Biomedical subjects

E Martinotti

Publications and source records attributed to E Martinotti.

52 records · Page 3Linked to original sources

PubMed1985

Gastric pharmacological activities of tripotassium dicitrato bismuthate in rats and dogs.

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.

Animals↗

PubMed1985

An interdisciplinary approach to the design of new structures active at the beta-adrenergic receptor. Aliphatic oxime ether derivatives.

On the basis of results previously obtained from structural and theoretical studies on beta-adrenergic drugs, a series of aliphatic oxime ether derivatives (AOEDs) was synthesized. As expected, pharmacological in vitro tests showed that compounds examined exhibit a marked and competitive antagonism at beta-adrenoceptors; the beta 2/beta 1 selectivity ratio indicated that they are more active on the tracheal than on the cardiac beta-receptor. The chemical reactivity of the AOEDs was studied through the calculation of the electrostatic molecular potential (EMP) on a model compound in its preferred conformation. The results showed that the EMP trend agrees with that previously calculated for other beta-blocking drugs.

Adrenergic beta-Antagonists↗

PubMed1984

Evidence for two opposite effects of clonidine on gastric acid secretion in the dog.

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.

Animals↗

PubMed1984

Comparative study of pA2 values of pirenzepine and atropine for guinea-pig gastric fundus and gastric smooth muscle.

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.

Animals↗

PubMed1984

Comparative study with oxmetidine and ranitidine on acid secretion and gastrin release in the dog.

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.

Animals↗

PubMed1984

Gastric cytoprotection by pirenzepine: role of endogenous catecholamines.

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.

Animals↗

PubMed1984

Gastric cytoprotection by pirenzepine is not mediated by catecholamines.

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.

Animals↗

PubMed1983

Conformational effects on the activity of drugs. 10. Synthesis, conformation, and pharmacological properties of 1-(2,5-dimethoxyphenyl)-2-aminoethanols and their morpholine analogues.

In order to obtain a better understanding of the effects that structural parameters have on the changes of adrenergic activity when 1-aryl-2-aminoethanol derivatives are converted into their corresponding 2-arylmorpholine cyclic analogues, we synthesized 1-(2,5-dimethoxyphenyl)-2-aminoethanol derivatives 5-7 and their morpholine analogues 8-10. The preferred conformation of amino alcohols and their cyclic analogues have been determined through an H NMR and IR study. Compounds 5 and 6 showed both alpha-stimulating and alpha-blocking activity on rat vas deferens, the effect depending on the concentration employed; on the same isolated tissue, N-isopropyl derivative 7 and the morpholine analogues 8-10 exhibited only alpha-blocking activity. As for the beta-adrenergic activity, only the open-chain compound 7 possessed a moderate blocking effect on isolated guinea pig atria. The results of this work seem to indicate that the changes of pharmacological activity involved in the transformation of the adrenergic drugs into their morpholine analogues are influenced more by characteristic features of the aromatic moiety than by the ethanolamine or propanolamine structure of the drugs.

Animals↗

PubMed1982

Pharmacological studies on the mechanisms underlying the inhibitory and excitatory effects of clonidine on gastric acid secretion.

The effects of clonidine on gastric acid secretion were investigated using various pharmacological preparations both in vivo and in vitro. In conscious pylorus-ligated rats clonidine produced a marked reduction of gastric secretion which was prevented by yohimbine, while in anesthetized pylorus-ligated rats the drug failed to affect gastric secretion. In stomach lumen-perfused rats, insulin-stimulated secretion was inhibited by clonidine; in contrast, the drug markedly potentiated bethanechol-evoked gastric secretion; this increase was fully prevented by cimetidine. In isolated preparations of guinea-pig gastric fundus, both spontaneous and bethanechol-induced hypersecretion were significantly enhanced by clonidine; this enhancement was also inhibited by cimetidine. The release of acetylcholine, measured at rest and during vagus nerve stimulation of both guinea-pig and rat isolated stomachs, was significantly inhibited by clonidine: this effect was prevented by yohimbine. Overall results indicate that clonidine possesses both inhibitory and excitatory effects on gastric acid secretion. The inhibitory effect appears to be mediated through the activation of presynaptic alpha 2-receptors which modulate acetylcholine release from the vagus nerve, while the excitatory action seems to depend on histamine-like properties of the drug.

Acetylcholine↗

PubMed1982

The effect of pirenzepine on gastric acid secretion and gastrin release induced by bombesin and meal in the dog.

Pirenzepine exerted a powerful inhibitory effect on gastric acid secretion from both the gastric fistula and the Heidenhain pouch of the dog, following intravenous infusion of bombesin. Similar results were obtained from the Heidenhain pouch when hypersecretion was stimulated by the meal test. The rise in plasma levels of radioimmunological gastrin, obtained by either bombesin or food administration, was not significantly affected by pirenzepine. The overall results indicate that the inhibitory effect of pirenzepine on gastric acid secretion in the dog was independent from the release of endogenous gastrin.

Animals↗

PubMedDate not supplied

QT prolongation in anaesthetized guinea-pigs: an experimental approach for preliminary screening of torsadogenicity of drugs and drug candidates.

