Inhibition of cytochrome P-450 attenuates hypoxemia of acute lung injury in dogs.
The intravenous administration of ethchlorvynol (ECV), in dogs, resulted in an acute lung injury (ALI) characterized by a 200 +/- 80% increase in venous admixture and a 142 +/- 30% increase in extravascular lung water (EVLW). Pretreatment with the cytochrome P-450 inhibitor 8-methoxypsoralen prevented the ECV-induced increase in venous admixture but not the increased EVLW. These findings parallel those reported for cyclooxygenase inhibition in ECV-induced ALI and suggest that an arachidonic acid (AA) metabolite of pulmonary cytochrome P-450 activity may mediate the increase in venous admixture of ALI. We demonstrate that canine pulmonary microsomes metabolize [1-(14)C]AA to a variety of products, including the cytochrome P-450 metabolites 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid (EET). In prostaglandin F2 alpha-contracted, isolated pulmonary venous rings, 5,6-EET induced relaxation in a concentration-dependent manner. This action of 5,6-EET was prevented by indomethacin (10(-5) M). These results suggest that may serve as the cyclooxygenase-dependent endogenous pulmonary vasodilator responsible for the increase in venous admixture of ECV-induced ALI.
Stephenson
A H
AH
Department of Pharmacological and Physiological Science, Saint Louis University, School of Medicine, Missouri 63104, USA.
Sprague
R S
RS
Weintraub
N L
NL
McMurdo
L
L
Lonigro
A J
AJ
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D004984:Ethchlorvynol / Q000494:pharmacology; D000860:Hypoxia / Q000209:etiology* / Q000503:physiopathology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D055370:Lung Injury; D008297:Male; D008730:Methoxsalen / Q000494:pharmacology; D008861:Microsomes / Q000378:metabolism; D014677:Pharmaceutical Vehicles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D065607:Cytochrome P-450 Enzyme Inhibitors; D014677:Pharmaceutical Vehicles; D004984:Ethchlorvynol; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; D015237:Dinoprost; D015126:8,11,14-Eicosatrienoic Acid; D008730:Methoxsalen