The effects of GABA agonists and antagonists on rat gastric acid secretion.
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Animals↗
Biomedical subjects
M Del Tacca
Publications and source records attributed to M Del Tacca.
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.
Acetylcholine↗
Plasma pharmacokinetics of cinmetacin following oral administration in healthy volunteers.
The pharmacokinetics of a single 600 mg oral dose of 1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid (cinmetacin, Cindomet) was studied in 8 healthy volunteers of both sexes. Plasma levels of the drug were assayed by using an HPLC technique ad hoc devised. Following administration, the Cmax was reached at the 2nd h in 7 out of 8 subjects with an average value of 18.19 micrograms/ml; 12 h after the dose (last sampling time) appreciable plasma levels of cinmetacin were measured, corresponding to 17.2% of the maximum average concentration. The mean values +/- S.E. concerning the elimination half-life, the total volume of distribution, the total plasma clearance and the total area under the curve were 3.80 +/- 0.21 h, 0.28 +/- 0.03 l/kg, 0.051 +/- 0.005 l/kg/h, and 125.64 +/- 15.97 micrograms.h/ml, respectively. The plasma decay of cinmetacin was monophasic and the data were interpreted according to a one-compartment open model. Overall results indicate that cinmetacin is well and rapidly absorbed orally and widely distributed in body fluids.
Adult↗
A pharmacokinetic study of clofoctol in human plasma and lung tissue by using a microbiological assay.
A microbiological assay was undertaken to measure the amounts of clofoctol in human plasma and pulmonary tissue, and to investigate its pharmacokinetics. Clofoctol was extracted from samples using ethanol and the concentration of drug in the extracts was determined by the broth macrodilution method using as reference microorganisms S. aureus ATCC 29213 and B. cereus NCIB 8122, whose MIC values were 0.537 and 1.074 micrograms/ml respectively. This procedure allows the almost complete recovery of the drug and makes it possible to detect amounts of clofoctol as low as 5.5 micrograms/ml. Results indicate that clofoctol is well absorbed after a single rectal dose of 1.5 g, with a plasma Cmax at the 30th min after administration and an average AUC value of 80.91 micrograms/ml/h. The Cmax of lung tissue (which was higher than the plasmatic one) occurred at the 90th min and the average AUC value was 229.65 micrograms/ml/h, indicating good penetration of clofoctol into human lung tissue and appreciable tissue storage of the drug.
Biological Assay↗
The effects of the antimuscarinic drugs pirenzepine and atropine on plasma portal levels of somatostatin and gastrin in the dog.
The effects of the antimuscarinic drugs pirenzepine and atropine on somatostatin and gastrin portal levels under basal conditions and during bethanechol infusion have been investigated in anesthetized dogs. Iv bolus administration of pirenzepine (1 mg/kg) or atropine (0.1 mg/kg), decreased gastrin concentrations, but did not affect basal somatostatin levels. During 120 min of bethanechol infusion (160 micrograms/kg/h) gastrin levels increased but somatostatin levels were unchanged. Pirenzepine (1 mg/kg iv bolus), administered at the 60th min of bethanechol infusion, decreased the gastrin concentrations, and markedly enhanced somatostatin levels. Under the same conditions atropine (0.1 mg/kg iv bolus) decreased gastrin levels, but had little or no effect on somatostatin levels. These results indicate that muscarinic receptors with similar affinity for pirenzepine and atropine mediate excitatory cholinergic influences on gastrin release. By contrast, muscarinic receptors with higher affinity for pirenzepine seem to be involved in the cholinergic inhibition of somatostatin release: by selectively blocking these receptors, pirenzepine may increase portal somatostatin levels.
Animals↗
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.
Animals↗
Penetration of clofoctol into human lung.
