Effect of the antrum and vagus nerve on the stimulation of the rat stomach by betazol in the perfusion test]

In the perfusion model on Wistar rats the action of a single s. c. injection of betazol (Histalog) in a dose of 50 mg/kg b. w. in dependence on various types of stomach operations was studied. The following effects were observed: 1. the vagotomy shortly before the perfusion test did not reduce the effect of betazol. 2. If the vagotomy dated back at least 4 weeks, a reduction of the stimulated maximum secretion to half of the controls was seen. 3. The combination of the vagotomy with a pyloroplasty led to a reduction of the stimulated maximum acid secretion to half the amount. Futhermore, the betazol effect was shortened considerably and was demonstrable for no more than 2 h after the injection. 4. The antrectomy without vagotomy, however, casued a retardation of the answer to betazol with a maximum of the stimulated secretion in the 4th hour after s.c. injection. The dissociation of the effect of betazol caused by vagotomy or antrectomy leads to the conclusion that betazol has a direct site of action in the parietal cell and a second one in the cholinergic stimulation of the vagal system.     

The stimulatory effect of forskolin on gastric acid secretion in rats

Adenylate cyclase is involved in the histamine pathway of the parietal cell. We therefore studied the effect of forskolin, a direct activator of the membrane-bound adenylate cyclase, on gastric acid secretion in anaesthetized rats. Forskolin in the range of 0.1-1 mg/kg i.v. caused a dose-dependent stimulation of acid secretion. Higher doses were not tolerated. The duration of action of the forskolin-induced acid secretion was also dose-related. The combined infusion of forskolin (0.3 mg/kg per h i.v.) and histamine at a low rate (0.5 mg/kg per h i.v.) produced a maximal stimulation of acid secretion which was comparable to that with a histamine infusion of 10 mg/kg per h i.v. without forskolin. Administration of desglugastrin at a low rate (10 micrograms/kg per h i.v.) plus forskolin by i.v. infusion produced similar results. In contrast, infusion of carbachol (3 micrograms/kg per h i.v.) together with forskolin caused only an additive effect on acid secretion. Including an isobutyl-methyl-xanthine (IBMX) i.v. injection of 3 mg/kg at the beginning of the forskolin infusion (0.3 mg/kg per h i.v.) produced an acid output after 60 min which was approximately 50% of the maximal stimulation during a histamine (10 mg/kg per h i.v.) infusion. The IBMX/forskolin-induced stimulation was completely inhibited by 0.5 mg/kg omeprazole i.v. while the equipotent antisecretory dose (during histamine stimulation) of cimetidine caused only a weak decrease in acid output.     

Gastric acid inhibitory action of a GABA-related compound, 3-amino-3-phenylpropionic acid, in the rat

The acid inhibitory properties of 3-amino-3-phenylpropionic acid, a structural GABA analogue, were studied in the perfused rat stomach preparation. 3-Amino-3-phenylpropionic acid, 10 and 30 mg/kg i.v., dose dependently suppressed the gastric acid secretion induced by baclofen (2 mg/kg s.c.). This secretagogue action had been shown to be unaffected by either GABAA or GABAB receptor antagonists. The i.v. administration of 3-amino-3-phenylpropionic acid (3 and 10 mg/kg) was also effective to abolish the acid stimulatory effects of muscimol (1 mg/kg i.v.) and 2-deoxy-D-glucose (200 mg/kg i.v.). 3-Amino-3-phenylpropionic acid, even at the high dose (30 mg/kg i.v.) had no influence on the acid output in response to histamine and bethanechol. Furthermore, 3-amino-3-phenylpropionic acid had no significant effect on the acid secretion induced by electrical vagal stimulation. These results indicate that the antisecretory effect of 3-amino-3-phenylpropionic acid is different from those of antimuscarinics, H2-receptor antagonists and vagal blockade. Together, the results suggest that 3-amino-3-phenylpropionic acid might act in the brain to inhibit central regulation mechanisms of gastric acid secretion, probably through GABA mechanisms.     

