Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilation and sodium channel inhibition

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.

Two Pools of Epoxyeicosatrienoic Acids in Humans

“…Although no such evidence has been published, this speculation is consistent with increased vasodilator tone in normotensive or hypertensive experimental models when production of vascular EETs is enhanced by dietary means 15 or by administration of EET analogs. 16 These observations likely reflect EET attenuation of vascular myogenic responses in resistance arterioles, as shown in sEH knockout mice or with sEH inhibitors. 17 The correlation between DHET and plasma aldosterone in SR could reflect parallel dichotomization of both parameters by changes in salt balance (inhibition by salt loading and stimulation by salt depletion).…”

Epoxyeicosatrienoic Acids, Hypertension, and Kidney Injury

“…Cyp2c44 (-/-) mice develop hypertension when fed a high K + or high Na + salt diet. 8,11,22 Similarly, Cyp4a10 (-/-) mice have decreased renal Cyp2c44 epoxygenase activity in response to high Na + salt and develop salt-sensitive hypertension. 23 Differences in renal EET generation and blood pressure in response to dietary NaCl intake between the Cyp2c44 (-/-) mice and Cyp4a10 (-/-) mice provide additional evidence for a critical contribution for EETs in blood pressure regulation.…”

“…The fact that amiloride lowers blood pressure in Cyp2c44 (-/-) and Cyp4a10 (-/-) mice fed a high salt diet suggests a significant contribution for ENaC. 11,22,23 …”

“…8,11,22 Actions of 11,12-EET on basolateral inwardly rectifying K + channels and apical ENaC channels on the cortical collecting duct (CCD) epithelium can explain the salt-sensitive blood pressure regulation in response to high K + or Na + salt diets. Hypertensive Cyp2c44 (-/-) mice show a hyperactive ENaC and reduction in ERK1/2 and ENaC subunit phosphorylation.…”

Cardiotonic Pill Reduces Myocardial Ischemia-Reperfusion Injury via Increasing EET Concentrations in Rats

“…The instability of EETs limits their use as a therapeutic drug. However, EET analogs are still being tested using in vivo and in vitro models (Hye Khan et al, 2014). Thus, as a result of the present study, the CP is the first herbal preparation for CVD treatment that has been shown to increase EET concentrations in I/R rats.…”