Faculty Collaboration Database

Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilation and sodium channel inhibition. Clin Sci (Lond) 2014 Oct;127(7):463-74

Date

04/09/2014

Pubmed ID

24707975

Pubmed Central ID

PMC4167712

DOI

10.1042/CS20130479

Scopus ID

2-s2.0-84903999535 (requires institutional sign-in at Scopus site)   62 Citations

Abstract

Epoxyeicosatrienoic acids (EETs) contribute to haemodynamics, electrolyte homoeostasis and blood pressure regulation, leading to the concept that EETs can be therapeutically targeted for hypertension. In the present study, multiple structural EET analogues were synthesized based on the EET pharmacophore and vasodilator structure-activity studies. Four EET analogues with 91-119% vasodilatory activity in the isolated bovine coronary artery (EC50: 0.18-1.6 μM) were identified and studied for blood-pressure-lowering in hypertension. Two EET analogues in which the COOH group at carbon 1 of the EET pharmacophore was replaced with either an aspartic acid (EET-A) or a heterocyclic surrogate (EET-X) were administered for 14 days [10 mg/kg per day intraperitoneally (i.p.)]. Both EET-A and EET-X lowered blood pressure in spontaneously hypertensive rats (SHRs) and in angiotensin II (AngII) hypertension. On day 14, the mean arterial pressures in EET analogue-treated AngII-hypertensive and SHRs were 30-50 mmHg (EET-A) and 15-20 mmHg (EET-X) lower than those in vehicle-treated controls. These EET analogues (10 mg/kg per day) were further tested in AngII hypertension by administering orally in drinking water for 14 days and EET-A lowered blood pressure. Additional experiments demonstrated that EET-A inhibits epithelial sodium channel (ENaC) activity in cultured cortical collecting duct cells and reduced renal expression of ENaC subunits in AngII hypertension. In conclusion, we have characterized EET-A as an orally active antihypertensive EET analogue that protects vascular endothelial function and has ENaC inhibitory activity in AngII hypertension.

Author List

Hye Khan MA, Pavlov TS, Christain SV, Neckář J, Staruschenko A, Gauthier KM, Capdevila JH, Falck JR, Campbell WB, Imig JD

Author

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

8,11,14-Eicosatrienoic Acid
Animals
Antihypertensive Agents
Blood Pressure
Hemodynamics
Hypertension
Male
Mice
Rats
Rats, Inbred SHR
Rats, Sprague-Dawley
Sodium Channel Blockers
Vasodilation