nerves, whereas the extrinsic vagal supply has no effect.     

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.     

Coordinated regulation of gastric chloride secretion with both acid and alkali secretion

Gastric secretion of hydrochloric acid requires protons and chloride, yet the mechanisms and regulation of gastric chloride secretion remain unclear. We developed an in vivo technique to simultaneously measure acid/base and chloride secretion into the gastric lumen of anesthetized rats. The cannulated stomach lumen was perfused with weakly pH-buffered chloride-free solution containing a chloride-sensitive fluorophore [5 microM N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE)]. Gastric acid and chloride secretion was detected in gastric effluents by 1) flow-through pH electrode and 2) MQAE fluorescence. Gastric effluent was also collected at 1-min intervals for independent determination of chloride amount by chloridometer. In all conditions, both optical and chemical determinations of chloride report similar amounts of secreted chloride. During luminal perfusion with pH 5 solution, net acid and chloride secretion into the lumen was observed. Pentagastrin stimulated both secretions. In contrast, proton pump inhibition (omeprazole) caused alkalinization of the gastric effluent, but chloride secretion was not diminished. During luminal pH 3 perfusion, net alkali secretion was observed, and chloride secretion at luminal pH 3 was greater than pH 5. When tissue is pretreated with omeprazole at luminal pH 3, the addition of prostaglandin E2 synchronously stimulates both alkali and chloride secretion. Results suggest that both acid and alkali secretions are separately coupled with chloride secretion.     

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).     

Effect of beta-endorphin on gastric acid secretion and serum gastrin concentration in humans

The effect of synthetic human β-endorphin on gastric acid secretion was studied in 9 healthy subjects. Neither 2.5 mg or 15 mg β-endorphin had a significant effect on acid secretion or on serum gastrin concentration despite the fact that this dose of opiate caused a significant increase in serum prolactin concentrations. The role of endogenous opiate-like peptides on gastric secretion is discussed.