Peripheral 2-hydroxy-saclofen-sensitive GABA-B receptors mediate both vagal-dependent and vagal-independent acid secretory responses in rats.

1. The present study investigates the effects of peripherally administered baclofen on gastric acid secretion from the perfused stomach of anaesthetized rats. 2. Intravenous (i.v.) baclofen caused a marked dose-dependent increase in acid secretion which was antagonized by i.v. 2-hydroxy-saclofen, whereas intracerebroventricular (i.c.v.) 2-hydroxy-saclofen and i.c.v. or i.v. phaclofen and bicuculline were ineffective. In addition, 2-hydroxy-saclofen did not affect acid hypersecretion stimulated by histamine. 3. The secretagogue action of baclofen was fully prevented by cimetidine, but only partially attenuated by atropine, proglumide or bilateral cervical vagotomy. Moreover, the vagotomy-resistant excitatory effect of baclofen was abolished by 2-hydroxy-saclofen or cimetidine, but not by atropine or proglumide. 4. In vagotomized rats whose gastric secretion was maximally increased by electrical stimulation of the left vagus nerve, i.v. injection of baclofen further potentiated acid output, this action being prevented by cimetidine. 5. Taken together, the present results provide evidence that peripheral GABA-B receptors mediate the gastric hypersecretory effect of parenterally administered baclofen to anaesthetized rats, and suggest that both vagal cholinergic and extravagal pathways are involved in the stimulant effect.

Phaclofen-sensitive GABA-B receptors do not mediate excitatory effects of baclofen on gastric secretion.

The present study investigates the effects of centrally or peripherally administered baclofen on gastric acid secretion from pylorus-ligated rats. The influence of baclofen on basal acid secretion from isolated guinea-pig gastric fundus was also evaluated. At all doses employed, intracerebroventricular baclofen significantly decreased acid secretion, this inhibitory action being antagonized by intracerebroventricular phaclofen. Intravenous baclofen induced both gastric inhibitory and excitatory responses at low and high doses, respectively. Intracerebroventricular phaclofen prevented the inhibitory effect, while neither intracerebroventricular nor intravenous phaclofen modified the stimulant action of parenteral baclofen. Both central and parenteral muscimol did not influence gastric acid secretion. Moreover, baclofen or muscimol were without effect on basal acid secretion from isolated guinea-pig gastric fundus, whereas bethanechol caused a marked and concentration-dependent stimulant action. The present results provide further evidence for the inhibitory role of central phaclofen-sensitive GABA-B receptors in the regulation of acid secretion. In addition they indicate that the hypersecretory effect exerted by parenteral baclofen may depend upon the activation of putative peripheral non-A and phaclofen-insensitive GABA-B receptors. Finally, peripheral GABA receptors do not appear to be significantly involved in the direct control of gastric secretion.

Modulation of gastric acid secretion by peripheral presynaptic alpha 2-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.

Alpha 2-adrenoceptor-mediated inhibitory and excitatory effects of detomidine on rat gastric acid secretion.

The effects of the selective alpha 2-adrenoceptor agonist detomidine on gastric acid secretion from pylorus-ligated and stomach-perfused rats have been investigated. In pylorus-ligated rats i.p. injection of detomidine markedly inhibited acid secretion, this effect being prevented by yohimbine or idazoxan. Under the same conditions, idazoxan significantly increased secretion in a dose-independent fashion. In non-vagotomized and vagotomized stomach-perfused rats i.p. detomidine stimulated acid secretion: this excitatory effect was antagonized by idazoxan. The present results suggest that both inhibitory and excitatory gastric secretory effects of detomidine are mediated by alpha 2-adrenoceptors on cholinergic and adrenergic nerves, respectively. The stimulant activity of idazoxan on gastric secretion from pylorus-ligated rats may be interpreted in terms of increased excitatory vagal tone following the blockade of inhibitory alpha 2-adrenoceptors.

