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M L Schubert

Publications and source records attributed to M L Schubert.

At least 55 records · Page 3Linked to original sources
PubMed1991

Regulation of acid secretion by bombesin/GRP neurons of the gastric fundus.

Intramural neurons in the fundus of the isolated mouse stomach were activated by 1,1-dimethyl-4-phenylpiperazinium (DMPP) or by electrical field stimulation and the participation of cholinergic and bombesin/gastrin-releasing peptide (GRP) neurons in the regulation of acid secretion evaluated with atropine and a selective bombesin/GRP antagonist, [Leu13-psi(CH2NH)-Leu14]bombesin. For both DMPP and field stimulation, atropine inhibited acid secretion and augmented somatostatin secretion. The bombesin/GRP antagonist had an opposite effect, augmenting acid secretion and inhibiting somatostatin secretion to below basal levels. The combination of the two antagonists restored DMPP- and field-stimulated acid and somatostatin secretion to basal levels. The results indicate that neurally stimulated acid secretion in the isolated mouse stomach is regulated by cholinergic neurons that mediate stimulation and bombesin/GRP neurons that mediate inhibition of acid secretion. Cholinergic neurons exert their stimulatory effect by acting directly on parietal cells and indirectly by eliminating the inhibitory influence of somatostatin. Bombesin/GRP neurons exert their inhibitory effect mainly by inducing release of somatostatin; an additional direct inhibitory effect of bombesin/GRP neurons on parietal cells is possible.

Animals↗
PubMed1991

Bombesin/GRP-stimulated somatostatin secretion is mediated by gastrin in the antrum and intrinsic neurons in the fundus.

The mechanism of action of bombesin, also known as gastrin-releasing peptide (GRP), on somatostatin secretion was examined separately in superfused segments of rat antral and fundic mucosa. Bombesin/GRP (1 nM) stimulated somatostatin secretion from both regions. In fundic segments, the somatostatin response was strongly inhibited (86%; P less than 0.01) by tetrodotoxin (5 microM) but augmented by atropine (1 microM) (P less than 0.01). In antral segments, both tetrodotoxin and atropine augmented the somatostatin response to bombesin/GRP by 42-45% (P less than 0.01), whereas the gastrin antagonist L 365260 (1 microM) abolished it. The gastrin antagonist augmented the gastrin response to bombesin/GRP by 103% (P less than 0.01). The results indicate that bombesin/GRP stimulates somatostatin secretion by distinct mechanisms in the fundus and antrum. In the fundus, bombesin/GRP acts indirectly on somatostatin cells by activating stimulatory noncholinergic neurons and, to a lesser extent, inhibitory cholinergic neurons. In the antrum, bombesin/GRP acts indirectly on somatostatin cells by stimulating release of gastrin and, to a lesser extent, by activating inhibitory cholinergic neurons. A dual paracrine pathway links gastrin and somatostatin secretion in the antrum.

Animals↗
PubMed1991

The effect of vasoactive intestinal polypeptide on gastric acid secretion is predominantly mediated by somatostatin.

The mechanism of action of vasoactive intestinal polypeptide on gastric acid secretion was examined in the isolated, luminally perfused mouse stomach. Vasoactive intestinal polypeptide caused a weak, transient increase in basal and histamine-stimulated acid secretion and a sustained increase in somatostatin secretion. The sustained increase in somatostatin despite return of acid to basal levels indicated that somatostatin secretion was a direct response to vasoactive intestinal polypeptide and not mediated by intraluminal acidification. The increase in somatostatin secretion was partly responsible for the weak, transient nature of the acid response since incubation with pertussis toxin, which is known to block the inhibitory effect of exogenous and endogenous somatostatin, converted the acid response to a sustained increase throughout the period of stimulation. The inhibitory influence of somatostatin was confirmed with selective vasoactive intestinal polypeptide antagonists. The antagonists inhibited vasoactive intestinal polypeptide-induced somatostatin secretion but caused a sustained increase in acid secretion. The pattern of response implied that somatostatin secretion was more sensitive than acid secretion to vasoactive intestinal polypeptide and vasoactive intestinal polypeptide antagonists and that suppression of somatostatin eliminated the main inhibitory influence on acid secretion. In addition, both vasoactive intestinal polypeptide antagonists inhibited basal somatostatin secretion, implying that input from tonically active vasoactive intestinal polypeptide neurons is responsible, at least in part, for basal somatostatin secretion.

