Inhibition of cytochrome p-450 attenuates the hypoxemia of acute
lung injury in dogs.
Stephenson, Alan H., Randy S. Sprague, Neal L. Weintraub, Lorraine
McMurdo, and Andrew J. Lonigro.
Departments of Pharmacological and Physiological Science and
Internal Medicine, Saint Louis University School of Medicine, St.
Louis, Missouri, USA 63104
APStracts 2:0417H, 1995.
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
acute lung injury (ALI) and suggest that an arachidonic acid (AA)
metabolite of pulmonary cytochrome P-450 activity may mediate the
increase in venous admixture of ALI. Here, 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 PGF2[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 5,6-EET may
serve as the cyclooxygenase-dependent endogenous pulmonary
vasodilator responsible for the increase in venous admixture of ECV
-induced ALI.
Received 31 October 1994; accepted in final form 6 September
1995.
APS Manuscript Number H965-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 31 October 95