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 (5 x 10(-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.
Nemmar
A
A
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Liège, Belgium.
Delaunois
A
A
Beckers
J F
JF
Sulon
J
J
Bloden
S
S
Gustin
P
P
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D017442:Histamine Agonists / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D011863:Radioimmunoassay; D018100:Receptors, Histamine H3 / Q000187:drug effects; D013373:Substance P / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
D017442:Histamine Agonists; D007093:Imidazoles; D018100:Receptors, Histamine H3; D013373:Substance P; C077430:imetit; D002217:Carbachol; D013890:Thiourea; D002211:Capsaicin