Morphine inhibits the gastric acid secretion stimulated by 2-deoxy-D-glucose via a central mechanism in anesthetized rats

The effect of morphine on the gastric acid secretion induced by 2-deoxy-D-glucose (2-DG) was investigated in the perfused stomach of anesthetized rats. The intravenous infusion of morphine (0.01-1.0 mg/kg per h for 2 h) dose dependently suppressed the gastric acid secretion stimulated by 2-DG. This inhibitory effect of morphine was completely reversed by naloxone (1.0 mg/kg i.v.) pretreatment. On the other hand, even the higher dose of morphine (1.0 mg/kg per h for 70 min) had no effect on the gastric acid secretion evoked peripherally by electrical stimulation of the vagus nerve. These observations indicate that morphine suppressed the 2-DG-induced gastric acid secretion via a central mechanism(s), probably mediated by the opiate receptor(s).     

The actions of bombesin on gastric secretion of the dog and the rat

1. Bombesin stimulated acid secretion from the denervated fundic pouch of the dog. Whereas the concentration of hydrochloric acid in bombesin-produced juice was always higher than in control juice this did not occur for pepsin, the concentration of which remained below the basal values. The threshold dose of bombesin was 5-30 ng/kg by the subcutaneous route and 0·05-0·2 (μg/kg)/h by intravenous infusion. At low doses bombesin was more active than caerulein, even on a molar basis, and at high dose levels was as active as caerulein. In contrast to gastrin and caerulein, bombesin elicited a moderate secretory response also following rapid intravenous injection.

2. The acid secretion provoked by bombesin was almost completely inhibited by atropine and reduced by approximately 50% by hexamethonium.

3. Bombesin did not stimulate acid secretion in the lumen-perfused preparation of the rat stomach when administered by subcutaneous injection (up to 10 μg/kg) or by intravenous infusion (up to 10 (μg/kg)/hour). An irregular increase in acid output was observed only following rapid intravenous injection and this was of doubtful significance.

4. The mechanism of the secretagogue action of bombesin on the dog stomach is discussed.

     

D-myo-inositol-1,2,6-trisphosphate is a selective antagonist of neuropeptide Y-induced pressor responses in the pithed rat.

The antagonistic effects of a new inositol phosphate derivative, D-myoinositol-1,2,6-trisphosphate (PP56), on pressor responses to preganglionic sympathetic nerve stimulation and exogenously administered phenylephrine or neuropeptide Y (NPY) were investigated in vivo in the pithed rat. In this model an intravenous (i.v.) bolus administration of PP56 (1-50 mg/kg) dose dependently inhibited the increase in mean arterial blood pressure (MAP) induced by a continuous infusion of NPY (2 micrograms/kg per min for 10 min). PP56 in a dose of 5 mg/kg i.v. bolus reduced the entire NPY dose-response curve (0.4-8 microgram/kg per min 10 min infusion) without any shift to the right indicating a non-competitive interaction. Furthermore, PP56 (10-50 mg/kg i.v.) was found to inhibit the pressor response to preganglionic sympathetic nerve stimulation and i.v. bolus injection of the alpha 1-adrenoceptor agonist, phenylephrine. The dose-response curves for increasing doses of phenylephrine and incremental preganglionic sympathetic nerve stimulation were not significantly altered by a lower dose of PP56 (5 mg/kg i.v. bolus). We conclude that PP56, representing a new class of synthetic drugs, can antagonize the actions of exogenous and endogenous NPY in vivo, an action which is specific for NPY within a limited dose range.     

Role of central prostaglandin E2 in the regulation of gastric acid secretion in the rat.

The central action of prostaglandin E2 (PGE2) on gastric acid secretion was investigated in rats by comparing the effects of intracisternal (i.ci.) and i.v. administration of PGE2 and the influence of i.ci. injection of indomethacin on acid secretion and PGE2 generation in the brain and stomach. I.ci. injections of PGE2 (1-10 micrograms) or the stable analog, 16,16-dimethyl PGE2, (0.01-0.1 micrograms) induced a dose dependent inhibition of baclofen-stimulated gastric acid secretion by 0-82% and by 7-87% respectively. I.v. infusion of PGE2 also induced a dose related inhibition of baclofen-stimulated acid secretion, but 10 fold higher doses were required. I.ci. or i.v. injection of indomethacin in doses ranging from 50 to 500 micrograms/rat, produced a similar dose dependent inhibition of the PGE2 generation in both the gastric mucosa and brain cortex measured 1 h post injection. I.ci. injection of indomethacin (500 micrograms) increased within 10 min acid secretion with a peak response at 20-30 min; 60-120 min post injection, when prostaglandin synthesis was inhibited by 90%, basal and baclofen-stimulated acid output were not altered. These results further establish that PGE2 acts in the brain to inhibit vagally stimulated gastric acid secretion in rats, and do not support a tonic inhibitory influence of endogenous brain PGE2 in the regulation of gastric acid secretion. In addition, these data showed that indomethacin injected i.ci. at 500 micrograms does not induce a selective inhibition of prostaglandin synthesis in the brain.     

