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Hendrik Timmerman - One of the best experts on this subject based on the ideXlab platform.
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Cardiovascular effects of the novel histamine H2 receptor agonist Amthamine: interaction with the adrenergic system.
Naunyn-Schmiedeberg's archives of pharmacology, 1996Co-Authors: Gabriella Coruzzi, Giulio Bertaccini, E. Gambarelli, Hendrik TimmermanAbstract:The cardiovascular effects of the new histamine H2 receptor agonist Amthamine were studied in the anaesthetized rat, with particular reference to a possible interaction with the adrenergic system. Amthamine (0.03–3 μmol/kg i.v.) caused vasodepressor responses which were antagonized by famotidine (3 μmol/kg i.v.). At higher doses (30–100 μmol/kg i.v.), Amthamine induced a modest increase in the mean arterial pressure, which was significantly enhanced by the blockade of H2 receptors and significantly reduced by the α2 adrenoceptor antagonist yohimbine (1 μmol/kg i.v.). The vasopressor response to Amthamine was not modified in rats pre-treated with reserpine or 6-hydroxydopamine, and was only minimally modified in adrenalectomized animals, thus suggesting a predominant interaction with postjunctional α2 adrenoceptors in the vascular muscle. The H2 receptor agonist dimaprit (0.3–100 μmol/kg i.v.) caused a reduction in arterial pressure, which was antagonized by famotidine, no pressor response being unmasked.
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AMSELAMINE, A NEW SELECTIVE HISTAMINE H2-RECEPTOR AGONIST
Bioorganic & Medicinal Chemistry Letters, 1994Co-Authors: Henk Van Der Goot, J C Eriks, Rob Leurs, Hendrik TimmermanAbstract:Abstract The synthesis of amselamine (2-amino-5(2-aminoethyl)-4-methyl-1,3-selenazole), a potent histamine H2-agonist, has been described. At the guinea pig right atrium amselamine revealed to be slightly more active than its sulfur analogue Amthamine and histamine. Moreover negligible effects on H1 and H3-receptors were observed.
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Pharmacological characterization of the human histamine H2 receptor stably expressed in Chinese hamster ovary cells.
British Journal of Pharmacology, 1994Co-Authors: Rob Leurs, Martine J. Smit, Wiro M.b.p. Menge, Hendrik TimmermanAbstract:1. The gene for the human histamine H2 receptor was stably expressed in Chinese hamster ovary (CHO) cells and characterized by [125I]-iodoaminopotentidine binding studies. In addition, the coupling of the expressed receptor protein to a variety of signal transduction pathways was investigated. 2. After cotransfection of CHO cells with pCMVhumH2 and pUT626, a phleomycine-resistant clonal cell line (CHOhumH2) was isolated that expressed 565 +/- 35 fmol kg-1 protein binding sites with high affinity (0.21 +/- 0.02 nM) for the H2 antagonist, [125I]-iodoaminopotentidine. 3. Displacement studies with a variety of H2 antagonists indicated that the encoded protein was indistinguishable from the H2 receptor identified in human brain membranes and guinea-pig right atrium. The Ki-values observed in the various preparations correlated very well (r2 = 0.996-0.920). 4. Displacement studies with histamine showed that a limited fraction (32 +/- 6%) of the binding sites showed a high affinity for histamine (2 +/- 1.2 microM); the shallow displacement curves were reflected by a Hill-coefficient significantly different from unity (nH = 0.58 +/- 0.09). The addition of 100 microM Gpp(NH)p resulted in a steepening of the displacement curve (nH = 0.79 +/- 0.02) and a loss of high affinity sites for histamine. 5. Displacement studies with other agonists indicated that the recently developed specific H2 agonists, Amthamine and amselamine, showed an approximately 4-5 fold higher affinity for the human H2 receptor than histamine. 6. Stimulation of CHOhumH2 cells with histamine resulted in a rapid rise of the intracellular cyclic AMP levels. After 10 min an approximately 10 fold increase in cyclic AMP could be measured. TheEC50 value for this response was 7 +/- 1 nM for histamine. This response was effectively blocked by tiotidine and cimetidine, resulting in Ki values of 8 +/- 1 nM and 0.56 +/- 0.24 MicroM respectively.7. Stimulation of CHOhumH2 cells with histamine neither inhibited the A23187-induced release of[3H]-arachidonic acid nor changed the intracellular IP3 levels.8. These results show that the cloned human gene encodes a histamine H2 receptor that is indistinguishable from the H2 receptor identified in human brain tissue. This receptor is functionally coupled to the adenylate cyclase in CHO cells, but does not influence the inositolphosphate turnover or arachidonic acid release.
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In vitro cardiac pharmacology of the new histamine H2-receptor agonist Amthamine: comparisons with histamine and dimaprit.
