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Hendrik Timmerman – One of the best experts on this subject based on the ideXlab platform.

  • Cardiovascular effects of the novel histamine H2 receptor agonist Amthamine: interaction with the adrenergic system.
    Naunyn-Schmiedeberg's archives of pharmacology, 1996
    Co-Authors: Gabriella Coruzzi, Giulio Bertaccini, E. Gambarelli, Hendrik Timmerman

    Abstract:

    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, 1994
    Co-Authors: Henk Van Der Goot, J C Eriks, Rob Leurs, Hendrik Timmerman

    Abstract:

    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, 1994
    Co-Authors: Rob Leurs, Martine J. Smit, Wiro M.b.p. Menge, Hendrik Timmerman

    Abstract:

    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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Giulio Bertaccini – One of the best experts on this subject based on the ideXlab platform.

  • Effects of histamine H2 receptor agonists and antagonists on the isolated guinea pig gallbladder.
    Fundamental & Clinical Pharmacology, 1999
    Co-Authors: Gabriella Coruzzi, Enzo Poli, Cristina Pozzoli, Gabriella Coppelli, Giulio Bertaccini

    Abstract:

    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, 1998
    Co-Authors: Gabriella Coruzzi, Giulio Bertaccini, Enzo Poli, Cristina Pozzoli, Henk Timmerman

    Abstract:

    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, 1996
    Co-Authors: Gabriella Coruzzi, Giulio Bertaccini, E. Gambarelli, Hendrik Timmerman

    Abstract:

    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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Gabriella Coruzzi – One of the best experts on this subject based on the ideXlab platform.

  • Pharmacological characterization of the new histamine H4 receptor agonist VUF 8430.
    British Journal of Pharmacology, 2009
    Co-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 Leurs

    Abstract:

    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, 1999
    Co-Authors: Gabriella Coruzzi, Enzo Poli, Cristina Pozzoli, Gabriella Coppelli, Giulio Bertaccini

    Abstract:

    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, 1998
    Co-Authors: Gabriella Coruzzi, Giulio Bertaccini, Enzo Poli, Cristina Pozzoli, Henk Timmerman

    Abstract:

    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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