Comparative study of the pulmonary effects of intravenous leukotrienes and other bronchoconstrictors in anaesthetized guinea pig

Abstract

Pulmonary responses to intravenous leukotrienes C 4, D 4 and E 4 administered as a bolus injection and by continuous infusion were studied in anesthetized guinea pigs. LTD 4, LTC 4 and LTE 4 (respective ED 50 of 0.21 ± .1, 0.64 ± .2 and 2.0 ± .1 μg kg −1) produced dose-dependent increases in insufflation pressure when given as a bolus injection to anesthetized guinea pigs (Konzett-Rössler). Bronchoconstriction was antagonized by FPL-55712 (50–200 μg kg −1), and indomethacin (50–200 μg kg −1) but was not significantly altered by mepyramine (1.0 mg kg −1), methysergide (0.1 mg kg −1), intal (10 mg kg −1) mepacrine (5 mg kg −1) or dexamethasone (10 mg kg −1). The beta adrenoceptor blocker, timolol (5 μg kg −1) produced a significantly greater potentiation of the responses to the leukotrienes than to arachidonic acid, histamine and acetylcholine. Responses to bolus injection of LTE 4 but not LTD 4 or LTC 4 were partially antagonized by atropine (100 μg kg −1) and bilateral vagotomy. In experiments of a different design, continuous infusion of LTD 4 and LTE 4 (2.8–3.2 μg kg −1 min −1) into indomethacin-treated animals produced slowly developing increases in pulmonary resistance and decreases in compliance. The increase in resistance produced by LTE 4 and LTD 4 was partly reversed by intravenous FPL-55712 (1.0 mg kg −1) and atropine (100 μg kg −1) but was almost completely reversed by FPL-55712 (3 – 10 mg kg −1). These findings indicate that leukotrienes can produce bronchoconstriction in guinea pigs through cyclooxygenase-dependent and cyclooxygenase independent mechanisms both of which are blocked by FPL-55712. Cholinergic mechanisms are involved in the mediation of part of the response to bolus injection of LTE 4 as well as a small part of the initial response to continuous infusion of LTD 4 and LTE 4. Intrinsic beta adrenoceptor activation serves to down modulate responses to the leukotrienes to a greater extent than responses to arachidonic acid, histamine and acetylcholine.