Differential effects of calcium channel blockers on leukotriene C4- and D4-induced contractions in guinea pig pulmonary parenchymal strips.
Leukotriene (LT)C4 and LTD4-induced contractile effects in guinea pig pulmonary parenchyma were distinguished by their sensitivity to calcium channel blockers. LTC4-induced contractions were inhibited in a noncompetitive manner in the presence of calcium channel blockers, whereas LTD4 contractions were unaffected. In the presence of diltiazem, maximum LTC4-induced (1 X 10(-7) M) contractions were reduced by 24% and the concentration-effect curve was shifted to the right in a nonparallel manner; diltiazem had no significant effect on the LTD4 response. We used this differential sensitivity to calcium channel blockade to permit pharmacological characterization in guinea pig pulmonary parenchyma of the interaction of the competitive LT blocker FPL55712 and the putative LTD4 receptor, LTRd. We showed, using [3H]LTC4, that at least 15% of LTC4 is converted to LTD4 under our experimental conditions. We performed a Schild analysis of the inhibition of LTD4-induced contractions by FPL55712 in the presence of the calcium channel blocker diltiazem (0.67 mM). The Kb derived from this analysis (3.2 X 10(-7) M) agrees closely with the Ki derived for the interaction of FPL55712 and specific LTD4 binding in lung membranes. A Schild analysis of the interaction of FPL55712 and LTC4 in the presence of diltiazem resulted in competitive inhibition with a Kb of 4.7 X 10(-7) M. This apparent competitive inhibition, combined with the similarity of these binding constants, suggests that diltiazem is effective in blocking LTC4-mediated responses and that when these effects are blocked, LTC4 induced contractions are mediated through LTRd. The differential effects of calcium blockade on these two agonists provides evidence for distinct coupling mechanisms for LT receptors in this tissue.
Israel
E
E
Beth Israel Hospital, Department of Medicine, Harvard Medical School, Massachusetts.
Robin
J L
JL
Drazen
J M
JM
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin / Q000187:drug effects; D013189:SRS-A / Q000378:metabolism / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects
D002121:Calcium Channel Blockers; D002867:Chromones; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D013189:SRS-A; C006312:FPL 55712