Modulation Of Gastric Acid Secretion Research Articles

Ghrelin as a promising biological marker in cardiovascular disease

This review highlights the current literature data on the peptide hormone ghrelin. Ghrelin is a 28-amino-acid peptide, which is the only known peptide hormone modified with fatty acids. Ghrelin is a natural receptor ligand that stimulates the secretion of growth hormones. In addition to the stomach, ghrelin is expressed in many organs such as the duodenum, jejunum, ileum, colon, lungs, heart, pancreas, kidneys, testicles, pituitary gland, and hypothalamus. The main biological functions of this peptide include growth hormone secretion, appetite stimulation, modulation of gastric acid secretion and motility, and an increase in endocrine and exocrine pancreatic secretions. Reference intervals for ghrelin are 8.50216.6 pg/mL. The studies analyzed have shown a strong relationship between ghrelin and cardiovascular system function. Studies have also described the cardioprotective effects of ghrelin. However, the molecular mechanisms underlying the effects of ghrelin on the heart are not fully understood. A further deeper understanding of the role of ghrelin and future clinical studies are necessary to determine the diagnostic, prognostic, and possibly therapeutic significance of this biomarker.

Modulation of gastric acid secretion by cannabinoids in rats.

The current study aimed to evaluate the role of cannabinoid receptors in the regulation of gastric acid secretion and oxidative stress in gastric mucosa. To fulfill this aim, gastric acid secretion stimulated with histamine (5 mg/kg, subcutaneous [SC]), 2-deoxy- d-glucose (D-G) (200 mg/kg, intravenous) or -carbachol (4 μg/kg, SC) in the 4-hour pylorus-ligated rats. The CB1R agonist ( N-arachidonoyl dopamine, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and carbachol but not in histamine, reduced pepsin content, and increased mucin secretion. Furthermore, it decreased malondialdehyde (MDA) and nitric oxide (NO) contents with an increase in glutathione (GSH) and paraoxonase 1 (PON-1). Meanwhile, CB2R antagonist (AM630, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and reduced MDA and NO contents with an increase in GSH and PON-1. Meanwhile, CB1R antagonist rimonabant or CB2R agonist GW 405833 had no effect on stimulated gastric acid secretion. Therefore, both CB1R agonist and CB2R antagonist may exert antisecretory and antioxidant potential in the stomach.

Broad tissue expression of membrane progesterone receptor Alpha in normal mice

The broad tissue distribution of membrane progesterone receptor alpha (mPRalpha) in vertebrates suggests multiple physiological functions of the receptor. Current knowledge regarding the receptor distribution, however, is largely obtained via non-histological assays. In this study, the tissue distribution of mPRalpha in mice of both sexes was described using both histological and non-histological methods. Immunohistochemical analysis revealed that abundant expression of mPRalpha was consistently detected in the cytoplasm and membrane of smooth muscles in vasculatures, gastro-intestines, and uterus. It was also observed in myoepithelial cells of mammary gland and intra-ovarian myofibroblasts. These findings suggest that mPRalpha may function as a mediator of P4 in regulating function of smooth muscles or smooth muscle-like cells in numerous physiological processes such as vasodilation, transportation of contents within luminary organs, relaxation of the uterine myometrium during pregnancy, release of oocytes, and milk secretion. In addition, strong mPRalpha expression was identified in the parietal cells of gastric glands, indicating the potential roles of P4/mPRalpha signaling in the modulation of gastric acid secretion. Surprisingly, in the testis of male mice mPRalpha was mainly seen in the nuclei, rather than cytoplasm and/or membrane, of the primary and secondary spermatocytes, suggesting a direct role of the receptor in gene regulation. Our results indicate that mPRalpha may function as a key modulator of P4 in the modulation of multiple physiological functions in normal mice.

Stimulation of neurons in rat ARC inhibits gastric acid secretion via hypothalamic CRF1/2- and NPY-Y1 receptors.

