Effects of arachidonic acid metabolism on hypoxic vasoconstriction in rabbit lungs.
Hypoxic pulmonary vasoconstriction is an essential mechanism that matches lung perfusion to ventilation, thus optimising pulmonary gas exchange. Despite its pathophysiological relevance, the mechanism of hypoxic pulmonary vasoconstriction still remains enigmatic. We investigated whether arachidonic acid metabolism is involved in the regulation of hypoxic pulmonary vasoconstriction in isolated, buffer-perfused rabbit lungs. Seven inhibitors were employed to determine the contribution of different vasoactive lipoxy- and cyclooxygenase mediators as well as cytochrome P450 products on the magnitude of hypoxic pulmonary vasoconstriction. Hypoxic pulmonary vasoconstriction was not affected by (i) the cyclooxygenase inhibitor acetylsalicylic acid, (ii) the thromboxane A2 receptor antagonist BM13.505, (iii) the 5'-lipoxygenase inhibitor MK886, and (iv) the lipoxygenase and cyclooxygenase inhibitor BW755c. The hypoxia-elicited pressor response was prominently inhibited by (i) nordihydroguaiaretic acid (50-150 microM), an inhibitor of lipoxygenase and cyclooxygenase and (ii) methoxsalen (100 microM) and 1-aminobenzotriazole (1-10 mM), two inhibitors of cytochrome P450-derived metabolites. However, no specificity for the regulation of hypoxic pulmonary vasoconstriction was found, as corresponding inhibitory potency of these agents was noted when vasoconstriction was achieved by the stable thromboxane analogue U46619 under conditions of normoxia. We conclude that there is no evidence for a specific involvement of different pathways of arachidonic acid metabolism in the mechanism of hypoxic pulmonary vasoconstriction in rabbits.
Department of Internal Medicine, Justus-Liebig-University Giessen, Germany.
N
N
Weissmann
W
W
Seeger
J
J
Conzen
L
L
Kiss
F
F
Grimminger
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001241:Aspirin / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D002722:Chlorobenzenes
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D016718:Arachidonic Acid; D001241:Aspirin; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol; C060893:MK-886; D002722:Chlorobenzenes