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This Article Full Text Full Text (PDF) All Versions of this Article: 583/2/731    most recent jphysiol.2007.139352v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Breunig, E. Articles by Schemann, M. Search for Related Content PubMed PubMed Citation Articles by Breunig, E. Articles by Schemann, M. Related Collections Alimentary

¹ Department of Human Biology, Technische Universität München, Freising
² Department of Surgery, Clinical Centre Freising, Freising
³ Department of Pathology, Technische Universität München, Munich

Histamine is a major mast cell mediator of immunoneural signalling in the gut and mast cells play a role in the pathophysiology of functional and inflammatory bowel diseases. Histamine receptors are therefore promising drug targets to treat gut disorders. We aimed to study the so far unknown effect of histamine on neural activity in the human enteric nervous system (ENS) and to identify the pharmacology of histamine response. We used fast imaging techniques in combination with the potentiometric dye di-8-ANEPPS to monitor directly membrane potential changes and thereby neuronal excitability in the human submucous plexus from surgical specimens of 110 patients (2137 neurones, 273 ganglia). Local microejection of histamine resulted in action potential discharge in 37% of neurones. This excitatory effect was mimicked by the H₁ agonist HTMT-dimaleat, H₂ agonist dimaprit, H₃ agonist (R)-(–)--methylhistamine and H₄ agonist 4-methylhistamine. The excitatory actions of the agonists were specifically and selectively blocked by the H₁, H₂, H₃ or H₄ receptor antagonists pyrilamine, ranitidine, clobenpropit or J1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ 7777120), respectively. Clobenproprit reduced the excitatory response to histamine. Unlike in the guinea-pig ENS (R)-(–)--methylhistamine had no presynaptic actions in human submucous plexus. Application of agonists revealed receptor clustering which was as follows: 29% H₁/H₃, 27% H₂, 20% H₁/H₂/H₃, 10% H₃, 7% H₁/H₂ and 7% H₂/H₃. Histamine excites human enteric neurones and this effect involves all four histamine receptors; most striking was the identification of an excitatory H₃ mediated component and the discovery of H₄ mediated neuronal excitation. These data may form the basis of identification of new targets to treat inflammatory and functional gut disorders.

(Received 22 June 2007; accepted after revision 11 July 2007; first published online 12 July 2007)
Corresponding author M. Schemann: Human Biology, TU München, Hochfeldweg 2, D-85350 Freising-Weihenstephan, Germany. Email: schemann{at}wzw.tum.de

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