Inflammation Research, 1993Co-Authors: Enzo Poli, Gabriella Coruzzi, Giulio Bertaccini, Cristina Pozzoli, Hendrik TimmermanAbstract:The cardiac activity of the novel histamine H2-receptor agonist Amthamine was investigated in a variety of isolated heart preparations from guinea pigs and humans and in the isolated rabbit aorta. Amthamine caused an increase in the sinus rate of spontaneously beating guinea-pig atria (pD2=6.72) and in the contractility of the electrically driven guinea-pig papillary muscle (pD2=6.17) and of the human atrium (pD2=5.38). In all these systems, Amthamine behaved as a full agonist with a potency comparable to or slightly higher than that of histamine and 10 times higher than that of dimaprit. The positive effects of Amthamine were competitively antagonized by ranitidine which had pA2 values (6.46 and 6.25 in the guinea-pig atria and papillary muscle, respectively) comparable with those calculated against histamine and dimaprit. In the isolated rabbit aorta Amthamine was devoid of H1-mediated activities up to 3×10−4M. These results indicate that Amthamine is a potent and selective histamine H2-receptor agonist which can be considered a valuable tool for investigating H2-receptor mediated effects in cardiac tissues.
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The new potent and selective histamine H_2 receptor agonist Amthamine as a tool to study gastric secretion
Naunyn-Schmiedeberg's Archives of Pharmacology, 1993Co-Authors: Gabriella Coruzzi, Hendrik Timmerman, Maristella Adami, Giulio BertacciniAbstract:The new histamine H_2 receptor agonist Amthamine, [2-amino-5-(2-aminoethyl)-4-methylthiazole], was tested for its activity on gastric acid secretion in different in vivo and in vitro experimental models. Amthamine induced a dose-related increase in acid secretion both in conscious cats with a gastric fistula (ED_50 = 0.069 μmol/kg/h) and in anaesthetized rats with a lumen-perfused stomach (ED_50 = 11.69 gmol/kg i.v.). In this last preparation the efficacy of Amthamine was significantly higher than that of histamine and dimaprit. Amthamine was an effective secretagogue also in the rat isolated gastric fundus, behaving as a full agonist (EC_50 = 18.9 μmol/l). In all the experimental models Amthamine was more potent than dimaprit (from 3 to 10 fold) and approximately equipotent with histamine, and its effect was competitively antagonized by the histamine H_2 receptor antagonists famotidine or ranitidine. Experiments with H_1 and H_3 receptor antagonists indicated that Amhamine is devoid of stimulatory activity at H_1 and H_3 receptors. The present data indicate that Amthamine is a full agonist at histamine H_2 receptors and, being more effective and selective than the other compounds of the family, it may represent a good alternative to the other available histamine H_2 receptor agonists for the study of gastric acid secretion.
Giulio Bertaccini - One of the best experts on this subject based on the ideXlab platform.
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Effects of histamine H2 receptor agonists and antagonists on the isolated guinea pig gallbladder.
Fundamental & Clinical Pharmacology, 1999Co-Authors: Gabriella Coruzzi, Enzo Poli, Cristina Pozzoli, Gabriella Coppelli, Giulio BertacciniAbstract:Histamine H 2 receptor-mediated responses were examined on cholecystokinin-octapeptide (CCK-8)-precontracted guinea pig gallbladder in vitro, testing histamine and a series of specific histamine H 2 receptor agonists and antagonists. Among the antagonists tested, zolantidine and compound SKF 92857 were previously shown to antagonize H 2 receptor-mediated responses in the heart, but not in the stomach. Histamine, in the presence of the H 1 receptor antagonist mepyramine (10 μM), and the H 2 receptor agonists dimaprit, impromidine and Amthamine, inhibited CCK-8 (3 nM)-induced contractions in a concentration-dependent fashion, with the following rank orders of potency: impromidine > Amthamine > histamine > dimaprit (pD 2 values were 6.73 ± 0.04, 5.44 ± 0.07, 4.64 ± 0.04 and 3.71 ± 0.05, respectively). The maximal relaxation produced by dimaprit was significantly lower than that produced by histamine, as well as by impromidine and Amthamine, which behaved as full agonists. All the H 2 receptor antagonists examined were able to inhibit Amthamine-induced relaxation. Famotidine (pA 2 = 7.09 ± 0.26), zolantidine (pA 2 = 6.54 ± 0.11), compound SKF 92857 (pA 2 = 6.58 0.13) and aminopotentidine (pA 2 = 6.86 ± 0.06) competitively antagonised the Amthamine-induced effect, while iodoaminopotentidine produced surmountable antagonism only at low concentrations ( 1 μM, pA 2 =*6.83 ± 0.21). Finally, the slowly-dissociable antagonist loxtidine caused a non-parallel displacement to the right of the concentration-response curve to Amthamine (pK B = 7.55 ± 0.24), with a significant depression of the maximal response to the agonist, even at the lowest effective concentration (0.3 μM). In conclusion, histamine H 2 receptors in guinea pig gallbladder resemble those of the heart, as regards their sensitivity to zolantidine and compound SKF 92857, which, by contrast, were unable to antagonize histamine effects at gastric H 2 receptors in different experimental models.
