Diphenhydramine blocks the leukotriene-C4 enhanced mucus secretion in canine trachea in vivo

Leukotrienes (C4, D4) have been shown to enhance mucus secretion in both isolated human airway tissue and intact canine trachea in vivo. They also have been implicated as putative mediators in several airways diseases. In previous canine studies the mucus enhancing effect of leukotriene-C4 was blocked by atropine, FLP 55,712, and hexamethonium but not by cutting the superior laryngeal and vagus nerves. We anesthetized mongrel dogs with chloralose (100 mg/kg) and urethane (500 mg/kg) and ventilated them on a pump. To visualize the secretions from submucosal glands, we exposed the mucosa of the upper trachea and coated its surface with powdered tantalum. Secretions from the glands formed elevation in the tantalum layer (hillocks) with time: the number of tracheal hillocks (an index of mucus secretion) was measured at one or more of the four time points on six dogs after each treatment of the treatment sequence: no LTC4, LTC4, no LTC4 + blocker, and LTC4 + blocker. The potential blocker was diphenhydramine, an H1 antagonist for histamine. LTC4 was injected into the cranial thyroid artery which directly feeds the tracheal segment. We observed hillocks through a dissecting microscope, and the number of hillocks per 1.2 cm2 were counted for a 1-4 min interval. In 6 dogs with 12 responses, LTC4 (10 micrograms) gave a positive response that was significantly different from control (p less than 0.01-0.05) at 2-4 min. Diphenhydramine (n = 6), 0.5 mg/kg, a dose which blocked a histamine challenge without blocking an acetylcholine challenge of secretion, gave a statistically significant (p less than 0.01-0.05) reduction in mucus secretion at 1-4 min. These results support the conclusion that leukotriene C4 induces mucus secretion in dogs that is blocked by prior diphenhydramine administration. This would indicate histamine has a role, but as yet an unknown mechanism in the action of leukotriene-C4 in enhancing mucus.