Animals↗
PubMed1990

Gastric somatostatin: a paracrine regulator of acid secretion.

The presence of acid in the lumen of the gastric fundus induces release of somatostatin close to the parietal cells; this acts to attenuate acid secretion in response to secretagogues, such as histamine and gastrin. The release of somatostatin within the stomach is further regulated by the activity of cholinergic neurons that inhibit somatostatin release and thus augment acid secretion (disinhibition), and noncholinergic (bombesin) neurons that stimulate somatostatin release and thus attenuate acid secretion. The influence of these neurons and the participation of somatostatin as a paracrine regulator of acid secretion has been probed and validated by the use of selective antagonists (atropine and a bombesin antagonist), somatostatin antiserum and pertussis toxin. Similar mechanisms exist in the distal antral segment of the stomach for the paracrine regulation of gastrin release by somatostatin.

Acetylcholine↗
PubMed1990

Functionally distinct muscarinic receptors on gastric somatostatin cells.

The present study was designed to examine the mode of action of muscarinic agonists on somatostatin secretion in intact gastric tissues, i.e., mucosal segments from the fundus and antrum of rat and the isolated luminally perfused mouse stomach. Methacholine caused similar decreases in somatostatin secretion in segments from the fundus (35 +/- 3%; P less than 0.001) and antrum (35 +/- 2%; P less than 0.001) of rat stomach, and in whole mouse stomach (43 +/- 3%; P less than 0.001). The decrease was the net effect of a dominant inhibition and a lesser stimulation of somatostatin secretion. Pretreatment with the permeant derivative of the acetomethoxy ester form of the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA/AM, 15 microM) caused a further decrease in methacholine-induced somatostatin secretion, implying that a stimulatory component existed that was mediated by intracellular calcium. Pretreatment with pertussis toxin (125 ng/ml) for 60 min converted the decrease in somatostatin secretion to an increase above basal levels. The increase induced by pretreatment with pertussis toxin was abolished by additional pretreatment with BAPTA/AM. Procaine (5 mM), which blocks release of calcium from intracellular stores, produced an effect on somatostatin secretion similar to that of BAPTA/AM. The results indicate that 1) methacholine exerts dual inhibitory and stimulatory effects on somatostatin cells of rat and mouse stomach, 2) the dominant effect is inhibitory and sensitive to pertussis toxin, and 3) a concurrent stimulatory effect, mediated by calcium, is unmasked after blockade of the inhibitory effect with pertussis toxin.

Animals↗
PubMed1990

Control of acid secretion.

Receptors for the main neural (acetylcholine), hormonal (gastrin) and paracrine (histamine) secretory stimulants and the signal transduction pathways to which these receptors are coupled have been identified on the parietal cell. The stimulatory effect of histamine is mediated via an increase in adenylate cyclase activity, whereas the effect of acetylcholine and gastrin are mediated via an increase in cytosolic levels of calcium. Strong synergism between histamine and either gastrin or acetylcholine may reflect postreceptor interaction between the distinct pathways. Acetylcholine and gastrin are also capable of releasing histamine from the gastric mucosa, probably from ECL cells. The inhibitory effects of somatostatin and prostaglandin E on acid secretion are mediated 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, ultimately responsible for acid secretion. The intramural neural and paracrine pathways involved in the regulation of gastrin secretion in the antrum and acid secretion in the fundus have also been identified. Of prime importance is the somatostatin cell, which exerts a paracrine restraint on gastrin secretion and acid secretion. Elimination of this restraint or disinhibition is one of the mechanisms by which the stimulatory influence of cholinergic neurons is exerted on gastrin and parietal cells. Gastrin secretion is regulated by a cholinergic neuron that causes inhibition of somatostatin secretion and thus stimulation of gastrin secretion (disinhibition) and a noncholinergic neuron that causes direct stimulation of gastrin secretion by releasing the neurotransmitter, bombesin (or gastrin-releasing peptide). Acid secretion is regulated by a cholinergic neuron that causes direct stimulation of the parietal cell and indirect stimulation by decreasing somatostatin secretion, thus eliminating its inhibitory effect on the parietal cell (disinhibition). In addition, a regulatory feedback mechanism exists whereby intraluminal acidification stimulates somatostatin secretion, which in turn attenuates acid secretion. Gastric acid secretion may also be regulated by one or more intestinal inhibitory hormones, the most likely candidates being secretin, intestinal somatostatin, and neurotensin. Enterogastrone activity probably reflects the combined effect of all these hormones. Precise information on receptors and signal transduction mechanisms as well as on intramural neural and paracrine regulatory pathways has led to the development of new drugs capable of inhibiting acid secretion. These include antagonists that interact with stimulatory receptors (histamine H2-receptor antagonists, muscarinic receptor antagonists, and gastrin receptor antagonists), agonists that interact with inhibitory receptors (somatostatin and prostaglandin E analogues), and irreversible inhibitors of the luminal enzyme, H+K(+)-ATPase.