Neuropeptide Y (NPY) neuronal projections from the arcuate nucleus (ARC) have been proposed to target corticotropin-releasing factor (CRF)-positive neurons in the paraventricular nucleus (PVN) as part of the ARC-PVN axis. The existence of a positive feedback loop involving CRF receptors in the PVN has been suggested. Exogenous NPY and CRF in the PVN have been shown to inhibit gastric acid secretion. Recently, we have demonstrated that activation of ARC neurons inhibits gastric acid secretion via vagal pathways. To what extent NPY- and CRF-mediated mechanisms in the PVN contribute to the CNS modulation of gastric acid secretion is still an open question. In the present study, we performed consecutive bilateral microinjections of antagonists to NPY receptor subtypes Y1 and Y2 and to CRF1/2 receptors in the PVN and of the excitatory amino acid kainate in the ARC to assess the role of NPY- and CRF-mediated mechanisms in the kainate-induced effects on gastric acid secretion. Gastric acid secretion was measured at the basal condition and during pentagastrin (16 microg/kg body wt) stimulation. Microinjection of vehicle in the PVN and kainate in the ARC decreased gastric acid secretion. Microinjection of the specific NPY-Y1 receptor antagonist BIBP-3226 (200 pmol) and the nonspecific CRF1/2 antagonist astressin (30 pmol) in the PVN abolished the inhibitory effect of neuronal activation in the ARC by kainate on gastric acid secretion. The CRF antagonist astressin was more effective. Pretreatment with the NPY-Y2 receptor antagonist BIIE-0246 (120 pmol) in the PVN had no significant effect. Our results indicate that activation of neurons in the ARC inhibits gastric acid secretion via CRF1/2 and NPY-Y1 receptor-mediated pathways in the PVN.

Characterization of α2-adrenoceptor subtypes involved in the modulation of gastric acid secretion

The effects of several α 2-adrenoceptor agonists and antagonists were examined on gastric acid secretion from reserpinized rats undergoing electrical stimulation of the left vagus nerve. Both detomidine and oxymetazoline inhibited vagal acid hypersecretion, their effects being fully prevented by idazoxan, 7,8-(methylenedioxy)-14-α-hydroxyalloberbane (CH 38083), or 2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline (RX 821002), and partly antagonized by yohimbine or rauwolscine. 2-(2,4-( O-methoxy-phenyl)-piperazin-1-yl)-ethyl-4,4-dimethyl-1,3-(2 H,4 H)-isoquinolindione (ARC 239) did not affect the antisecretory action of the two agonists, while prazosin at the highest dose was partly effective only against detomidine. Atropine markedly reduced vagally evoked acid output. It is suggested that acid secretion induced by vagal cholinergic stimulation is modulated by α 2A-like adrenoceptor subtypes.

Histamine, histamine H2-receptor antagonists, gastric acid secretion and ulcers: an overview.

Histamine, a biogenic amine, is involved in allergic reactions and asthma. The involvement of histamine in peptide ulcers is reviewed here. The discovery, distribution, synthesis, catabolism, and pharmacological effects of histamine are briefly described. Histamine actions are mediated by more than one type of receptor. The discovery, development and mode of action of H2-antagonists is discussed. A brief comparison of the clinical profiles (dosage regimen, metabolism and drug interactions) of the four currently used H2-antagonists (cimetidine, ranitidine, nizatidine and famotidine) is given. Furthermore, due to their ability to bind to cytochrome P-450, these compounds have the potential to interfere with the hepatic clearance of other drugs which are also metabolised by the mixed-function oxidase system in man. Therefore, a brief discussion of their adverse effects and drug interactions is included. Modulation of gastric acid secretion, in particular the role of cAMP and the proton pump, is described. Peptic ulcer is a major disease in the Western world and the aetiology and treatment of peptic ulcer are summarised.

