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Biomedical subjects

G Bertaccini

Publications and source records attributed to G Bertaccini.

270 records · Page 15Linked to original sources
PubMedDate not supplied

Antisecretory activity of omeprazole in the conscious gastric fistula cat: comparison with famotidine.

The antisecretory activity of the H+/K+ ATPase inhibitor omeprazole was studied in the conscious gastric fistula cat in comparison with the H2-blocker famotidine. Omeprazole caused a dose-dependent inhibition of the dimaprit-induced acid secretion, being approximately fivefold less potent than famotidine (intravenous ID50S were 0.34 +/- 0.03 and 0.067 +/- 0.015 mumol/kg for omeprazole and famotidine, respectively). Omeprazole caused a non-competitive inhibition of the dose-response curve to dimaprit, whereas famotidine induced a parallel shift to the right without depressing the maximum response. Conversely from famotidine, the antisecretory effect of omeprazole was found to be dependent on the acid secretory state of the stomach, the effect being more evident when the compound was administered at the plateau of acid secretion. The inhibitory effect of omeprazole was very long lasting (25% inhibition was still present 24 h after administration of the drug) whereas that of famotidine was overcome by dimaprit infusion within 3-4 h. The antisecretory effect of omeprazole concerned to the same extent the volume and the acid concentration of the gastric juice, whereas famotidine reduced mainly the volume. When the stimulus was represented by pentagastrin the intravenous ID50 values were 0.57 +/- 0.03 and 0.088 +/- 0.015 mumol/kg for omeprazole and famotidine. respectively. From the above data it may be concluded that the antisecretory profile of omeprazole differed markedly from that of famotidine, independently from the potency and the efficacy of the two drugs.

Animals↗
PubMedDate not supplied

SAR studies on H2 antagonists containing alkylamino substituted 1,2, 5-thiadiazole 1-oxide moieties.

A number of ranitidine analogues in which the diamino-1,2,5-thiadiazole 1-oxide substructure bearing alkyl chains of different length is present as the urea equivalent group, were synthesised and studied for their lipophilic and H2 antagonist properties. Derivatives which displayed a logP < or = 3 behaved as competitive antagonists of histamine at H2 receptors present on guinea pig right atrium. The remaining more lipophilic members of the series showed an insurmountable antagonism not completely reversible after prolonged washing. A binding study suggested that an increase in the length of alkyl chain gave rise to hydrophobic interactions with the receptor which were responsible for the apparent irreversible H2 antagonism shown by the higher homologues of the series.

Animals↗
PubMedDate not supplied

Different mechanisms are responsible for the contractile effects of histaminergic compounds on isolated intestinal smooth muscle cells.

The effects of histamine and dimaprit on intestinal smooth muscle contractility were investigated on isolated cells from longitudinal muscle of the guinea pig ileum. Both histamine (10(-14)-10(-10) M) and dimaprit (10(-13)-10(-10) M) exerted a concentration-dependent contraction of intestinal cells, causing a maximum decrease in cell length of about 20%. This effect was not significantly different from that induced by cholecystokinin-octapeptide (CCK-8) 10(-9) M. The concentration-response curves to histamine and dimaprit were shifted to the left in the presence of the histamine H2-receptor antagonist famotidine (10(-7) M) indicating the occurrence in the smooth muscle of H2 receptors mediating relaxation. Whereas the contraction produced by histamine was competitively antagonized by the H1 receptor antagonist mepyramine (10(-8) M), neither mepyramine (10(-7) M) nor temelastine (10(-7) M) did modify the contractile effect of dimaprit. In contrast, atropine (10(-8) M) significantly depressed the maximum response to dimaprit without affecting that exerted by histamine. These data indicate that histamine and dimaprit can modify intestinal contractility, by acting via different mechanisms; while the contractile action of histamine is related to H1 receptor activation, that produced by dimaprit involves cholinergic pathways.

Animals↗
PubMedDate not supplied

Comparison between beta 3 and beta 2 adrenoceptor agonists as inhibitors of gastric acid secretion.

