Abstract 531: Regulation of Plasma 20-HETE and Soluble Epoxide Hydrolase by Salt Balance in Normotensive Subjects

Abstract

The tissue sources of circulating and urinary 20-HETE and EETs are not well known. We have previously shown urine 20-HETE abnormalities in salt-sensitive (SS) hypertension. We studied plasma 20-HETE and EETs in normotensive volunteers classified as SS or salt resistant (SR) with an acute protocol of salt loading (HS, 460 mmol diet and iv) and depletion (LS, 10 mmol and furosemide). Plasma 20-HETE and total (EET+DHET) or active EET did not differ between SR and SS during baseline (B, UNaV 146±17 mmol/24hr), HS (422±20) or LS (24±6). In normal SR subjects, HS did not affect the levels of either eicosanoid but reduced degradation of EETs into DHETs by decreasing the activity of soluble epoxide hydrolase (sEH or DHET/[EET+DHET]). No major clinical or biochemical correlates for plasma 20-HETE were identified in B, HS or LS. In SR but not SS, EET+DHET (r=0.57, p<0.003) and DHET (r=0.45, p<0.03) correlated with aldosterone during B and HS. LS stimulated 20-HETE in both SS and SR and also unexpectedly increased EET+DHET in SR subjects. This did not lead to increased EETs because of concomitant stimulation of sEH with increased degradation into DHETs. In SR, stimulation of 20-HETE by LS correlated with greater natriuresis (r=0.71, p<0.02), greater reduction of MAP (r=0.66, p<0.03) and lesser stimulation of aldosterone (r=0.64, p<0.04), relationships not observed in SS. Finally, in SR subjects only, during B and HS, plasma 20-HETE correlated with the activity of sEH (r=0.56, p<0.005) and levels of DHET (r=0.63, p<0.001), but not with total or active EETs. Our data on stimulation of plasma 20-HETE by LS and its correlates (markers of severity of sodium depletion) suggest recruitment of systemic vasoconstrictor 20-HETE for maintenance of BP. Plasma EET responses to HS and LS are not consistent with its renal natriuretic role but correlate with aldosterone responses to salt balance, perhaps reflecting modulation of aldosterone actions on extrarenal ENaC. Although no significant correlations were detected between blood pressure and EETs, there was a direct relationship between plasma 20-HETE, sEH activity and degradation of EETs into DHETs. This suggests coordinated vasoconstriction and vasodilation by these eicosanoids in normal SR humans, which is disrupted in normotensive SS.