Effect of L‐glutamic acid on acid secretion and immunohistochemical localization of glutamatergic neurons in the rat stomach

Glutamatergic neurons in the rat stomach were localized immunohistochemically using antibodies against L-glutamate (L-Glu) as well as glutamate synthesizing enzyme, glutaminase (GLNase). Myenteric ganglia and nerve bundles in the circular muscle and the longitudinal muscle were found to contain GLU- and GLNase-positive nerve fibers, while submucosa and mucosa were devoid of glutamatergic innervation. The distribution of glutamatergic neurons and their processes in both myenteric ganglia and circular muscle is heterogeneous within the stomach. The effect of L-Glu on gastric acid secretion was investigated on an everted preparation of isolated rat stomach. L-Glu at 10(-7) and 10(-8) M alone had no effect on acid secretion. It was found that the oxotremorine-, histamine-, or gastrin-stimulated acid secretion was markedly reduced by L-Glu at 10(-8) M, whereas L-Glu had little effect on the acid secretion stimulated by dimethyl-phenylpiperazinium (DMPP) at this concentration. However, at higher concentration, e.g., 10(-7) M, L-Glu also markedly reduced DMPP-induced acid secretion. Among L-Glu receptor agonists tested, quisqualic acid (QA) is most potent, followed by kainic acid (KA) and N-methyl-D-aspartic acid (NMDA) in inhibiting oxotremorine-stimulated acid secretion. Furthermore, this inhibitory effect of L-Glu on oxotremorine-stimulated acid secretion is blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a specific non-NMDA receptor antagonist. All these results suggest that glutamatergic neurons are involved in the modulation of gastric acid secretion via ionotropic QA/KA receptors, probably through openings of Ca2+ channels.

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 α 2 antagonist, yohimbine, was used to evaluate the role of the α 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 α 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 α 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 α 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.

The role of peripheral opioid receptor subtypes in the modulation of gastric acid secretion and plasma gastrin in dogs

The peripheral opioid receptor subtypes involved in the regulation of gastric acid secretion were studied in dogs with both a gastric fistula and a Heidenhain pouch, by using the putative μ-opioid receptor agonist dermorphin, the δ-opioid receptor agonist [ D-Ala 2, D-Leu 5]enkephalin (DADLE) and the κ-opioid receptor agonist dynorphin-(1–13). Dermorphin caused a significant increase in basal acid secretion from both the gastric fistula and the Heidenhain pouch, while DADLE and dynorphin-(1–13) did not. Acid secretion stimulated by 2-deoxy- D-glucose from the gastric fistula was not modified by dermorphin and dynorphin-(1–13), while DADLE significantly inhibited it; at the same time gastric secretion from the Heidenhain pouch was significantly increased by dermorphin and unmodified by DADLE and dynorphin-(1–13). Dermorphin, DADLE or dynorphin-(1–13) did not modify plasma gastrin during basal or 2-deoxy- D-glucose-stimulated conditions. Submaximal bethanechol-stimulated secretion was increased by dermorphin and DADLE but unaffected by dynorphin-(1–13). Acid secretion from the gastric fistula stimulated by pentagastrin was enhanced by dermorphin, inhibited by DADLE and unaffected by dynorphin-(1–13). Dermorphin and DADLE significantly increased acid secretion from the Heidenhain pouch stimulated by pentagastrin, while dynorphin-(1–13) was ineffective. Naloxone prevented the stimulatory effects of dermorphin and DADLE on the Heidenhain pouch, but it reduced acid secretion from the gastric fistula further when given with DADLE. The inhibitory effects of DADLE on secretion from the gastric fistula were prevented by naltrindole, a selective antagonist of δ-opioid receptors. We conclude that peripheral μ-opioid receptors mediate excitatory effects, δ-opioid receptors produce mainly inhibitory effects, while κ-opioid receptors do not seem to be involved in the regulation of acid secretion. Further, measurements of plasma gastrin suggest that the opioid-induced changes in acid secretion are not due to variations in gastrin release.

Effect of luminal administration of thyrotropin-releasing hormone or somatostatin on gastric pH and interaction of these peptides in rats.