Centrally mediated inhibitory effect of 5-[2-(diethylamino)ethyl]amino-5,11-dihydro[1]benzoxepino[3,4- b]pyridine trihydrochloride (KW-5805) on gastric acid secretion in rats

KW-5805, 5-[2-(diethylamino)ethyl]amino-5,11-dihydro[1]benzoxepino[3,4- b]pyridine trihydrochloride, is a new tricyclic compound with antiulcer activities. Its effect on stimulated gastric acid secretion was investigated in the perfused stomach of anesthetized rats. KW-5805 at 0.3-10 mg/kg, i.v., dose-dependently inhibited gastric acid secretion stimulated by 2-deoxy-D-glucose (2-DG). On the other hand, the compound at 10-20 mg/kg, i.v., exerted a moderate decrease in gastric acid secretion stimulated by bethanechol; and at 10 mg/kg, i.v., it produced no change in gastric acid secretion evoked peripherally by vagal electrical stimulation. When applied intracerebroventricularly at 1-5 micrograms/rat, this compound dose-relatedly reduced gastric acid secretion stimulated by 2-DG. Three main metabolites (KF-10504, KF-9530 and KF-10847) of KW-5805 at 1 mg/kg, i.v., caused no significant decrease in gastric acid secretion stimulated by 2-DG. Doxepin, a tricyclic compound, definitely depressed the 2-DG stimulated gastric acid secretion at 1 mg/kg, i.v. It is suggested that intravenous administration of KW-5805 inhibits gastric acid secretion stimulated by 2-DG, mainly via centrally mediated mechanisms, and that biotransformation of KW-5805 to the metabolites contributes little to the development of the antisecretory effect.     

Effects of GABA antagonists and structural GABA analogues on baclofen stimulated gastric acid secretion in the rat

The effects of GABA receptor antagonists (bicuculline and phaclofen) and structural GABA-analogues on baclofen stimulated gastric acid secretion were studied in standardized perfused rat stomach preparations. Pretreatment with bicuculline, a GABAA-receptor antagonist, in the doses of 1 and 3 mg/kg, subcutaneously, had no influence on the gastric acid response to baclofen. In addition, phaclofen, a GABAB antagonist, in the doses of 3 to 30 mg/kg, intravenously, was found to have no significant effect on the acid response to baclofen. However, GABA-analogues (MOPS and ABA; 10-30 mg/kg, i.v.) and lipophilic GABA derivatives structurally related to beta-amino acids (APPA and APHA; 30 mg/kg, i.v.) significantly counteracted the secretagogue action of baclofen. Further experiments on APPA action showed that the antisecretory effect of APPA could be overcome by higher doses of baclofen. APPA did not affect bethanechol stimulated acid secretion. These results suggest that the secretagogue action of baclofen is independent to GABAA- and GABAB-receptors and that APPA may interact with baclofen in regulation mechanisms of acid secretion, although further investigations are necessary to define the mode of action of APPA on the GABA-ergic system.     

Effects of gallamine on the contractile response of the stomach in cats

Stimulation of the vagal trunk in cats anesthetized with pentobarbital sodium produced a contractile response of the stomach during stimulation (initial contraction). Pretreatment with either hexamethonium (0.3 to 30 mg/kg, i.v.) or gallamine (1 to 100 mg/kg, i.v.) dose-dependently produced a delayed contraction, following the initial contraction after stimulation. After the administration of either hexamethonium or gallamine produced a maximum delayed contraction, then an additional dose of gallamine or hexamethonium was administered. The subsequent treatment further augmented the delayed contraction. The results indicate that gallamine induced the delayed contraction by a mechanism different from hexamethonium.     

