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Biomedical subjects

M L Schubert

Publications and source records attributed to M L Schubert.

At least 37 records · Page 2Linked to original sources
PubMed1997

Histamine, acting via H3 receptors, inhibits somatostatin and stimulates acid secretion in isolated mouse stomach.

BACKGROUND & AIMS: The role of histamine H3 receptors in the regulation of gastric acid secretion is unclear. The present study was designed to characterize the location of H3 receptors in the fundus of the stomach and the mechanism by which these receptors regulate acid secretion. METHODS: Acid, somatostatin, and histamine secretions were measured in the isolated mouse stomach. RESULTS: Thioperamide (H3 antagonist) increased somatostatin and decreased histamine and acid secretion in a concentration-dependent manner. (r)-alpha-Methylhistamine (H3 agonist) had the opposite effect, decreasing somatostatin and increasing histamine and acid secretion. The pattern implies that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on somatostatin secretion. Somatostatin antibody increased basal histamine secretion and abolished the decrease in histamine and acid secretion induced by thioperamide, confirming that changes in histamine and acid secretion induced by the activation of H3 receptors reflected changes in somatostatin secretion. Similar effects were obtained when acid secretion was stimulated by histamine: thioperamide augmented somatostatin and thus inhibited acid secretion, and (r)-alpha-methylhistamine attenuated somatostatin and increased acid secretion. CONCLUSIONS: Reciprocal inhibitory paracrine pathways link histamine and somatostatin cells in the gastric fundus. Histamine, acting via H3 receptors, augments acid secretion by eliminating the inhibitory influence of somatostatin.

Animals↗
PubMed1997

Reciprocal inhibitory paracrine pathways link histamine and somatostatin secretion in the fundus of the stomach.

The present study was designed to examine the functional linkage between histamine and somatostatin secretion in the fundus of the stomach. In segments of rat fundic mucosa, superfusion with thioperamide (H3 antagonist) increased somatostatin and decreased histamine secretion; superfusion with (R)(-)-alpha-methylhistamine (H3 agonist) had the opposite effect, decreasing somatostatin and increasing histamine secretion. The pattern implied that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on somatostatin secretion. Superfusion with somatostatin antibody (1:250) increased histamine secretion, implying that endogenous somatostatin, in turn, exerts an inhibitory paracrine influence on histamine secretion. Somatostatin antibody also abolished the decrease in histamine secretion induced by thioperamide and the increase in histamine secretion induced by (R)(-)-alpha-methylhistamine, implying that changes in histamine secretion induced by activation of H3 receptors reflect changes in somatostatin secretion. Superfusion with the muscarinic agonist methacholine alone and in the presence of either H3 agonist or H3 antagonist confirmed the existence of reciprocal inhibitory pathways linking somatostatin and histamine. We conclude that fundic histamine and somatostatin secretion are linked via reciprocal inhibitory paracrine pathways that serve to amplify the regulatory influence of somatostatin.

Animals↗
PubMed1996

Somatostatin receptor subtype 2 mediates inhibition of gastrin and histamine secretion from human, dog, and rat antrum.

BACKGROUND & AIMS: In gastric antrum, somatostatin exerts a tonic inhibitory influence on gastrin and histamine secretion. Five different subtypes of somatostatin receptors, designated sst1-5, have been identified. sst2, sst3, and sst5 subtypes have been localized to the stomach by molecular biological techniques. The aim of this study was to identify the sst subtype regulating gastrin and histamine secretion in human, dog, and rat stomach. METHODS: Mucosal segments from human, dog, and rat antrum were superfused with various concentrations of somatostatin 14 and somatostatin analogues selective for sst2, sst3, and sst5. Gastrin and histamine were measured by radioimmunoassay. RESULTS: Somatostatin 14 and the sst2 agonist EC 5-20 inhibited gastrin and histamine secretion from all three species in a concentration-dependent manner, whereas the sst3 and sst5 agonists had no significant effect. Neutralization of endogenous somatostatin with the somatostatin antibody increased gastrin and histamine secretion. The increases were not affected by the gastrin antagonist but were abolished by the sst2 agonist, implying that the inhibitory influence of ambient somatostatin is exerted directly on the histamine cell rather than indirectly via changes in gastrin secretion. CONCLUSIONS: Somatostatin inhibits gastrin and histamine secretion in human, dog, and rat antrum by activating sst2 receptors on gastrin and histamine cells.

