Characterization of the vasorelaxant mechanisms of the endocannabinoid anandamide in rat aorta

Herradón, Esperanza; Martín, M. I. Fernández San; López‐Miranda, Visitación

doi:10.1038/sj.bjp.0707404

Cited by 48 publications

(68 citation statements)

References 54 publications

(89 reference statements)

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“…This is evidenced by the fact that the vasorelaxant effects of AEA and 2-AG can be inhibited by FAAH, MAGL, cyclooxygenase (COX) and cytochrome P450 inhibition (Ellis et al 1995;Fleming et al 1999;Gauthier et al 2005;Herradon et al 2007;Awumey et al 2008;Czikora et al 2012;Stanley and O'Sullivan 2014b). The metabolites produced include arachidonic acid, prostaglandins and epoxyeicosatrienoic acids (Pratt et al 1998;Stanke-Labesque et al 2004), which can themselves have direct vascular effects, or be further metabolised into vasoactive substances.…”

Section: Metabolic Products Of Cannabinoidsmentioning

confidence: 96%

“…However, there is no role for CB e in the vasorelaxant effects of 2-AG (Kagota et al 2001) or PEA (White and Hiley 1998). Vasorelaxation induced by the activation of CB e may involve the release of endothelium-derived hyperpolarising factor O'Sullivan et al 2004b), BK ca channel modulation (Hoi and Hiley 2006) and NO production (Mukhopadhyay et al 2002;Herradon et al 2007;McCollum et al 2007). …”

Section: 3mentioning

confidence: 96%

“…Activation of this receptor by AEA has been confirmed in numerous studies. In rabbit aortic rings, AEA causes vasorelaxation through a pertussis toxin (PTX)-sensitive endothelial receptor (Mukhopadhyay et al 2002), and in the rat aorta, AEA-induced relaxation is sensitive to endothelium denudation, PTX and O-1918 (a proposed antagonist of CB e that has no affinity for CB 1 or CB 2 receptors), but not to CB 1 or CB 2 antagonism (Herradon et al 2007). Similar results have been obtained in rat resistance mesenteric arteries (O'Sullivan et al 2004a).…”

Section: 3mentioning

confidence: 97%

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Endocannabinoids and the Cardiovascular System in Health and Disease

O’Sullivan

2015

Handbook of Experimental Pharmacology

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The endocannabinoid system is widely distributed throughout the cardiovascular system. Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders. In shock, endocannabinoids released within blood mediate the associated hypotension through CB(1) activation. In hypertension, there is evidence for changes in the expression of CB(1), and CB(1) antagonism reduces blood pressure in obese hypertensive and diabetic patients. The endocannabinoid system is also upregulated in cardiac pathologies. This is likely to be cardioprotective, via CB(2) and CB(1) (lesser extent). In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids. Endocannabinoids have positive (CB(2)) and negative effects (CB(1)) on the progression of atherosclerosis. However, any negative effects of CB(1) may not be consequential, as chronic CB(1) antagonism in large scale human trials was not associated with significant reductions in atheroma. In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB(1), CB(2), TRPV1 and PPARα. Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.

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Section: Metabolic Products Of Cannabinoidsmentioning

confidence: 96%

Section: 3mentioning

confidence: 96%

Section: 3mentioning

confidence: 97%

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Endocannabinoids and the Cardiovascular System in Health and Disease

O’Sullivan

2015

Handbook of Experimental Pharmacology

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“…Two other receptors that seem to play roles in AEA signaling are the vanilloid receptors and a non-CB1/ non-CB-2 cannabinoid receptor. These receptors are believed to play roles in mediating AEA-dependent vasorelaxant effects (De Petrocellis et al, 2001;Herradón et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Effects of a Commonly Occurring Genetic Polymorphism of Human CYP3A4 (I118V) on the Metabolism of Anandamide

