Mesenteric Vasodilation Mediated by Endothelial Anandamide Receptors

Wagner, Jens A.; Varga, K; Járai, Zoltán; Kunos, George

doi:10.1161/01.hyp.33.1.429

Cited by 237 publications

(227 citation statements)

References 38 publications

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“…The increase in K ϩ current by abn-cbd was unaffected by relevant concentrations of SR141716 or SR144528, which argues against the involvement of CB 1 and CB 2 receptors, respectively. This is further supported by the lack of effect on K ϩ currents of HU-210, a potent CB 1 /CB 2 receptor agonist, which is devoid of mesenteric vasodilator activity (11). On the other hand, the abn-cbd-induced increase in K ϩ current was effectively inhibited by O-1918, a structural analog of cannabidiol, which produced no effect by itself.…”

Section: Discussionmentioning

confidence: 90%

G Protein-coupled Endothelial Receptor for Atypical Cannabinoid Ligands Modulates a Ca2+-dependent K+ Current

Begg

Offertáler

et al. 2003

Journal of Biological Chemistry

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The cannabinoid analog "abnormal cannabidiol" (abn-cbd) causes endothelium-dependent vasodilation in rat isolated mesenteric arteries through a G protein-coupled receptor distinct from CB 1 or CB 2 . We examined the actions of abn-cbd on the electrophysiology of human umbilical vein endothelial cells (HU-VEC), using the whole cell version of the patch clamp technique. Voltage steps produced noninactivating outward currents, which were abolished by iberiotoxin or by chelation of intracellular calcium. The presence of a BK Ca channel in HUVEC was documented by reverse transcriptase-PCR. Abn-cbd concentration dependently potentiated the outward current produced by a single voltage step. This potentiation was abolished by the cannabidiol analog O-1918 or by pertussis toxin but was unaffected by CB 1 or CB 2 antagonists. HU-210, a CB 1 /CB 2 receptor agonist, had no effect on the outward current. Clamping The marijuana plant contains more than 60 chemical substances of which ⌬ 9 -tetrahydrocannabinol is the main psychoactive ingredient (1).

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Section: Discussionmentioning

confidence: 90%

G Protein-coupled Endothelial Receptor for Atypical Cannabinoid Ligands Modulates a Ca2+-dependent K+ Current

Begg

Offertáler

et al. 2003

Journal of Biological Chemistry

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“…A more detailed overview of in vitro effects of anandamide can be found in the following reviews Ho¨gestatt & Zygmunt, 2002;Randall et al, 2002). Some studies have implicated the endothelium in relaxant responses to anandamide (Pratt et al, 1998;Chaytor et al, 1999;Wagner et al, 1999), with the release of prostanoids (Ellis et al, 1995;Fleming et al, 1999), nitric oxide (Deutsch et al, 1997) or endothelial-derived hyperpolarising factor (EDHF) (Chaytor et al, 1999). Some, but not all, studies have reported that anandamide acts through the stimulation of cannabinoid CB 1 receptors, although the intracellular pathway(s) coupling to vasodilatation have not been clearly identified (White & Hiley, 1997).…”

Section: Introductionmentioning

confidence: 99%

The complexities of the cardiovascular actions of cannabinoids

Randall

Kendall

O’Sullivan

2004

British J Pharmacology

142

122

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The cardiovascular actions of cannbinoids are complex. In general they cause vasorelaxation in isolated blood vessels, while in anaesthetised animals they cause multiphasic responses which involve an early bradycardia and long-lasting hypotension. However, in conscious animals, the picture is one of bradycardia followed by pressor responses. Clearly, the responses to cannabinoids are dependent on the experimental conditions and synthetic cannabinoids and endocannabinoids exhibit different pharmacologies. In terms of mechanisms involved in the vascular responses to cannabinoids, the following have been implicated: the involvement of 'classical' cannabinoid receptors, the involvement of a novel endothelial cannabinoid receptor, the release of nitric oxide, the release of endotheliumderived hyperpolarising factor (EDHF), the activation of vanilloid receptors, metabolism of endocannabinoids to vasoactive molecules, and both peripheral inhibition and central excitation of the sympathetic nervous system.

