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Beneficial Changes in Rat Vascular Endocannabinoid System In International Journal of Molecular Sciences Article Beneficial Changes in Rat Vascular Endocannabinoid System in Primary Hypertension and under Treatment with Chronic Inhibition of Fatty Acid Amide Hydrolase by URB597 Marta Baranowska-Kuczko 1,2,* , Hanna Kozłowska 1, Monika Kloza 1, Ewa Harasim-Symbor 3, Michał Biernacki 4 , Irena Kasacka 5 and Barbara Malinowska 1 1 Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland; [email protected] (H.K.); [email protected] (M.K.); [email protected] (B.M.) 2 Department of Clinical Pharmacy, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland 3 Department of Physiology, Medical University of Białystok, ul. Mickiewicza 2C, 15-222 Białystok, Poland; [email protected] 4 Department of Analytical Chemistry, Medical University of Białystok, ul. Mickiewicza 2D, 15-222 Białystok, Poland; [email protected] 5 Department of Histology and Cytophysiology, Medical University of Białystok, ul. Mickiewicza 2C, 15-222 Białystok, Poland; [email protected] * Correspondence: [email protected]; Tel./Fax: +48-85-74-856-99 Citation: Baranowska-Kuczko, M.; Abstract: Our study aimed to examine the effects of hypertension and the chronic administration of Kozłowska, H.; Kloza, M.; the fatty acid amide hydrolase (FAAH) inhibitor URB597 on vascular function and the endocannabi- Harasim-Symbor, E.; Biernacki, M.; noid system in spontaneously hypertensive rats (SHR). Functional studies were performed on small Kasacka, I.; Malinowska, B. Beneficial mesenteric G3 arteries (sMA) and aortas isolated from SHR and normotensive Wistar Kyoto rats Changes in Rat Vascular (WKY) treated with URB597 (1 mg/kg; twice daily for 14 days). In the aortas and sMA of SHR, Endocannabinoid System in Primary endocannabinoid levels and cannabinoid CB receptor (CB R) expression were elevated. The CB R Hypertension and under Treatment 1 1 1 with Chronic Inhibition of Fatty Acid antagonist AM251 diminished the methanandamide-evoked relaxation only in the sMA of SHR and Amide Hydrolase by URB597. Int. J. enhanced the vasoconstriction induced by phenylephrine and the thromboxane analog U46619 in Mol. Sci. 2021, 22, 4833. https:// sMA in SHR and WKY. In the sMA of SHR, URB597 elevated anandamide levels, improved the doi.org/10.3390/ijms22094833 endothelium-dependent vasorelaxation to acetylcholine, and in the presence of AM251 reduced the vasoconstriction to phenylephrine and enhanced the vasodilatation to methanandamide, and Academic Editor: tended to reduce hypertrophy. In the aortas, URB597 elevated endocannabinoid levels improved the Joaquín García-Estañ endothelium-dependent vasorelaxation to acetylcholine and decreased CB1R expression. Our study showed that hypertension and chronic administration of URB597 caused local, resistance artery- Received: 29 March 2021 specific beneficial alterations in the vascular endocannabinoid system, which may bring further Accepted: 29 April 2021 advantages for therapeutic application of pharmacological inhibition of FAAH. Published: 2 May 2021 Keywords: FAAH inhibitor; URB597; SHR; endocannabinoids; cannabinoid CB1 receptor Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Hypertension is a devastating disease, affecting 20–50% of the world’s population. The endocannabinoid system is overactivated in hypertension (for reviews, see [1–3]). It consists of endocannabinoids, such as anandamide and 2-arachidonoyl glycerol (2- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. AG), the enzymes responsible for their synthesis (for details, see 2) and degradation— This article is an open access article fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively distributed under the terms and as well as cannabinoid CB1 and CB2, receptors. Endocannabinoids may also act in non- conditions of the Creative Commons CB1/CB2 receptor manner, i.e., activating transient channel vanilloid type 1 (TRPV1), Attribution (CC BY) license (https:// calcium-dependent potassium channels (KCa) or via vasoconstrictor (i.e., thromboxanes) creativecommons.org/licenses/by/ and vasodilator (i.e., prostaglandin E2, prostacyclin) arachidonic acid breakdown products 4.0/). derived from endocannabinoids (Figure1; for reviews, see [1–3]). Int. J. Mol. Sci. 2021, 22, 4833. https://doi.org/10.3390/ijms22094833 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 4671 2 of 22 CB1/CB2 receptor manner, i.e., activating transient channel vanilloid type 1 (TRPV1), calcium-dependent potassium channels (KCa) or via vasoconstrictor (i.e., thromboxanes) Int. J. Mol. Sci. 2021, 22, 4833 and vasodilator (i.e., prostaglandin E2, prostacyclin) arachidonic acid breakdown2 of 