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 Ca2+-activated K+ 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.
Keywords: 20-hete; cytochrome p450; eets; eicosanoids; hypertension
Document Type: Review Article
Affiliations: Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA.
Publication date: 01 June 2004
- Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts. - Editorial Board
- Information for Authors
- Subscribe to this Title
- Ingenta Connect is not responsible for the content or availability of external websites
- Access Key
- Free content
- Partial Free content
- New content
- Open access content
- Partial Open access content
- Subscribed content
- Partial Subscribed content
- Free trial content