Pratt-Hyatt¹,

Zhang²,

Snider³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The endocannabinoid system plays an important role in numerous physiological processes including mood, appetite, and pain sensation. A critical compound in maintaining cannabinoid tone is the endocannabinoid anandamide (AEA). We have recently shown that AEA is metabolized by several different human cytochromes P450 (P450) to form a number of metabolites, one of which exhibits increased biological activity. CYP3A4, one of the major P450s involved in the metabolism of AEA, produces four major metabolites. One of these metabolites, 5,6-epoxyeicosatrienoic acid ethanolamide (5,6-EET-EA), exhibits a much higher affinity than AEA for the cannabinoid 2 receptor (CB-2), which leads to a marked decrease in intracellular cAMP levels in cells expressing CB-2. There are multiple human alleles of CYP3A4, and the CYP3A4.4 allele has been shown to exhibit a significant decrease in activity.Recombinant CYP3A4*4 was expressed in Escherichia coli and was demonstrated to produce 60% less 6-hydroxytestosterone than the wild-type (WT) 3A4 in a reconstituted system. The metabolism of AEA by the WT and the CYP3A4.4 variant was investigated. The mutant produced 60% less of the four EET-EA metabolites than the WT. The mutant also produced a new peak on liquid chromatography-mass spectrometry not seen with the WT, which corresponded to 19-hydroxyeicosatetraenoic acid-ethanolamide. In addition, the mutant produces four novel peaks at m/z 380, which correspond to the addition of two oxygen atoms, possibly to form a peroxide bond. These data indicate that individuals expressing the CYP3A4.4 allele may exhibit significant variations in the metabolism of AEA as well as any other compounds resembling AEA.

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“…Based on these results, especially CB1 receptors have been proposed as promising therapeutic targets for the treatment of arterial hypertension (2). Endocannabinoids are also known to potentially act via their intracellular enzymatic metabolization by the fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) to (vaso)active intermediates (3,4), but these pathways are considered less important for the regulation of vascular tone in systemic vessels.…”

mentioning

confidence: 99%

Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction

Wenzel

Matthey²,

Bîndilă

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Endocannabinoids are important regulators of organ homeostasis. Although their role in systemic vasculature has been extensively studied, their impact on pulmonary vessels remains less clear. Herein, we show that the endocannabinoid anandamide (AEA) is a key mediator of hypoxic pulmonary vasoconstriction (HPV) via fatty acid amide hydrolase (FAAH)-dependent metabolites. This is underscored by the prominent vasoconstrictive effect of AEA on pulmonary arteries and strongly reduced HPV in FAAH −/− mice and wild-type mice upon pharmacological treatment with FAAH inhibitor URB597. In addition, mass spectrometry measurements revealed a clear increase of AEA and the FAAH-dependent metabolite arachidonic acid in hypoxic lungs of wild-type mice. We have identified pulmonary vascular smooth muscle cells as the source responsible for hypoxia-induced AEA generation. Moreover, either FAAH −/− mice or wild-type mice treated with FAAH inhibitor URB597 are protected against hypoxia-induced pulmonary hypertension and the concomitant vascular remodeling in the lung. Thus, the AEA/ FAAH pathway is an important mediator of HPV and is involved in the generation of pulmonary hypertension. pulmonary vascular tone | cannabinoid E ndocannabinoids have been shown to induce vasorelaxation in systemic vessels which is primarily mediated by the specific cannabinoid 1 and 2 (CB1/CB2) and also other G protein-coupled receptors (e.g., non-CB1/CB2 receptors) (1, 2). Based on these results, especially CB1 receptors have been proposed as promising therapeutic targets for the treatment of arterial hypertension (2). Endocannabinoids are also known to potentially act via their intracellular enzymatic metabolization by the fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) to (vaso)active intermediates (3, 4), but these pathways are considered less important for the regulation of vascular tone in systemic vessels.Pulmonary arteries are unique because of their prominent vasoconstriction in response to hypoxia. Hypoxic vasoconstriction is responsible for adapting perfusion to ventilation in the lungs and therefore also plays an important role in pathophysiological situations characterized by a high ventilation/perfusion mismatch such as acute lung injury or liver cirrhosis (5, 6). In addition, this mechanism potentially contributes to the onset of pulmonary hypertension in response to hypoxia occurring in high altitude or in various respiratory diseases such as chronic obstructive pulmonary disease or fibrosis (7-9). Pulmonary arterial smooth muscle cells are suggested to play a major role in hypoxic vasoconstriction (10), but the precise mechanisms and the underlying signals are still not well understood. Earlier experimental evidence suggested that the endocannabinoid anandamide (AEA) can either enhance (11) or reduce (12) pulmonary arterial tone, and this prompted us to reexplore the role of endocannabinoids in basic physiological and pathophysiological responses of pulmonary arteries using experimental in vitro, ex vivo, and in viv...

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Characterization of the vasorelaxant mechanisms of the endocannabinoid anandamide in rat aorta

Cited by 48 publications

References 54 publications

Endocannabinoids and the Cardiovascular System in Health and Disease

Endocannabinoids and the Cardiovascular System in Health and Disease

Effects of a Commonly Occurring Genetic Polymorphism of Human CYP3A4 (I118V) on the Metabolism of Anandamide

Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction

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