Effect of beta-adrenoreceptor stimulation on gastric secretion stimulated by histamine, acetylcholine, and pentagastrin

In chronic experiments on dogs with gastric and duodenal fistulas and catheters implanted into the jugular vein, it was established that the beta-adrenoagonist novodrin inhibits gastric secretion stimulated with acetylcholine or pentagastrin but does not alter secretion stimulated with histamine. The inhibitory effect of novodrin on gastric secretion is a consequence of its direct action on beta-adrenoreceptors of the gastric mucosa. The scheme demonstrating interrelations of beta-adrenoreceptors to acetylcholine, gastrin and histamine is offered.     

Inhibitory role on gastric secretion of a central NK-3 tachykinin receptor agonist, senktide

When administered intracerebroventricularly, the highly selective NK-3 tachykinin receptor agonist senktide possesses a potent and dose-related inhibitory effect on gastric acid secretion. The central mechanism governing the antisecretory effect of senktide was examined in perfused-stomach rats by studying its influence on gastric acid secretion elicited by the secretagogues histamine, pentagastrin and bethanechol. Given intracerebroventricularly, senktide reduced the acid response to histamine, but not that to pentagastrin or bethanechol. Stimulation of NK-3 receptors in rat brain thus appears to inhibit gastric acid secretion through histaminergic pathways.     

Dual action of prostaglandin E2 on gastric acid secretion through different EP-receptor subtypes in the rat

We examined the role of prostaglandin E (EP) receptor subtypes in the regulation of gastric acid secretion in the rat. Under urethane anesthesia, the stomach was superfused with saline, and the acid secretion was determined at pH 7.0 by adding 50 mM NaOH. The acid secretion was stimulated by intravenous infusion of histamine or pentagastrin. Various EP agonists were administered intravenously, whereas EP antagonists were given subcutaneously 30 min or intravenously 10 min before EP agonists. PGE(2) suppressed the acid secretion stimulated by either histamine or pentagastrin in a dose-dependent manner. The acid inhibitory effect of PGE(2) was mimicked by sulprostone (EP(1)/EP(3) agonist) but not butaprost (EP(2) agonist) or AE1-329 (EP(4) agonist). The inhibitory effect of sulprostone, which was not affected by ONO-8711 (EP(1) antagonist), was more potent against pentagastrin- (50% inhibition dose: 3.6 mug/kg) than histamine-stimulated acid secretion (50% inhibition dose: 18.0 mug/kg). Pentagastrin increased the luminal release of histamine, and this response was also inhibited by sulprostone. On the other hand, AE1-329 (EP(4) agonist) stimulated the acid secretion in vagotomized animals with a significant increase in luminal histamine. This effect of AE1-329 was totally abolished by cimetidine as well as AE3-208 (EP(4) antagonist). These results suggest that PGE(2) has a dual effect on acid secretion: inhibition mediated by EP(3) receptors and stimulation through EP(4) receptors. The former effect may be brought about by suppression at both parietal and enterochromaffin-like cells, whereas the latter effect may be mediated by histamine released from enterochromaffin-like cells.     

Modification by histamine H2-receptor blockade of acid secretion stimulated by histamine, pentagastrin and methacholine in the isolated whole mouse stomach.

The direct influences of the blockade of the gastric histamine H2-receptors on the secretory actions induced by histamine, pentagastrin and methacholine, have been studied on the isolated perfused whole mouse stomach. According to the results cimetidine did not modify the spontaneous basal acid secretion. The interactions of cimetidine with the secretagogues were of a competitive nature with histamine and non-competitive with pentagastrin, while no modification of methacholine stimulated acid secretion.     

Stimulatory effects of endogenous and exogenous nitric oxide on gastric acid secretion in anesthetized rats