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Histamine Receptor-Independent Muscle Relaxation Elicited by a Series of Histamine H2-receptor Agonists on the Isolated Guinea Pig Duodenum: A Study into the Mechanism of Action
General Pharmacology: The Vascular System, 1998Co-Authors: Gabriella Coruzzi, Giulio Bertaccini, Enzo Poli, Cristina Pozzoli, Henk TimmermanAbstract:Abstract 1. The histamine H 2 receptor agonists, dimaprit, impromidine, Amthamine, and several dimaprit- and impromidine-analogues were investigated for their spasmolytic activity on the guinea pig duodenum, precontracted with acetylcholine or KCl. 2. Almost all the H 2 receptor agonists exerted a histamine H 2 receptor-independent muscle relaxation, which was more evident on acetylcholine- than on KCl-precontracted preparations. 3. The relaxing activity of these compounds was independent of inhibitory receptors, like β-adrenergic, GABA-ergic, serotoninergic, etc. Similarly, modifications of cyclic nucleotide metabolism and nitric oxide production did not appear to be involved. 4. The behavior of histamine H 2 −receptor agonists was shared only by the Na + -blocker procaine, the intracellular Ca 2+ -antagonist ruthenium red and, at least in terms of efficacy, by the protein kinase C inhibitor, chelerithrine. 5. This spasmolytic effect is probably due to an impairment of receptor-mediated depolarization at the plasma membrane level and/or an inhibitory activity on the protein kinase C-dependent activation of the contractile machinery. 6. Finally, our findings suggest that the histamine H 2 receptor-independent muscle relaxation is a general feature shown by H 2 receptor agonists endowed with different chemical structure and the putative spasmolytic “receptor” prefers a (substituted) thiazole over a (substituted) imidazole.
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Cardiovascular effects of the novel histamine H2 receptor agonist Amthamine: interaction with the adrenergic system.
Naunyn-Schmiedeberg's archives of pharmacology, 1996Co-Authors: Gabriella Coruzzi, Giulio Bertaccini, E. Gambarelli, Hendrik TimmermanAbstract:The cardiovascular effects of the new histamine H2 receptor agonist Amthamine were studied in the anaesthetized rat, with particular reference to a possible interaction with the adrenergic system. Amthamine (0.03–3 μmol/kg i.v.) caused vasodepressor responses which were antagonized by famotidine (3 μmol/kg i.v.). At higher doses (30–100 μmol/kg i.v.), Amthamine induced a modest increase in the mean arterial pressure, which was significantly enhanced by the blockade of H2 receptors and significantly reduced by the α2 adrenoceptor antagonist yohimbine (1 μmol/kg i.v.). The vasopressor response to Amthamine was not modified in rats pre-treated with reserpine or 6-hydroxydopamine, and was only minimally modified in adrenalectomized animals, thus suggesting a predominant interaction with postjunctional α2 adrenoceptors in the vascular muscle. The H2 receptor agonist dimaprit (0.3–100 μmol/kg i.v.) caused a reduction in arterial pressure, which was antagonized by famotidine, no pressor response being unmasked.
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Positive inotropic activity of the novel histamine H2-receptor agonist, Amthamine, on the human heart in vitro
General Pharmacology: The Vascular System, 1994Co-Authors: Enzo Poli, Cristina Pozzoli, I Spaggiari, Giulio BertacciniAbstract:Abstract 1. 1. We tested the novel thiazole derivative, Amthamine, for its ability to stimulate histamine H 2 -receptors in the human myocardium. 2. 2. Experiments were carried out on isolated, electrically-driven pectinate muscle segments, excised from atrial appendages of patients undergoing corrective heart surgery. 3. 3. Amthamine (0.3–100μM) 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. 4. The selective histamine H 2 -blocker, famotidine antagonized in a competitive fashion the Amthamine-induced positive inotropic effect. p A 2 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. 5. The effect of Amthamine was not modified by β-adrenoceptor blockade, excluding direct or indirect sympathomimetic activities of the compound. 6. 6. These data provide evidence that Amthamine is a selective and full acting histamine H 2 -receptor agonist in the human heart in vitro .
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In vitro cardiac pharmacology of the new histamine H2-receptor agonist Amthamine: comparisons with histamine and dimaprit.
Inflammation Research, 1993Co-Authors: Enzo Poli, Gabriella Coruzzi, Giulio Bertaccini, Cristina Pozzoli, Hendrik TimmermanAbstract:The cardiac activity of the novel histamine H2-receptor agonist Amthamine was investigated in a variety of isolated heart preparations from guinea pigs and humans and in the isolated rabbit aorta. Amthamine caused an increase in the sinus rate of spontaneously beating guinea-pig atria (pD2=6.72) and in the contractility of the electrically driven guinea-pig papillary muscle (pD2=6.17) and of the human atrium (pD2=5.38). In all these systems, Amthamine behaved as a full agonist with a potency comparable to or slightly higher than that of histamine and 10 times higher than that of dimaprit. The positive effects of Amthamine were competitively antagonized by ranitidine which had pA2 values (6.46 and 6.25 in the guinea-pig atria and papillary muscle, respectively) comparable with those calculated against histamine and dimaprit. In the isolated rabbit aorta Amthamine was devoid of H1-mediated activities up to 3×10−4M. These results indicate that Amthamine is a potent and selective histamine H2-receptor agonist which can be considered a valuable tool for investigating H2-receptor mediated effects in cardiac tissues.
Gabriella Coruzzi - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological characterization of the new histamine H4 receptor agonist VUF 8430.
British Journal of Pharmacology, 2009Co-Authors: Herman D. Lim, Gabriella Coruzzi, Maristella Adami, Ralf Gutzmer, Thomas Werfel, Elena Guaita, Rogier A. Smits, Iwan J. P. De Esch, Remko A. Bakker, Rob LeursAbstract:Background and purpose: We compare the pharmacological profiles of a new histamine H4 receptor agonist 2-(2-guanidinoethyl)isothiourea (VUF 8430) with that of a previously described H4 receptor agonist, 4-methylhistamine. Experimental approach: Radioligand binding and functional assays were performed using histamine H4 receptors expressed in mammalian cell lines. Compounds were also evaluated ex vivo in monocyte-derived dendritic cells endogenously expressing H4 receptors and in vivo in anaesthetized rats for gastric acid secretion activity. Key results: Both VUF 8430 and 4-methylhistamine were full agonists at human H4 receptors with lower affinity at rat and mouse H4 receptors. Both compounds induced chemotaxis of monocyte-derived dendritic cells. VUF 8430 also showed reasonable affinity and was a full agonist at the H3 receptor. Agmatine is a metabolite of arginine, structurally related to VUF 8430, and was a H4 receptor agonist with micromolar affinity. At histamine H3 receptors, agmatine was a full agonist, whereas 4-methylhistamine was an agonist only at high concentrations. Both VUF 8430 and agmatine were inactive at H1 and H2 receptors, whereas 4-methylhistamine is as active as histamine at H2 receptors. In vivo, VUF 8430 only caused a weak secretion of gastric acid mediated by H2 receptors, whereas 4-methylhistamine, dimaprit, histamine and Amthamine, at equimolar doses, induced 2.5- to 6-fold higher output than VUF 8430. Conclusions and implications: Our results suggest complementary use of 4-methylhistamine and VUF 8430 as H4 receptor agonists. Along with H4 receptor antagonists, both agonists can serve as useful pharmacological tools in studies of histamine H4 receptors.
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Effects of histamine H2 receptor agonists and antagonists on the isolated guinea pig gallbladder.
Fundamental & Clinical Pharmacology, 1999Co-Authors: Gabriella Coruzzi, Enzo Poli, Cristina Pozzoli, Gabriella Coppelli, Giulio BertacciniAbstract:Histamine H 2 receptor-mediated responses were examined on cholecystokinin-octapeptide (CCK-8)-precontracted guinea pig gallbladder in vitro, testing histamine and a series of specific histamine H 2 receptor agonists and antagonists. Among the antagonists tested, zolantidine and compound SKF 92857 were previously shown to antagonize H 2 receptor-mediated responses in the heart, but not in the stomach. Histamine, in the presence of the H 1 receptor antagonist mepyramine (10 μM), and the H 2 receptor agonists dimaprit, impromidine and Amthamine, inhibited CCK-8 (3 nM)-induced contractions in a concentration-dependent fashion, with the following rank orders of potency: impromidine > Amthamine > histamine > dimaprit (pD 2 values were 6.73 ± 0.04, 5.44 ± 0.07, 4.64 ± 0.04 and 3.71 ± 0.05, respectively). The maximal relaxation produced by dimaprit was significantly lower than that produced by histamine, as well as by impromidine and Amthamine, which behaved as full agonists. All the H 2 receptor antagonists examined were able to inhibit Amthamine-induced relaxation. Famotidine (pA 2 = 7.09 ± 0.26), zolantidine (pA 2 = 6.54 ± 0.11), compound SKF 92857 (pA 2 = 6.58 0.13) and aminopotentidine (pA 2 = 6.86 ± 0.06) competitively antagonised the Amthamine-induced effect, while iodoaminopotentidine produced surmountable antagonism only at low concentrations ( 1 μM, pA 2 =*6.83 ± 0.21). Finally, the slowly-dissociable antagonist loxtidine caused a non-parallel displacement to the right of the concentration-response curve to Amthamine (pK B = 7.55 ± 0.24), with a significant depression of the maximal response to the agonist, even at the lowest effective concentration (0.3 μM). In conclusion, histamine H 2 receptors in guinea pig gallbladder resemble those of the heart, as regards their sensitivity to zolantidine and compound SKF 92857, which, by contrast, were unable to antagonize histamine effects at gastric H 2 receptors in different experimental models.
