Abstract
Palmitoylethanolamide (PEA), a peroxisome proliferator-activated receptor-α agonist, has been demonstrated to reduce blood pressure and kidney damage secondary to hypertension in spontaneously hypertensive rat (SHR). Currently, no information is available concerning the putative effect of PEA on modulating vascular tone. Here, we investigate the mechanisms underpinning PEA blood pressure lowering effect, exploring the contribution of epoxyeicosatrienoic acids, CYP-dependent arachidonic acid metabolites, as endothelium-derived hyperpolarizing factors (EDHF), and renin angiotensin system (RAS) modulation. To achieve this aim SHR and Wistar-Kyoto rats were treated with PEA (30 mg/kg/day) for five weeks. Functional evaluations on mesenteric bed were performed to analyze EDHF-mediated vasodilation. Moreover, mesenteric bed and carotid were harvested to measure CYP2C23 and CYP2J2, the key isoenzymes in the formation of epoxyeicosatrienoic acids, and the soluble epoxide hydrolase, which is responsible for their degradation in the corresponding diols. Effect of PEA on RAS modulation was investigated by analyzing angiotensin converting enzyme and angiotensin receptor 1 expression. Here, we showed that EDHF-mediated dilation in response to acetylcholine was increased in mesenteric beds of PEA-treated SHR. Western blot analysis revealed that the increase in CYP2C23 and CYP2J2 observed in SHR was significantly attenuated in mesenteric beds of PEA-treated SHR, but unchanged in the carotids. Interestingly, in both vascular tissues, PEA significantly decreased the soluble epoxide hydrolase protein level, accompanied by a reduced serum concentration of its metabolite 14-15 dihydroxyeicosatrienoic acid, implying a reduction in epoxyeicosatrienoic acid hydrolisis. Moreover, PEA treatment down-regulated angiotensin receptor 1 and angiotensin converting enzyme expression, indicating a reduction in angiotensin II-mediated effects. Consistently, a damping of the activation of angiotensin receptor 1 underlying pathways in mesenteric beds was shown in basal conditions in PEA-treated SHR. In conclusion, our data demonstrate the involvement of epoxyeicosatrienoic acids and renin angiotensin system in the blood pressure lowering effect of PEA.
Highlights
The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing a spectrum of vasoactive substances [1]
spontaneously hypertensive rat (SHR) rats had a significant increase in systolic blood pressure (SBP) values compared to Wistar Kyoto normotensive (WKY) rats (220.2±11.1 vs 156.8±3.3; P
In order to visualize the contribution of endotheliumderived hyperpolarizing factors (EDHF) in mesenteric bed, as NO synthase (NOS)- and COX-independent relaxation, a concentration-response curve to Ach (1–1000 pmoles) in Krebs solution medicated with INDO (10 μM) and L-NAME (100 μM) was performed on MTX stable tone
Summary
The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing a spectrum of vasoactive substances [1]. Endothelium-derived NO mediates vascular relaxation of relatively large, conduit arteries (i.e., aorta and epicardial coronary arteries), while EDHF plays an important role in modulating vascular tone in small resistance arteries in rodents [2,3,4] and in human forearm microcirculation [5,6]. EETs are hydrolyzed by soluble epoxide hydrolase (sEH) in the corresponding inactive diols, dihydroxyeicosatrienoic acids (DHETs), resulting in attenuation of the vasodilation and anti-inflammatory effect of EETs. Recent studies on rat models have shown a positive correlation between sEH expression, angiotensin (Ang) II, and the elevation of blood pressure. EET hydrolysis has been found to be increased in renal fractions of spontaneously hypertensive rat (SHR), an animal model of Ang II-mediated hypertension [13]. The enhanced hydrolysis of EETs in DHETs by sEH would unbalance vascular tone and increase systemic blood pressure
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