Many non-cardiovascular drugs can prolong the QT interval of the electrocardiogram (ECG); this is an accessory property not necessary for their pharmacological action and generally linked to the block of the potassium HERG channels and delayed cardiac repolarization. The QT prolongation can lead to a dangerous tachyarrhythmia, called torsade de pointes, and potentially to fatal ventricular fibrillation. The experimental approaches, aimed at an early identification of this undesidered property, often require sophisticated and expensive equipment or the use of superior animal species (dog, primates) that cannot be employed easily for ethical and/or economic reasons. This work aimed to study drug-induced QT prolongation in anaesthetized guinea-pigs and to evaluate the reliability of such an experimental approach to obtain a satisfying predictive parameter of the torsadogenicity of drugs in humans. Seven drugs that were torsadogenic in humans (astemizole, cisapride, haloperidol, quinidine, sotalol, terfenadine and thioridazine) and two that were non-torsadogenic (chlorprotixene and diazepam) were administered i.v. to guinea-pigs under pentobarbital anaesthesia. The ECGs were recorded by four electrodes inserted in the subcutaneous layer of the limbs. Both RR and QT intervals were measured in Leads II and III and then the correct QT values were calculated by Bazett and Fridericia algorithms (QTcB and QTcF, respectively). All the drugs, with the exception of chlorprotixene and diazepam, produced a dose-dependent prolongation of the QT and RR intervals and a significant increase of QTcB and QTcF values. It can be concluded that this method represents a rapid and low-cost procedure to evaluate the cardiac safety pro fi le in the preliminary screening of a high number of drugs or drug candidates.

Animals↗

PubMedDate not supplied

Effects of gonadotropin-releasing hormone (GnRH) on gastric secretion and gastrin release in the dog.

The effects of GnRH on gastric secretion and gastrin release from dogs provided with gastric fistulae and Heidenhain pouches have been investigated. A transient yet significant inhibition of pentagastrin-stimulated secretion from gastric fistulae was observed, while secretion from Heidenhain pouches was unchanged. The maximal inhibitory effect of GnRH on both acid and pepsin secretion stimulated by 2-deoxy-D-glucose was obtained from gastric fistulae. On the contrary, GnRH failed to affect either acid secretion stimulated by bethanechol or acid secretion and gastrin release induced by bombesin. The present results indicate that GnRH possesses an inhibitory action on gastric secretion from the vagally innervated stomach of the dog. The most likely inhibitory mechanism seems to be represented by a decrease of the vagal activity.

Animals↗

PubMedDate not supplied

Beta-adrenoceptor reactivity after epithelium removal in guinea-pig trachea in vitro.

In guinea-pig isolated tracheae precontracted with pilocarpine (2 x 10(-5)M) mechanical removal of the epithelium did not significantly modify the degree of relaxation induced by three different adrenergic agonists: epinephrine (adrenaline), isoproterenol (isoprenaline) and salbutamol. The failure of epithelium removal to modify isoproterenol relaxant activity was observed in both spontaneous tone and pilocarpine precontracted tracheae. In tracheae obtained from actively sensitized (ovalbumin) guinea-pigs, log-concentration response curves of epinephrine and salbutamol were unchanged by epithelium damage, whereas that of isoproterenol was slightly shifted to the left. In ovalbumin sensitized tracheae exposed to the antigen (ovalbumin, 50 micrograms/ml) epithelium removal enhanced the relaxant activity of the three adrenergic agonists used. Beta-adrenoceptor desensitization (isoproterenol, 10(-6)M for 20 min twice) carried out in ovalbumin actively sensitized tracheae with or without epithelium, shifted the log-concentration response curves of isoproterenol to a similar rightward position. The present data suggest that the airway epithelium plays a minor role in the regulation of guinea-pig tracheal sensitivity to beta-adrenoceptor agonists, which is evident only in a classical model of experimental asthma.

Albuterol↗

PubMedDate not supplied

5-(4'-Substituted-2'-nitroanilino)-1,2,3-triazoles as new potential potassium channel activators. I.

By the hypothesised correlation with the large conductance Ca(++)-activated potassium channel (BK(Ca)) openers NS 004 and NS 1619, bearing a benzimidazolone ring, a series of new 5-(4'-substituted-2'-nitroanilino)-1,2,3-triazoles were synthesised and tested on in vitro isolated vascular preparation. The compounds were prepared starting from the appropriately substituted 2-nitro-phenylazides by 1,3-dipolar cycloaddition reaction to cyanoacetamide and following Dimroth isomerisation of the corresponding 1-arylsubstituted-5-amino-1,2,3-triazoles. The analogous 5-(4'-substituted-2'-amino-anilino)-1,2,3-triazoles were also prepared to assess the role of the nitro group in the pharmacophoric model. Almost all the nitro compounds showed a vasorelaxant activity on endothelium-denuded rat aortic rings with a potency comparable to that recorded for the reference compound NS 1619. Such a vasorelaxing activity was significantly reduced by the increase of the level of membrane depolarisation and by the potassium channel blocker 4-aminopyridine with a pharmacodynamic behaviour consistent with a potassium channel activation.

Animals↗

PubMedDate not supplied

Synthesis and evaluation of antihypertensive activity of 1,8-naphthyridine derivatives. Part X.

A series of 4-(N-methylencycloalkylamino)-1,8-naphthyridine derivatives variously substituted in positions 2 and 7 were synthesized and pharmacologically investigated for possible antihypertensive activity. These compounds were tested to determine a possible vasodilator mechanism of action. Compounds 22, 23, 27-29, 47 and 48 showed satisfactory levels of potency (pIC(50)>5), which in one case (compound 23) reached a really interesting value (pIC(50) 6.92). Furthermore, for some selected compounds (19, 22, 23, 26, 28, 29, 47), the vasorelaxing activity was also evaluated in the presence of the guanylate cyclase blocker ODQ or of the adenylate cyclase blocker SQ 22536, and some of these can be considered as possible guanylate-cyclase inhibitors. Finally, compounds 19, 22 and 23 were also tested in the presence of the ATP-sensitive potassium channel blocker glybenclamide and seem to possess activating properties on these potassium channels.

Animals↗

PubMedDate not supplied

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.

Anesthesia↗