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Histamine Receptor-Independent Muscle Relaxation Elicited by a Series of Histamine H2-receptor Agonists on the Isolated Guinea Pig Duodenum: A Study into the Mechanism of Action
General Pharmacology: The Vascular System, 1998Co-Authors: Gabriella Coruzzi, Giulio Bertaccini, Enzo Poli, Cristina Pozzoli, Henk TimmermanAbstract:Abstract 1. The histamine H 2 receptor agonists, dimaprit, impromidine, Amthamine, and several dimaprit- and impromidine-analogues were investigated for their spasmolytic activity on the guinea pig duodenum, precontracted with acetylcholine or KCl. 2. Almost all the H 2 receptor agonists exerted a histamine H 2 receptor-independent muscle relaxation, which was more evident on acetylcholine- than on KCl-precontracted preparations. 3. The relaxing activity of these compounds was independent of inhibitory receptors, like β-adrenergic, GABA-ergic, serotoninergic, etc. Similarly, modifications of cyclic nucleotide metabolism and nitric oxide production did not appear to be involved. 4. The behavior of histamine H 2 −receptor agonists was shared only by the Na + -blocker procaine, the intracellular Ca 2+ -antagonist ruthenium red and, at least in terms of efficacy, by the protein kinase C inhibitor, chelerithrine. 5. This spasmolytic effect is probably due to an impairment of receptor-mediated depolarization at the plasma membrane level and/or an inhibitory activity on the protein kinase C-dependent activation of the contractile machinery. 6. Finally, our findings suggest that the histamine H 2 receptor-independent muscle relaxation is a general feature shown by H 2 receptor agonists endowed with different chemical structure and the putative spasmolytic “receptor” prefers a (substituted) thiazole over a (substituted) imidazole.
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Cardiovascular effects of the novel histamine H2 receptor agonist Amthamine: interaction with the adrenergic system.
Naunyn-Schmiedeberg's archives of pharmacology, 1996Co-Authors: Gabriella Coruzzi, Giulio Bertaccini, E. Gambarelli, Hendrik TimmermanAbstract:The cardiovascular effects of the new histamine H2 receptor agonist Amthamine were studied in the anaesthetized rat, with particular reference to a possible interaction with the adrenergic system. Amthamine (0.03–3 μmol/kg i.v.) caused vasodepressor responses which were antagonized by famotidine (3 μmol/kg i.v.). At higher doses (30–100 μmol/kg i.v.), Amthamine induced a modest increase in the mean arterial pressure, which was significantly enhanced by the blockade of H2 receptors and significantly reduced by the α2 adrenoceptor antagonist yohimbine (1 μmol/kg i.v.). The vasopressor response to Amthamine was not modified in rats pre-treated with reserpine or 6-hydroxydopamine, and was only minimally modified in adrenalectomized animals, thus suggesting a predominant interaction with postjunctional α2 adrenoceptors in the vascular muscle. The H2 receptor agonist dimaprit (0.3–100 μmol/kg i.v.) caused a reduction in arterial pressure, which was antagonized by famotidine, no pressor response being unmasked.
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In vitro cardiac pharmacology of the new histamine H2-receptor agonist Amthamine: comparisons with histamine and dimaprit.
Inflammation Research, 1993Co-Authors: Enzo Poli, Gabriella Coruzzi, Giulio Bertaccini, Cristina Pozzoli, Hendrik TimmermanAbstract:The cardiac activity of the novel histamine H2-receptor agonist Amthamine was investigated in a variety of isolated heart preparations from guinea pigs and humans and in the isolated rabbit aorta. Amthamine caused an increase in the sinus rate of spontaneously beating guinea-pig atria (pD2=6.72) and in the contractility of the electrically driven guinea-pig papillary muscle (pD2=6.17) and of the human atrium (pD2=5.38). In all these systems, Amthamine behaved as a full agonist with a potency comparable to or slightly higher than that of histamine and 10 times higher than that of dimaprit. The positive effects of Amthamine were competitively antagonized by ranitidine which had pA2 values (6.46 and 6.25 in the guinea-pig atria and papillary muscle, respectively) comparable with those calculated against histamine and dimaprit. In the isolated rabbit aorta Amthamine was devoid of H1-mediated activities up to 3×10−4M. These results indicate that Amthamine is a potent and selective histamine H2-receptor agonist which can be considered a valuable tool for investigating H2-receptor mediated effects in cardiac tissues.