In order to investigate the role of beta 3 adrenoceptors in the regulation of gastric acid secretion we studied the effects of compound SR58611A (a selective agonist for atypical beta adrenoceptors), alone or in combination with beta-adrenoceptor antagonists, in the gastric fistula of a conscious cat. The effects of SR58611A were compared with those of clenbuterol, a selective agonist for beta 2 adrenoceptors. Intravenous infusion of SR58611A (0.3-3 mumol/kg/h) caused a dose-dependent, but partial, inhibition of the acid secretory response to 2-deoxy-D-glucose 100 mg/kg i.v., maximum effect not exceeding 40%. Clenbuterol (0.03-0.1 mumol/kg/h) caused a similar effect (maximum inhibition about 50%) at doses approximately 30 times lower. The acid secretion induced by the histamine H2-receptor agonist dimaprit (1 mumol/kg/h) was minimally affected by both beta adrenoceptor agonists. The inhibitory effect of SR58611A (3 mumol/kg/h) on 2-deoxy-D-glucose-induced acid secretion was not modified by pretreatment with the non-selective beta 1- and beta 2-adrenoceptor blocker propranolol, administered at doses (1.5 mumol/kg iv) that completely blocked the inhibitory effect of clenbuterol (0.1 mumol/kg/h). In contrast, bupranolol (10 mumol/kg i.v.) (a drug endowed with beta 3 antagonistic properties) prevented the inhibitory effects of both SR58611A and clenbuterol. The present data provide functional evidence that, besides beta 2-, also beta 3-adrenoceptors can have negative effects on gastric acid secretion, particularly when it is stimulated by indirect stimuli, like 2-deoxy-D-glucose. This gastric antisecretory activity may represent an additional mechanism for the physio-pharmacological control of gastric acid secretion.

Adrenergic beta-2 Receptor Agonists↗
PubMedDate not supplied

Histamine H3 receptors in the guinea pig ileum: evidence for a postjunctional location.

The effect of the selective histamine H3 receptor agonists (R)alpha-methylhistamine, (R)MHA and immepip (IMM) on intestinal smooth muscle contractility was investigated on isolated cells from the longitudinal muscle of the guinea pig ileum. (R)MHA (10(-13)-10(-8) M) and IMM (10(-13)-10(-8) M) did not significantly modify the basal length of intestinal cells; in contrast both agonists (10(-15)-10(-11) M) prevented the contraction produced by acetylcholine (10(-7) M). The (S)-isomer of alpha-methylhistamine, (S)MHA, was inactive both on basal contractility and on acetylcholine-induced contractions. The relaxant effect of (R)MHA was not modified by famotidine (10(-7) M), but totally prevented by the selective H3 receptor antagonist clobenpropit (10(-8) M), which per se did not modify either basal contractility or the contractile response to acetylcholine. These data indicate that inhibitory histamine H3 receptors are present on smooth muscle cells of the guinea pig ileum and can be activated by very low concentrations of selective agonists. It is not clear, however, whether they can have a functional importance in the regulation of intestinal contractility in an intact system.

Acetylcholine↗
PubMedDate not supplied

Histamine H3 receptors: an overview.

Histamine H3 receptors represent a new class of prejunctional receptors, which, first described as modulators of histamine synthesis and release in the central nervous system, were subsequently found to occur also in peripheral tissues. They may behave both as autoreceptors located in histaminergic neurons and as heteroreceptors localized in adrenergic, cholinergic, serotoninergic and NANC nerve endings. As far as the gastrointestinal tract is concerned, H3 receptors seem to negatively control gastric acid secretion induced by endogenous cholinergic stimuli as well as gastrointestinal motility, as observed in different isolated preparations electrically stimulated. So far experimental evidence suggests that these receptors are absent in the effector organs. The most selective agonist and antagonist of H3 receptors are (R) alpha-methylhistamine and thioperamide, respectively; however, a lot of similar compounds are being synthesized in a few laboratories. It is easy to foresee that in the near future the availability of such substances will help the investigators in enlarging our knowledge in this interesting field.

Animals↗
PubMedDate not supplied

Contractile effect of endothelin-2 on the isolated human saphenous vein.

The contractile effect of endothelin-2 was investigated in isolated human saphenous vein preparations. Spare segments taken from revascularized patients were set up in isolated organ chambers and mechanical activity was recorded under isometric conditions. Endothelin-2 (10(-11)-10(-7) M) evoked a dose-dependent contractile response, having the same efficacy as noradrenaline and 100 times its potency. Conversely, the "selective" ETB agonist, C-terminal hexapeptide endothelin (16-21), was completely ineffective. The activity of endothelin-2 was not modified by phentolamine, saralasin and indomethacin, thus excluding a direct or indirect activation of alpha-adrenoceptors and angiotensin receptors as well as the synthesis of cyclooxygenase products. Calcium removal from nutrient fluid depressed, but not fully abolished, the contractile effect of endothelin-2; furthermore, calcium channel blockers, verapamil and nifedipine, produced only a partial inhibition of the endothelin-2-induced contractions. These observations suggest that endothelin-2 induces a direct activation of specific receptors in the saphenous vein muscle and that both intracellular and extracellular calcium pools may be involved in the contractile effect of the peptide.

