MODULATION OF ACETYLCHOLINE, CAPSAICIN AND SUBSTANCE-P EFFECTS BY HISTAMINE H-3 RECEPTORS IN ISOLATED-PERFUSED RABBIT LUNGS

The modulatory role of histamine H-3 receptors in pulmonary oedema ind uced by acetylcholine, capsaicin and by exogenous substance P was inve stigated in isolated, ventilated rabbit lungs. Endothelial permeabilit y 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) in duced an increase in the Kf,c. Carboperamide, a novel histamine H-3 re ceptor antagonist, induced a significant leftward shift of the concent ration-response curve to acetylcholine and also enhanced the effect of capsaicin on the Kf,c, while it had no significant effect on the resp onse to substance P and 5-HT. Imetit, a new histamine H-3 receptor ago nist, strongly inhibited the effects of acetylcholine and capsaicin. I metit 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 acetylcholin e response. (R)-alpha-Methylhistamine, an other histamine H-3 receptor agonist, had the same protective effect against acetylcholine respons e as Imetit. We conclude that histamine H-3 receptors could protect th e lung against acetylcholine- and capsaicin-induced oedema via a preju nctional modulatory effect on the C-fibres. However, since the respons e to exogenous substance P was also inhibited by histamine H-3 recepto r stimulation, the presence of such receptors at a postsynaptic level, probably on mast cells, was also suggested.