The effect of intraluminal administration of thyrotropin-releasing hormone (TRH) on gastric pH and release of luminal somatostatin, and a possible interrelationship between TRH and somatostatin in the rat stomach were studied. TRH was administered into the stomach via an intragastric tube at various doses (50 pg/kg-10 micrograms/kg) and gastric pH was measured after 15 min. The intraluminal administration of TRH significantly decreased gastric pH at doses over 1.0 ng/kg. Time-course studies at a dose of 100 ng/kg TRH exhibited a significant decrease in gastric pH at 15, 30 and 60 min. Furthermore, TRH administration caused a significant increase in immunoreactive-somatostatin (ir-somatostatin) concentrations in the gastric wall and a significant decrease in ir-somatostatin concentrations in the gastric juice. On the other hand, intraluminal administration of somatostatin caused a significant increase in ir-TRH concentrations in the gastric wall and a significant decrease in ir-TRH concentrations in the gastric juice, and significantly raised gastric pH at 5 min. These findings suggest that luminal TRH may exert a regulatory effect on gastric acid secretion, and that TRH may have a possible interaction with somatostatin in the modulation of gastric acid secretion.

P-552 - Involvement of endogenous adenosine in modulation of gastric acid secretion in rats.

P-552 - Involvement of endogenous adenosine in modulation of gastric acid secretion in rats.

Modulation of gastric acid secretion by peripheral presynaptic α2‐adrenoceptors at both sympathetic and parasympathetic pathways

1. The effects of the alpha 2-adrenoceptor agonist detomidine, and the antagonists idazoxan and CH-38083 were examined on gastric acid secretion from non-vagotomized and vagotomized stomach lumen-perfused rats. The effects of detomidine on acid secretion from isolated guinea-pig gastric fundus were also evaluated. 2. In both non-vagotomized and vagotomized rats i.p. administration of detomidine significantly increased acid secretion, whereas i.c.v. detomidine was without effect. The stimulant action of i.p. detomidine was antagonized by both i.p. idazoxan and CH-38083 as well as by pretreatment with reserpine. 3. In vagotomized and reserpinized rats whose acid secretion was increased by electrical stimulation of the left vagus nerve, i.p. injection of detomidine caused inhibitory effects on acid secretion which were fully antagonized by both i.p. idazoxan and CH-38083. 4. Both idazoxan and CH-38083 caused a significant increase in acid secretion induced by vagal stimulation. At higher doses the two antagonists displayed a potentiating effect on vagally induced acid secretion only when they were associated to i.v. infusion of prazosin and propranolol. 5. Detomidine was without effect on acid secretion from isolated guinea-pig gastric fundus, whereas histamine or bethanechol caused a marked and dose-dependent stimulant action. 6. Overall, these results provide evidence that peripheral presynaptic alpha 2-adrenoceptors modulate both adrenergic inhibitory and cholinergic excitatory influences on rat gastric acid secretion.

Microinjection of TRH analogs into the raphe pallidus stimulates gastric acid secretion in the rat

The effects of microinjection of the stable thyrotropin-releasing hormone (TRH) analog, RX 77368, [pGlu-His-(3,3′-dimethyl)-Pro-NH 2] into the raphe pallidus on gastric acid secretion were studied in urethane-anesthetized rats with gastric fistula. RX 77368 microinjected into the raphe pallidus at doses of 0.07, 0.7 and 7.7 pmol induced a dose-dependent net stimulation of gastric acid secretion ( 7 ± 4, 50 ± 7and61 ± 12 μmol/h respectively). The peak acid response was reached within 30 min and returned to basal level 90 min post-injection. The stimulatory effect was abolished by bilateral cervical vagotomy and pirenzepine pretreatment (1 mg/kg, i.v.). RX 77368 (7.7 pmol) microinjected into the inferior olive or pyramidal tract induced smaller or no gastric acid secretory response. These results demonstrate that chemical stimulation of the raphe pallidus increases gastric acid secretion through vagal pathways and peripheral muscarinic receptors. These data suggest that the nucleus raphe pallidus may be involved in vagal modulation of gastric acid secretion in the rat.

