Biomedical subjects
Publications and source records attributed to G Soldani.
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.
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.
The effects of subcutaneous (s.c.), intraperitoneal (i.p.), intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of dermorphin (DER) on intestinal myoelectrical activity were examined in fed rats with chronically implanted electrodes on the small and large bowel. DER s.c. restored the 'fasting' pattern of duodenal activity, i.e., the migrating myoelectric complex (MMC), corresponding to an inhibition by about 40% of the fed pattern for 120 min at a dose as small as 0.5 nM per rat. DER i.p. strongly inhibited (about 65%) the fed pattern for 120 min. A fasting pattern lasting 80 min, or a marked inhibition lasting 150 min were recorded after 0.5 nM DER i.t. or i.c.v., respectively. On the contrary, the colonic pattern of activity was inhibited by DER whatever the route used, although the duration of inhibition was different from each other. For both the small and large intestine, similar doses of DER were more efficient by i.c.v. than by i.t. routes, and by i.p. than by s.c. routes. A plurality of sites of action is suggested, including local receptors which are activated, particularly at the duodenal level by i.p. DER (0.5 nM). The supraspinal component of the immediate effects of i.c.v. DER (0.1 nM) were demonstrated by a preferential effect on the colon that was even more intense than after i.t. DER.
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.
The effects of dermorphin and morphine on gastric acid secretion were studied in conscious dogs with both gastric fistulas (GF) and Heidenhain pouches (HP). Under basal conditions dermorphin and morphine, infused systemically at graded doses, produced a significant increase in acid secretion from both GF and HP. This increase was significantly inhibited by naloxone, naltrexone methylbromide and N-methyl-levallorphan methanesulphonate. Dermorphin did not modify the acid output stimulated by 2-deoxy-D-glucose from GF, while morphine significantly inhibited it; on the contrary acid secretion from HP was increased in this test by both dermorphin and morphine. Acid secretion from GF stimulated by pentagastrin was unaffected by morphine and significantly enhanced by dermorphin. Under these conditions a significant increase in acid secretion from HP was recorded with dermorphin and morphine. Naloxone and N-methyl-levallorphan methanesulphonate, given during pentagastrin-stimulated secretion, significantly inhibited acid output 'per se' from GF and HP and prevented the stimulatory effect of dermorphin and morphine. Bethanechol-induced secretion from GF and HP was significantly increased by both dermorphin and morphine. The present results demonstrate that opioids have simultaneous yet opposite effects on acid secretion in the dog and that mu receptors are involved in both the excitatory and inhibitory effects. Excitatory effects do not seem to be mediated via a vagal pathway (peripheral ?), in contrast to the inhibitory effects (central ?). The inhibitory effects of opiate antagonists on pentagastrin-stimulated secretion suggest a physiological role of peripheral opioid receptors in gastric acid secretion.
The effects of tripotassium dicitrato bismuthate (TDB) on gastric acid, pepsin and mucoprotein secretion in rats and on hydrochloric-peptic secretion and plasma gastrin levels in dogs were investigated. In Shay rats, TDB did not affect acid secretion but significantly lowered pepsin concentration and increased the amount of bound mucoproteins. In addition, gastric mucosal lesions were significantly prevented by the drug. In dogs, chronically fitted with both gastric fistulae and Heidenhain pouches, acid secretion and plasma gastrin levels stimulated by a meat meal were unaffected by TDB, while pepsin concentration and pepsin output were significantly decreased. On the basis of these results, the antiulcer activity of TDB appears to be ascribed to the protection of the gastric mucosa through an increase in mucoprotein synthesis and a decrease of pepsin activity.
Gallbladder motility was recorded as tonic and small amplitude (rhythmic) contractions in conscious sheep fitted with miniaturized strain-gauge force transducers located in the corpus and fundus. Nichrome wire electrodes were chronically implanted in the gastroduodenal area. Both tonic and superimposed rhythmic gallbladder contractions were increased during feeding. They decreased during the periodic phases of antroduodenal quiescence. The excitatory effects on gallbladder and antroduodenal motility were mimicked by pilocarpine and blocked by atropine. Cholecystokinin (CCK-OP) and caerulein elicited motor responses of the gallbladder in a dose-related manner without antroduodenal stimulation. In contrast, pentagastrin induced gallbladder motor responses with concomitant stimulation of the antroduodenal area. The results suggest that feeding may act to trigger gallbladder motor activity through a mechanism related to the increased antroduodenal activity. Direct effects of CCK-OP and caerulein confirm that gallbladder motor function is also mediated through specific receptor sites.
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The effects of clonidine on gastric acid secretion were studied in conscious dogs with both gastric fistulae and Heidenhain pouches. Clonidine infused systemically at graded doses under basal conditions produced a significant increase in acid secretion from both gastric fistulae and Heidenhain pouches. Acid secretion from gastric fistulae submaximally stimulated by pentagastrin was dose-dependently reduced by clonidine while 2-deoxy-D-glucose-induced secretion was completely suppressed. Under these conditions a significant enhancement of secretion from Heidenhain pouches was recorded. An increase in acid secretion from both main stomachs and Heidenhain pouches was observed for clonidine with submaximal doses of bethanechol and histamine as stimulants, though clonidine showed no effect on maximal stimulation by histamine. The stimulant effect of clonidine from gastric fistulae and Heidenhain pouches under basal conditions was fully prevented by cimetidine, while the inhibitory effect of clonidine on acid secretion stimulated by pentagastrin from gastric fistulae was reversed by yohimbine. The present results suggest that clonidine displays two simultaneous yet opposite effects on dog gastric secretion. The inhibitory effect might be mediated through a decrease of vagally released acetylcholine following the activation of alpha 2-adrenoceptors both at central and peripheral sites, while the stimulatory effect probably depends on the histamine-like properties of the drug.
