FUNCTIONAL SUBTYPING OF HISTAMINE-RECEPTORS ON THE CANINE PROXIMAL COLONIC MUCOSA

The receptors involved in the neural and non-neural effects of histami ne on the canine proximal colon in vitro were defined functionally by using selective agonists and antagonists. Two preparations, a ganglion ated mucosa and an aganglionated epithelium, were set up in Ussing cha mbers and short-circuit currents were monitored. The mucosa was obtain ed by removing the circular and longitudinal muscles, but keeping inta ct the muscularis mucosa and attendant submucosal plexuses, whereas th e epithelium was devoid of that layer as well. On the mucosal preparat ion, histamine, 2-methylhistamine (2-MH) and 2-pyridylethylamine (PEA) , a histamine (H)(1)-selective agonist elicited responses which were i nhibited by pretreatment with tetrodotoxin and H-1 antagonists (mepyra mine). Responses to dimaprit (H-2 agonist) were seen only at high conc entrations and these were unaffected by tetrodotoxin; no responses wer e noted with any of the other agonists tested. By contrast, responses on the epithelial preparation were seen with histamine as well as H-1 (PEA and 2-MH), H-2 (dimaprit, impromidine and 4-MH) and H-3-selective agonists [R(-)-alpha-MH]. Responses to PEA were inhibited selectively by mepyramine (H-1 antagonist), whereas those elicited by H-2 agonist s were antagonized only by ranitidine (H-2 antagonist). Both mepyramin e and ranitidine significantly reduced the epithelial responses of 2-M H. Responses to [R(-)-alpha-MH] (H-3 agonist) were seen only at high c oncentrations and were inhibited by ranitidine, but not by thioperamid e (H-3 antagonist). The effects of histamine were unaffected by pretre atment with indomethacin. Thus, neural effects are mediated by the occ upation of H-1 receptors (presumably on the submucosal neurons), where as the non-neural (direct) effects result from the occupation of eithe r H-1 or H-2 receptors. H-3 receptors are functionally absent. Flux ex periments showed that histamine, dimaprit and PEA produced marked incr eases in short circuit current that were accompanied by significant in creases in J(sm)(Cl) leading to decreases in J(net)(Cl). Dimaprit stim ulated an increase in J(net)(Na), largely as a result of increases in J(ms)(Na). A negative residual flux (J(res)) was seen with all three a gonists. Thus, neural effects involve H-1 receptors; non-neural effect s involve both H-1 and H-2 receptors. Cl- secretion results from occup ation of either receptor subset. Only the selective H-2-agonist, dimap rit, produced significant changes in J(net)(Na). H-3 receptors are fun ctionally absent.