G. Bertaccini - One of the best experts on this subject based on the ideXlab platform.
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Cardiovascular effects of the novel histamine H_2 receptor agonist Amthamine: interaction with the adrenergic system
Naunyn-Schmiedeberg's Archives of Pharmacology, 1996Co-Authors: G. Coruzzi, G. Bertaccini, E. Gambarelli, H. TimmermanAbstract:The cardiovascular effects of the new histamine H_2 receptor agonist Amthamine were studied in the anaesthetized rat, with particular reference to a possible interaction with the adrenergic system. Amthamine (0.03–3 μmol/kg i.v.) caused vasodepressor responses which were antagonized by famotidine (3 μmol/kg i.v.). At higher doses (30–100 μmol/kg i.v.), Amthamine induced a modest increase in the mean arterial pressure, which was significantly enhanced by the blockade of H_2 receptors and significantly reduced by the α_2 adrenoceptor antagonist yohimbine (1 μmol/kg i.v.). The vasopressor response to Amthamine was not modified in rats pre-treated with reserpine or 6-hydroxydopamine, and was only minimally modified in adrenalectomized animals, thus suggesting a predominant interaction with postjunctional α_2 adrenoceptors in the vascular muscle. The H_2 receptor agonist dimaprit (0.3–100 μmol/kg i.v.) caused a reduction in arterial pressure, which was antagonized by famotidine, no pressor response being unmasked. Dimaprit (0.1–30 μmol/kg i.v.) did not modify heart rate but caused a modest bradycardia at 100 μmol/kg i.v. Amthamine (1-100 μmol/kg i.v.) induced a dose-dependent tachycardia, which was only partially (approximately 20%) reduced by famotidine and was totally blocked by propranolol (0.3 mg/kg i.v.). This effect was significantly reduced in rats pre-treated with reserpine or 6-hydroxydopamine and was further reduced by cocaine, thus suggesting a tyramine-like action of Amthamine. In conclusion, these data demonstrate that the H_2 receptor agonist Amthamine can also interact with the adrenergic system when used at doses higher than those necessary to activate H2 receptors. Whereas the increase in blood pressure induced by Amthamine seems to be mainly mediated by a direct activation of postjunctional α_2 adrenoceptors, the increase in heart rate is predominantly due to neuronal release of catecholamines. These effects should be considered when using Amthamine in cardiovascular or other studies when high doses are employed.
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Presynaptic histamine H_2 receptors modulate the sympathetic nerve transmission in the isolated rat vas deferens; no role for H_3-receptors
Agents and Actions, 1994Co-Authors: E. Poli, C. Pozzoli, S. Todorov, G. BertacciniAbstract: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 (H_1, H_2 and H_3) were tested on electrically-driven preparations in vitro . Low-frequency stimulation (0.1 Hz) evoked muscle contractions almost completelysustained by ATP release, while at high-frequency stimulation (5–10 Hz) norepinephrine was mainly involved. The H_1 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 H_1-blocking drugs, mepyramine and phenyramine, but only at high concentrations (10 μmol/l). All these H_1-antagonists strongly enhanced muscle response to electrical stimulation. The H_2 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 H_2-blocking drugs, ranitidine and famotidine. The H_3 receptor agonist, R (α)-methylhistamine, reduced the electrically evoked muscle contractions, the effect being not modified by the selective H_3-blocking drug, thioperamide, but prevented by famotidine. These data suggest that rat vas deferens contains presynaptic histamine H_2 receptors, able to mediate inhibitory effects on the sympathetic transmission, while histamine H_3 receptors are apparently not involved. On the contrary, the role of H_1 is still unclear, since both agonists and antagonists may have the same effects.
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Presynaptic histamine H2 receptors modulate the sympathetic nerve transmission in the isolated rat vas deferens; no role for H3-receptors.
Agents and Actions, 1994Co-Authors: E. Poli, C. Pozzoli, S. Todorov, G. BertacciniAbstract: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.
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In vitro cardiac pharmacology of the new histamine H_2-receptor agonist Amthamine: Comparisons with histamine and dimaprit
Agents and Actions, 1993Co-Authors: E. Poli, C. Pozzoli, G. Coruzzi, G. Bertaccini, H. TimmermanAbstract:The cardiac activity of the novel histamine H_2-receptor agonist Amthamine was investigated in a variety of isolated heart preparations from guinea pigs and humans and in the isolated rabbit aorta. Amthamine caused an increase in the sinus rate of spontaneously beating guinea-pig atria (pD_2=6.72) and in the contractility of the electrically driven guinea-pig papillary muscle (pD_2=6.17) and of the human atrium (pD_2=5.38). In all these systems, Amthamine behaved as a full agonist with a potency comparable to or slightly higher than that of histamine and 10 times higher than that of dimaprit. The positive effects of Amthamine were competitively antagonized by ranitidine which had pA_2 values (6.46 and 6.25 in the guinea-pig atria and papillary muscle, respectively) comparable with those calculated against histamine and dimaprit. In the isolated rabbit aorta Amthamine was devoid of H_1-mediated activities up to 3×10^−4 M . These results indicate that Amthamine is a potent and selective histamine H_2-receptor agonist which can be considered a valuable tool for investigating H_2-receptor mediated effects in cardiac tissues.
