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Biomedical subjects

G Bertaccini

Publications and source records attributed to G Bertaccini.

At least 37 records · Page 2Linked to original sources
PubMed1996

Cardiac and gastric effects of histamine H2 receptor antagonists: no evidence for a correlation between lipophilicity and receptor affinity.

1. A series of histamine H2 receptor antagonists with different lipophilicity were tested in cardiac and gastric assays in order to reveal possible differences in receptor affinity. Lipophilicity of the compounds was expressed as CLOG P (theoretically-determined logarithm of octanol:water partition coefficient) and log k' (logarithm of capacity factor, experimentally-determined by reverse-phase high performance liquid chromatography). 2. Aminopotentidine (APT) and iodoaminopotentidine (I-APT), which are both lipophilic compounds, behaved as insurmountable antagonists of histamine responses in rat isolated gastric fundus (pKB = 6.20 +/- 0.16 and 6.89 +/- 0.19, respectively) and guinea-pig isolated papillary muscle (pKB = 6.34 +/- 0.37 and 6.81 +/- 0.26, respectively). They were approximately as effective as ranitidine (RAN) in reducing histamine-induced acid secretion in the anaesthetized rat, ID50 values being 0.018 +/- 0.02, 0.020 +/- 0.03 and 0.036 +/- 0.01 mumol kg-1 i.v. for APT, I-APT and RAN, respectively. Both APT and I-APT had a significantly longer duration of action than RAN. 3. The hydrophilic compound, SK&F 92857, was inactive up to 10 microM in modifying histamine-induced acid secretion in the isolated rat stomach. In the papillary muscle, low concentrations (0.1-1 microM) of this compound produced a competitive antagonism of the histamine responses (pA2 value = 7.38 +/- 0.11), while a higher concentration (10 microM) significantly reduced the maximal response to histamine. 4. RAN competitively antagonized histamine effects with a comparable affinity in cardiac and gastric preparations (pA2 values were 6.42 +/- 0.09 and 6.78 +/- 0.38 in heart and stomach, respectively). 5. Results obtained in this study clearly showed that the discrepancies between gastric and cardiac effects observed for some H2 antagonists are not explained solely by differences in lipophilicity of compounds. Moreover, the significant correlation found between CLOG P and log k' parameter, which takes into account, besides their lipophilicity, the ionization of the molecules, suggests that ionization has a similar influence for all the molecules on the partition between the lipophilic and aqueous phase.

Animals↗
PubMed1996

Prevention by (R)-alpha-methylhistamine of ethanol-induced gastric mucosal lesions in rats: importance of adherent mucus gel layer.

The ability of (R)-alpha-methylhistamine, the selective agonist of histamine H3 receptors, to reduce ethanol-induced gastric damage was examined in the rat. (R)-alpha-methylhistamine (1-100 mg/kg intragastrically) caused a dose-related reduction in the amount of damage produced by ethanol. This protective effect was not shared by the S enantiomer of alpha-methylhistamine. Thioperamide, selective H3 receptor antagonist, inhibited the protective effect of 10 but not 100 mg/kg of (R)-alpha-methylhistamine. Pretreatment with (R)-alpha-methylhistamine, 100 mg/kg i.g., resulted in a significant increase in the thickness of adherent mucus gel layer, which may contribute to the protective action of the compound.

Analysis of Variance↗
PubMed1996

Stimulatory effect of (R) alpha-methylhistamine on duodenal HCO3- secretion in anaesthetized rats.

The effect of the histamine H3 receptor agonist (R) alpha-methylhistamine on duodenal bicarbonate secretion was investigated in the anaesthetized rat. (R) alpha-methylhistamine (3-30 mumol/kg i.v.) caused a dose-dependent increase in alkaline secretion which was completely blocked by the H3 receptor antagonist clobenpropit (3 mumol/kg i.v.). This antagonist caused a slight reduction (19%) of the secretory response to PGE2 50 micrograms/kg i.v. These data indicate that the alkaline response to (R) alpha-methylhistamine is related to the activation of histamine H3 receptors and suggest that this could be an additional mechanism involved in the previously observed gastroprotective effect of this compound.