Central GABAA excitatory and GABAB inhibitory receptors regulate gastric acid secretion in rats.

The present study investigates the effects of GABAA- and GABAB-receptor agonists and antagonists on gastric secretion after their i.c.v. administration to conscious pylorus-ligated rats and anaesthetized stomach lumen-perfused rats. Muscimol was without effect in pylorus-ligated rats, whereas baclofen produced a significant decrease in acid secretion, which was fully prevented by phaclofen. Under these conditions, a significant decrease in acid secretion was also obtained with bicuculline. In stomach lumen-perfused rats, muscimol caused a marked, dose-dependent increase in acid secretion, which was antagonized by bicuculline. Under the same conditions, baclofen induced a moderate, but significant, bicuculline-sensitive increase in acid secretion. Overall, our results suggest the presence of two central GABA pathways which mediate opposite effects: (a) a bicuculline-sensitive GABAA-receptor, the stimulation of which increases acid secretion under pharmacological depression of central vagal tone (anaesthetized rats); (b) a phaclofen-sensitive GABAB-receptor, the activation of which decreases vagally stimulated acid secretion (pylorus-ligated rats).

Differential affinities of AF-DX 116, atropine and pirenzepine for muscarinic receptors of guinea pig gastric fundus, atria and urinary bladder: might atropine distinguish among muscarinic receptor subtypes?

The pA2 values and the Schild plots of the antimuscarinic drugs AF-DX 116, atropine and pirenzepine for muscarinic receptors of isolated guinea pig gastric fundus (acid secretion) and atrial and urinary bladder preparations (contractile force) obtained from the same animals were calculated against bethanechol as the agonist. The antimuscarinic drugs concentration-dependently shifted the concentration-response curves to bethanechol to the right without any change in the maximum response. The analysis of data based on Schild plots was consistent with a simple competitive antagonism, since regression slopes did not differ significantly from unity. The pA2 values indicated a significantly higher affinity of AF-DX 116 and atropine for atrial muscarinic receptors with respect to those of the gastric mucosa or urinary bladder. By contrast, in the case of pirenzepine the pA2 values for the three tissues did not differ significantly. These results suggest that each examined tissue apparently contains homogeneous population of acetylcholine muscarinic (M2) receptors. The pA2 values found for AF-DX 116 and atropine suggest, however, that the putative M2 subtype of atrial muscarinic receptor differs from both those of the gastric fundus and those of the urinary bladder.

Pirenzepine prevents cysteamine-induced formation of gastroduodenal ulcers and reduction of mesenteric circulation.

The effects of pirenzepine on gastric and duodenal ulceration and barrier mucus levels, as well as on changes of superior mesenteric artery diameter caused by cysteamine, were investigated in rats and compared with those of atropine. Cysteamine induced severe gastric and duodenal ulcers and decreased both barrier mucus levels and mesenteric blood flow. Pirenzepine reduced gastric and duodenal ulceration induced by cysteamine. Moreover, pirenzepine significantly increased basal mesenteric artery diameter and fully prevented cysteamine-induced decrease in mesenteric blood flow. Under the same conditions, atropine failed to prevent gastric and duodenal ulceration or mesenteric artery changes caused by cysteamine. Both pirenzepine and atropine were without any effect on cysteamine-induced inhibition of gastric and duodenal barrier mucus levels. The present results are consistent with the view that pirenzepine protects against gastroduodenal ulceration caused by cysteamine by increasing blood flow at the level of the ulcerated mucosa. The higher affinity of pirenzepine for the muscarinic receptors of sympathetic ganglia may explain the difference between the effects of pirenzepine and atropine. In addition to this, the measurement of superior mesenteric artery diameter changes may represent an accurate and reproducible method, suitable for studying the gastrointestinal protective mechanisms of the drugs.

GABA-A-mediated gastrin release induced by baclofen in the isolated vascularly perfused rat stomach.

