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,Hanna Kozłowska,Barbara Malinowska,Monika Kloza,Irena Kasacka,Ewa Harasim-Symbor,Michał Biernacki

doi:10.3390/ijms22094833

Marta Baranowska-Kuczko, Hanna Kozłowska + Show 5 more

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https://doi.org/10.3390/ijms22094833

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Abstract

Our study aimed to examine the effects of hypertension and the chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on vascular function and the endocannabinoid system in spontaneously hypertensive rats (SHR). Functional studies were performed on small mesenteric G3 arteries (sMA) and aortas isolated from SHR and normotensive Wistar Kyoto rats (WKY) treated with URB597 (1 mg/kg; twice daily for 14 days). In the aortas and sMA of SHR, endocannabinoid levels and cannabinoid CB1 receptor (CB1R) expression were elevated. The CB1R antagonist AM251 diminished the methanandamide-evoked relaxation only in the sMA of SHR and enhanced the vasoconstriction induced by phenylephrine and the thromboxane analog U46619 in sMA in SHR and WKY. In the sMA of SHR, URB597 elevated anandamide levels, improved the endothelium-dependent vasorelaxation to acetylcholine, and in the presence of AM251 reduced the vasoconstriction to phenylephrine and enhanced the vasodilatation to methanandamide, and tended to reduce hypertrophy. In the aortas, URB597 elevated endocannabinoid levels improved the endothelium-dependent vasorelaxation to acetylcholine and decreased CB1R expression. Our study showed that hypertension and chronic administration of URB597 caused local, resistance artery-specific beneficial alterations in the vascular endocannabinoid system, which may bring further advantages for therapeutic application of pharmacological inhibition of FAAH.

Highlights

Hypertension is a devastating disease, affecting 20–50% of the world’s population.The endocannabinoid system is overactivated in hypertension.It consists of endocannabinoids, such as anandamide and 2-arachidonoyl glycerol (2AG), the enzymes responsible for their synthesis and degradation—fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively as well as cannabinoid CB1 and CB2, receptors
To understand whether the normal endocannabinoid tone controls vasoconstrictive response in control and hypertensive animals, we examined concentration-dependent contraction of mesenteric G3 arteries and aortas stimulated by phenylephrine and U46619 www.mdpi.com/journal/ijms in the presence of the CB1 receptor antagonist, AM251 that antagonizes endocannabinoid signaling
We found that the chronic administration of URB597 (1 mg/kg twice daily for two weeks), an inhibitor of the enzyme responsible for anandamide degradation, increased vascular anandamide and 2-AG levels and caused locally beneficial changes for primary hypertension, in terms of the function and morphology of the vasculature, in a vessel-sizedependent manner

Summary

Introduction

Hypertension is a devastating disease, affecting 20–50% of the world’s population.The endocannabinoid system is overactivated in hypertension (for reviews, see [1,2,3]).It consists of endocannabinoids, such as anandamide and 2-arachidonoyl glycerol (2AG), the enzymes responsible for their synthesis (for details, see 2) and degradation—fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively as well as cannabinoid CB1 and CB2, receptors. The endocannabinoid system is overactivated in hypertension (for reviews, see [1,2,3]). Endocannabinoids may act in nonCB1 /CB2 receptor manner, i.e., activating transient channel vanilloid type 1 (TRPV1), calcium-dependent potassium channels (KCa ) or via vasoconstrictor (i.e., thromboxanes) and vasodilator (i.e., prostaglandin E2 , prostacyclin) arachidonic acid breakdown products derived from endocannabinoids (Figure 1; for reviews, see [1,2,3]). CB1/CB2 receptor manner, i.e., activating transient channel vanilloid type 1 (TRPV1), calcium-dependent potassium channels (KCa) or via vasoconstrictor (i.e., thromboxanes) and vasodilator (i.e., prostaglandin E2, prostacyclin) arachidonic acid breakdown products derived from endocannabinoids (Figure 1; for reviews, see [1,2,3]).

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