Effects of cyclo- and lipoxygenase inhibitors on hypoxic vasoconstriction in isolated ferret lungs.
To evaluate the role of leukotrienes in hypoxic pulmonary vasoconstriction, we measured steady-state pressor responses to graded hypoxia in isolated ferret lungs perfused with autologous blood containing 0.001, 0.03, 1, or 3 mM nordihydroguaiaretic acid (NDGA), 1 mM BW 755C, or 0.02-0.05 mM indomethacin. Untreated lungs served as controls. Perfusate concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha, measured by radioimmunoassay, were markedly reduced in all treated lungs, indicating inhibition of cyclooxygenase. The maximum pressor response to hypoxia measured at a blood flow of 50 ml.min-1. kg-1 averaged 26.6 +/- 2.4 Torr in untreated lungs and was not affected by BW 755C or 0.001-0.03 mM NDGA. Because BW 755C and NDGA inhibited cyclooxygenase at concentrations that did not affect hypoxic vasoconstriction and because both agents are thought to inhibit lipoxygenase with a potency greater than or equal to that with which they inhibit cyclooxygenase, these results do not support the possibility that hypoxic pulmonary vasoconstriction was mediated by leukotrienes. At concentrations of 1 and 3 mM, NDGA inhibited the maximum hypoxic pressor response by 57 and 95%, respectively. The mechanism of this attenuation is unknown; however, it was apparently not due to cyclooxygenase inhibition, since indomethacin enhanced the maximum hypoxic pressor response by 45%. Nor was it due to blockade of calcium entry or interference with the contractile process in pulmonary vascular smooth muscle, since 1 mM NDGA did not inhibit vasoconstrictor responses to KCl or prostaglandin F2 alpha.
Gottlieb
J E
JE
Department of Medicine, Johns Hopkins Medical Institutions, Francis Scott Key Medical Center, Baltimore, Maryland 21224.
McGeady
M
M
Adkinson
N F
NF
Sylvester
J T
JT
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001784:Blood Gas Analysis; D001794:Blood Pressure; D002396:Catechols / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors; D015237:Dinoprost; D005289:Ferrets; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D007975:Leukotriene B4 / Q000502:physiology; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000098:blood supply*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010100:Oxygen / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D011460:Prostaglandins F / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002396:Catechols; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011460:Prostaglandins F; D011720:Pyrazoles; D007975:Leukotriene B4; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D011189:Potassium Chloride; D009637:Masoprocol; D015237:Dinoprost; D010100:Oxygen; D007213:Indomethacin