In order to investigate the role of peripheral GABA-B receptors, the effects of the putative GABA-B agonist baclofen on immunoreactive gastrin release from an isolated vascularly perfused rat stomach preparation were examined. The vascular infusion of baclofen at graded concentrations induced a dose-dependent increase in gastrin release; this was unaffected by the GABA-B antagonist delta-aminovaleric acid, but was fully prevented by the selective GABA-A antagonist bicuculline as well as by atropine or tetrodotoxin. These results suggest that the stimulant effects of baclofen are mediated by nervous cholinergic structures associated with GABA-A receptors, and indicate that this GABA-B agonist must be regarded as a partial agonist of peripheral GABA-A receptors.

[A selective antimuscarinic agent: pirenzepine. Review of its pharmacologic and clinical properties]. / Un antimuscarinico selettivo: la pirenzepina. Rassegna delle sue proprietà farmacologiche e cliniche.

The heterogeneity of muscarinic receptors has been well supported by differential characteristics between pirenzepine and atropine both in receptor binding and in whole tissue pharmacology studies. Under these conditions pirenzepine has been classified as a selective receptor antagonist with high affinity for M1 receptors. The antisecretory properties of pirenzepine on gastric acid and pepsin secretion may be attributed to the antagonistic activity of the drug on muscarinic M1 receptors of gastric intramural plexuses, whereas the effect on parietal muscarinic M2 receptors seems of less importance. Additional inhibitory mechanisms on gastric secretion may be represented by pirenzepine-induced increase in somatostatin release from gastrointestinal system. Significant cytoprotective properties of pirenzepine have been observed on a variety of experimentally induced peptic ulcerations. This protective activity may be due to pirenzepine-induced increase in gastric mucosal blood flow as well as to the increase in gastric transmural electric potential difference. In accordance with this pharmacodynamic profile of pirenzepine, numerous clinical studies have revealed its efficacy in the treatment of both duodenal and gastric ulcerations. In addition to this, the clinical usefulness of the drug has been demonstrated in Zollinger-Ellison syndrome, in stress ulceration, in acute gastrointestinal bleeding as well as in gastritis, duodenitis and non-ulcer dyspepsia. In most of the studies pirenzepine has been found to be well tolerated with a low incidence of antimuscarinic effects which may occur at salivary, ocular, cardiac and urinary sites. The clinical use of pirenzepine alone or in association with H2 blockers is recommended in the treatment of peptic ulcer patients, in the case of acute gastrointestinal haemorrhage and in patients non responders to H2 antagonists.

Evidence for both inhibitory and excitatory effects of morphine on gastric secretion in the rat.

The relationship between a wide range of doses of i.p. morphine and the effects of gastric secretion in several rat experimental models was investigated. In unoperated rats, morphine 5-15 mg/kg dose-dependently decreased gastric acidity, but an excitatory effect was observed with 0.5-1.5 mg/kg. A dose-dependent inhibition was also obtained in conscious pylorus-ligated rats with morphine 5-15 mg/kg, whereas no significant effects were found at lower doses. By contrast, acid concentration was enhanced with morphine 0.5-15 mg/kg in anaesthetized pylorus-ligated rats and in stomach lumen perfused rats. The changes of pepsin concentration correlated with the changes in gastric secretory volume. An increase in the volume was associated with a decrease in pepsin concentration, while pepsin amount per stomach was dose-dependently increased in all the conditions under which morphine increased gastric acidity. All the effects of morphine on acid and pepsin secretion were prevented by naloxone 1 mg/kg i.p. Overall results indicate that morphine may induce both excitatory and inhibitory effects on gastric secretion in the rat: these effects depend on the dose of morphine and the experimental conditions.

Fructose-1,6-diphosphate reduces acute ECG changes due to doxorubicin in isolated rat heart.

Doxorubicin (DXR) (0.17 x 10(-4) M) induces an acute cardiotoxicity in isolated rat heart; there is a progressive widening of the S alpha T segment, with a decrease in force derivatives and in the coronary flow. Concurrent perfusion with fructose-1,6-diphosphate (FDP) (10(-5)-10(-4) M) dose-dependently reduces the S alpha T enlargement but fails to affect the reduction in force derivatives and coronary flow. The target of cardiac protection by FDP might be the ionic mechanisms underlying the action potential configuration.

Excitatory and inhibitory cholinergic effects of yohimbine on isolated guinea-pig small intestine.

The interaction of yohimbine with the cholinergic intestinal system was investigated in the isolated guinea-pig ileum using a wide range of drug concentrations from 3 x 10(-13) to 2 x 10(-4) g/ml. Low concentrations of yohimbine (3 x 10(-13) to 3 x 10(-11) g/ml) caused dose-dependent contractions of the ileal longitudinal muscle, which were potentiated by eserine 1 x 10(-8) g/ml and prevented by tetrodotoxin 1 x 10(-6) g/ml or by atropine 1 x 10(-12) g/ml; methysergide and diphenydramine were ineffective up to 3 x 10(-7) g/ml dose. Submaximal stimulatory responses evoked by twitch stimulation or by acetylcholine were significantly potentiated by the same concentrations of yohimbine (3 x 10(-13) to 3 x 10(-11) g/ml) and blocked by atropine 1 x 10(-12) g/ml. By contrast, high concentrations of yohimbine (1 x 10(-6) to 2 x 10(-4) g/ml) displayed dose-dependent inhibitory effects on cholinergic responses. The stimulant effect of yohimbine seems to be indirect and mediated by the increase in the release of acetylcholine, while the inhibitory action may be due to a molecular interaction with the muscarinic receptors allowing non-specific receptor blockade.

Peripheral opioid receptors mediate gastrointestinal secretory and motor effects of dermorphin N-terminal tetrapeptide (NTT) in the dog.

Dermorphin N-terminal-tetrapeptide-amide (NTT) increased both basal and pentagastrin- or histamine-induced secretion in conscious dogs chronically implanted with both gastric fistulae and Heidenhain pouches. These excitatory effects were significantly prevented by the opioid receptor antagonists naloxone and N-methyl-levallorphan-methanesulphonate. In conscious dogs fitted with electrodes and strain-gauges in different parts of gastrointestinal tract, a premature phase III of the migrating myoelectric complex (MMC) in the duodeno-jejunum was triggered by NTT, while the activity of the antrum was not significantly modified. Further, the peptide enhanced the contractile activity of both proximal and distal portions of the colon, including a long-lasting period of increased muscle tone on the distal colon. Either naloxone or N-methyl-levallorphan-methanesulphonate completely prevented motor effects of NTT on gastrointestinal tract. It is concluded that NTT displays significant opiate-like activity on gastric acid secretion and intestinal motility of the dog by activating peripheral mu opioid receptors.

The pharmacokinetic profile of clofoctol in rat plasma and tissues after oral and rectal administration.

The pharmacokinetics of clofoctol was investigated in rat plasma and tissues after both oral and rectal treatment at a single dose of 300 mg/kg. After oral administration the plasmatic peak was 2.12 +/- 0.92 microgram/ml, occurring at the 90th min, with T/2 of 121.45 +/- 23.41 min. After rectal administration a plasmatic peak of 1.97 +/- 0.61 microgram/ml was reached at the 20th min with T/2 of 41.07 +/- 12.30 min. The kinetic profile of the drug in tissues exhibited a pattern similar to that in the plasma, since the maximal peak of clofoctol in tissues following rectal administration occurred before that obtained after oral administration. Tissue concentrations significantly higher than plasmatic ones were obtained through both administration routes. The present results indicate that clofoctol is well absorbed after both oral and rectal administration; however rectal treatment produces more rapid absorption and elimination compared with oral treatment.