Carlos Davio - One of the best experts on this subject based on the ideXlab platform.
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Involvement of histamine H1 and H2 receptor inverse agonists in receptor's crossregulation.
European Journal of Pharmacology, 2019Co-Authors: Antonela Díaz Nebreda, Federico Monczor, Carlos Davio, Natalia Fernández, Carlos Daniel Zappia, Angela Rodríguez González, Ana Sahores, Máximo H. Sosa, Valeria Burghi, Carina ShayoAbstract:Abstract Histamine [2-(4-Imidazolyl)-ethylamine] modulates different biological processes, through histamine H1 and H2 receptors, and their respective blockers are widely used in treating allergic and gastric acid-related disorders. Histamine H1 and H2 receptor crossdesensitization and cointernalization induced by its agonists have been previously described. In this study, we show how this crosstalk determines the response to histamine H1 and H2 receptor inverse agonists and how histamine H1 and H2 receptor inverse agonists interfere with the other receptor's response to agonists. By desensitization assays we demonstrate that histamine H1 and H2 receptor inverse agonists induce a crossregulation between both receptors. In this sense, the histamine H1 receptor inverse agonists desensitize the cAMP response to Amthamine, a histamine H2 receptor agonist. In turn, histamine H2 receptor inverse agonists interfere with histamine H1 receptor signaling. We also determine that the crossdesensitization induced by histamine H1 or H2 receptor agonists alters the histamine inverse agonists receptor response: activation of histamine H1 receptor affects cAMP response induced by histamine H2 receptor inverse agonists, whereas histamine H2 receptor agonist induces a negative regulation on the anti-inflammatory response of histamine H1 receptor inverse agonists. Binding studies revealed that histamine H1 and H2 receptors cointernalize after stimulus with histamine receptor inverse agonists. In addition, the inhibition of the internalization process prevents receptor crossregulation. Our study provides new insights in the mechanisms of action of histamine H1 and H2 receptors that explain the effect of histamine H1 and H2 receptor inverse agonists and opens up new venues for novel therapeutic applications.
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PI3K pathway is involved in ERK signaling cascade activation by histamine H2R agonist in HEK293T cells.
Biochimica et Biophysica Acta (BBA) - General Subjects, 2016Co-Authors: Natalia Alonso, Antonela Díaz Nebreda, Federico Monczor, J. Silvio Gutkind, Carlos Davio, Natalia Fernández, Carina ShayoAbstract:Abstract Background Histamine, through histamine H2 receptor (H2R), modulates different biological processes, involving the modulation of PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways. Many evidences have demonstrated the existence and importance of the crossregulation between these two signaling pathways. The aim of the present work was to determine the molecular mechanisms leading to PI3K and ERK pathways modulation induced by the H2R agonist Amthamine and to evaluate the possible interplay between them. Methods Phosphorylation levels of ERK and Akt were examined by Western blot in HEK293T cells expressing the human H2R, in the presence of H2R agonist and dominant negative mutants or pharmacological inhibitors of different proteins/pathways. Transcriptional activity assays were assessed to determine SRE activity. Amthamine-mediated cellular proliferation was investigated in MA-10A cells in the presence of PI3K inhibitor. Results H2R agonist inhibits PI3K/Akt/mTOR and stimulates Ras/MEK/ERK pathways. Moreover, PI3K/Akt/mTOR signaling inhibition is necessary to achieve H2R mediated ERK activation. In the presence of a constitutive active mutant of Akt, Amthamine is not able to mediate ERK activation. This crosstalk affects classical ERK downstream targets such as Elk1 phosphorylation and the transcriptional activity of the SRE, classically associated to proliferation. We further demonstrate that Amthamine-induced proliferation in Leydig MA-10 tumor cells, is enhanced by LY294002, a PI3K inhibitor. Conclusions These results describe a crosstalk between PI3K/AKT/mTOR and Ras/MEK/ERK pathways induced by H2R stimulation with implications in cell proliferation. General significance This work indicates that the modulation of PI3K/AKT/mTOR pathway by H2R in turn regulates Ras/MEK/ERK activation conditioning the proliferative capacity of the cells.