We previously reported the stimulatory effect of endogenous nitric oxide (NO) on gastric acid secretion in the isolated mouse whole stomach and histamine release from gastric histamine-containing cells. In the present study, we investigated the effects of endogenous and exogenous NO on gastric acid secretion in urethane-anesthetized rats. Acid secretion was studied in gastric-cannulated rats stimulated with several secretagogues under urethane anesthesia. The acid secretory response to the muscarinic receptor agonist bethanechol (2 mg/kg, s.c.), the cholecystokinin(2) receptor agonist pentagastrin (20 microg/kg, s.c.) or the centrally acting secretagogue 2-deoxy-D-glucose (200 mg/kg, i.v.) was dose-dependently inhibited by the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA, 10 or 50 mg/kg, i.v.). This inhibitory effect of L-NNA was reversed by a substrate of NO synthase, L-arginine (200 mg/kg, i.v.), but not by D-arginine. The histamine H(2) receptor antagonist famotidine (1 mg/kg, i.v.) completely inhibited the acid secretory response to bethanechol, pentagastrin or 2-deoxy-D-glucose, showing that all of these secretagogues induced gastric acid secretion mainly through histamine release from gastric enterochromaffin-like cells (ECL cells). On the other hand, histamine (10 mg/kg, s.c.)-induced gastric acid secretion was not inhibited by pretreatment with L-NNA. The NO donor sodium nitroprusside (0.3-3 mg/kg, i.v.) also dose-dependently induced an increase in acid secretion. The sodium nitroprusside-induced gastric acid secretion was significantly inhibited by famotidine or by the soluble guanylate cyclase inhibitor methylene blue (50 mg/kg, i.v.). These results suggest that NO is involved in the gastric acid secretion mediated by histamine release from gastric ECL cells.     

Sympathetic and parasympathetic component of bradycardia triggered by stimulation of NTS P2X receptors

We have previously shown that activation of P2X purinoceptors in the subpostremal nucleus tractus solitarius (NTS) produces a rapid bradycardia and hypotension. This bradycardia could occur via sympathetic withdrawal, parasympathetic activation, or a combination of both mechanisms. Thus we investigated the relative roles of parasympathetic activation and sympathetic withdrawal in mediating this bradycardia in chloralose-urethane anesthetized male Sprague-Dawley rats. Microinjections of the selective P2X purinoceptor agonist alpha,beta-methylene ATP (25 pmol/50 nl and 100 pmol/50 nl) were made into the subpostremal NTS in control animals, after atenolol (2 mg/kg i.v.), a beta1-selective antagonist, and after atropine methyl bromide (2 mg/kg i.v.), a muscarinic receptor antagonist. The bradycardia observed with activation of P2X receptors at the low dose of the agonist is mediated almost entirely by sympathetic withdrawal. After beta1-adrenergic blockade, the bradycardia was reduced to just -5.1 +/- 0.5 versus -28.8 +/- 5.1 beats/min in intact animals. Muscarinic blockade did not produce any significant change in the bradycardic response at the low dose. At the high dose, both beta1-adrenergic blockade and muscarinic blockade attenuated the bradycardia similarly, -37.4 +/- 6.4 and -40.6 +/- 3.7 beats/min, respectively, compared with -88.0 +/- 11 beats/min in control animals. Double blockade of both beta1-adrenergic and muscarinic receptors virtually abolished the response (-2.5 +/- 0.8 beats/min). We conclude that the relative contributions of parasympathetic activation and sympathetic withdrawal are dependent on the extent of P2X receptor activation.     

Histamine dependence of pentagastrin-stimulated gastric acid secretion in rats.

Does gastrin stimulate gastric acid secretion by direct action on oxyntic cells, by releasing histamine, or by being potentiated by histamine? Previous studies in the mouse pointed to gastrin-regulated histamine release. Guinea pig and rat are well known to vary in their sensitivity to histamine. Therefore, the effects of histamine and pentagastrin were compared quantitatively on isolated, lumen-perfused, stomach preparations from these species in the absence and presence of histamine H2-receptor blockade. The loss of potency of histamine in the rat was mirrored by a loss of potency of pentagastrin consistent with the idea that pentagastrin acts by releasing histamine. In the rat, a well-defined pentagastrin curve was obtained in the presence of histamine H2-receptor block as though pentagastrin acts both directly on the oxyntic cell and indirectly by releasing histamine. It was not necessary to invoke a potentiating interaction between histamine and pentagastrin at the oxyntic cell; the two effects appeared simply to add. Potentiation was observed, however, between other combinations of stimuli, for example, between vagal nerve and pentagastrin stimulation. The physiological consequences of these results are discussed.     

Necessity of intracellular cyclic AMP in inducing gastric acid secretion via muscarinic M3 and cholecystokinin2 receptors on parietal cells in isolated mouse stomach

The existence of a direct action of acetylcholine and gastrin on muscarinic M3 and cholecystokinin2 (CCK2) receptors on gastric parietal cells has not yet been convincingly established because these stimulated acid secretions are remarkably inhibited by histamine H2 receptor antagonists. In the present study, we investigated the necessity of intracellular cyclic AMP in inducing gastric acid secretion via muscarinic M3 and CCK2 receptors on parietal cells using an isolated mouse stomach preparation. Bethanechol (10-300 microM) produced a marked increase in acid output and this increase was completely blocked by famotidine (10 microM). In the presence of famotidine, bethanechol (1-30 microM) augmented the acid secretory response to dibutyryl AMP (200 microM) in a concentration-dependent manner. The augmentation was blocked by atropine (1 microM), 4-DAMP (0.1 microM), a muscarinic M3-selective antagonist, and by Ca2+ exclusion from the serosal nutrient solution. Pentagastrin (0.3-3 microM) also concentration-dependently stimulated gastric acid secretion, but the effect was completely inhibited by famotidine. In the presence of famotidine, pentagastrin (0.1-0.3 microM) elicited a definite potentiation of the acid secretory response to dibutyryl cyclic AMP (200 microM). This potentiation was inhibited by YM022 (1 microM), a CCK2 receptor antagonist, and by exclusion of Ca2+ from the serosal nutrient solution. The present results suggest that gastric acid secretion via the activation of muscarinic M3 and CCK2 receptors on the parietal cells is induced by activation of the cyclic AMP-dependent secretory pathway.     

Prostaglandin synthesis inhibition reverses the gastric antisecretory activity of somatostatin in anaesthetized rats

The inhibitory action on somatostatin (ST) on the spontaneous and stimulated (pentagastrin 18 micrograms/kg/h i.v. and histamine 5 mg/kg/h i.v.) gastric acid secretion and its modification after pretreatment with an inhibitor of endogenous prostaglandins biosynthesis (indomethacin 5 mg/kg i.v.) has been studied in the anaesthetized rat. ST 30 micrograms/kg/h i.v. inhibits basal and stimulated gastric acid secretion. In the presence of indomethacin the inhibition elicited by ST on basal and pentagastrin induced gastric acid secretion was partially attenuated, whereas in the histamine group the inhibitory action was totally abolished. The antagonism elicited by indomethacin was not surmounted by increasing (X 3.3) the dose of ST. These findings suggest that endogenous prostaglandins may be involved in the mechanism by which ST exerts its antisecretory effect in this model.     

Inhibition of gastric acid secretion in dogs by neurotensin

Neurotensin is a tridacapeptide which has been isolated from bovine hypothalamus. The action of synthetic neurotensin was studied on gastric acid secretion in dogs provided with gastric pouches. Intravenously infused neurotensin, 50 ng × kg^?1 × min^?1, was found to produce a considerable inhibition of pentagastrin stimulated gastric acid secretion. On the other hand, there was no sign of inhibition of histamine induced gastric acid secretion. The experiments show that neurotensin, isolated from the central nervous system is a potent gastric secretory inhibitor and that it has a selective action in inhibiting gastric acid responses to pentagastrin but not to histamine.     

Noradrenergic stimulation of BDNF synthesis in astrocytes: mediation via alpha1- and beta1/beta2-adrenergic receptors

Brain-derived neurotrophic factor (BDNF) synthesis in astrocytes induced by noradrenaline (NA) is a receptor-mediated process utilizing two parallel adrenergic pathways: beta1/beta2-adrenergic/cAMP and the novel alpha1-adrenergic/PKC pathway. BDNF is produced by astrocytes, in addition to neurons, and the noradrenergic system plays a role in controlling BDNF synthesis. Since astrocytes express various subtypes of alpha- and beta-adrenergic receptors that have the potential to be activated by synaptically released NA, we focused our present study on the mediatory role of adrenergic receptors in the noradrenergic up-regulation of BDNF synthesis in cultured neonatal rat cortical astrocytes. NA (1 microM) elevates BDNF levels by four-fold after 6 h of incubation. Its stimulation was partly inhibited by either the beta1-adrenergic antagonist atenolol, the beta2-adrenergic antagonist ICI 118,551, or by the alpha1-adrenergic antagonist prazosin, while the alpha2-adrenergic antagonist yohimbine showed no effect. BDNF levels in astrocytes were increased by the specific beta1-adrenergic agonist dobutamine and the beta2-adrenergic agonist salbutamol, as well as by adenylate cyclase activation (by forskolin) and PKA activation (by dBcAMP). However, none of the tested agonists or mediators of the intracellular beta-adrenergic pathways were able to reach the level of NA's stimulatory effect. BDNF cellular levels were also elevated by the alpha1-adrenergic agonist methoxamine, but not by the alpha2-adrenergic agonist clonidine. The increase in intracellular Ca2+ by ionophore A23187 showed no effect, whereas PKC activation by phorbol 12-myristate 13-acetate (TPA) potently stimulated BDNF levels in the cells. The methoxamine-stimulated BDNF synthesis was inhibited by desensitizing pretreatment with TPA, indicating that the alpha1-stimulation was mediated via PKC activation. In conclusion, the synthesis of astrocytic BDNF stimulated by noradrenergic neuronal activity is an adaptable process using multiple types (alpha1 and beta1/beta2) of adrenergic receptor activation.     

beta-Adrenergic receptor subtypes in melanophores of the marine gobies Tridentiger trigonocephalus and Chasmichthys gulosus.

The subtype of beta-adrenergic receptors in melanophores of the marine gobies Tridentiger trigonocephalus and Chasmichthys gulosus was studied. Pigment of denervated melanophores in isolated, split caudal fins was preliminarily aggregated by incubating the specimens in a physiological saline containing 10 microM phentolamine and 30-100 microM verapamil or 2-10 nM melatonin, and the responses of the melanophores to a beta-adrenergic agonist added to the incubating medium were recorded photoelectrically. The beta-adrenergic agonists noradrenaline, adrenaline, isoproterenol, salbutamol and, dobutamine were all effective in evoking a dispersion of melanophore pigment in the presence of phentolamine and verapamil or melatonin. The pigment-dispersing effect of noradrenaline (beta 1-selective agonist) was inhibited by metoprolol (beta 1-selective antagonist), propranolol,- and butoxamine. Whereas, the effect of salbutamol (beta 2-selective agonist) was hardly inhibited by metoprolol, though it was considerably inhibited by propranolol and ICI-118551. It was estimated that beta 1- and beta 2-adrenergic receptors coexist at ratios of 8.6:91.4, in the melanophore of Tridentiger trigonocephalus, and 25:75, in the melanophore of Chasmichthys gulosus, through the analyses of Hofstee plots of the effects of the beta-adrenergic drugs. It was suggested that the relation between the pigment-dispersing effect of a beta-adrenergic agonist on the melanophores and the concentration of the drug follows mass action kinetics, when the effect is mainly caused by the activation of beta 2-adrenergic receptors of the melanophores. However, when it is mainly caused by the activation of beta 1-adrenergic receptors of the melanophores, the relation does not follow mass action kinetics.     

The stomach divalent ion-sensing receptor scar is a modulator of gastric acid secretion

Divalent cation receptors have recently been identified in a wide variety of tissues and organs, yet their exact function remains controversial. We have previously identified a member of this receptor family in the stomach and have demonstrated that it is localized to the parietal cell, the acid secretory cell of the gastric gland. The activation of acid secretion has been classically defined as being regulated by two pathways: a neuronal pathway (mediated by acetylcholine) and an endocrine pathway (mediated by gastrin and histamine). Here, we identified a novel pathway modulating gastric acid secretion through the stomach calcium-sensing receptor (SCAR) located on the basolateral membrane of gastric parietal cells. Activation of SCAR in the intact rat gastric gland by divalent cations (Ca(2+) or Mg(2+)) or by the potent stimulator gadolinium (Gd(3+)) led to an increase in the rate of acid secretion through the apical H+,K+ -ATPase. Gd(3+) was able to activate acid secretion through the omeprazole-sensitive H+,K+ -ATPase even in the absence of the classical stimulator histamine. In contrast, inhibition of SCAR by reduction of extracellular cations abolished the stimulatory effect of histamine on gastric acid secretion, providing evidence for the regulation of the proton secretory transport protein by the receptor. These studies present the first example of a member of the divalent cation receptors modulating a plasma membrane transport protein and may lead to new insights into the regulation of gastric acid secretion.     

Beta 3-adrenergic receptors regulate retinal endothelial cell migration and proliferation

Sympathetic nerves may play a role in vascular disorders of the eye. In the present study, we hypothesized that activation of beta3-adrenergic receptors on retinal endothelial cells would promote migration and proliferation of these cells, two markers of an angiogenic phenotype. We show, for the first time, expression of beta3-adrenergic receptors on cultured retinal endothelial cells. Activation of these receptors with BRL37344, a specific beta3-adrenergic receptor agonist, promoted migration that was blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K), the mitogen activated protein kinase component MEK, and matrix metalloproteinases (MMPs) 2 and 9. BRL37344 stimulated proliferation, which could be blocked by inhibitors of Src, PI3K, and MEK. These cells also express the beta1-adrenergic receptor with no beta2-adrenergic receptor expression observed. Stimulation of the beta1-adrenergic receptor with xamoterol, a specific partial agonist, did not promote proliferation or migration. These results support the hypothesis that beta3-adrenergic receptors play a role in proliferation and migration of cultured human retinal endothelial cells.     

