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

Abstract

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. LTC4 (2 nM) had no effect on either the EC50 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. LTD4 (0.05-0.20 nmol kg-1, i.v.) dose-dependently enhanced histamine (9-36 nmol kg-1, i.v.)-induced increases in airways resistance, whereas equibronchoconstrictor doses of LTC4 (0.1-0.4 nmol kg-1, i.v.), failed to enhance histamine-induced increases in airways resistance. Aerosols of LTC4 and LTD4 generated from solutions of 1-16 microM and administered for 30 s, elicited concentration-dependent bronchoconstrictions comprising decreases in dynamic compliance and increases in airways resistance. At 20 min after exposure to these aerosols, the potency of histamine (9-36 nmol kg-1, i.v.) was significantly increased on both airways resistance and dynamic compliance. The potentiation induced by LTC4 (4 microM, 30 s) was maintained up to 60 min after aerosol exposure whereas that induced by LTD4 (4 microM, 30 s) was maintained up to 40 min after aerosol exposure but was not significantly different (P greater than 0.05, unpaired Student's t test) to saline-exposed animals at 60 min. LTC4 as has been previously reported for LTD4, does not enhance the histamine-induced contraction of isolated 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.