Cytochrome P-450 arachidonate metabolites in rat kidney: characterization and hemodynamic responses.
Rat kidney cortical and medullary microsomal fractions catalyzed cytochrome P-450-linked metabolism of arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) (56 +/- 6% of total products in cortex and 10% in medulla) and 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-OHAA) (36 +/- 4% in cortex and 90% in medulla). In addition, endogenous renal generation of EETs was established by negative ion-chemical ionization mass spectrometry. The total amount of EETs present in the rat kidney was approximately 1 microgram/g wet tissue. The responses to renal arterial administration of 20-OHAA and 5,6-EET were evaluated in anesthetized euvolemic rats. 20-OHAA resulted in ipsilateral dose-dependent natriuresis without affecting systemic or renal hemodynamics or glomerular filtration rate (GFR). Equimolar doses of 5,6-EET resulted in dose-dependent renal vasoconstriction and reduced GFR but were without effect on arterial pressure or sodium excretion. During cyclooxygenase inhibition, 5,6-EET caused renal vasodilatation and augmentation of GFR. These data establish the capacity of rat kidney to metabolize AA through cytochrome P-450-dependent oxygenases and demonstrate the endogenous formation of the resulting eicosanoids. Monooxygenase and epoxygenase products exert effects on renal blood flow, GFR, and urinary sodium excretion rate, suggesting their potential relevance in the regulation of renal function.
Takahashi
K
K
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232.
Capdevila
J
J
Karara
A
A
Falck
J R
JR
Jacobson
H R
HR
Badr
K F
KF
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D007052:Ibuprofen / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D001095:Arachidonic Acids; D016718:Arachidonic Acid; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D015126:8,11,14-Eicosatrienoic Acid; D007052:Ibuprofen