Increases in plasmatrans-EETs and blood pressure reduction in spontaneously hypertensive rats

Abstract

Epoxyeicosatrienoic acids (EETs) are vasodilator, natriuretic, and antiinflammatory lipid mediators. Both cis- and trans-EETs are stored in phospholipids and in red blood cells (RBCs) in the circulation; the maximal velocity (V(max)) of trans-EET hydrolysis by soluble epoxide hydrolase (sEH) is threefold that of cis-EETs. Because RBCs of the spontaneously hypertensive rat (SHR) exhibit increased sEH activity, a deficiency of trans-EETs in the SHR was hypothesized to increase blood pressure (BP). This prediction was fulfilled, since sEH inhibition with cis-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid (AUCB; 2 mg·kg(-1)·day(-1) for 7 days) in the SHR reduced mean BP from 176 ± 8 to 153 ± 5 mmHg (P < 0.05), whereas BP in the control Wistar-Kyoto rat (WKY) was unaffected. Plasma levels of EETs in the SHR were lower than in the age-matched control WKY (16.4 ± 1.6 vs. 26.1 ± 1.8 ng/ml; P < 0.05). The decrease in BP in the SHR treated with AUCB was associated with an increase in plasma EETs, which was mostly accounted for by increasing trans-EET from 4.1 ± 0.2 to 7.9 ± 1.5 ng/ml (P < 0.05). Consistent with the effect of increased plasma trans-EETs and reduced BP in the SHR, the 14,15-trans-EET was more potent (ED(50) 10(-10) M; maximum dilation 59 ± 15 μm) than the cis-isomer (ED(50) 10(-9) M; maximum dilation 30 ± 11 μm) in relaxing rat preconstricted arcuate arteries. The 11,12-EET cis- and trans-isomers were equipotent dilators as were the 8,9-EET isomers. In summary, inhibition of sEH resulted in a twofold increase in plasma trans-EETs and reduced mean BP in the SHR. The greater vasodilator potency of trans- vs. cis-EETs may contribute to the antihypertensive effects of sEH inhibitors.

Role of haem oxygenase in the renoprotective effects of soluble epoxide hydrolase inhibition in diabetic spontaneously hypertensive rats

“…Although the same trends are seen in plasma and cortex, it is worth mentioning that the EETs/DHETEs ratio is much higher in kidney cortex than in plasma because DHETEs are predominantly located in plasma due to their higher polarity whereas EETs are largely located in the tissue. Inhibition of sEH has been shown to lower blood pressure in SHR [23,24]; however, t-AUCB did not lower blood pressure in diabetic SHR. Our data are consistent with the previously published data of Olearczyk et al [25], who showed that sEH inhibition had no effect on mean arterial pressure nor on blood glucose levels in hypertensive Goto-Kakizaki rats, as well as with our recent findings where knocking out of the sEH gene did not lower blood pressure or blood glucose in streptozotocin-induced diabetic mice [9].…”

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

“…The cis-and trans-11,12-and -14,15-EETs were equally potent in stimulating GPR40. Cis-and trans-EET have been measured in the plasma and red blood cells and relax rat renal arcuate arteries equally (57,58). In contrast, the cis-14,15-EET was more potent than the trans-isomer in relaxing bovine coronary arteries (59).…”

A novel vascular EET synthase: role of CYP2C7

“…Indeed, given the cardiovascular actions of EETs, the concept can be advanced that EETs and the modulation of their metabolic pathway could be therapeutically targeted for the treatment of hypertension and other cardiovascular diseases. For instance, EET agonists, as well as upregulation of CYP epoxygenase, have been administered chronically in experimental animal models of hypertension and metabolic syndrome and have been demonstrated to decrease blood pressure, attenuate hypertension-induced renal injury (18,22), and improve insulin signaling and vascular function (17,19,38).…”