Calcium↗
PubMedDate not supplied

Gastric antisecretory activity of telenzepine, a new M1-selective muscarinic antagonist: comparison with pirenzepine.

The new M1-receptor antagonist telenzepine has been studied for its antisecretory effect in different in vitro and in vivo experimental models in comparison with pirenzepine. Telenzepine was found to be from 3 to 10 times more potent than pirenzepine in inhibiting bethanechol-, pentagastrin- and dimaprit-induced acid secretion in the conscious gastric fistula cat. Also, in the lumen-perfused stomach of the anaesthetized rat, telenzepine was more active than pirenzepine as an inhibitor of bethanechol-induced acid secretion; the inhibitory effect of telenzepine lasted more than 3 hr, while that of pirenzepine disappeared within 1 hr. In the isolated gastric fundus from immature rats, telenzepine and pirenzepine did not modify the spontaneous acid secretion, whereas both drugs caused a competitive inhibition of bethanechol-induced acid secretion (pA2 values were 7.96 and 6.81 for telenzepine and pirenzepine, respectively). These data indicate that telenzepine is a potent antisecretory agent both in vitro and in vivo.

Anesthesia↗
PubMedDate not supplied

Drug-induced alterations of the hypothalamus-hypophysis axis.

Omitting hormonal variations caused by other drugs already objects of research, the behaviour pattern of GH, PRL, TSH, following acute administration of cimetidine, nomifensine, domperidone has been considered in normal subjects, in patients with pituitary non-secreting and PRL-secreting adenomas and in patients with amenorrhea-galactorrhea syndrome without evidence of adenoma. The results confirm the influence which drugs employed in the therapy of non-endocrine diseases provide a way to alter the functions of the hypothalamus, sometimes relatively specifically, and the secretion of pituitary hormones provides us with a possibility of analyzing the CNS output.

Adenoma↗
PubMedDate not supplied

Different effects of the histamine H2 receptor blockers, famotidine and zolantidine, on the human atrium in vitro.

The effects of the histamine H2 receptor blocker famotidine were investigated on the human isolated myocardium, in comparison with zolantidine, a new member of the same family. Experiments were performed on human atrial fragments, taken from patients undergoing reconstructive heart surgery. Electrical pacing was applied and H2 receptor-evoked positive inotropic responses were induced with histamine. Famotidine (0.1-10 microM) shifted the concentration-response curve of histamine to the right in a competitive fashion, without affecting the basal contraction and the noradrenaline-induced positive inotropic activity up to 100 microM. Zolantidine (1-100 microM) antagonized the histamine-induced positive inotropic effect, but the rightward shifts were nonparallel and the maximum response was depressed, probably due to a nonspecific cardiodepressive activity at concentrations above 1 microM. Data obtained in the present study confirm the ability of famotidine to block cardiac histamine H2 receptors, but, in contrast with several studies on healthy volunteers, nonspecific effects on the myocardial contractility cannot be demonstrated. Conversely, zolantidine depresses the myocardial contractility with a mechanism differing from that of slow-channel blockers.

Benzothiazoles↗
PubMedDate not supplied

Effect of fedotozine on human distal colon.

Fedotozine was rested in colonic strips removed during surgery from patients suffering from different diseases of the colon; the effects were compared to those of morphine and of the selective opiate agonist U-69593. Fedotozine did not affect the spontaneous motility of human colonic strips, unless very high concentrations were used. Fedotozine (10(-6)-3 x 10(-4) M) induced a concentration-dependent reduction of the excitatory effect induced by field stimulation, an effect which was partially mimicked by compound U-69593 and by morphine but not inhibited by naloxone. The cumulative dose-response curve to exogenous acetylcholine was inhibited by fedotozine (3 x 10(-4) M), whereas morphine had no effect up to 3 x 10(-4) M. In colonic strips incubated with [3H]-choline, fedotozine (10(-5)-10(-4) M) induced an erratic decrease of acetylcholine-release induced by electric stimulation. In our experimental model, the inhibitory effect of fedotozine does not seem to be related to opioid receptor activation.

Acetylcholine↗