The disposition of clofoctol was determined in plasma and lung tissue from 34 patients undergoing pulmonary resection for lung cancer. Clofoctol 1.5 g was given as a rectal suppository; samples of plasma and pulmonary tissue were collected between 15 and 270 min post-dose. Plasma and lung peak concentrations of the drug were 38.07 +/- 0.73 mg/l and 93.13 +/- 6.68 mg/kg at 30 and 90 min, respectively. Mean values for areas under the concentration-time curve and half-life for plasma and lung were 80.91 mg/l/h, 229.65 mg/h, and 1.18 h and 1.21 h, respectively. Tissue to plasma ratios were 0.85 +/- 0.06, 3.82 +/- 0.21 and 6.19 +/- 0.63 at 30, 90 and 180 min post-dose, respectively. Clofoctol is well absorbed from the rectum and accumulates in lung tissue. This may explain its efficacy in bacterial respiratory infections.
Aged↗
Effects of morphine on gastric ulceration, barrier mucus and acid secretion in pylorus-ligated rats.
The effects of intraperitoneal (IP) or intracerebroventricular (ICV) administration of morphine on acid and pepsin secretion, gastric ulceration and gastric bound mucoproteins were investigated in pylorus-ligated rats. Morphine, administered IP, produced a dose-dependent inhibition of the gastric secretion volume, acidity, pepsin output and bound mucoproteins. By contrast, the effect of morphine on gastric ulcers was not dose-dependent: a significant increase in gastric lesions was obtained with morphine 5 mg/kg IP. Naloxone IP prevented the effects of morphine on gastric secretory volume, acidity and pepsin output, but not on gastric mucus and ulcer score. ICV administration of morphine induced a dose-dependent inhibition of secretory volume, acidity and ulcer score, whereas no modification of gastric mucus was observed. Naloxone ICV prevented the effects of ICV morphine. Overall results suggest that morphine inhibits gastric secretion through both central and peripheral opioid receptors, whereas the inhibitory effect of morphine on bound mucus appears to be exerted on mucus synthesis through peripheral opioid receptors. This inhibitory effect on barrier mucus accounts at least in part for the gastric ulcerogenic action of morphine.
Animals↗
Staining methods for morphometric studies of parietal and gastrin cells in the rat stomach.
In order to select the most suitable procedures for quantitative microscopy of both parietal and gastrin cell populations in the rat stomach, various staining methods were compared. For parietal cell identification in particular, the following procedures were tested: i) the modification of the haematoxylin-eosin method proposed by Marks and Drysdale, ii) the haematoxylin-eosin-saffron fluorochrome stain on paraffin sections, iii) the haematoxylin-azophloxin-saffron fluorochrome stain on paraffin sections, and iv) the May-Grunwald-Giemsa stain on thin sections from plastic-embedded specimens. This last provided the best results in parietal cell individualization and seemed to be the most suitable method for an accurate image analysis. Immunohistochemistry was the only unequivocal way to identify gastrin cells. Two variant procedures were examined; a) the agar-paraffin embedding technique, and b) the combination of a mucin staining with the immunoperoxidase reaction. The first technique provided an easier procedure for handling seriate strips of gastric mucosa for proper enumeration of immunostained cells. The second was presented as a promising variant procedure for a combined investigation of both G-cell population and mucin secretion patterns under differnt experimental conditions in the same specimen.
Animals↗
Pharmacological evidence of morphine-induced inhibition of gastric mucus synthesis in rats.
The effects of morphine, administered at graded doses by either intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) routes, have been investigated on acid and pepsin outputs, secretory volume, ulcer score, free and bound gastric mucus, in pylorus-ligated rats. Morphine i.c.v. induced a dose-dependent inhibition of secretory volume, acid and pepsin outputs and ulcer score, without modification of either free or bound mucoproteins. Naloxone i.c.v. had no effect per se, but prevented the inhibitory effects of i.c.v. morphine. Morphine i.p. produced a dose-dependent inhibition of gastric secretory volume, acid and pepsin outputs, as well as both free and wall-bound mucoproteins. By contrast, the effect of i.p. morphine on ulcer score was not dose-dependent: the dose of 5 mg/kg induced significant exacerbation of gastric lesions. Naloxone at 0.8 mg/kg i.p. had no effect per se, whereas at the dose of 4 mg/kg it significantly increased bound gastric mucus. The dose of 0.8 mg/kg antagonized the effects of morphine on gastric secretory volume, acidity, pepsin and ulcer score, but not on gastric mucus. These results indicate that morphine affects gastric acidity through central and peripheral opiate receptors, whereas gastric mucus synthesis appears to be regulated through peripheral opioid pathways.