Anesthesia↗
PubMed1995

Cardiovascular effects of selective agonists and antagonists of histamine H3 receptors in the anaesthetized rat.

The cardiovascular responses to a series of selective histamine H3 receptor agonists, (R) alpha-methylhistamine, imetit and immepip and selective antagonists, thioperamide, clobenpropit and clophenpropit, were studied in anaesthetized rats. At 0.003-1 mumol/kg i.v. doses, H3 agonists failed to produce any significant change in the basal blood pressure and heart rate. Larger doses of (R) alpha-methylhistamine increased the blood pressure and heart rate and higher doses of imetit caused vasodepressor responses and reduced heart rate, whereas immepip proved virtually inactive. While (R) alpha-methylhistamine-induced effects were not blocked by histamine H1-, H2- and H3-receptor antagonists, they were however reduced by idazoxan and propranolol, which indicates that the mechanisms involved are adrenergic. The effects induced by imetit are not related to histamine H3 receptors but are mediated by indirect (via 5HT3 receptors) cholinergic mechanisms, since these effects were prevented by 1 mg/kg i.v. atropine and by 0.1 mg/kg i.v. ondansetron. Similarly, the H3 antagonists per se failed to change basal cardiovascular function up to 10 mumol/kg i.v. and only at 30 mumol/kg i.v. were marked decreases observed in the blood pressure and heart rate with a significant reduction in the effects of noradrenaline. These data indicate that in anaesthetized rats, histamine H3 receptor activation or blockade has no effect on basal cardiovascular function. The effects recorded after the administration of large doses of (R) alpha-methylhistamine and imetit are clearly unrelated to histamine H3 receptors and should be taken into account when using these compounds as H3 ligands for "in vivo" experiments.

Analysis of Variance↗
PubMed1995

An update on histamine H3 receptors and gastrointestinal functions.

The distribution and functions of histamine H3 receptors in the gastrointestinal tract is reviewed with particular reference to the effects on gastric acid secretion, mucosal protection, and intestinal motility. Histamine H3 receptor activation has negative effects on acid secretion induced by indirect secretagogues in cats, dogs, and rabbits; less clear effects were found in rats. An inhibitory effect on histamine release induced by different stimuli was observed in rats, rabbits, and dogs after H3 receptor agonists, thus supporting the idea that H3 receptors occur in ECL cells. (R)-alpha-methylhistamine has a marked protective effect against gastric lesions induced by ethanol in rats, being slightly less effective against aspirin and stress. H3 receptor activation decreases the intestinal motility induced by electrical stimulation in a variety of gut preparations, reducing both cholinergic and NANC neurotransmitter release. In this tissue the inhibitory effects mediated by histamine H3 receptors seem to be coupled, via a G protein, to a restriction of Ca2+ access into the nerve terminal; other mechanisms, however, have been suggested in the gastric mucosa. Histamine H3 receptors have already been subdivided into two receptor subtypes, H3A and H3B, the former being the subtype predominant in the gastrointestinal tissue. The increasing availability of selective agonists and antagonists of H3 receptors will unravel possible novel actions and physiological roles of histamine.

Animals↗
PubMed1995

Gastric antisecretory activity of lansoprazole in different experimental models: comparison with omeprazole.

1. The activity of the novel proton pump with inhibitor lansoprazole was examined in different gastric secretion models in vitro and in vivo, in comparison with omeprazole. 2. In the conscious cat with gastric fistula lansoprazole (0.25-2 mumol/kg i.v.) caused a dose-dependent reduction of the acid secretion induced by dimaprit, pentagastrin, 2-deoxy-D-glucose and bombesin, being approximately as potent as omeprazole (0.25-1.5 mumol/kg i.v.). Similar to omeprazole, lansoprazole was also more effective when administered in hyperacidic states. 3. In the anaesthetized rat with lumen perfused stomach lansoprazole (0.03-1 mumol/kg i.v.) was approximately 3 times more potent than omeprazole (0.1-3 mumol/kg i.v.) in inhibiting the acid secretion induced by histamine, 2-deoxy-D-glucose and forskolin. 4. In the isolated gastric fundus from the immature rat lansoprazole (1-30 microM) reduced basal acid secretion and the acid response to histamine and forskolin, with a potency not significantly different from that of omeprazole. 5. No significant differences were found in the different species between lansoprazole and omeprazole as for the duration of action. 6. In conclusion, lansoprazole exerts a marked antisecretory effect in a variety of gastric secretion models from different species. However, it did not significantly differ from omeprazole when considering either the potency or the duration of action.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

