We tested drugs acting at histamine H-3 receptors in mice on the gastrointestinal transit of a charcoal meal in vivo and on neurogenic contractions of isolated ileal preparations. The agonist (R)-alpha-methylhistamine (100 mumol/kg) caused a maximum 25% reduction of gastrointestinal transit, an effect mimicked by immepip (100 mumol/kg) and antagonized by thioperamide (20 mumol/kg) or clobenpropit (20 mumol/kg). In the isolated ileum, (R)-alpha-methylhistamine (10-100 muM) caused a slight, thioperamide-insensitive, reduction (maximum 15%) of electrically evoked cholinergic contractions. In comparison, the alpha(2)-adrenoceptor agonist clonidine (0.1 mumol/kg) caused a 35.2% inhibition of the gastrointestinal transit and almost completely reduced (maximum 82% at 1 muM) the cholinergic contraction of the isolated ileum, both effects being antagonized by idazoxan (0.4 mumol/kg and 1 muM, respectively). These results suggest that histamine H-3 receptors, located outside the myenteric plexus, mediate an inhibition of the gastrointestinal transit in vivo. Conversely, the presence of alpha(2)-adrenoceptors in the cholinergic nerve endings and their inhibitory role in the control of gastrointestinal propulsion is confirmed.
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