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1 Department of Physiology, Cardiovascular Research Center, 6 Department of Medicine, and 2 Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; 4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75235; 5 Department of Physiology, University of South Alabama, Mobile, Alabama 36688; and 3 Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Park, North Carolina 27709
Little information is
available regarding the vasoactive effects of epoxyeicosatrienoic acids
(EETs) in the lung. We demonstrate that 5,6-, 8,9-, 11,12-, and
14,15-EETs contract pressurized rabbit pulmonary arteries in a
concentration-dependent manner. Constriction to 5,6-EET
methyl ester or 14,15-EET is blocked by indomethacin or ibuprofen
(10
5 M), SQ-29548, endothelial denuding,
or submaximal preconstriction with the thromboxane mimetic U-46619.
Constriction of pulmonary artery rings to phenylephrine is blunted by
treatment with the epoxygenase inhibitor
N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide. Pulmonary arteries and peripheral lung microsomes
metabolize arachidonate to products that comigrate on reverse-phrase
HPLC with authentic regioisomers of 5,6-, 8,9-, 11,12-, and
14,15-EETs, but no cyclooxygenase products of EETs could be
demonstrated. Proteins of the CYP2B, CYP2E, CYP2J, CYP1A, and CYP2C
subfamilies are present in pulmonary artery and peripheral lung
microsomes. Constriction of isolated rabbit pulmonary arteries to EETs
is nonregioselective and depends on intact endothelium and
cyclooxygenase, consistent with the formation of a pressor prostanoid
compound. These data raise the possibility that EETs may contribute to
regulation of pulmonary vascular tone.
cytochrome P-450; pulmonary vascular tone; vasodilator; eicosanoid metabolism; arachidonic acid
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