Gastroprotective activity of the novel proton pump inhibitor lansoprazole in the rat.

1. The protective activity of lansoprazole was evaluated on gastric mucosal lesions induced by intragastric 25% NaCl (1 ml/rat for 1 hr) and by indomethacin (20 mg/kg for 6 hr) in the rat and compared with that of omeprazole. 2. Lansoprazole (3, 10 and 10 mumol/kg i.g.) dose-dependently prevented the formation of indomethacin-induced lesions, the inhibition being 99% at the highest dose. Omeprazole, 10 mumol/kg i.g., enhanced the damage by indomethacin while higher doses caused a reduction, lesion index being reduced by 98% at 100 mumol/kg. 3. Histologically in lansoprazole- as well as in omeprazole-pretreated rats, indomethacin-induced necrosis of the mucosa was absent, luminal epithelium being intact. 4. Lansoprazole (30, 100 and 300 mumol/kg) and omeprazole (30, 100 and 300 mumol/kg) dose-dependently reduced the formation of lesions by hypertonic saline. 5. Present results indicated that lansoprazole and omeprazole protect the gastric mucosa in different experimental models of gastric ulceration.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

Indomethacin-induced morphological changes in the rat gastric mucosa, with or without prior treatment with two proton pump inhibitors.

BACKGROUND: The mechanisms responsible for the gastric ulcerogenic effect of indomethacin are unclear. The importance of basal acid secretion on morphological changes by indomethacin was investigated. METHODS: Gastric lesions were macroscopically evaluated 6 h after indomethacin, 20 mg/kg intragastrically, in rats pre-treated with omeprazole (10-100 mumol/kg intragastrically) or lansoprazole (3-30 mumol/kg intragastrically). Glandular mucosa was processed for light, scanning and transmission electron microscopy 3 and 6 h after indomethacin in rats pre-treated with omeprazole (100 mumol/kg) or lansoprazole (30 mumol/kg). RESULTS: After 3 h, indomethacin caused extensive vasocongestion, oedema in the subepithelial region and superficial erosions. After 6 h, deeply extending focal necrosis involved 11% of the tissue. Leukocyte margination was occasionally seen at 3 h and consistently present at 6 h. Only at 6 h were endothelial cells altered. In rats pre-treated with omeprazole (100 mumol/kg) or lansoprazole (30 mumol/kg) grossly visible lesions were prevented. Oedema, erosions and necrosis were absent. Vasocongestion, vascular leakage and leukocytic margination were seen both at 3 and 6 h while no major damage of endothelial cells was observed. CONCLUSION: Indomethacin appears primarily to alter microcirculation, and microcirculation damage is dependent on acid for the progression to haemorrhagic lesions.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

(R)-alpha-methylhistamine inhibits ethanol-induced gastric lesions in the rat: involvement of histamine H3 receptors?

This study examined the gastroprotective effect of (R)-alpha-methylhistamine (MHA), a selective agonist of histamine H3 receptors. Gastric lesions were induced in the rat by administering absolute ethanol in a volume of 1 ml. Stomachs were removed 1 h later and lesions evaluated both macroscopically and histologically. MHA dose-dependently inhibited ethanol-induced lesions in the range 1-100 mg/kg both by the intragastric and intraperitoneal route. Histological findings indicated that the number of mucous granules in surface and neck cells was increased and the process of reepithelialization was rapidly promoted by MHA. Thioperamide, at 10 mg/kg, inhibited the protective effect of 10 but not of 100 mg/kg of MHA. Larger doses of thioperamide could not be tested because of an interaction with ethanol causing central nervous system effects. Famotidine and indomethacin pretreatment only partially counteracted the MHA effect. The results indicate that MHA is highly effective in preventing ethanol-induced lesions but the exact mechanism is still uncertain.

