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.
Xu
Fengyun
F
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, California 94143, USA.
Straub
Wesley O
WO
Pak
Winnie
W
Su
Ping
P
Maier
Kristopher G
KG
Yu
Ming
M
Roman
Richard J
RJ
Ortiz De Montellano
Paul R
PR
Kroetz
Deanna L
DL
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