Effects of ranitidine, a new histamine H2-receptor antagonist, on secretagogue-stimulated gastric secretion in rats: comparison with cimetidine (author's transl)

Antisecretory effects of ranitidine on secretagogue-stimulated gastric secretion in acute fistula rats were studied. Histamine 2HCl (8 mg/kg/hr), pentagastrin (125 micrograms/kg/hr) or carbachol (128 micrograms/kg/hr) was continuously given i.v. by an infusion pump, through the tail vein to acute fistula rats. Gastric secretion was collected hourly for 5 hr and analyzed for its components. Cimetidine was used as a reference drug. Both drugs were given i.v. by a bolus injection in the tail vein 30 min after the injection of each stimulant. Both ranitidine (1 and 10 mg/kg) and cimetidine (10 and 60 mg/kg) significantly (P less than 0.05) inhibited the histamine-stimulated gastric secretion (volume, acid and pepsin output) for 1 to 4 hr. Both ranitidine (10 mg/kg) and cimetidine (60 mg/kg) significantly (P less than 0.05) inhibited the pentagastrin-stimulated gastric secretion for 2 to 3 hr. both ranitidine (10 mg/kg) and cimetidine (10 and 60 mg/kg) markedly inhibited the gastric acid secretion in response to carbachol. However, cimetidine (10 or 60 mg/kg) significantly (P less than 0.05) stimulated the volume and pepsin output by carbachol. We conclude that ranitidine is about 6 times more potent than cimetidine for histamine- or pentagastrin-stimulated gastric secretion and almost equal to cimetidine for carbachol-stimulated gastric acid output in rats.     

Effects of topical application of KT1-32 on transmucosal potential difference and acid secretion in the rat stomach

Effects of intragastric application of azuletil sodium (KT1-32), a novel antiulcer drug, on transmucosal potential difference (PD) and acid secretion were investigated in the rat stomach. The stomach was mounted on a Lucite chamber and perfused with saline before and after exposure to KT1-32 for 10 min. KT1-32 (3-30 mg/kg) produced an elevation of PD in a dose-dependent manner with a rise of the luminal pH. The increased PD response caused by KT1-32 (10 mg/kg) persisted after removal of the agent from the stomach, but this PD generating effect was significantly mitigated by pretreatment with omeprazole (60 mg/kg, i.p.). KT1-32 raised PD under basal conditions, but did not significantly affect the reduced PD response caused by 30% ethanol. In addition, topical application of KT1-32 significantly reduced acid secretion caused by histamine (4 mg/kg/hr, i.v.) and carbachol (20 micrograms/kg/hr, i.v.). In the in vitro study, KT1-32 at 3.9 x 10(-4) M showed 50% inhibition of the H/K ATPase activity prepared from the hog gastric mucosa. These results suggest that KT1-32 exerts locally antisecretory and PD generating effects. The latter may be accounted for by the antisecretory action, which is probably related to the H/K ATPase inhibition.     

Induction of gastric lesions by 2-deoxy-D-glucose in rats following chemical ablation of capsaicin-sensitive sensory neurons.

Effects of chemical ablation of capsaicin-sensitive sensory nerves on functional and mucosal ulcerogenic responses to 2-deoxy-D-glucose (2DG) were investigated in the rat stomach, in comparison with those of indomethacin, a prostaglandin (PG) biosynthesis inhibitor. Intravenous injection of 2DG (200 mg/kg) followed by infusion of this agent (100 mg/kg/hr, i.v.) significantly increased gastric acid secretion and motility, but rarely induced macroscopic damage in the gastric mucosa of normal conscious rats. Chemical ablation of capsaicin-sensitive sensory nerves or pretreatment with indomethacin (5 mg/kg, s.c.) did not significantly affect the acid secretory and motility responses to 2DG, but induced severe hemorrhagic lesions in the stomach within 4 hr. Gastric mucosal blood flow (GMBF) determined by laser Doppler flowmetry under anesthetized conditions did not consistently change during 2DG treatment in any of these three groups, but the rise in GMBF in response to mucosal acidification (0.2 N HCl) was significantly inhibited in the animals pretreated with indomethacin or following chemical deafferentation. We conclude that functional ablation of capsaicin-sensitive sensory neurons, similar to the PG deficiency, increases the gastric mucosal vulnerability during 2DG infusion (acid hypersecretion and hypermotility due to vagal excitation), resulting in hemorrhagic lesions, and that the mechanism may be accounted for at least partly by the impairment of gastric mucosal blood flow response to mucosal acidification.     