Animals↗
PubMed1994

Regulation of gastric acid secretion by histamine H3 receptors in the dog: an investigation into the site of action.

The involvement of histamine H3 receptors in the regulation of gastric acid secretion was investigated in the conscious dog with gastric fistula, by the use of the selective agonist (R)alpha-methylhistamine and the selective antagonist thioperamide. (R)alpha-methylhistamine (0.3-1.2 mumol/kg/h) induced a dose-related inhibition of the acid secretion induced by pentagastrin and by bombesin, maximum inhibition not exceeding 60-65%. The inhibitory effect of the H3 agonist (0.6 mumol/kg/h) was inhibited by thioperamide (0.1 mumol/kg/h), suggesting that the effect was entirely mediated by H3 receptors. Thioperamide was also able to enhance the acid response to submaximal doses of pentagastrin and bombesin. The acid secretion induced by histamine was not modified by (R)alpha-methylhistamine (0.3-1.2 mumol/kg/h) but it was significantly enhanced by thioperamide (0.1 mumol/kg/h). Neither (R)alpha-methylhistamine nor thioperamide significantly modified the increase in plasma gastrin levels induced by bombesin. In conclusion these data demonstrate that histamine H3 receptors may represent an effective mechanism for the negative control of stimulated gastric acid secretion in the dog; however, since the inhibition was mainly evident against stimuli which involve the release of histamine, a location of H3 receptors in paracrine cells of the gastric mucosa rather than in gastrin producing cells or parietal cells seems more likely.

Animals↗
PubMed1994

Presynaptic histamine H2 receptors modulate the sympathetic nerve transmission in the isolated rat vas deferens; no role for H3-receptors.

The modulatory activity mediated by histamine receptors on the sympathetic nerve transmission was investigated in the rat vas deferens. Agonists and antagonists acting at the different histamine receptor subtypes (H1, H2 and H3) were tested on electrically-driven preparations in vitro. Low-frequency stimulation (0.1 Hz) evoked muscle contractions almost completely-sustained by ATP release, while at high-frequency stimulation (5-10 Hz) norepinephrine was mainly involved. The H1 receptor agonists, pyridilethylamine and 2-(2 aminoethyl)thiazole, enhanced the electrically evoked twitch responses, but not contractions induced by exogenously-applied norepinephrine and ATP. These effects were prevented by the H1-blocking drugs, mepyramine and phenyramine, but only at high concentrations (10 mumol/l). All these H1-antagonists strongly enhanced muscle response to electrical stimulation. The H2 receptor agonists, dimaprit, amthamine and impromidine, reduced the contractions evoked by field stimulation, but not by exogenously applied norepinephrine and ATP, the effect being antagonised by H2-blocking drugs, ranitidine and famotidine. The H3 receptor agonist, R(alpha)-methylhistamine, reduced the electrically evoked muscle contractions, the effect being not modified by the selective H3-blocking drug, thioperamide, but prevented by famotidine. These data suggest that rat vas deferens contains presynaptic histamine H2 receptors, able to mediate inhibitory effects on the sympathetic transmission, while histamine H3 receptors are apparently not involved. On the contrary, the role of H1 is still unclear, since both agonists and antagonists may have the same effects.

Animals↗
PubMed1994

Positive inotropic activity of the novel histamine H2-receptor agonist, amthamine, on the human heart in vitro.