Animals↗
The effects of prolonged administration of cimetidine or pirenzepine on gastric mucosal cell kinetics, serum gastrin levels and acid secretory responses in rats.
60 days' treatment of rats with cimetidine 160 mg/kg/die per os produced a significant increase in total gastrin cell number, gastrin cell density of antral mucosa as well as parietal cell density of fundic mucosa as compared with controls. By contrast, the same parameters significantly decreased in rats treated for 60 days with pirenzepine 16 mg/kg/die per os. Under the same conditions, immunoreactive serum gastrin levels were found to be significantly enhanced in cimetidine-treated rats, but not significantly changed in rats treated with pirenzepine. 48 hours after drug withdrawal, gastric secretory responses to pentagastrin were found to be significantly increased in cimetidine-treated rats and decreased in pirenzepine-treated rats. These results suggest that a feed-back reaction to cimetidine-induced prolonged hypochlorhydria mediates hyperactivity of the gastrin cell system which, in turn, induces parietal-cell hyperplasia. The hyperplasia accounts for hypersecretive responses in cimetidine-treated rats. The inhibitory activity displayed by pirenzepine on the same parameters may be due to the blockade of vagal trophic influences on gastric mucosal cells and/or to the release of inhibitory factors such as somatostatin.
Animals↗
Indirect stimulation by thyrotropin-releasing hormone of canine gallbladder motility.
Thyrotropin-releasing hormone (TRH) was unable to induce any noticeable contraction of canine isolated gallbladder strips up to the dose of 10(-4) g/ml, while caerulein (CAER) was spasmogenic in a dose-related manner beyond 10(-11) g/ml. This effect of CAER was unaffected by either atropine or tetrodotoxin. In conscious dogs, the intravenous bolus of TRH (20 micrograms/kg) or CAER (0.2-2.0 micrograms/kg) caused gallbladder emptying. The TRH response, unlike that of an equipotent dose of CAER, was prevented by atropine. In experiments on electrical activity of the digestive tract in conscious dogs, both TRH or CAER induced a concomitant increase on the myoelectrical activity in the proximal part of the small intestine. The excitatory effects were prevented by atropine only in the case of TRH. These results demonstrate that TRH stimulates indirectly the gallbladder and proximal duodenum of the dog. They suggest the involvement of a cholinergic pathway in this excitatory action.
Action Potentials↗
Guanabenz as inhibitor of copper-containing amine oxidases.
The effects of guanabenz on some copper containing amine oxidases are described. Guanabenz 'in vitro' inhibits pig plasma benzylamine oxidase with a IC50 M 5.1 +/- 0.8 X 10(-6) M. It also inhibits pig kidney diamine oxidase and rat liver mitochondrial monoamine oxidase at higher concentrations. The significance of this property of guanabenz is discussed.
Amine Oxidase (Copper-Containing)↗
Measurement of the S alpha T segment as the most reliable electrocardiogram parameter for the assessment of adriamycin-induced cardiotoxicity in the rat.
