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Effect of histamine H4 receptor ligands on cholinergic neurotransmission of the rat duodenum
No full textThe recently cloned histamine H4 receptor (H4R) was found to play a role in inflammatory and immune responses. Recently, immunohistochemical data have provided evidence that the H4R is also expressed in myenteric neurons of the rodent gastrointestinal tract, suggesting a role for this receptor in the regulation of intestinal peristalsis (1). In the present study we examined whether H4Rs have a role in the regulation of intestinal neurotransmission, by testing selective H4R ligands in the isolated rat duodenum.
Twitch responses of longitudinal muscle strips to electrical field stimulation were abolished by atropine (1 μM) and partially reduced by hexamethonium (10 μM), suggesting that pre- and postganglionic cholinergic neurons were activated. Under these experimental conditions, the H4R agonist VUF8430 (2) and histamine, in the presence of H1-, H2- and H3-receptor blockade, did not change electrically-evoked contractions. Similarly ineffective were the selective H4R antagonists VUF10148 and VUF10214 (3), when tested at 10 nM and 100 nM. At higher concentrations (1-10 μM), these compounds evoked a dose-dependent inhibition of electrically evoked contractions, which, however, was mimicked by VUF10181, a chemically related analog, endowed with a 1000-fold lower affinity at H4R (3).
In conclusion, functional experiments on isolated rat duodenum did not unravel any role of H4Rs in
the control of intestinal neurotransmission.
(1) Chazot, PL et al. XXXVI EHRS Meeting, Florence, May 9-12th 2007, p.27
(2) Lim, HD et al J Med Chem 2006;49:6650-6651
(3) Coruzzi, G et al. XXXVI EHRS Meeting, Florence, May 9-12th 2007, p.10
Effect of histamine and related compounds on gastric emptying of the conscious rat.
No full textIn conscious rats, histamine given intraperitoneally produced a delay in gastric emptying. A dose-dependent relationship was observed. The threshold dose was about 1 mg/kg, the calculated maximum dose 35 mg/kg. The inhibitory effect of histamine on gastric emptying was abolished by pretreatment with H1-receptor antagonists and mimicked by 2-aminoethylthiazole; on the contrary, an H2-receptor agonist (dimaprit) and H2 antagonists were completely ineffective. This suggested that receptors involved in delay of gastric emptying are of the H1 type. The inhibitory effect of histamine on gastric emptying was not modified by pretreatment with the well-known inhibitors of gastric secretion, metiamide and cimetidine. This is consistent with the idea that the delay in gastric emptying observed with histamine may not be related to the gastric properties of this compound
Role of histamine H(3) receptors in the control of gastrointestinal motility. An overview.
No full textOver the last few years, the biochemical and functional characterization of H3 receptors has been a matter for extensive investigation, culminating in the cloning of the human, guinea pig and rat receptor protein from brain tissues. This discovery contributed to determine the distribution of receptors in the body and to define the molecular mechanisms which follow activation. The major breakthrough in the histamine H3 receptor field came with the synthesis of selective and potent agonists and antagonists, which unravelled the function of this receptor subtype in the different tissues. As expected from the ubiquitous location of histamine in the body, histamine H3 receptors have also been identified in virtually every tissue, although they are quantitatively less abundant than H1 and H2 receptors. Concerning the gastrointestinal tract, this new receptor subtype seems to have multiple cellular locations, which include neurons, enteric ganglia, paracrine and immune cells and, in some tissues, also smooth muscle cells. Therefore it might be regarded as a general regulatory system of different digestive functions, including motility. The effects mediated by histamine H3-receptors mainly reflect the presynaptic inhibition of the release of either excitatory or inhibitory neurotransmitters from the myenteric plexus. The molecular mechanism of presynaptic inhibition seems to involve a restriction of calcium entry into the nerve endings, but other mechanisms (reduction of cAMP), possibly associated to different H3 receptor subtypes, may be involved. Despite the widespread distribution and the well defined inhibitory effects evoked in the majority of in vitro models of intestinal motility, no clear cut evidence of its involvement in the control of peristalsis could be provided. In vivo models of gastrointestinal transit, indeed, did not reveal a defined effect of histamine H3 receptor ligands, even though the possibility of a central inhibition was pointed out in several studies. Therefore, it is not clear at the present what is the physiological meaning of the histamine H3 receptor in the control of gastrointestinal motility and whether it could represent a potential target for novel therapeutic interventions in deranged motility, taking into account that human gastrointestinal tissues are apparently devoid of this receptor
Effects of alkyl analogues of histamine and metiamide on the isolated guinea pig heart.
No full textThe effects of some substitutions in position 5(4) of the imidazole ring in the histamine and metiamide molecule were studied by means of isolated heart preparations from the guinea pig (atria and papillary muscle). Among the histamine analogues 5-methyl and 5-ethyl histamine were found to possess approximately the same intrinsic activity as histamine whereas 5-isopropylhistamine was shown to be absolutely inactive. Among the metiamide analogues the 5-ethyl derivative (etiamide) was found less effective than the parent substance but showed the same kind of competitive antagonism; the isopropyl derivative (isopropiamide) was found to be inactive up to a concentration of 3 X 10(-5) mol/l and to exert a non-competitive antagonism with 3 X 10(-4) mol/l. On the whole the atria and the papillary muscle preparations behaved quite similarly in regard to both the agonistic and the antagonistic compound
Role of K+ in the histamine H3 receptor- and adenosine A1 receptor-mediated effects on the isolated guinea pig duodenum
No full textGastric antisecretory effects of compound BP 2-94, a prodrug of the histamine H3 receptor agonist (R)α-methylhistamine
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Novel non-steroidal anti-inflammatory drugs: what we have learned from animal studies
No full textThe use of non-steroidal anti-inflammatory drugs (NSAIDs) is frequently associated with serious adverse effects related to the inhibition of cyclooxygenase (COX) in tissues where prostanoids exert physiological effects, such as gastric mucosal defence, renal homeostasis and platelet aggregation. The discovery of a second COX isoform (COX-2) specifically induced in pathological tissues led to the development of selective COX-2 inhibitors, believed to have an improved safety profile compared to traditional NSAIDs. Animal studies, however, have revealed a protective role for the COX-2 enzyme in the stomach, kidney, heart, vasculature and reproductive system, and therefore, the safety of COX-2 selective inhibitors needs to be reassessed. On the other hand, new therapeutic indications have emerged as a result of the role played by COX-2 overexpression in cancer or Alzheimer's disease. A second approach aimed at obtaining safer NSAIDs is based on the gastroprotective effects of nitric oxide (NO). Traditional NSAIDs chemically linked to NO-releasing moieties retain the therapeutic efficacy, but not the adverse effects, of the parent NSAIDs. Moreover, additional therapeutic applications in cardiovascular diseases, Alzheimer's disease and cancer have been suggested. Animal data, however, need to be confirmed in large clinical trials. Finally, the increase in endogenous NO via a selective increase in inducible NO synthase in the gastric mucosa is the mechanism underlying the good gastric tolerability and the gastroprotective effects of the non-selective NSAID amtolmetin guacyl, documented to date in the ra
Role of K+ in the histamine H3 receptor- and adenosine A1 receptor-mediated effects in the guinea-pig isolated duodenum.
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