Treatment of Primary Aldosteronism Increases Plasma Epoxyeicosatrienoic Acids

Abstract

Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules formed from arachidonic acid by the action of CYP450s. EETs cause vasodilation, exert anti-inflammatory effects, and enhance insulin secretion and sensitivity in rodents. EETs are metabolized to less active dihydroxyeicosatrienoic acids (DHETs) by sEH (soluble epoxide hydrolase), and 14,15-DHET has been reported to be increased in patients with primary aldosteronism, but the effects of aldosterone on EET concentrations and sEH activity are unknown. We tested the hypothesis that treatment of primary aldosteronism would alter EET concentrations in humans. We studied 9 patients with primary aldosteronism before and at least 3 months after unilateral adrenalectomy (6) or treatment with a mineralocorticoid antagonist (3). Circulating total EET concentrations increased to 18.5±12.6 from 11.9±5.9 nmol/L with treatment of primary aldosteronism (P=0.027). Among the regioisomers of EETs, 14,15-EET significantly increased after treatment, whereas 11,12-EET and 8,9 EET were unaltered. Total DHET concentrations and specific regioisomers of DHET did not change significantly. Circulating total EETs (ρ=-0.52, P=0.026), 14,15-EET (ρ=-0.56, P=0.015), and 11,12-EET (ρ=-0.48, P=0.042) correlated inversely with aldosterone. We also assessed EETs after a 12-hour aldosterone or vehicle infusion in a randomized cross-over study in healthy volunteers. Plasma EETs were similar after 12-hour aldosterone or vehicle infusion. Lastly, 3-day infusion of aldosterone in mice decreased EET concentrations in adipose and muscle and increased sEH expression as determined by molar ratio of DHETs to EETs and soluble epoxide hydrolase (Ephx2) mRNA expression in adipose tissue. These studies suggest that prolonged exposure to increased aldosterone decreases EET concentrations.