21 products derived from endocannabinoids (Figure 1; for reviews, see [1–3]). Figure 1.1. Summary of thethe mechanismsmechanisms ofof thethe vasodilatoryvasodilatory effectseffects ofof endocannabinoidsendocannabinoids andand theirtheir interactioninteraction withwith chosenchosen vasoconstrictorsvasoconstrictors inin thethe resistanceresistance vasculature.vasculature. TheThe mesentericmesenteric arteriesarteries areare used as an example. Endocannabinoids Endocannabinoids anandamide anandamide and and 2-arachidonoylglycerol 2-arachidonoylglycerol (2-AG), (2-AG), as aswell well as methanandamide (MethAEA, synthetic stable analog of anandamide), induce relaxation of the as methanandamide (MethAEA, synthetic stable analog of anandamide), induce relaxation of the mesenteric arteries via CB1-dependent and CB1-independent mechanisms (non-CB1). CB1 receptors mesenteric arteries via CB1-dependent and CB1-independent mechanisms (non-CB1). CB1 recep- are located in smooth muscle or endothelial cells. Non-CB1-mediated pathways include CB2 tors are located in smooth muscle or endothelial cells. Non-CB -mediated pathways include CB receptors, transient receptor potential vanilloid type-1 (TRPV1) 1and others. Stimulation of CB1 and2 receptors,non-CB1 pathways, transient receptorin turn, may potential result vanilloid in the activa type-1tion (TRPV1) of calcium-dependent and others. Stimulation potassium of CBchannels1 and non-CB(KCa) and1 pathways, hyperpolarization in turn, may of resultsmooth in themuscle activation cells. ofIn calcium-dependent addition, anandamide potassium and 2-AG channels are (KmetabolizedCa) and hyperpolarization to arachidonic acid of smooth(AA) via muscle fatty ac cells.id amide In addition,hydrolase anandamide (FAAH) and andmonoacylglycerol 2-AG are me- tabolizedlipase (MAGL), to arachidonic respectively. acid AA (AA) may via be fatty further acid converted amide hydrolase into either (FAAH) vasodilator and monoacylglycerol or vasoconstrictor lipaseeicosanoids (MAGL), (reviewed respectively. in AA[1,3]). may Vasoconstrictors be further converted (e.g., into agonists either vasodilatorof α1-adrenergic or vasoconstrictor receptors, phenylephrine or thromboxane TP receptors, thromboxane A2 analog—U46619) in addition to their eicosanoids (reviewed in [1,3]). Vasoconstrictors (e.g., agonists of α1-adrenergic receptors, phenyle- direct contractile effects, indirectly mediate the rapid biosynthesis of endocannabinoids. phrine or thromboxane TP receptors, thromboxane A2 analog—U46619) in addition to their direct Endocannabinoids may then activate the CB1- and non-CB1-dependent vasodilatory effects. The contractile effects, indirectly mediate the rapid biosynthesis of endocannabinoids. Endocannabinoids above-mentioned endocannabinoid negative feedback leads to the reduction of the agonist-induced mayvasoconstriction. then activate The the components CB1- and non-CB of the 1endocanna-dependentbinoid vasodilatory system and effects. drugs The that above-mentioned were considered endocannabinoidin this study are marked negative in feedback black frames. leads toAM251—the the reduction antagonist of the agonist-induced of CB1 receptors; vasoconstriction. URB597—the TheFAAH components inhibitor; T—endocannabinoid of the endocannabinoid membrane system andtransporter; drugs that black were and considered gray arrows in designate this study CB are1- markedand non-CB in black1-mediated frames. receptor AM251—the changes, antagonist respectively; of CB the1 receptors; red minus URB597—the sign indicates FAAH reduction. inhibitor; T—endocannabinoid membrane transporter; black and gray arrows designate CB1- and non-CB1- mediatedThe receptorendocannabinoid changes, respectively; system has the redbeen minus demonstrated sign indicates to reduction. play—at least locally—a protective role in the vasculature. First, in rats with primary hypertension (spontaneously hypertensive;The endocannabinoid SHR) and in systemdifferent has models been demonstratedof secondary tohypertension, play—at least cannabinoids locally—a protective(e.g., anandamide role in the and vasculature. its stable First,analog in methanandamide; rats with primary hypertensionMethAEA) exerted (spontaneously stronger hypertensive;vasodilatory and SHR) hypotensive and in different effects than models in normotensive of secondary controls. hypertension, Moreover, cannabinoids inhibitors (e.g.,of fatty anandamide acid amide andhydrolase its stable (FAAH; analog URB597 methanandamide; and AM3506), MethAEA) an enzyme exerted responsible stronger for vasodilatoryendocannabinoid and hypotensivedegradation, effects reduced than blood in normotensive pressure, which
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