Effects of a new bronchodilator, (alpha RS)-3-formamido-4-hydroxy-alpha-[[[(alpha RS)-p-methoxy-alpha-methylphenethyl] amino] methyl] benzyl alcohol fumarate dihydrate (BD 40A) on gastric acid secretion and gastrointestinal motility (author's transl)

Effects of a new beta 2-adrenoceptive agonist, BD 40A on gastric acid secretion and gastrointestinal motility were studied in comparison with those of isoproterenol, hexoprenaline and cimetidine. BD 40A (0.3 and 1 microgram/kg i.v.) inhibited dose-dependently gastric acid secretion produced by continuous i.v. infusion of tetragastrin (8 microgram/kg-hr), whereas acid secretion in response to histamine infusion (160 microgram/kg-hr) was resistant to the inhibitory action of BD 40A in pentobarbital anesthetized dogs with gastric pouches. Cimetidine (0.3 and 1 mg/kg) blocked acid secretion induced by either tetragastrin or histamine. When intraduodenally administered to pylorus-ligated rats in a dose of 1 mg/kg, BD 40A and hexoprenaline produced a reduction in acid output. Both drugs (1 microgram/kg i.v.) decreased the amplitude of gastric, duodenal and ileal motility measured by the balloon method in anesthetized dogs. The inhibitory effects of BD 40A on acid secretion induced by tetragastrin and on spontaneous motility of the gastrointestinal tract were antagonized by 1 mg/kg of propranolol. These pharmacological properties of BD 40A were qualitatively similar to those of isoproterenol and may be ascribable to the activation of beta-adrenergic receptors in the gastrointestinal tissue.     

Endotoxin inhibition of distension-stimulated gastric acid secretion in rat: mediation by NO in the central nervous system.

1. The involvement of nitric oxide in the acute inhibitory effects of low doses of endotoxin, following intracerebroventricular (i.c.v.) or intravenous (i.v.) administration, on gastric acid secretion stimulated by distension or i.v. infusion of pentagastrin has been investigated in the continuously perfused stomach of the anaesthetized rat. 2. The i.c.v. administration of E. coli endotoxin (800 ng kg-1) abolished the acid secretory response induced by gastric distension (20 cm water intragastric pressure) within 30 min of administration. 3. By contrast, submaximal rates of acid secretion induced by i.v. infusion of pentagastrin (8 micrograms kg-1 h-1) were not inhibited by i.c.v. administration of endotoxin (800 ng kg-1). 4. Prior i.c.v. administration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 800 micrograms kg-1) restored the acid secretory responses to distension in rats treated with endotoxin (i.c.v.). 5. Likewise, i.v. administration of endotoxin (5 micrograms kg-1) abolished the acid secretory response induced by gastric distension within 30 min of administration. Prior i.c.v. injection of L-NAME (800 micrograms kg-1) or its i.v. administration (10 mg kg-1) restored acid secretory responses in rats receiving i.v. endotoxin. 6. The reversal by L-NAME (i.v.) of the acid inhibitory effects of endotoxin (i.v.) was prevented by L-arginine (12 mg kg-1, i.c.v. or 100 mg kg-1, i.v.), but not by its enantiomer D-arginine. 7. The present results imply the existence of an acute response to endotoxin involving NO synthesis in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sympatho-adrenomedullary system mediation of the bombesin-induced central inhibition of gastric acid secretion