Animals↗
PubMed1995

Dual inhibitory pathways link antral somatostatin and histamine secretion in human, dog, and rat stomach.

BACKGROUND & AIMS: The secretion and function of antral histamine are not known. The aims of this study were to characterize the mechanisms of histamine release from the gastric antrum of humans, dogs, and rats and to determine whether histamine can influence the secretion of somatostatin and gastrin. METHODS: Somatostatin, gastrin, and histamine secretion from superfused antral segments was measured using radioimmunoassay. RESULTS: Superfusion with thioperamide (H3 antagonist) increased somatostatin and decreased gastrin and histamine secretion in all three species; superfusion with (r)-alpha-methylhistamine (H3 agonist) had the opposite effect. The pattern implied that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on somatostatin secretion, which in turn regulates gastrin secretion. Superfusion with somatostatin antibody increased histamine secretion; the increase was not affected by the gastrin antagonist L-365,260, implying that it was not mediated by the concurrent increase in gastrin but by suppression of an inhibitory pathway linking somatostatin and histamine. Superfusion with methacholine alone and in the presence of either the H3 agonist or antagonist confirmed the existence of reciprocal inhibitory pathways linking somatostatin and histamine. CONCLUSIONS: Antral histamine in humans, dogs, and rats is linked to antral somatostatin via reciprocal inhibitory paracrine pathways that serve to amplify the regulatory influence of somatostatin.

Animals↗
PubMed1993

Gastrin secretion induced by distention is mediated by gastric cholinergic and vasoactive intestinal peptide neurons in rats.

BACKGROUND: The present study was designed to identify the mechanism by which distention regulates gastrin secretion. METHODS: The distal stomach of the isolated vascularly perfused rat was distended to varying degrees for 10-minute periods with an air-filled balloon. RESULTS: Low distention caused a decrease in gastrin (39% +/- 5%; P < 0.001) and an increase in somatostatin (58% +/- 4%; P < 0.001) secretion. High distention caused an opposite effect, i.e., an increase in gastrin (49% +/- 11%; P < 0.01) and a decrease in somatostatin (44% +/- 11%; P < 0.01) secretion. All responses were abolished by the axonal blocker, tetrodotoxin. Atropine had no effect on the responses to low distention, but converted the pattern of response with high distention to that observed with low distention. Both high and low distention were accompanied by a sustained increase in vasoactive intestinal peptide (VIP) secretion. The selective VIP antagonist, VIP[10-28], abolished both the gastrin and somatostatin responses to low distention. CONCLUSIONS: Low gastric distention activates preferentially VIP neurons that stimulate somatostatin and thus inhibit gastrin secretion. Increasing distention leads to progressive recruitment of cholinergic neurons that cause a reversal in the pattern to one of increase in gastrin and decrease in somatostatin secretion.

Animals↗
PubMed1993

Pharmacology of gastric acid inhibition.

Gastric acid secretion is precisely regulated by neural (acetylcholine), hormonal (gastrin), and paracrine (histamine; somatostatin) mechanisms. The stimulatory effect of acetylcholine and gastrin is mediated via increase in cytosolic calcium, whereas that of histamine is mediated via activation of adenylate cyclase and generation of cAMP. Potentiation between histamine and either gastrin or acetylcholine may reflect postreceptor interaction between the distinct pathways and/or the ability of gastrin and acetylcholine to release histamine from mucosal ECL cells. The prime inhibitor of acid secretion is somatostatin. Its inhibitory paracrine effect is mediated predominantly by receptors coupled via guanine nucleotide binding proteins to inhibition of adenylate cyclase activity. All the pathways converge on and modulate the activity of the luminal enzyme, H+,K(+)-ATPase, the proton pump of the parietal cell. Precise information on the mechanisms involved in gastric acid secretion and the identification of specific receptor subtypes has led to the development of potent drugs capable of inhibiting acid secretion. These include competitive antagonists that interact with stimulatory receptors (e.g. muscarinic M1-receptor antagonists and histamine H2-receptor antagonists) as well as non-competitive inhibitors of H+,K(+)-ATPase (e.g. omeprazole). The histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine and roxatidine acetate) continue as first-line therapy for peptic ulcer disease and are effective in preventing relapse. Although they are generally well tolerated, histamine H2-receptor antagonists may cause untoward CNS, cardiac and endocrine effects, as well as interfering with the absorption, metabolism and elimination of various drugs. The dominance of the histamine H2-receptor antagonists is now being challenged by omeprazole. Omeprazole reaches the parietal cell via the bloodstream, diffuses through the cytoplasm and becomes activated and trapped as a sulfenamide in the acidic canaliculus of the parietal cell. Here, it covalently binds to H+,K(+)-ATPase, the hydrogen pump of the parietal cell, thereby irreversibly blocking acid secretion in response to all modes of stimulation. The main potential drawback to its use is its extreme potency which sometimes leads to virtual anacidity, gastrin cell hyperplasia, hypergastrinaemia and, in rats, to the development of carcinoid tumours. The cholinergic receptor on the parietal cell has recently been identified as an M3 subtype and that on postganglionic intramural neurones of the submucosal plexus as an M1 subtype.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Peptone stimulates gastrin secretion from the stomach by activating bombesin/GRP and cholinergic neurons.

