Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid omega-hydroxylase activity.
The cytochrome P-450 eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that is implicated in the regulation of blood pressure. The identification of selective inhibitors of renal 20-HETE formation for use in vivo would facilitate studies to determine the systemic effects of this eicosanoid. We characterized the acetylenic fatty acid sodium 10-undecynyl sulfate (10-SUYS) as a potent and selective mechanism-based inhibitor of renal 20-HETE formation. A single dose of 10-SUYS caused an acute reduction in mean arterial blood pressure in 8-wk-old spontaneously hypertensive rats. The decrease in mean arterial pressure was maximal 6 h after 10-SUYS treatment (17.9 +/- 3.2 mmHg; P < 0.05), and blood pressure returned to baseline levels within 24 h after treatment. Treatment with 10-SUYS was associated with a decrease in urinary 20-HETE formation in vivo and attenuation of the vasoconstrictor response of renal interlobar arteries to ANG II in vitro. These results provide further evidence that 20-HETE plays an important role in the regulation of blood pressure in the spontaneously hypertensive rat.
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, California 94143, USA.
Fengyun
F
Xu
Wesley O
WO
Straub
Winnie
W
Pak
Ping
P
Su
Kristopher G
KG
Maier
Ming
M
Yu
Richard J
RJ
Roman
Paul R
PR
Ortiz De Montellano
Deanna L
DL
Kroetz
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001160:Arterioles / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000201:enzymology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009318:Natriuresis / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010105:Oxygenases / Q000032:analysis / Q000378:metabolism; D011188:Potassium / Q000652:urine; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012077:Renal Artery / Q000187:drug effects; D012964:Sodium / Q000652:urine; D014661:Vasoconstriction / Q000187:drug effects
D000959:Antihypertensive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; C048289:10-undecynoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000090762:Cytochrome P-450 CYP2J2; C409986:cytochrome P-450 omega-hydroxylase; D011451:Prostaglandin-Endoperoxide Synthases; D011188:Potassium