A new method is described for the assessment of the early cardiotoxic effects of adriamycin and related drugs on rat electrocardiographic parameters. Evidence is presented that during repeated treatment with adriamycin, no changes occur concerning the PR and RR intervals, QTc, or R- and S-wave voltages, whereas significant changes in the QRS complex, R alpha T and alpha TP intervals, and T-wave voltage are detectable. However, the earliest and most consistent electrocardiogram alteration observed during adriamycin treatment is a progressive, irreversible widening of the S alpha T segment. The S alpha T enlargement becomes significant during the first week of treatment and may be detected in all the tracings at all the times examined. The electrocardiogram changes are accompanied by cardiac histological lesions that gradually increase in severity during the study. These results indicate that the measurement of the S alpha T segment provides a rapid, sensitive, and reliable method for the evaluation of electrocardiogram toxicity induced by adriamycin and related anthracyclines in the rat.
Animals↗
The effects of alpha-2 agonists and antagonists on gastric acid secretion.
The effects of alpha-2 agonists clonidine, xylazine and guanabenz as well as those of alpha-2 antagonists tolazoline and yohimbine on gastric acid secretion were investigated in Shay rats, Schild rats and isolated guinea-pig gastric fundus. In Shay rats clonidine, xylazine and guanabenz displayed marked antisecretory effects, whereas tolazoline and yohimbine had no effect. Under the same conditions, yohimbine fully prevented the actions of clonidine, xylazine and guanabenz, while tolazoline showed partial antagonism. In Schild rats both clonidine and xylazine displayed a stimulant secretory action, but guanabenz was without effect; cimetidine fully prevented the excitatory effects of clonidine and xylazine. Both tolazoline and yohimbine increased gastric acid secretion in Schild rats: the effect of tolazoline was inhibited by cimetidine, while the effect of yohimbine was prevented by pirenzepine or vagotomy. On isolated guinea-pig gastric fundus, clonidine, xylazine and tolazoline exerted a stimulatory activity, whereas guanabenz and yohimbine had no effect: these excitatory responses were fully prevented by cimetidine. Overall results indicate that clonidine and xylazine have both inhibitory and excitatory effects on gastric acid secretion, while guanabenz produces only inhibitory effects. The inhibitory activity appears to be mediated by activation of presynaptic alpha-2 receptors on the vagus nerve, whereas the excitatory effects seem to be mediated by histaminergic pathway. The stimulant secretory action of tolazoline may be due to its imidazoline-like structure allowing interaction with histamine H2-receptors: accordingly, this effect is lacking for guanabenz, which is structurally unrelated to imidazoline. The excitatory effect of yohimbine appears to be exerted on central cholinergic sites, as indicated by its disappearance in vagotomized rats.
Adrenergic alpha-Agonists↗
[Clinical efficacy of clofoctol in treating odontogenic infections].
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Adolescent↗
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.
Animals↗
The influence of amrinone on cardiac toxicity induced by adriamycin in rats.
The influence of amrinone (AM), a positive inotropic drug, on cardiotoxicity induced by repeated adriamycin (ADR) administration, was studied in rats. AM, administered at various doses, did not affect rat body weight gain, heart rate, electrocardiographic parameters (QRS complex, S alpha T segment, T-wave), or the histological cardiac picture. By contrast, ADR markedly inhibited rat body weight increase and induced the appearance of early ECG alterations, especially S alpha T widening, as well as morphological cardiac changes consisting of macrovacuolation of myocytes, atrophy, necrosis and fibrosis. When given with ADR, AM reduced the toxicity of ADR limiting the deleterious effects of the drug on body weight gain and delaying the appearance of ECG abnormalities, particularly S alpha T widening and T-wave flattening. The severity of cardiac lesions histologically evaluated at the end of the experiment, however, was similar in rats given ADR or AM plus ADR. These results may be explained by taking into account the ability of AM to increase the Ca2+ influx through the slow channels in myocardial cells, thus counteracting the decreased inward slow Ca2+ currents due to ADR. The failure of AM to improve histological cardiac alterations significantly, seems to indicate that among the numerous pathogenetic mechanisms of ADR-induced cardiotoxicity, the changes in cellular Ca2+ fluxes play an important, but not a fundamental role.
Amrinone↗