Epoxy Fatty Acids: From Salt Regulation to Kidney and Cardiovascular Therapeutics: 2019 Lewis K. Dahl Memorial Lecture

Hypertension. 2020 Jul;76(1):3-15. doi: 10.1161/HYPERTENSIONAHA.120.13898. Epub 2020 Jun 1.

Abstract

Epoxyeicosatrienoic acids (EETs) are epoxy fatty acids that have biological actions that are essential for maintaining water and electrolyte homeostasis. An inability to increase EETs in response to a high-salt diet results in salt-sensitive hypertension. Vasodilation, inhibition of epithelial sodium channel, and inhibition of inflammation are the major EET actions that are beneficial to the heart, resistance arteries, and kidneys. Genetic and pharmacological means to elevate EETs demonstrated antihypertensive, anti-inflammatory, and organ protective actions. Therapeutic approaches to increase EETs were then developed for cardiovascular diseases. sEH (soluble epoxide hydrolase) inhibitors were developed and progressed to clinical trials for hypertension, diabetes mellitus, and other diseases. EET analogs were another therapeutic approach taken and these drugs are entering the early phases of clinical development. Even with the promise for these therapeutic approaches, there are still several challenges, unexplored areas, and opportunities for epoxy fatty acids.

Keywords: diuretics; epithelial sodium channels; epoxide hydrolase; natriuresis; renin.

Publication types

  • Lecture
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8,11,14-Eicosatrienoic Acid / analogs & derivatives*
  • 8,11,14-Eicosatrienoic Acid / metabolism
  • Animals
  • Arachidonic Acid / metabolism
  • Cardiovascular Diseases / drug therapy*
  • Cardiovascular Diseases / metabolism
  • Cytochrome P-450 Enzyme System / metabolism
  • Disease Models, Animal
  • Epoxide Hydrolases / antagonists & inhibitors
  • Epoxide Hydrolases / physiology
  • Forecasting
  • Humans
  • Hypertension / etiology
  • Hypertension / metabolism
  • Kidney / metabolism*
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / metabolism
  • Mice
  • Natriuresis / physiology
  • Potassium / metabolism
  • Rats
  • Rats, Inbred Dahl
  • Sodium Chloride / metabolism*
  • Sodium Chloride, Dietary / adverse effects
  • Sodium Chloride, Dietary / pharmacokinetics
  • Vasodilation / physiology
  • Water-Electrolyte Balance / physiology*
  • Water-Electrolyte Imbalance / drug therapy
  • Water-Electrolyte Imbalance / physiopathology

Substances

  • Sodium Chloride, Dietary
  • cytochrome P-450 CYP2C subfamily
  • Arachidonic Acid
  • Sodium Chloride
  • 11,12-epoxy-5,8,14-eicosatrienoic acid
  • 5,6-epoxy-8,11,14-eicosatrienoic acid
  • 8,9-epoxyeicosatrienoic acid
  • 14,15-epoxy-5,8,11-eicosatrienoic acid
  • Cytochrome P-450 Enzyme System
  • Epoxide Hydrolases
  • 8,11,14-Eicosatrienoic Acid
  • Potassium