Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB<sub>1</sub>, CB<sub>2</sub>, TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequency- and dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoylethanolamide in animals receiving i.v. bolus of the antagonists NIDA41020 (CB<sub>1</sub>), AM630 (CB<sub>2</sub>), capsazepine (TRPV1), and/or cannabidiol (GPR55). Palmitoyletha-nolamide (0.1-3.1 μg/kg/min) dose-dependently inhibited the sympathetically induced and noradrenaline-induced vasopressor responses. Both inhibitions were: (i) partially blocked by 100 μg/kg NIDA41020, 100 μg/kg capsazepine, or 31 μg/kg cannabidiol; (ii) unaffected by 310 μg/kg AM630; and (iii) abolished by the combination NIDA41020 + capsazepine + cannabidiol (100, 100, and 31 μg/kg, respectively). The resting blood pressure was decreased by palmitoylethanolamide (effect prevented by NIDA41020, capsazepine or cannabidiol, but not by AM630). These results suggest that: (i) palmitoylethanolamide inhibits the vasopressor responses to sympathetic stimulation and exogenous noradrenaline and that it induces hypotension; and (ii) all these effects are mediated by prejunctional and vascular CB<sub>1</sub>, TRPV1 and probably GPR55, but not by CB<sub>2</sub>, receptors.

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Keywords Cannabinoid CB1 receptor · GPR55 receptor · Sympathetic vasopressor outflow
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Journal Journal of Vascular Research
Marichal-Cancino, B.A, González-Hernández, A, Maassen van den Brink, A, Ramírez-San Juan, E, & Villalón, C.M. (2020). Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats. Journal of Vascular Research. doi:10.1159/000506158