Beneficial Changes in Rat Vascular Endocannabinoid System in Primary Hypertension and under Treatment with Chronic Inhibition of Fatty Acid Amide Hydrolase by URB597

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.

Fatty Acid Amide Hydrolase (FAAH) Inhibition Plays a Key Role in Counteracting Acute Lung Injury

“…The inhibition of FAAH has been shown to be useful in different experimental models, such as cisplatin- and nicotine-induced vomiting in Suncus murinus [ 15 ], naloxone-precipitated morphine withdrawal [ 16 ], gaping elicited by a lithium-paired context in the rat [ 17 ] or chronic cerebral hypoperfusion [ 18 ]. Additionally, URB597, the FAAH inhibitor most used as a pharmacological tool [ 19 ], has also shown its beneficial effects on other pathologies, such as anxiety and depression [ 20 , 21 , 22 , 23 ], neuropathic pain [ 24 ], 6-OHDA-induced Parkinson’s model [ 25 ], stress [ 26 , 27 ], hypertension [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ], and lung problems [ 35 , 36 , 37 ]. Particular attention is mainly due to the fact that the inhibition of FAAH showed no adverse cardiovascular or gastrointestinal hemorrhaging as is commonly seen with cyclo-oxygenase-2 (COX-2) inhibitors [ 38 , 39 ] and, for this reason, it has become an alternative therapeutic strategy for inflammation-related diseases.…”

Cannabinoids—A New Perspective in Adjuvant Therapy for Pulmonary Hypertension

“…Cannabinoids in systemic circulation cause the relaxation of the blood vessels, which was extensively described by Stanley et al, in 2014. In this review, we focus on papers published after Stanley et al (Table 2) [14]. The relaxation induced by various cannabinoids might be dependent on the endothelium [22,[35][36][37][38][39][40][41][42] and/or receptors (e.g., CB 1 -Rs) [22,35,37,38,[40][41][42][43] (Table 2). The potency of individual compounds depends on the vascular bed and species.…”

“…In this review, we focus on papers published after Stanley et al ( Table 2 ) [ 14 ]. The relaxation induced by various cannabinoids might be dependent on the endothelium [ 22 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ] and/or receptors (e.g., CB 1 -Rs) [ 22 , 35 , 37 , 38 , 40 , 41 , 42 , 43 ] ( Table 2 ). The potency of individual compounds depends on the vascular bed and species.…”

“…The potency of individual compounds depends on the vascular bed and species. As shown in Table 2 , according to the negative logarithm of the concentration causing a half-maximum effect (pEC 50 ) value, methanandamide (MethAEA) [ 42 ] dilated rat mesenteric arteries (rMAs) most strongly, while the weakest effects were observed for Abn-CBD in rat retinal capillaries [ 44 ] and arachidonyl cyclopropylamide (APCA) in rat aortas [ 43 ].…”

“…Conversely, in systemic vessels, CB 1 -Rs are involved in AEA- [ 38 ], CBD- [ 22 , 37 ], Meth-AEA- [ 42 , 47 ], and ACPA-induced relaxation [ 41 ] in human and animal mesenteric arteries (see Table 2 ). In systemic circulation, however, it has not yet been confirmed that the mechanism underlying the 2-AG-induced relaxation of hMAs depends on CB 1 -Rs.…”