1. We tested the novel thiazole derivative, amthamine, for its ability to stimulate histamine H2-receptors in the human myocardium. 2. Experiments were carried out on isolated, electrically-driven pectinate muscle segments, excised from atrial appendages of patients undergoing corrective heart surgery. 3. Amthamine (0.3-100 microM) induced a positive inotropic activity, resembling histamine in terms of potency and efficacy. In comparison, impromidine was 10-30 times more active than histamine and amthamine, but its maximum effect was significantly lower, while dimaprit was as effective as histamine, but 10 times less potent. 4. The selective histamine H2-blocker, famotidine antagonized in a competitive fashion the amthamine-induced positive inotropic effect. pA2 value of famotidine against amthamine (7.21 +/- 0.45) was close to that measured against histamine (6.88 +/- 0.31) in the same conditions. 5. The effect of amthamine was not modified by beta-adrenoceptor blockade, excluding direct or indirect sympathomimetic activities of the compound. 6. These data provide evidence that amthamine is a selective and full acting histamine H2-receptor agonist in the human heart in vitro.

Cardiotonic Agents↗
PubMed1994

Activity of the new histamine H2-receptor antagonist zolantidine at cardiac and gastric H2-receptors.

The effect of the new histamine H2-receptor antagonist zolantidine was studied in different cardiac and gastric H2-receptor assays in comparison with ranitidine. Zolantidine (0.1-10 mumol/l) competitively antagonized the positive effects of histamine in the spontaneously beating guinea pig atria and in the electrically stimulated guinea pig papillary muscle (pA2 values were 6.98 and 6.78, respectively). At the highest concentrations zolantidine also reduced basal heart rate and cardiac contractility. In the isolated rat gastric fundus zolantidine up to 100 mumol/l did not modify histamine-induced acid secretion; it was similarly ineffective against dimaprit-induced acid secretion in the gastric fistula of conscious cats (up to 3 mumol/kg i.v.) and against histamine in the anesthetized rat with lumen-perfused stomach (up to 30 mumol/kg i.v.). In all these gastric secretory models ranitidine, as expected, antagonized histamine H2-receptor-mediated responses, showing a potency comparable to that found in cardiac preparations (pA2 values were 6.84, 6.38 and 6.78 in the atria, papillary muscle and gastric fundus, respectively). These data clearly showed that zolantidine is a very peculiar histamine H2-receptor antagonist, capable of distinguishing between cardiac and gastric H2-receptors; however, it still has to be elucidated whether this depends on a true heterogeneity in the histamine H2-receptor population or on the physicochemical properties of the drug.

Animals↗
PubMed1994

Signal transducing mechanisms coupled to histamine H3 receptors and alpha-2 adrenoceptors in the guinea pig duodenum: possible involvement of N-type Ca++ channels.

The signaling pathways following histamine H3 receptor activation by (R)alpha-methylhistamine (MHA) have been examined in the isolated guinea pig duodenum, in which selective excitation of cholinergic neurons was induced by electrical field stimulation (EFS). The effect of MHA on electrically evoked contractions was compared with that induced by the alpha-2 adrenoceptor agonist clonidine (CLON). The inhibitory effect of MHA on EFS-induced contractions was significantly reduced by increasing CA++ content in the nutrient fluid from 2.5 to 5 mM and by the Ca++ agonist Bay K 8644 (10(-8) M); conversely, the effect of MHA was significantly enhanced by lowering Ca++ content in the medium (from 2.5 to 1.25 mM) and by the N-type Ca++ channel blocker omega-conotoxin (CTX) (10(-8) M). The L-type Ca++ channel blocker nifedipine (NIF) (10(-7) M) did not modify the effect of MHA, although it significantly reduced both EFS- and exogenous acetylcholine (ACH)-induced contractions. Similar to MHA, the inhibitory effect elicited by CLON was enhanced by low external Ca++ and by CTX, but it was slightly affected by the compound Bay K 8644 (10(-7) M) or by high Ca++ concentrations (5 mM) and it was unaffected by NIF. 4-Aminopyridine (4-AP) (10(-4) M) reduced the effects of both MHA and CLON. The present data indicate that histamine H3 receptor activation in electrically stimulated duodenum is closely associated with a restriction of Ca++ access into the nerve terminal through N-type Ca++ channels; the same mechanism appears to be responsible for the inhibitory effect induced by alpha-2 adrenoceptor activation.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