Two Pools of Epoxyeicosatrienoic Acids in Humans

Abstract

E poxyeicosatrienoic acids (EETs) are products of epoxygenation of arachidonic acid. They participate in cardiovascular regulation via vasodilator and natriuretic effects. Research on their actions used urine or plasma measurements of their 4 active regioisomers (5,8,11,and 14, and their relatively inactive derivatives, the dihydroxyeicosatrienoic acids [DHETs]. The latter are produced by enzymatic (soluble epoxide hydrolase [sEH]) or nonenzymatic (eg, pH, oxidative stress) degradation.Previous studies in animals suggested that urine and plasma EETs may reflect 2 distinct pools with different functions. The volume of distribution of intravenous radiolabeled 14,15-EET in dogs approximates their plasma volume, and no radioactivity can be detected in their urine.1 Plasma EET responses to regulatory PPARα (peroxisome proliferatoractivated receptor α) ligands in mice run parallel to Cyp2c epoxygenase expression and EET biosynthesis in the liver. These studies suggest that plasma EETs reflect a systemic, not a renal pool. Conversely, increased renal EET content produced by dopamine agonists in mice is not associated with changes in plasma EETs,3 indicating that the renal EET pool might be better reflected by urine measurements. Our first aim was to assess whether these putative pools could be uncovered by studying clinical and biochemical correlates of urine and plasma EETs in normal volunteers; that is, normotensive, saltresistant (SR) subjects, during salt loading and depletion.EETs may play a role in salt sensitivity of blood pressure (BP). Salt stimulates renal microsomal biosynthesis of EETs in normal Sprague Dawley 4 and Dahl-R rats, 5 whereas this response is absent in the salt-sensitive (SS) Dahl-S strain, leading to hypertension with reduced renal expression of the epoxygenase CYP2C23 and urine excretion of EETs. 5 In SR rats, the epoxygenase inhibitor clotrimazole decreases urinary EETs and reproduces SS hypertension.5 Cyp4a10 knockout mice, which have reduced renal epoxygenase (Cyp2c44) activity, 6 and the Cyp2c44 knockout, 7 have diminished urine EETs and amiloride-sensitive hypertension. This is associated with decreased inactivating threonine phosphorylation of γENaC (epithelial sodium channel), 7 which is reversible by the PPARα ligands that stimulate epoxygenases.6 Our second aim was to investigate whether SS subjects exhibit differences in urine or plasma EETs levels or in their responses to changes in salt balance or in their clinical or biochemical correlates compared with SR. To avoid confounding effects of established hypertension, we performed these studies in normotensive volunteers.Abstract-We measured epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) in 21 normotensive subjects classified as salt resistant (13) or salt sensitive (8) with an inpatient protocol of salt loading (460 mEq Na + /24 hours, HiNa) and depletion (10 mEq Na + /24 hours+furosemide 40 mg×3, LoNa). No urine EETs were detected; hence, enzyme linked innumosorbent assay 14,15-DHETs (dihydroxyeicosatrie...

Hypothesis: Unrecognized actions of ENaC blockade in improving refractory-resistant hypertension and residual cardiovascular risk

“…Although there is no proof for a deficit of epoxygenases in the CYP4A11 rs3890011 CC homozygous Black hypertensive patients, their aldosterone-independent ENaC hyperactivity and their responsiveness to amiloride strongly suggest that a similar mechanism may underlie their hypertension. This is consistent with otherwise documented decreased levels of EETs in salt-sensitive hypertension in Dahl rats and humans [ 10 ].…”

Myeloid Cell Glucocorticoid, Not Mineralocorticoid Receptor Signaling, Contributes to Salt-Sensitive Hypertension in Humans via Cortisol

“…Blood was collected in EDTA tubes, centrifuged at room temperature, and separated immediately. Urine specimens for four periods (24-hour baseline, 24-hour salt loading, 12-hour furosemide-induced diuresis, and 12-hour salt depletion) were collected and refrigerated as described previously 27 .…”

Diabetes risk associated with plasma epoxylipid levels

“…Moreover, other pools of EETs and DHETs in humans need to be considered. Studies on salt-sensitive blood pressure control in humans have found that urine EET and DHET levels represent the generation of EETs and DHETs in the kidney [9] . These urine EET levels were found to be involved in renal salt handling while plasma EET levels did not correlate with aldosterone and salt regulation [9] .…”

“…Studies on salt-sensitive blood pressure control in humans have found that urine EET and DHET levels represent the generation of EETs and DHETs in the kidney [9] . These urine EET levels were found to be involved in renal salt handling while plasma EET levels did not correlate with aldosterone and salt regulation [9] . Interestingly, a role for kidney sEH to glucose regulation in type 1 diabetes and high fat diet induced insulin resistance in mice has been demonstrated [10] .…”