P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function

Abstract

Recent studies have indicated that arachidonic acid is primarily metabolized by cytochrome P-450 (CYP) enzymes in the brain, lung, kidney, and peripheral vasculature to 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) and that these compounds play critical roles in the regulation of renal, pulmonary, and cardiac function and vascular tone. EETs are endothelium-derived vasodilators that hyperpolarize vascular smooth muscle (VSM) cells by activating K+channels. 20-HETE is a vasoconstrictor produced in VSM cells that reduces the open-state probability of Ca2+-activated K+channels. Inhibitors of the formation of 20-HETE block the myogenic response of renal, cerebral, and skeletal muscle arterioles in vitro and autoregulation of renal and cerebral blood flow in vivo. They also block tubuloglomerular feedback responses in vivo and the vasoconstrictor response to elevations in tissue Po2both in vivo and in vitro. The formation of 20-HETE in VSM is stimulated by angiotensin II and endothelin and is inhibited by nitric oxide (NO) and carbon monoxide (CO). Blockade of the formation of 20-HETE attenuates the vascular responses to angiotensin II, endothelin, norepinephrine, NO, and CO. In the kidney, EETs and 20-HETE are produced in the proximal tubule and the thick ascending loop of Henle. They regulate Na+transport in these nephron segments. 20-HETE also contributes to the mitogenic effects of a variety of growth factors in VSM, renal epithelial, and mesangial cells. The production of EETs and 20-HETE is altered in experimental and genetic models of hypertension, diabetes, uremia, toxemia of pregnancy, and hepatorenal syndrome. Given the importance of this pathway in the control of cardiovascular function, it is likely that CYP metabolites of arachidonic acid contribute to the changes in renal function and vascular tone associated with some of these conditions and that drugs that modify the formation and/or actions of EETs and 20-HETE may have therapeutic benefits.