Modulatory effect of imetit, a histamine H₃ receptor agonist, on C-fibers, cholinergic fibers and mast cells in rabbit lungs in vitro

The pharmacological mechanisms involved in the interactions between C-fibers, cholinergic fibers and mast cells were investigated in tracheally perfused rabbit lungs by measuring the simultaneous release of substance P and histamine in lung effluents. The amounts of substance P and histamine released in lung superfusates were measured by radioimmunoassay (RIA) after administration of capsaicin and carbachol. Capsaicin (10^-4 M) induced a simultaneous 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%). The effect of capsaicin was prevented by pretreating the lungs with the tachykinin NK₁ 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 release (136±7%) which was significantly greater in lungs perfused with the neutral endopeptidase inhibitor, thiorphan (10^-5 M) (272±35%). This effect was prevented by atropine (10^-6 M). Pretreatment of lungs with imetit (5x10^-8 M), a selective H₃ receptor agonist, prevented the capsaicin-induced release of both mediators. Imetit also blocked the carbachol-induced release of substance P but not of histamine. Exogenous substance P-evoked histamine release was inhibited by imetit. Therefore, it can be concluded that substance P released through the action of capsaicin can activate cholinergic fibers, leading to cholinoceptor stimulation with subsequent activation of C-fibers and mast cells. While the presence of presynaptic H₃ receptors modulating substance P-induced acetylcholine release was only surmised, the existence of modulating histamine H₃ receptors on C-fibers was confirmed. Copyright (C) 1999 Elsevier Science B.V.