Tissue distribution and functional correlation of [³H]leukotriene C₄ and [³H]leukotriene D₄ binding sites in guinea-pig uterus and lung preparations

To determine the distribution of leukotriene (LT) C₄ and LTD₄ receptors and functional significance of each receptor, we used [³H]LTC₄ and [³H]LTD₄ to measure the binding activity in various tissue homogenates and to correlate the relative ability of the LT agonists to inhibit binding and their contractile responses in guinea-pig uterine or lung parencymal preparations. Guinea-pig brain contained the highest binding activity of 1 to 2 nM [³H]LTC₄ followed by small intestine, heart, lung, kidney, uterus, etc., whereas guinea-pig lung had at least 2.7-fold greater [³H]LTD₄ binding activity than any other tissues tested. In the brain and uterine homogenates, the rank order of potency for the compounds in competing with [³H]LTC₄ for binding sites was LTC₄ >> LTD₄ > LTE₄ > FPL-55712 = arachidonic acid. The in vitro functional study showed that the ability of the LT agonists to produce uterine contraction was in the order of LTC₄ > LTD₄ > LTE₄, which is compatible with their relative effect for inhibition of uterine or brain [³H]LTC₄ binding. In the lung homogenate, either LTC₄, LTD₄ or LTE₄ inhibited effectively [³H]LTD₄ binding and the potency order for the [³H]LTD₄ competition study was LTD₄ > LTE₄ > LTC₄ >> FPL-55712 > arachidonic acid. These LT agonists also produced lung contraction effectively and the difference among their contractile ability was not significant. We conclude that 1) there are distinct functional LTC₄ and LTD₄ receptors, 2) activation of the LTC₄ receptor could account for the uterine contraction due to the LT agonists and 3) the lung contraction induced by LTC₄, LTD₄ and LTE₄ is at least mediated partly by the LTD₄ receptor.