The mechanism by which partly digested protein (peptone) stimulates gastrin secretion was examined in isolated antral tissues with intact intramural innervation. In the isolated vascularly perfused rat stomach, luminal perfusion with 0.5% peptone increased gastrin (62 +/- 14 pg/min; P less than 0.01) and decreased somatostatin (74 +/- 19; P less than 0.01) secretion. The axonal blocker tetrodotoxin (TTX) abolished the gastrin and somatostatin responses indicating that the responses were neurally mediated. Atropine partly inhibited the gastrin response (50%) and converted the somatostatin response to an increase above basal level. The selective bombesin/gastrin-releasing peptide (GRP) antagonist [Leu13-psi(CH2NH)-Leu14]-bombesin partly inhibited the gastrin response (65%) and caused a further decrease in somatostatin secretion. A combination of atropine and the bombesin/GRP antagonist, like TTX, abolished the gastrin and somatostatin responses. The pattern of response to peptone in superfused antral segments was identical to that in the vascularly perfused stomach. In fundic segments that do not secrete gastrin, the somatostatin response to peptone alone and with various antagonists was identical to that in antral segments. The results indicate that peptone stimulates gastrin secretion by activating stimulatory cholinergic and bombesin/GRP neurons. Cholinergic neurons stimulate gastrin directly as well as indirectly by eliminating the inhibitory paracrine influence of somatostatin.

Animals↗
PubMed1992

Control of gastric acid secretion. Histamine H2-receptor antagonists and H+K(+)-ATPase inhibitors.

Gastric acid secretion is regulated by an intricate interplay of neural (acetylcholine), hormonal (gastrin), and paracrine (histamine, somatostatin) mechanisms. Receptors for each of these agents and the signal transduction pathways to which these receptors are coupled have been identified on the parietal cell. The stimulatory effect of acetylcholine and gastrin is mediated by an increase in cytosolic calcium, whereas that of histamine is mediated by activation of adenylate cyclase and generation of cAMP. Strong potentiation between histamine and either gastrin or acetylcholine reflects postreceptor interaction between the distinct pathways as well as the ability of acetylcholine and gastrin to release histamine from mucosal ECL cells. The inhibitory effects of somatostatin on acid secretion are mediated by receptors coupled by guanine nucleotide-binding proteins to inhibition of adenylate cyclase activity. All the pathways converge on and modulate the activity of the luminal enzyme, H+K(+)-ATPase, the proton pump of the parietal cell. Precise information on the mechanisms involved in gastric acid secretion has led to the development of potent drugs capable of inhibiting acid secretion. These include competitive antagonists that interact with stimulatory receptors (e.g., histamine H2-receptor antagonists) as well as noncompetitive inhibitors of H+K(+)-ATPase (e.g., omeprazole). The histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, and nizatidine) continue as first-line therapy for peptic ulcer disease and are effective in preventing relapse. Although they are generally well tolerated, histamine H2-receptor antagonists may cause untoward CNS, cardiac, and endocrine effects as well as interference with the absorption, metabolism, and elimination of various drugs. Omeprazole is a weak base that reaches the parietal cell through the bloodstream, diffuses through the cytoplasm, and becomes activated and trapped as a sulfenamide in the acidic canaliculus of the parietal cell. It covalently binds to H+K(+)-ATPase, thereby irreversibly blocking acid secretion in response to all modes of stimulation. The main drawback to its use is its extreme potency, which leads to virtual anacidity, gastrin and ECL cell hyperplasia, hypergastrinemia, and, in rats, to the development of carcinoid tumors.

Absorption↗