Modulation of acetylcholine, capsaicin and substance P effects by histamine H3 receptors in isolated perfused rabbit lungs.
The modulatory role of histamine H3 receptors in pulmonary oedema induced by acetylcholine, capsaicin and by exogenous substance P was investigated in isolated, ventilated rabbit lungs. Endothelial permeability was evaluated by measuring the capillary filtration coefficient (Kf,c). Acetylcholine (10(-8) to 10(-4) M), substance P (10(-10) to 10(-6) M), capsaicin (10(-4) M) and 5-hydroxytryptamine (5-HT) (10(-4) M) induced an increase in the Kf,c. Carboperamide, a novel histamine H3 receptor antagonist, induced a significant leftward shift of the concentration-response curve to acetylcholine and also enhanced the effect of capsaicin on the Kf,c, while it had no significant effect on the response to substance P and 5-HT. Imetit, a new histamine H3 receptor agonist, strongly inhibited the effects of acetylcholine and capsaicin. Imetit also strongly protected the lung against substance P effects but did not prevent the 5-HT-induced increase in the Kf,c. Carboperamide completely blocked the inhibitory effect of Imetit on the acetylcholine response. (R)-alpha-Methylhistamine, an other histamine H3 receptor agonist, had the same protective effect against acetylcholine response as Imetit. We conclude that histamine H3 receptors could protect the lung against acetylcholine- and capsaicin-induced oedema via a prejunctional modulatory effect on the C-fibres. However, since the response to exogenous substance P was also inhibited by histamine H3 receptor stimulation, the presence of such receptors at a postsynaptic level, probably on mast cells, was also suggested.
D000109:Acetylcholine / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000378:metabolism; D011817:Rabbits; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism / Q000633:toxicity; D013373:Substance P / Q000378:metabolism / Q000633:toxicity*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D010880:Piperidines; D018100:Receptors, Histamine H3; C096970:carboperamide; D012701:Serotonin; D013373:Substance P; C077430:imetit; D013890:Thiourea; D000109:Acetylcholine; D002211:Capsaicin