Acetylcholine↗
PubMed1989

Inhibition of acid secretion by bombesin is partly mediated by release of fundic somatostatin.

The effect and mode of action of bombesin on gastric acid secretion was examined in the isolated, luminally perfused mouse stomach. Bombesin caused a concentration-dependent inhibition of basal and histamine-stimulated acid secretion and an increase in somatostatin secretion. Pertussis toxin was used to determine the contribution of somatostatin to the observed inhibition of acid secretion. Previous studies have shown that at a concentration of 125 ng/ml, pertussis toxin reverses completely the inhibition of acid secretion induced by exogenous and endogenous somatostatin. Preincubation of the stomach for 60 min with pertussis toxin (125 and 1250 ng/ml) reversed partially the inhibitory effect of bombesin on basal and histamine-stimulated acid secretion by 51%-59%, implying that bombesin-induced inhibition was partly mediated by release of somatostatin. The residual inhibition may represent a direct effect of bombesin on parietal cells.

Animals↗
PubMed1989

Linkage between somatostatin and acid secretion: evidence from use of pertussis toxin.

Pertussis toxin was used to examine the functional linkage between somatostatin and acid secretion and the mode of action of somatostatin at the cellular level in the isolated luminally perfused mouse stomach. Pretreatment of the stomach with pertussis toxin (125-1,250 ng/ml) for 60 min 1) caused a significant twofold increase in histamine-stimulated acid secretion (from 42 +/- 7 to 82 +/- 12 nmol/min; P less than 0.01) but not pentagastrin-stimulated secretion and 2) blocked the inhibitory effect of somatostatin on basal and histamine-stimulated acid secretion but not on pentagastrin-stimulated acid secretion. The ability of pertussis toxin to reverse selectively the inhibitory effect of somatostatin on histamine-stimulated acid secretion is consistent with the ability of pertussis toxin to inactivate a guanine nucleotide binding protein, which couples somatostatin receptors to inhibition of adenylate cyclase; histamine, but not gastrin, stimulates acid secretion via activation of adenylate cyclase. Secretagogue-stimulated acid secretion was accompanied by a parallel increase in somatostatin secretion that is largely determined by luminal acidity. The augmentation of histamine-stimulated acid secretion after treatment with pertussis toxin implied that the concomitant increase in somatostatin secretion is coupled to acid secretion and acts to attenuate it. The results confirm the role of gastric somatostatin as a paracrine regulator of acid secretion.

Adenylate Cyclase Toxin↗
PubMed1988

Regulation of gastric somatostatin secretion in the mouse by luminal acidity: a local feedback mechanism.

The present study was designed to determine whether somatostatin secretion induced by histamine or pentagastrin in the isolated luminally perfused mouse stomach was a direct effect of the secretagogues on gastric somatostatin cells or an indirect effect mediated by the increase in luminal acidity. Perfusion of the lumen with exogenous acid (80-480 nmol/min) caused an increase in somatostatin secretion in proportion to the increase in luminal acidity. The increase in somatostatin secretion was resistant to tetrodotoxin and attained maximal levels (61.6% +/- 8.7% above basal level) similar to those elicited by maximal doses of secretagogues. Conversely, neutralization of basal acid secretion with bicarbonate (20-160 nmol/min) caused a decrease in somatostatin secretion in proportion to the decrease in luminal acidity. Similarly, neutralization of the secretagogue-induced increments in acid secretion with bicarbonate or inhibition of the increments with cimetidine abolished the corresponding increments in somatostatin secretion. It is proposed that acid-induced release of somatostatin in proximity to parietal cells serves as a negative feedback mechanism restraining acid secretion.

Animals↗