Aerosolized and intravenously administered leukotrienes: effects on the bronchoconstrictor potency of histamine in the guinea‐pig

Abstract

1 The effects of leukotrienes C4 and D4 (LTC4 and LTD4), administered intravenously or by aerosol, on the bronchoconstrictor potency of intravenously administered histamine have been investigated in anaesthetized, mechanically ventilated guinea-pigs.2 LTC4 (2 nM) had no effect on either the ECv or the maximum contractile response to histamine on the isolated trachea of the guinea-pig. At 10 nM, LTC4 induced a rightward shift in the histamine concentration-response curve without affecting the maximum response.3 LTD4 (0.05-0.20nmolkg,'i.v.) dose-dependently enhanced histamine (9-36nmolkg-', i.v.)-induced increases in airways resistance, whereas equibronchoconstrictor doses of LTC4 (0.1-0.4 nmol kg', i.v.), failed to enhance histamine-induced increases in airways resistance. 4 Aerosols of LTC4 and LTD4 generated from solutions of 1-16 JM and administered for 30s, elicited concentration-dependent bronchoconstrictions comprising decreases in dynamic compliance and increases in airways resistance. At 20 min after exposure to these aerosols, the potency ofhistamine (9-36 nmol kg-, i.v. ) was significantly increased on both airways resistance and dynamic compliance. 5 The potentiation induced by LTC4 (4 JiM, 30 s) was maintained up to 60 min after aerosol exposure whereas that induced by LTD4 (4 gAM, 30 s) was maintained up to 40 min after aerosol exposure but was not significantly different (P >0.05, unpaired Student's t test) to saline-exposed animals at 60 min. 6 LTC4, as has been previously reported for LTD4, does not enhance the histamine-induced contraction ofisolated airways smooth muscle. In contrast to LTD4, intravenously administered LTC4 does not appear to enhance histamine-induced bronchoconstriction. On the other hand, aerosols of either LTC4 or LTD4 potentiate histamine in vivo in a concentration-dependent manner. These data suggest that leukotrienes may contribute to the regulation of airways reactivity to histamine in the guinea-pig.

Lipoxygenase metabolites mediate increased airways resonsiveness to histamine after acute platelet activating factor exposure in the guinea-pig

“…or LTC4 or LTD, (aerosol) enhanced airways responsiveness to histamine (i.v.) [14,15]. The time course of the enhanced airways responsiveness induced by exogenous LT aerosol was of comparable duration to that observed in the present study subsiding over a 40-60 min period.…”

“…LTs per se are implicated as mediators of increased airways responsiveness. LTB4 causes air-ways hyperresponsiveness in the guinea-pig [12] and studies from our laboratory have demonstrated that th e cysteinyl-containing leukotrienes, LTC, and LTD4, cause increased airways responsiveness to histamine in the guinea-pig in vivo by augmenting a cholinergic vagal afferent reflex mechanism [13][14][15]. The objective of the present study was to determine whether the release of arachidonic acid metabolites, particularly the LTs, mediate an altered airways sensitivity to histamine after acute exposure of guinea-pigs to Paf in vivo.…”

Active sensitization of guinea-pig airways in vivo enhances in vivo and in vitro responsiveness

“…Indeed, following allergen challenge of sensitized subjects, the airways become hyperresponsive to histamine, methacholine, cold air and exercise, a state which may last for many weeks after a single allergen exposure [4]. The mechanisms iiwolved in the disordered airway physiology associated with hyperresponsiveness are diverse and involve the participation of inflammatory leucocytes with release of potent pro-inflammatory chemical mediators [1, [5][6][7]. In particular, eosinophilia is a marked feature of the human airways response to antigen challenge [8,9).…”

Effects of REV 5901, a 5‐lipoxygenase inhibitor and leukotriene antagonist, on pulmonary responses to platelet activating factor in the guinea‐pig

“…Exogenous LTD4 increased airways responsiveness to histamine in the guinea-pig (Stewart et al, 1984;Fennessy et al, 1986) whereas in healthy humans LTD4 augmented airways responses to methacholine (Kern et al, 1986) and prostaglandin F2. (Barnes et al, 1984a) but not to histamine (Barnes et al, 1984b).…”