Differentiation of the mechanisms by which leukotrienes C 4 and D 4 elicit contraction of the guinea pig trachea

Abstract

The contraction elicited by leukotriene (LT) C 4 and D 4 on isolated guinea pig trachea were characterized under conditions in which LTC 4 to LTD 4 metabolism was blocked by presence of 45 mM ℓ-serine-borate complex (SB). The presence of Sb caused a shift of the LTC 4-concentration-response curve to the left by 7.5-fold, and blocked the bioconversion of LTC 4 to LTD 4 by the trachea as estimated by HPLC analysis of the LTs present in the tissue bath fluid. The potency of FPL 55712 as an antagonist of the LTC 4-induced contractions in the presence of SB was 15-30-fold less than its potency as an antagonist of the LTD 4-induced contractions. In contrast, another LT antagonist, Sk&F 101132, equally antagonized the contractions elicited by LTC 4 and LTD 4 in either the presence or absence of SB. The differential antagonism of LTC 4 and LTD 4 implies the existence of multiple pharmacologic receptors for the LTs. The calcium channel entry blockers, nifedipine and verapamil, at concentrations as high as 10 μM, suppressed the maximal LTC 4-induced contraction by no more than 20%. whereas the purported intracellular calcium antagonist, TMB-8, completely suppressed the LTC 4 concentration-response curve in the presence of SB, a profile identical to that previously reported for LTD 4. Thus, if multiple LT receptors exist, they appear to mobilize calcium in a qualitatively similar fashion following LT stimulation.