The effect of dibutyril cyclic guanosine monophosphate,a competitive antagonist to cholecystokinin-pancreozymin,on gastric acid secretion in the isolated mouse stomach

Dibutyryl cyclic guanosine monophosphate (dbcGMP), a specific competitive inhibitor of the gastrin, cholecystokinin-pancreozymin (CCK-PZ) family of peptides in pancreas, gallbladder and ileum, had no effect on basal acid secretion in the isolated mouse stomach nor on secretion stimulated by bethanechol or histamine. Secretion evoked by low doses of pentagastrin were likewise unaffected by dbcGMP but responses to high doses of pentagastrin were augmented. CCK-PZ and glucagon each inhibited acid secretion evoked by pentagastrin. DbcGMP blocked CCK-PZ-mediated inhibition but was without effect on inhibition by glucagon. These observations suggest that in the gastric glands there exist two receptors with different affinities for gastrin and CCK-PZ which mediate excitation and inhibition respectively.     

Temporal integration of alpha 1-adrenergic responses in BC3H-1 muscle cells. Regulation of glycogen phosphorylase activity

Regulation of Ca2+-dependent glycogen phosphorylase activity by alpha 1-adrenergic and H1-histamine receptors has been examined in BC3H-1 muscle cells. Stimulation by either norepinephrine or histamine elevates the phosphorylase activity ratio within 5 s from a resting value of 0.37 +/- 0.03 to maximal values of 0.8-0.9. Phosphorylase activation by alpha-adrenergic agonists is sustained over 20-30 min of agonist exposure, whereas histamine exposure only transiently activates phosphorylase during the initial 5 min of stimulation. The initial activation of phosphorylase by either receptor is not attenuated by treated cells with Ca2+-deficient and [ethylenebis(oxyethylenenitrilo)]tetraacetic acid-supplemented buffer, whereas the response to sustained adrenergic stimulation depends largely, but not totally, upon extracellular Ca2+. The involvement of protein kinase C in agonist responses was tested by treating cells with phorbol 12-myristate 13-acetate. Phorbol 12-myristate 13-acetate inhibits receptor-mediated mobilization of intracellular Ca2+ (IC50 = 3.6 nM) yet activates phosphorylase independently of agonist. Phorbol 12-myristate 13-acetate has no effect on cellular 45Ca2+ fluxes in the absence of agonist. Thus, the two receptors coordinately regulate intracellular signaling through Ca2+- and protein kinase C-mediated pathways. alpha 1-Adrenergic receptors elicit sustained phosphorylase activation whereas H1-histaminergic receptors desensitize.     

Gastric secretion in dogs following three day fasting and resumed feeding

The investigation into the influence of a three-day starvation on the gastric secretion in dogs with Pavlov pouches stimulated by meat, histamine and pentagastrin, was carried out. A 72-hour starvation did not change the summary volume of the gastric juice, debit of the gastric acid, and quantity of pepsin. At the same time the starvation decreased the average rate of gastric juice secretion, gastric acid and pepsin secretion in response to histamine and decreased the pepsin secretion in response to pentagastrin. In this way re-feeding enhanced the average rate of gastric juice secretion and gastric acid secretion on 3-day and pepsin on 5-day in response to meat. The average rate of gastric juice secretion increased on the 5-day after refeeding in response to histamine and the average rate of gastric juice, gastric acid and pepsin secretion in response to pentagastrin.     

The influence of a new prostaglandin E2 analogue (FCE 20700) on gastric acid and pepsin secretion in the dog.

The effects of FCE 20700, a new prostaglandin E₂ analogue, on gastric acid and pepsin secretion stimulated by different secretagogues were studied in dogs. Intravenous FCE 20700 produced a significant inhibition of total acid output (TAO) induced by pentagastrin or histamine in gastric fistula (GF) dogs. This effect was short-lasting and mainly due to a reduction in the volume of gastric juice with little acid concentration change. TAO and pepsin output stimulated by 2-deoxy-D-glucose were simililarly inhibited by intravenous FCE 20700. In dogs chronically fitted with both GF and Heidenhain pouch (HP), intragastric FCE 20700 significantly inhibited TAO stimulated by pentagastrin or histamine from HP, while acid secretion from GF was not significantly affected. It is concluded that FCE 20700 possesses a weak antisecretory activity in dogs. Consequently the antiulcer effects of this prostaglandin derivative seem to be largely independent from its influence on gastric acid and pepsin secretion.