Effect of calcium antagonists on leukotriene D4-induced contractions of the guinea-pig trachea and lung parenchyma

BM Weichman, RM Muccitelli, SS Tucker and MA Wasserman

The directly mediated contractile activity of leukotriene (LT) D4 on isolated guinea-pig trachea and lung parenchyma was dependent upon the presence of calcium in the bathing buffer. Whereas 8-(N,N-diethylamino)- octyl-3,4,5-trimethoxybenzoate (TMB-8), a calcium antagonist believed to act intracellularly, completely antagonized the LTD4-induced contraction, the calcium channel entry blockers, nifedipine and verapamil, only partially inhibited LTD4 contractile activity; diltiazem was inactive. TMB-8, nifedipine and verapamil were more effective in blocking the contraction of the trachea elicited by KCl- induced membrane depolarization than the contraction induced by LTD4. Of the channel entry blockers, only nifedipine appeared capable of partially relaxing an established LTD4-contracted trachea, whereas TMB- 8 almost completely reversed the LTD4 contraction. On the lung parenchyma, the LTD4-induced contraction was suppressed, but not abolished in Ca++-free buffer; this contraction was antagonized by meclofenamic acid, thus suggesting it could be due in part to the indirect thromboxane (Tx) A2-mediated pathway of LT action. In Ca++- free buffer, LTD4 was still capable of generating TxB2, although lower amounts were found when compared to Ca++-containing buffer. Incremental addition of calcium to the parenchyma in Ca++-free buffer containing LTD4 elicited greater than control LTD4-induced contraction and TxB2 generation. Neither the contraction of the parenchyma nor the generation of TxB2 was antagonized by nifedipine; conversely, TMB-8 blocked both completely. Thus, based upon the use of pharmacological antagonists of calcium, these results suggest that LTD4 contractile activity in the respiratory system is dependent upon calcium, with calcium of intracellular origin potentially of significance.

Volume 225, Issue 2, pp. 310-315, 05/01/1983
Copyright © 1983 by American Society for Pharmacology and Experimental Therapeutics

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