A formyl peptide contracts guinea pig lung: role of arachidonic acid metabolites.
We studied the role of cyclooxygenase and lipoxygenase products of arachidonic acid metabolism in mediating N-formyl-methionyl-leucyl-phenylalanine- (FMLP) induced contractions of guinea pig lung parenchymal strips. The cyclooxygenase inhibitors indomethacin (10(-5) M) and aspirin (3 X 10(-5) to 10(-4) M), the lipoxygenase inhibitor nordihydroguaiaretic acid (10(-5) to 3 X 10(-5) M), and the combined cyclooxygenase/lipoxygenase inhibitors 1-phenyl-3-pyrazolidinone (Phenidone) (3 X 10(-5) to 3 X 10(-4) M) and BW 755C (10(-5) to 10(-4) M) each caused a decrease in the maximum force induced by FMLP (Fmax) and an increase in the concentration of FMLP required to produce 50% of Fmax (EC50). The thromboxane synthesis inhibitor imidazole (3 X 10(-3) M) also decreased Fmax. The leukotriene D4 receptor antagonist FPL 55712 (5.7 X 10(-6) to 1.9 X 10(-5) M) increased the EC50 for FMLP, whereas desensitization of lung parenchymal strips to leukotriene B4 by pretreatment with this leukotriene (10(-7) M) had no effect on FMLP-induced contraction. After exposure to FMLP (10(-6) M), guinea pig lung produced (as determined by high-performance liquid chromatography and radioimmunoassay) leukotrienes C4 and B4, thromboxane A2 (as measured by its stable degradation product thromboxane B2), and prostaglandin F2 alpha. Lung strips not exposed to FMLP showed no evidence of leukotriene production. We conclude that thromboxane A2 and leukotriene C4 generated in response to FMLP mediate a substantial fraction of the force induced by this peptide in guinea pig lung parenchymal strips.
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D012898:Autacoids / Q000037:antagonists & inhibitors; D002867:Chromones / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000494:pharmacology; D008168:Lung / Q000187:drug effects*; D008297:Male; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013618:Tachyphylaxis; D013777:Tetrazoles / Q000494:pharmacology
D000098:Acetophenones; D001095:Arachidonic Acids; D012898:Autacoids; D002867:Chromones; D011453:Prostaglandins; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D013189:SRS-A; D013777:Tetrazoles; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D006632:Histamine; C044660:LY 171883; C006312:FPL 55712