Modulatory effect of imetit, a histamine H-3 receptor agonist, on C-fibers, cholinergic fibers and mast cells in rabbit lungs in vitro

The pharmacological mechanisms involved in the interactions between C-fiber s, cholinergic fibers and mast cells were investigated in tracheally perfus ed rabbit lungs by measuring the simultaneous release of substance P and hi stamine in lung effluents. The amounts of substance P and histamine release d in lung superfusates were measured by radioimmunoassay (RIA) after admini stration of capsaicin and carbachol. Capsaicin (10(-4) M) induced a simulta neous increase in substance P (273 +/- 56% of baseline) and histamine (460 +/- 138%) release. Similarly, carbachol (10-4 M) caused an increase in the release of both substance P (367 +/- 111%) and histamine (1379 +/- 351%). T he effect of capsaicin was prevented by pretreating the lungs with the tach ykinin NK, receptor antagonist SR 140333 (10(-7) M), and atropine (10(-6) M ). SR 140333 prevented the carbachol-induced release of substance P but not of histamine. Exogenous substance P induced an increase in histamine relea se (136 +/- 7%) which was significantly greater in lungs perfused with the neutral endopeptidase inhibitor, thiorphan (10(-5) M) (272 +/- 35%). This e ffect was prevented, by atropine (10(-6) M). Pretreatment of lungs with ime tit (5 x 10(-8) M), a selective H-3 receptor agonist, prevented the capsaic in-induced release of both mediators. Imetit also blocked the carbachol-ind uced release of substance P but not of histamine. Exogenous substance P-evo ked histamine release was inhibited by imetit. Therefore, it can be conclud ed that substance P released through the action of capsaicin can activate c holinergic fibers, leading to cholinoceptor stimulation with subsequent act ivation of C-fibers and mast cells. While the presence of presynaptic H-3 r eceptors modulating substance P-induced acetylcholine release was only surm ised, the existence of modulating histamine H-3 receptors on C-fibers was c onfirmed. (C) 1999 Elsevier Science B.V. All rights reserved.