Receptor antagonism of leukotriene B4 myotropic activity by the 2,6 disubstituted pyridine analog U-75302: characterization on lung parenchyma strips.

Leukotriene B4 constricts guinea pig lung parenchyma strips in a concentration-dependent manner. The LTB4 structural analog U-75302, 6-(6-[3-hydroxy-1E,5 Z-undecadienyl]-2-pyridinyl)-1,5-hexanediol, was a partial agonist in this system with a potency 300-1000 times less than LTB4. U-75302 constricted lung parenchyma strips only at concentrations greater than 0.3 microM. At concentrations lacking agonist activity U-75302 was an effective antagonist, displacing the LTB4 dose-response curve. Half-maximal responses required 0.10 microM LTB4 in the presence of 0.3 microM U-75302 and 0.01-0.02 microM LTB4 in its absence. The maximal force of contraction was unaffected at this concentration. Concurrent with antagonism of the myotropic response, U-75302 inhibited the LTB4-dependent release of thromboxane B2 from lung parenchyma. This effect was attributable to receptor antagonism, not enzymatic inhibition of phospholipase, cyclooxygenase, or thromboxane synthase. For instance, 0.3 microM U-75302 did not inhibit thromboxane B2 formation by lung parenchyma stimulated with calcium ionophore A23187 and it did not inhibit thromboxane B2 formation by human platelets stimulated with arachidonic acid. U-75302 selectively antagonized the activity of LTB4 and not other myotropic agonists including the thromboxane A2 mimetic U-46619, LTC4, LTD4, AGEPC, PGF2 alpha, and histamine. Receptor antagonists of leukotriene B4 may have multiple beneficial effects on asthmatic or respiratory disorders. These include (i) direct antagonism of LTB4 myotropic actions; (ii) antagonism of LTB4-dependent mediator release; and (iii) antagonism of LTB4 chemotactic action associated with leukocyte infiltration during anaphylactic late phase reactions.