Renal cytochrome P-450-dependent metabolism of arachidonic acid in spontaneously hypertensive rats.
Renal cytochrome P-450-dependent monooxygenases metabolize arachidonic acid to products some of which affect vascular tone and (Na+,K+)ATPase activity. We measured these metabolites in spontaneously hypertensive (SHR) and control normotensive Wister-Kyoto (WKY) rats. Systolic tail blood pressure in SHR increased from 112 to 202 mm Hg and in WKY from 97 to 136 mm Hg at 5 and 20 weeks respectively. Renal cortical and outer medullary microsomes were incubated with [14C]arachidonic acid; metabolites formed via the cytochrome P-450 pathway were defined as those dependent on NADPH, inhibited by SKF-525A, and unaffected by indomethacin. The P-450-dependent metabolites were higher in SHR vs WKY at 5, 7 and 11 weeks in the cortex and at 7 and 11 weeks in the outer medulla. In the outer medulla, the formation of these metabolites peaked at 7 weeks. Using reverse-phase HPLC, the cytochrome P-450-dependent metabolites were separated into three radioactive peaks: peak I had a retention time of 17.5 min and comigrated as 11,12-dihydroxyeicosatrienoic acid standard. Peak II had a retention time of 19 min and comigrated with omega-hydroxylation compounds. Peak III had a retention time of 27 min and comigrated with 11,12-epoxyeicosatrienoic acid. In the renal cortex, peak I was higher in SHR vs WKY at 5, 7, and 9 weeks and peak III at 5, 7, 9 and 11 weeks. In the outer medulla, peak I was higher in SHR at 5 and 7 weeks, and peaks II and III at 7 weeks. Cytochrome P-450 content in the renal cortex was always higher in SHR vs WKY. We conclude that renal cytochrome P-450-dependent metabolites of arachidonic acid may participate in the circulatory changes of SHR, particularly during the developmental stage.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001794:Blood Pressure; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism*; D007679:Kidney Medulla / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D010105:Oxygenases / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR / Q000378:metabolism*; D011919:Rats, Inbred Strains / Q000378:metabolism*; D011921:Rats, Inbred WKY / Q000378:metabolism
D001095:Arachidonic Acids; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase