Functional subtyping of histamine receptors on the canine proximal colonic mucosa.
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The receptors involved in the neural and non-neural effects of histamine on the canine proximal colon in vitro were defined functionally by using selective agonists and antagonists. Two preparations, a ganglionated mucosa and an aganglionated epithelium, were set up in Ussing chambers and short-circuit currents were monitored. The mucosa was obtained by removing the circular and longitudinal muscles, but keeping intact the muscularis mucosa and attendant submucosal plexuses, whereas the epithelium was devoid of that layer as well. On the mucosal preparation, histamine, 2-methylhistamine (2-MH) and 2-pyridylethylamine (PEA), a histamine (H)1-selective agonist elicited responses which were inhibited by pretreatment with tetrodotoxin and H1 antagonists (mepyramine). Responses to dimaprit (H2 agonist) were seen only at high concentrations and these were unaffected by tetrodotoxin; no responses were noted with any of the other agonists tested. By contrast, responses on the epithelial preparation were seen with histamine as well as H1 (PEA and 2-MH), H2 (dimaprit, impromidine and 4-MH) and H3-selective agonists [R(-)-alpha-MH]. Responses to PEA were inhibited selectively by mepyramine (H1 antagonist), whereas those elicited by H2 agonists were antagonized only by ranitidine (H2 antagonist). Both mepyramine and ranitidine significantly reduced the epithelial responses of 2-MH. Responses to [R(-)-alpha-MH] (H3 agonist) were seen only at high concentrations and were inhibited by ranitidine, but not by thioperamide (H3 antagonist). The effects of histamine were unaffected by pretreatment with indomethacin. Thus, neural effects are mediated by the occupation of H1 receptors (presumably on the submucosal neurons), whereas the non-neural (direct) effects result from the occupation of either H1 or H2 receptors. H3 receptors are functionally absent. Flux experiments showed that histamine, dimaprit and PEA produced marked increases in short circuit current that were accompanied by significant increases in JsmCl leading to decreases in JnetCl. Dimaprit stimulated an increase in JnetNa, largely as a result of increases in JmsNa. A negative residual flux (Jres) was seen with all three agonists. Thus, neural effects involve H1 receptors; non-neural effects involve both H1 and H2 receptors. Cl- secretion results from occupation of either receptor subset. Only the selective H2-agonist, dimaprit, produced significant changes in JnetNa. H3 receptors are functionally absent.
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