Possible mechanisms of the inhibitory effect of bombesin on gastric acid secretion were examined in rats anesthetized with urethane. Intracerebroventricular (i.c.v.) administration of bombesin (0.1-3 nmol) dose dependently inhibited the increase in gastric acid secretion induced by both intravenous (i.v.) administration of 2-deoxy-D-glucose 60 mg/kg and electrical stimulation of the vagus nerve (1 mA, 0.5 ms, 3 Hz), but not increase due to i.v. infusion of bethanechol (10 micrograms/kg per min). Such an inhibitory effect of bombesin on the gastric response was markedly reduced by bilateral cutting of the greater splanchnic nerves. The inhibitory effect of bombesin on gastric acid secretion induced by stimulation of the vagus nerve was not modified either by chemical sympathectomy with 6-hydroxydopamine or by bilateral adrenalectomy alone. However, this inhibitory effect of bombesin was abolished under conditions of combined chemical sympathectomy and adrenalectomy. These results suggest that bombesin (i.c.v.) probably excites the sympatho-adrenomedullary system and thus induces inhibition of gastric acid secretion. Furthermore, a dysfunction of the sympathetic or of the adrenomedullary system may well be functionally compensated for by the system with unaltered function.     

Inhibitory effect of the cannabinoid receptor agonist WIN 55,212-2 on pentagastrin-induced gastric acid secretion in the anaesthetized rat

The effect of the cannabinoid (CB) receptor agonist WIN 55,212-2 on gastric acid secretion was studied in the anaesthetized rat after stimulation with pentagastrin. WIN 55,212-2 (0.5-2 mg/kg, i.v.) was inactive on basal secretion but caused a marked inhibition (80%) of the acid secretion stimulated by pentagastrin (10 microg/kg, i.v.). The enantiomer WIN 55,212-3 (1-3 mg/kg, i.v.) did not significantly modify basal or pentagastrin-induced acid secretion. The inhibitory effect of WIN 55,212-2 against pentagastrin was prevented by the administration of the selective cannabinoid CB1 receptor antagonists SR141716A (1 mg/kg, i.v.) and LY320135 (1 mg/kg, i.v.); by contrast, the CB2 receptor antagonist SR144528 (0.3-1 mg/kg, i.v.) was without effect. The selective CB2 receptor agonist JWH-015 (0.1-10 mg/kg, i.v.) was inactive on the increase of acid output stimulated by pentagastrin. These results suggest that the inhibitory effect of WIN 55,212-2 on pentagastrin-stimulated acid secretion in the anaesthetized rat is mediated by specific cannabinoid receptors. Moreover, the antagonism of WIN 55,212-2-induced effects by the selective CB1 receptor antagonists SR141716A and LY320135 together with the ineffectiveness of both the CB2 receptor agonist JWH-015 and the CB2 receptor antagonist SR144528 indicate that CB1 receptor subtypes are predominantly involved in the antisecretory effect of WIN 55,212-2.     

Pharmacological characterisation of the somatostatin analogue TT-232: effects on neurogenic and non-neurogenic inflammation and neuropathic hyperalgesia

The putative anti-inflammatory and anti-nociceptive activity of the heptapeptide somatostatin analogue TT-232 ( D-Phe-Cys-Tyr- D-Thr-Lys-Cys-Thr-NH(2)) was investigated in the rat and mouse, as well as its effect on neuropathic hyperalgesia, gastric ulceration and the release of sensory neuropeptides. In the rat, carrageenin-induced paw oedema was inhibited dose dependently by TT-232 (3x2.5-20 microg/kg i.v.). Evans blue accumulation induced by intraarticular bradykinin injection (0.5 nmol in 0.1 ml) was slightly, but significantly inhibited by a single TT-232 dose (5-20 microg/kg). Cutaneous neutrophil accumulation over a 3-h period after intradermal (i.d.) injection of carrageenin (1 mg/site) or interleukin 1beta (IL-1beta, 3 pmol/site) was inhibited significantly by TT-232 (3x80 microg/kg i.v.), while diclofenac (3x10 mg/kg i.v.) elicited significant inhibition only in the IL-1beta test. In the mouse, TT-232 potently decreased oedema formation induced by 2.5% capsaicin applied topically to the ear. Mechano-nociception in the rat hind-paw during neuropathic pain induced by partial sciatic nerve injury (model of Seltzer) was measured using the Randall-Selitto test. TT-232 (5-20 microg/kg i.p. on the 7th day after the operation) dose-dependently inhibited the mechano-nociceptive hyperalgesia. In vitro release of substance P (SP), calcitonin gene-related peptide (CGRP) and somatostatin from the isolated rat trachea in response to electrical field stimulation (40 V, 0.1 ms, 10 Hz, 120 s) of its nervous elements was inhibited significantly by 500 nM TT-232. The role of G protein-coupled receptors in the effect of TT-232 was indicated by the prevention of its inhibitory action on the release of sensory neuropeptides by incubation the tissue for 1 or 6 h with pertussis toxin (100 ng/ml). The release of sensory neuropeptides to in response to electrical nerve stimulation was not inhibited by a potent tyrosine kinase inhibitor, genistein (50 microM). TT-232 (up to 5 mg/kg i.p.) did not induce mucosal lesions in either the stomach or the duodenum.These data suggest that TT-232, a somatostatin analogue devoid of endocrine effects, is a promising lead molecule in the search for novel, broad-spectrum anti-inflammatory and analgesic agents.     