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Physiological implications of biased signaling at histamine H2 receptors
Frontiers in Pharmacology, 2015Co-Authors: Natalia Alonso, Federico Monczor, Carlos Davio, Carina Shayo, Carlos Daniel Zappia, Maia Diana Eliana Cabrera, Natalia FernándezAbstract:Histamine mediates numerous functions acting through its four receptor subtypes all belonging to the large family of seven transmembrane G-protein coupled receptors (GPCRs). In particular, histamine H2 receptor (H2R) is mainly involved in gastric acid production, becoming a classic pharmacological target to treat Zollinger-Ellison disease and gastric and duodenal ulcers. H2 ligands rank among the most widely prescribed and over the counter-sold drugs in the world. Recent evidence indicate that some H2R ligands display biased agonism, selecting and triggering some, but not all, of the signaling pathways associated to the H2R. The aim of the present work is to study whether famotidine, clinically widespread used ligand acting at H2R, exerts biased signaling. Our findings indicate that while famotidine acts as inverse agonist diminishing cAMP basal levels, it mimics the effects of histamine and the agonist Amthamine concerning receptor desensitization and internalization. Moreover, the treatment of HEK293T transfected cells with any of the three ligands lead to a concentration dependent pERK increment. Similarly in AGS gastric epithelial cells, famotidine treatment led to both, the reduction in cAMP levels as well as the increment in ERK phosphorylation, suggesting that this behavior could have pharmacological relevant implications. Based on that, histidine decarboxilase expression was studied by quantitative PCR in AGS cells and its levels were increased by famotidine as well as by histamine and Amthamine. In all cases, the positive regulation was impeded by the MEK inhibitor PD98059, indicating that biased signaling towards ERK1/2 pathway is the responsible of such enzyme regulation. These results support that ligand bias is not only a pharmacological curiosity but has physiological and pharmacological implications on cell metabolism.
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multidrug resistance protein 4 mrp4 abcc4 regulates camp cellular levels and controls human leukemia cell proliferation and differentiation
Journal of Biological Chemistry, 2011Co-Authors: Sabrina Copsel, Carina Shayo, Alberto Baldi, Corina I Garcia, Federico Diez, Monica Vermeulem, Liliana G Bianciotti, Frans G M Russel, Carlos DavioAbstract:Increased intracellular cAMP concentration plays a well established role in leukemic cell maturation. We previously reported that U937 cells stimulated by H2 receptor agonists, despite a robust increase in cAMP, fail to mature because of rapid H2 receptor desensitization and phosphodiesterase (PDE) activation. Here we show that intracellular cAMP levels not only in U937 cells but also in other acute myeloid leukemia cell lines are also regulated by multidrug resistance-associated proteins (MRPs), particularly MRP4. U937, HL-60, and KG-1a cells, exposed to Amthamine (H2-receptor agonist), augmented intracellular cAMP concentration with a concomitant increase in the efflux. Extrusion of cAMP was ATP-dependent and probenecid-sensitive, supporting that the transport was MRP-mediated. Cells exposed to Amthamine and the PDE4 inhibitor showed enhanced cAMP extrusion, but this response was inhibited by MRP blockade. Amthamine stimulation, combined with PDE4 and MRP inhibition, induced maximal cell arrest proliferation. Knockdown strategy by shRNA revealed that this process was mediated by MRP4. Furthermore, blockade by probenecid or MRP4 knockdown showed that increased intracellular cAMP levels induce maturation in U937 cells. These findings confirm the key role of intracellular cAMP levels in leukemic cell maturation and provide the first evidence that MRP4 may represent a new potential target for leukemia differentiation therapy.
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Multidrug Resistance Protein 4 (MRP4/ABCC4) Regulates cAMP Cellular Levels and Controls Human Leukemia Cell Proliferation and Differentiation
Journal of Biological Chemistry, 2011Co-Authors: Sabrina Copsel, Carina Shayo, Alberto Baldi, Corina I Garcia, Federico Diez, Monica Vermeulem, Liliana G Bianciotti, Frans G M Russel, Carlos DavioAbstract:Increased intracellular cAMP concentration plays a well established role in leukemic cell maturation. We previously reported that U937 cells stimulated by H2 receptor agonists, despite a robust increase in cAMP, fail to mature because of rapid H2 receptor desensitization and phosphodiesterase (PDE) activation. Here we show that intracellular cAMP levels not only in U937 cells but also in other acute myeloid leukemia cell lines are also regulated by multidrug resistance-associated proteins (MRPs), particularly MRP4. U937, HL-60, and KG-1a cells, exposed to Amthamine (H2-receptor agonist), augmented intracellular cAMP concentration with a concomitant increase in the efflux. Extrusion of cAMP was ATP-dependent and probenecid-sensitive, supporting that the transport was MRP-mediated. Cells exposed to Amthamine and the PDE4 inhibitor showed enhanced cAMP extrusion, but this response was inhibited by MRP blockade. Amthamine stimulation, combined with PDE4 and MRP inhibition, induced maximal cell arrest proliferation. Knockdown strategy by shRNA revealed that this process was mediated by MRP4. Furthermore, blockade by probenecid or MRP4 knockdown showed that increased intracellular cAMP levels induce maturation in U937 cells. These findings confirm the key role of intracellular cAMP levels in leukemic cell maturation and provide the first evidence that MRP4 may represent a new potential target for leukemia differentiation therapy.
