Role of cytochrome P450 metabolites of arachidonic acid in hypertension.
Considerable evidence has accumulated over the last decade implicating a role of cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA) in the pathogenesis of hypertension. Indeed, 20-hydroxyeicosatetraenoic acid (20-HETE) is produced by vascular smooth muscle (VSM) cells and is a potent vasoconstrictor that depolarizes VSM by blocking large conductance Ca+-activated K2+ channels. In contrast, epoxyeicosatrienoic acids (EETs) are synthesized by the vascular endothelium and have opposite effects on VSM (hyperpolarization and vasodilatation). Inhibition of the synthesis of 20-HETE attenuates myogenic tone and autoregulation of blood flow and modulates vascular responses to vasodilators (NO and CO) and vasoconstrictors (angiotensin II, endothelin). In the kidney, 20-HETE inhibits sodium transport in the proximal tubule by blocking Na+-K+-ATPase activity. In the thick ascending limb of the loop of Henle, 20-HETE inhibits Na+-K+-2Cl- transport, in part, by blocking a 70 pS apical K+ channel. EETs are produced in the proximal tubule where they inhibit Na+-H+ exchange and in the collecting duct where they inhibit sodium and water transport. Numerous studies have established that the formation of EETs and 20-HETE and the expression of CYP enzymes are altered in the kidney in many genetic and experimental animal models of hypertension and in some forms of human hypertension. However, the functional significance of these changes remains to be determined. Given the importance of this pathway in the control of renal function and vascular tone, it is likely that alterations in the renal formation of CYP-dependent metabolites of AA will be shown to participate in the development of hypertension in many of these models.
Sarkis
A
A
Medical College of Wisconsin, Department of Physiology, Milwaukee, 53226, USA. asarkis@mcw.edu
Roman
R J
RJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001693:Biological Transport, Active; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
D015777:Eicosanoids; D007527:Isoenzymes; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium