Mechanisms of leukotriene D4‐induced constriction in human small bronchioles

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Abstract
We examined the mechanisms underlying leukotriene D4‐ (LTD4) induced constriction of human small (300 – 500 μm i.d.) bronchioles, and the effect of LTD4 on ion currents and Ca2+ transients in smooth muscle cells (SMC) isolated from these bronchioles. LTD4 caused a concentration‐dependent bronchoconstriction with an EC50=0.58±0.05 nM (n=7) which was not easily reversible upon washout. This bronchoconstriction was entirely dependent on extracellular Ca2+. Blockade of L‐type Ca2+ channels with nifedipine (10 μM) reduced LTD4 response by 39±2% (n=8), whilst La3+, Gd3+ and SK&F 96,365 abolished LTD4‐induced bronchoconstriction completely and reversibly, suggesting the majority of Ca2+ entry was via non‐selective cation channels. Antagonists of PI‐PLC (U73,122 and ET‐18‐OCH3), PLD (propranolol) and PKC (cheleretrine and Ro31‐8220) were without any effect on LTD4‐induced bronchoconstriction, whilst the PC‐PLC inhibitor D609 caused complete relaxation. Inhibition of protein tyrosine kinase with tyrphostin A23 (100 μM) caused about 50% relaxation, although the inactive analogue tyrphostin A1 was without effect. In freshly isolated SMC from human small bronchioles LTD4 caused a slow increase of intracellular Ca2+ concentration, with a consequent rise of the activity of large conductance Ca2+‐dependent K+ channels and the amplitude of depolarization‐induced outward whole‐cell current. Again, no effect of LTD4 could be observed in the absence of extracellular Ca2+. We conclude that LTD4 causes constriction of these small bronchioles primarily by activating Ca2+ entry via non‐voltage gated channels, possibly by a PC‐PLC mediated pathway. British Journal of Pharmacology (2001) 133, 243–252; doi:10.1038/sj.bjp.0704076

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