Modulation of gastric acid secretion by hypnosis

The ability of hypnosis to both stimulate and inhibit gastric acid secretion in highly hypnotizable healthy volunteers was examined in two studies. In the first, after basal acid secretion was measured, subjects were hypnotized and instructed to imagine all aspects of eating a series of delicious meals. Acid output rose from a basal mean of 3.60 ± 0.48 to a mean of 6.80 ± 0.02 mmol H+/h with hypnosis, an increase of 89% (p = 0.0007). In a second study, subjects underwent two sessions of gastric analysis in random order, once with no hypnosis and once under a hypnotic instruction to experience deep relaxation and remove their thoughts from hunger. When compared to the no-hypnosis session, with hypnosis there was a 39% reduction in basal acid output (4.29 ± 0.93 vs. 2.60 ± 0.44 mmol H+/h, p < 0.05) and an 11% reduction in pentagastrin-stimulated peak acid output (28.69 ± 2.34 vs. 25.43 ± 2.98 mmol H+/h, p < 0.05). We have shown that different cognitive states induced by hypnosis can promote or inhibit gastric acid production, processes clearly controlled by the central nervous system. Hypnosis offers promise as a safe and simple method for studying the mechanisms of such central control.

Modulation of gastric acid secretion by adenosine in conscious rats.

Basal (nonstimulated) gastric acid output was determined in conscious rats fitted with indwelling gastric cannulae. The adenosine deaminase resistant analog of adenosine, R-phenylisopropyladenosine, elevated intraluminal pH beyond 7.0 and decreased gastric acid secretion when given at doses of 0.10 or 1.0 mg/kg, while S-phenylisopropyladenosine at similar doses did not affect either gastric acid output or pH. The potent adenosine receptor antagonist, 8-phenyltheophylline, given at doses of 0.1, 1.0, and 2.5 mg/kg augmented gastric acid output and, at doses of 0.01, 0.1, 1.0, and 2.5 mg/kg, blocked the acid-reducing effect of R-phenylisopropyladenosine (0.1 mg/kg). These data suggest that adenosine systems may be important regulators of gastric function.

Role of histamine H 2-receptors in gastric and pancreatic release of somatostatin-like immunoreactivity during the gastric phase of a meal

The present study was designed to determine the role of H 2-receptors in the postprandial release of somatostatin-like immunoreactivity (SLI) from the gastric fundus and antrum and from the pancreas. In dogs subjected to laparotomy, the pylorus was bisected and a gastric fistula was created, following which 250 ml 20% liver extract (LE) at pH 7 or 2 were instilled intragastrically. In the fundic vein the incremental SLI rise in response to LE at pH 7 was 2423 ± 540 pg/ml during a control infusion of saline and 4780 ± 863 pg/ml during the infusion of cimetidine (1 mg/kg per h) ( P < 0.05). In the antral vein the incremental SLI in response to LE at pH 7 was 2182 ± 530 pg/ml during the saline control but did not rise significantly during cimetidine infusion. In the pancreatic vein the incremental SLI level after LE at pH 7 was 1953 ± 358 pg/ml in the control experiments and 4430 ± 1024 pg/ml during cimetidine infusion ( P < 0.025). The incremental inferior vena cava SLI level was approximately 925 pg/ml in both groups (not significant). The instillation of LE at pH 2 during the saline control lowered fundic vein SLI by 500 pg/ml; this decline was abolished during cimetidine infusion. In the antral vein the incremental SLI level of 15 750 ± 2514 pg/ml during saline was lowered to only 6728 ± 2257 pg/ml during cimetidine (ifP < 0.025). After LE at pH 2 the incremental pancreatic vein SLI level of if5641 ± to be one regulatory component in the modulation of gastric acid secretion and gastrin release [21,26] during the gastric phase of a meal. The possible involvement of H 2-receptors in this regulatory system is schematized in Fig. 7. Pancreatic SLI release is also influenced by H 2-receptors but this appears to depend on the intragastric pH; stimulation of the receptors appears to lower the pancreatic SLI response to neutral protein and raise the response to acidified protein. If these effects are due to stimulation of gastric and/or pancreatic H 2-receptors can not be determined from the present data. These findings, in conjunction with previous studies [21–25], reveal a highly complex regulatory system for somatostin release during the gastric phase of meal, and indicate that, in addition to the influence of muscarinic-cholinergic [23], adrenergic mechanisms [24] and prostaglandins [25], reveal a histaminergic influence must now be recognized.