Inhibition of cytochrome P-450 attenuates hypoxemia of acute lung injury in dogs
Stephenson, A.H.; Sprague, R.S.; Weintraub, N.L.; McMurdo, L.; Lonigro, A.J.
American Journal of Physiology 270(4 Pt 2): H1355-H1362
1996
ISSN/ISBN: 0002-9513 PMID: 8967376 Document Number: 460798
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 (1-14C)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 F-2alpha-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 5,6-EET may serve as the cyclooxygenase-dependent endogenous pulmonary vasodilator responsible for the increase in venous admixture of ECV-induced ALI.