Capsaicin-sensitive vagal stimulation-induced gastric acid secretion in the rat: evidence for cholinergic vagal afferents.

1. The effects of electrical vagal stimulation on frequency-dependent gastric acid secretion were investigated in urethane-anaesthetized rats in vivo. 2. Stimulation at 4, 16 or 32 Hz was performed in rats treated with atropine (1 mg kg-1, i.v.), hexamethonium (10 mg kg-1, i.v. bolus and 1 mg kg-1 min-1, i.v. infusion) or atropine and hexamethonium (doses as above); in some experiments pentagastrin (1.2 micrograms kg-1 h-1, i.v. infusion) was infused prior to stimulation. 3. Maximal acid secretion occurred at 16 Hz. This was significantly reduced but not abolished by atropine or hexamethonium and completely abolished after atropine and hexamethonium. In the presence of pentagastrin, the acid secretory response to 16 Hz stimulation was augmented, atropine or hexamethonium reduced stimulated secretion by about 70%, whereas atropine and hexamethonium completely abolished stimulated secretion. 4. In rats in which the vagus nerve was pretreated with capsaicin 10-14 days before experimentation there was a significant reduction (by about 40%) in stimulated acid secretion at 16 Hz, which was virtually abolished by atropine treatment. After acute treatment of the vagus nerve with capsaicin (at the time of experimentation) maximally stimulated acid secretion was significantly reduced by about 50%. 5. Taken together, these results indicate that capsaicin-sensitive afferent fibres contribute to the acid secretory response induced by electrical vagal stimulation in the rat. Based on pharmacological evidence, the capsaicin-sensitive afferent fibres may be cholinergic, since atropine and hexamethonium totally abolish vagal stimulation-induced acid secretion.     

Mechanisms underlying the intestinal fluid secretion evoked by nociceptive serosal stimulation of the rat

Summary Intestinal net fluid transport was measured in vivo continuously with a gravimetric method. Chemical stimulation of the jejunal serosa with hydrochloric acid (0.1 M), ethanol (20%), cat bile or 7-deoxycholic acid (10 mM) evoked an intestinal fluid secretion. Hexamethonium (10 mg/kg b. wt. i. v.) or serosal application of lidocaine (1% solution) partially blocked this secretory response. Bradykinin and prostaglandin E₁, two important inflammatory mediators, elicited fluid secretion when applied to the serosal surface at a concentration of 10^–4M. This secretion was also partly inhibited by hexamethonium. Furthermore indomethacin (10 mg/kg b. wt. i. v.) or pyrilamine (10 mg/kg b. wt. i. v.), a H₁-receptor blocker, partly inhibited the secretory response caused by chemical stimulation of the serosa while cimetidine (1 mg/kg b. wt. i. v.), a H₂-receptor blocker, had no effect. Freeze sectioned samples from chemically stimulated intestines were examined by fluorescence microscopy. A leakage of i. v. administrated Evans blue labelled albumin into the interstitial space of the serosa and the outer layer of the muscularis was found.It is concluded: (1) The intestinal fluid secretion studied is mainly elicited by nociceptive stimulation of nerves in the serosa or the outer muscularis. (2) The reflex may be activated by the local release of histamine, kinins and prostaglandins. (3) The reflex studied is part of an inflammatory response.