title: Palmitoylethanolamide treatment reduces blood pressure in spontaneously hypertensive rats: involvement of cytochrome p450-derived eicosanoids and renin angiotensin system.
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.
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Mattace Raso
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pirozzi
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: d'Emmanuele di Villa Bianca
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy; The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Simeoli
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Lama
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Guida
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Russo
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: De Caro
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sorrentino
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Meli
mesh_terms: D000577:Amides; D000818:Animals; D001685:Biological Factors / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000378:metabolism*; D004983:Ethanolamines / Q000008:administration & dosage* / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D010169:Palmitic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012084:Renin-Angiotensin System / Q000187:drug effects*
chemical_list: D000577:Amides; D001685:Biological Factors; D015777:Eicosanoids; D004983:Ethanolamines; D010169:Palmitic Acids; C067410:endothelium-dependent hyperpolarization factor; C005958:palmidrol