Two histamine H2-receptor antagonists ranitidine and oxmetidine were tested for their effects on gastrointestinal motility in conscious fasted dogs chronically fitted with intraparietal electrodes on the antrum, duodenum and jejunum. Intravenous administration of ranitidine (3 mg/kg) stimulated gastrointestinal spiking activity through a cholinergic mechanism and increased the duration of the cycles of migrating myoelectric complexes. Oxmetidine at the same dose did not modify the gastrointestinal motor profile. These results showed clearcut differences in nonspecific effects of two H2-antagonists equipotent on gastric acid secretion.
Concentration-response curves of bethanechol were obtained from isolated guinea pig gastric fundus and gastric circular smooth muscle strips before and after exposure to pirenzepine or atropine. In the presence of pirenzepine and atropine these curves were shifted parallel to the right with no change in maximum response. Against bethanechol, mean pA2 values were 7.06 for pirenzepine and 8.16 for atropine on gastric fundus, with slopes of Schild plots close to unity for both antagonists, whereas in the case of gastric smooth muscle pA2 values were 6.52 for pirenzepine and 8.52 for atropine, with the slope of the Schild plot significantly less than -1 in the case of pirenzepine. The values of the Schild slope seem to indicate that pirenzepine interacts with a single, apparently homogeneous population of muscarinic receptors on gastric mucosa, at variance with the behaviour of pirenzepine on receptors of gastric smooth muscle.
Short-term and specific motor effects of ranitidine on gastrointestinal motility of conscious sheep were recorded. These effects were prevented by atropine, but tachyphylaxis was observed after a second injection. Short-term effects on motility were not obtained with oxmetidine. Long-term effects for both ranitidine and oxmetidine, at high doses, were reducing the frequency of reticular contractions and shortening the interval between MMCs in a similar manner.
The antisecretory potency of oxmetidine was compared with that of ranitidine for its action against gastric acid secretion induced by histamine and by 2-deoxy-D-glucose (2DG) in the conscious gastric-fistula dog. Oxmetidine, administered i.v. during histamine stimulation, was nearly as effective as ranitidine, with a similar duration of action, but it was about twice as potent as ranitidine against 2DG-stimulated acid secretion. In experiments with bombesin, both oxmetidine and ranitidine significantly decreased gastric acid secretion to a similar extent, without affecting plasma gastrin levels.
The effects of cimetidine and ranitidine, alone or combined with sulglycotide or carbenoxolone, and those of 16,16-dimethyl prostaglandin E2 were investigated on mucosal lesions induced in pylorus-ligated rats. The drugs were administered orally after pylorus ligation; 3 hr later the animals were killed, the stomachs removed and examined for the presence of mucosal lesions. Volume, pH, total acidity, pepsin, free and barrier mucus were determined. H2-antagonists both at nonantisecretory and antisecretory doses failed to prevent gastric mucosal lesions or to affect significantly mucus and pepsin. Sulglycotide and carbenoxolone inhibited pepsin secretion, the latter enhanced barrier mucus and both reduced lesion severity. A nearly complete prevention of mucosal damage was observed after anti-secretory doses of cimetidine plus sulglycotide or carbenoxolone. Data obtained compared with those of 16,16-dimethyl prostaglandin E2 suggest that mucus and pepsin might have a partial role in ulcer prevention.
Acute gastric ulcerations were produced in fasted rats by pylorus ligation or by administration of polymyxin B or absolute ethanol. In pylorus-ligated rats pirenzepine 25 mg/kg per os decreased by about 50% the ulceration score, without affecting gastric acid and pepsin output. A similar percentage inhibition of ulceration score with no change of gastric acidity was obtained with pirenzepine 5 mg/kg per os in the case of gastric lesions provoked by polymyxin B. Ethanol-induced gastric lesions were also markedly reduced by pirenzepine, with 50% inhibition occurring with the dose of 25 mg/kg. The release of catecholamines from rat isolated gastric tissue during stimulation of sympathetic periarterial nerves was significantly reduced by pirenzepine 1 X 10(-6) g/ml. The present results indicate that pirenzepine significantly reduced gastric lesions induced by various stimulants; the protective effect of pirenzepine did not appear to be related to increased sympathetic tone.
The effects of pirenzepine (in a dose of 25.0 mg X kg-1) and atropine (2.5 mg X kg-1) were studied on the development of gastric ulceration produced by pylorus ligation, polymyxin B and absolute ethanol, as well as on the gastric secretory responses and plasma level of noradrenaline. It was found that: (1) pirenzepine significantly decreased the development of ulcer formation produced by pylorus ligation, polymyxin B and absolute ethanol without any antisecretory response; (2) atropine inhibited gastric acid secretion, but no effect was obtained on ulcus produced by pylorus ligation, polymyxin B and absolute ethanol; (3) the plasma level of noradrenaline could be decreased by atropine and pirenzepine, although the difference did not reach statistical significance. It has been concluded that catecholamines are not involved in the gastric cytoprotective mechanism of pirenzepine.
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