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“…Marijuana, one of the most widely abused substances (1), mediates many of its psychotropic effects by targeting CB 1 receptors in the central nervous system, but studies with CB 1 and CB 2 knock-out mice indicate that the complex pharmacological properties on pain, mood, and memory exhibited by exogenous cannabinoids and the endogenous arachidonic acidbased endo-cannabinoids, including anandamide and 2-arachidonoylglycerol (2-AG), are not fully explained by their activation of CB 1 and CB 2 (2)(3)(4). The CB 1 and CB 2 receptors are 44% identical and signal through G i/o -mediated pathways.…”

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confidence: 99%

Atypical Responsiveness of the Orphan Receptor GPR55 to Cannabinoid Ligands

Kapur

Zhao

Sharir

et al. 2009

Journal of Biological Chemistry

251

289

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The cannabinoid receptor 1 (CB 1 ) and CB 2 cannabinoid receptors, associated with drugs of abuse, may provide a means to treat pain, mood, and addiction disorders affecting widespread segments of society. Whether the orphan G-protein coupled receptor GPR55 is also a cannabinoid receptor remains unclear as a result of conflicting pharmacological studies. GPR55 has been reported to be activated by exogenous and endogenous cannabinoid compounds but surprisingly also by the endogenous non-cannabinoid mediator lysophosphatidylinositol (LPI). We examined the effects of a representative panel of cannabinoid ligands and LPI on GPR55 using a ␤-arrestingreen fluorescent protein biosensor as a direct readout of agonist-mediated receptor activation. Our data demonstrate that AM251 and SR141716A (rimonabant), which are cannabinoid antagonists, and the lipid LPI, which is not a cannabinoid receptor ligand, are GPR55 agonists. They possess comparable efficacy in inducing ␤-arrestin trafficking and, moreover, activate the G-protein-dependent signaling of protein kinase C␤II. Conversely, the potent synthetic cannabinoid agonist CP55,940 acts as a GPR55 antagonist/partial agonist. CP55,940 blocks GPR55 internalization, the formation of ␤-arrestin GPR55 complexes, and the phosphorylation of ERK1/2; CP55,940 produces only a slight amount of protein kinase C␤II membrane recruitment but does not stimulate membrane remodeling like LPI, AM251, or rimonabant. Our studies provide a paradigm for measuring the responsiveness of GPR55 to a variety of ligand scaffolds comprising cannabinoid and novel compounds and suggest that at best GPR55 is an atypical cannabinoid responder. The activation of GPR55 by rimonabant may be responsible for some of the off-target effects that led to its removal as a potential obesity therapy.The CB 1 2 and CB 2 cannabinoid receptors comprise a twomember subfamily of G-protein-coupled receptors (GPCRs) that are notable as the targets of the tetrahydrocannabinol (THC) derivatives found in marijuana. More recently CB 1 receptors along with other GPCRs have been promoted as therapeutic pharmacological targets in the billion dollar weight loss market for controversial drugs such as rimonabant (SR141716A) and Fen-phen. Thus, an important utility of cannabinoid family receptors to society appears to arise from their role in regulating a broad spectrum of addiction-based behaviors, and the addition of new members to the cannabinoid receptor family may have social and economic implications that reach far beyond the initial scientific discovery. As a consequence, the re-classification of an orphan GPCR as a cannabinoid family member should be done with caution requiring strict criteria of receptor activation by THC derivatives or endogenous cannabinoid compounds and a widespread agreement of the results by the scientific community.Marijuana, one of the most widely abused substances (1), mediates many of its psychotropic effects by targeting CB 1 receptors in the central nervous system, but studies with CB 1 and CB 2 kno...

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Mesenteric Vasodilation Mediated by Endothelial Anandamide Receptors

Cited by 237 publications

References 38 publications

G Protein-coupled Endothelial Receptor for Atypical Cannabinoid Ligands Modulates a Ca2+-dependent K+ Current

G Protein-coupled Endothelial Receptor for Atypical Cannabinoid Ligands Modulates a Ca2+-dependent K+ Current

The complexities of the cardiovascular actions of cannabinoids

Atypical Responsiveness of the Orphan Receptor GPR55 to Cannabinoid Ligands

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