An Endogenous Cannabinoid as an Endothelium-Derived Vasorelaxant

doi:10.1006/bbrc.1996.1766

Biochemical and Biophysical Research Communications

Volume 229, Issue 1, 4 December 1996, Pages 114-120

https://doi.org/10.1006/bbrc.1996.1766 Get rights and content

Abstract

Since the identification of nitric oxide (NO) as an important mediator of endothelium-dependent relaxation, it has become clear that there is an additional endothelial relaxant factor, termed the endothelium-derived hyperpolarizing factor (EDHF). The identity of EDHF has remained elusive, but it is thought to be an arachidonic acid metabolite. We now report that EDHF-mediated relaxations in the rat mesenteric arterial bed are blocked by a highly selective cannabinoid receptor antagonist, SR141716A, consistent with EDHF being a cannabinoid-like substance. Furthermore, in conscious rats, the NO-independent depressor and regional vasodilator effects of bradykinin were inhibited by SR141716A. The relaxations in the isolated mesentery were accompanied by the accumulation of an arachidonic acid metabolite, which co-eluted on TLC separation with arachidonoylethanolamide (anandamide), an endogenous cannabinoid derived from arachidonate. We further report that anandamide is a potent vasorelaxant in the mesentery, acting via a hyperpolarizing mechanism. These findings suggest that an endogenous cannabinoid is an endothelium-derived vasorelaxant, which may be EDHF.

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Cited by (241)

Mechanisms of vasorelaxation induced by the cannabidiol analogue compound O-1602 in the rat small mesenteric artery
2015, European Journal of Pharmacology
Citation Excerpt :
Involvement of prostacyclin in O-1602-mediated relaxation can be ruled out as inhibition of its production, with indomethacin, did not show any significant inhibitory effect. This is in agreement with other studies which have demonstrated a minimal role for eicosanoids in cannabinoid-mediated vasorelaxation (AlSuleimani and Hiley, 2013; Ho and Hiley, 2003b; Plane and Garland, 1996; Randall et al., 1996; Randall and Kendall, 1997; White and Hiley, 1997) although some reports have indicated that relaxation to anandamide and ∆9-THC in cerebral arteries could be mediated by release and metabolism of arachidonic acid, as the effect was inhibited by indomethacin (Ellis et al., 1995). In addition, a recent study has pointed out that anandamide induced-relaxation in rat aorta was partially mediated by a COX-2 metabolite (Herradon et al., 2007).
Atypical cannabinoid O-1602 (5-Methyl-4-[(1R,6R)-3-methyl-6-(1-cyclohexen-1-yl]-1,3-benzenediol) induces vasorelaxation and activates the orphan G protein-coupled receptor GPR55 in human endothelial cells. This study investigates the underlying mechanisms of vasorelaxation induced by this compound. The vasodilator activity was assessed in the rat third order branch of the superior mesenteric artery using a wire myograph. The vasorelaxation was partially endothelium-dependent (pEC_50%=5.8±0.3). The endothelial component was antagonized by the putative endothelial receptor antagonists rimonabant (3 µM; pEC_50%=5.1±0.2) and O-1918 (10 µM; pEC_50%=5.3±0.2) but not by the CB₁ and CB₂ receptors antagonists AM 251 (10 µM) and AM 630 (10 µM), respectively. The vasorelaxation was not pertussis toxin-sensitive and not mediated through TRPVI receptors or by the release of NO, but was reduced by inhibition of Ca²⁺ sensitive K⁺ channels (K_Ca). In endothelium-denuded vessels, O-1602 abolished CaCl₂-induced contraction and the inhibition was apparently reversed by O-1918. O-1602 mediates its vasorelaxant effects partly by an endothelium-dependent pathway involving rimonabant- and O-1918-sensitive targets that are distinct from the classical CB₁ and CB₂ cannabinoid receptors and might involve activation of K_Ca. The endothelium-independent relaxation might involve interfering with Ca²⁺ entry.
Regulation of endocannabinoid release by G proteins: A paracrine mechanism of G protein-coupled receptor action
2012, Molecular and Cellular Endocrinology
Citation Excerpt :
Two early studies showed that the endothelium-dependent vasodilatory effects of bradykinin and/or carbachol can be antagonized by the CB1R inverse agonist SR141716A in the rat mesenteric artery. In both studies, application of the calcium ionophore A23187 also caused endothelium-dependent vasodilation, which was inhibited by SR141716A (Randall et al., 1996; White and Hiley, 1997). In the next few years, the presence of CB1 receptors on vascular smooth muscle (Gebremedhin et al., 1999) and endothelial cells (Liu et al., 2000), as well as on sympathetic nerve endings innervating the vessels (Ishac et al., 1996) was also documented.
In the past years, the relationship between the endocannabinoid system (ECS) and other hormonal and neuromodulatory systems has been intensively studied. G protein-coupled receptors (GPCRs) can stimulate endocannabinoid (eCB) production via activation of G_q/11 proteins and, in some cases, G_s proteins. In this review, we summarize the pathways through which GPCR activation can trigger eCB release, as well as the best known examples of this process throughout the body tissues. Angiotensin II-induced activation of AT₁ receptors, similar to other G_q/11-coupled receptors, can lead to the formation of 2-arachidonoylglycerol (2-AG), an important eCB. The importance of eCB formation in angiotensin II action is supported by the finding that the hypertensive effect of angiotensin II, injected directly into the hypothalamic paraventricular nucleus of anaesthetized rats, can be abolished by AM251, an inverse agonist of CB₁ cannabinoid receptors (CB₁Rs). We conclude that activation of the ECS should be considered as a general consequence of the stimulation of G_q/11-coupled receptors, and may mediate some of the physiological effects of GPCRs.
Anandamide induces endothelium-dependent vasoconstriction and CGRPergic nerve-mediated vasodilatation in the rat mesenteric vascular bed
2012, Journal of Pharmacological Sciences
An endogenous cannabinoid anandamide (N-arachidonoylethanolamide) has been shown to cause vasodilatation in vitro and a brief vasoconstriction followed by prolonged depressor response in vivo. This study investigated the vascular effects of anandamide and underlying mechanisms in rat mesenteric vascular beds. In preparations with an intact endothelium and active tone, anandamide at low concentrations (0.1 – 1 nM) caused a concentration-dependent decrease in perfusion pressure due to vasodilatation, but at high concentrations (10 nM – 1 μM) elicited an initial and sharp increase in perfusion pressure due to vasoconstriction followed by long-lasting vasodilatation in a concentration-dependent manner. Treatment with SR141716A [cannabinoid-1 (CB₁)-receptor antagonist] blunted both the vasoconstrictor and vasodilator responses. Also, removal of the endothelium and indomethacin (cyclooxygenase inhibitor), but not adrenergic denervation with 6-hydoxydopamine (adrenergic neurotoxin), markedly inhibited the vasoconstrictor response to anandamide, while these treatments did not affect vasodilatation. The vasodilatation, but not vasoconstriction, in response to anandamide was markedly attenuated by capsazepine [selective antagonist for transient receptor potential vanilloid-1 (TRPV1)], pretreatment with capsaicin [calcitonin gene–related peptide (CGRP)ergic-nerve depletor], or cold-storage denervation. These results suggest that in rat mesenteric vascular beds, anandamide causes CB₁-receptor–and prostanoid-mediated endothelium-dependent vasoconstriction and perivascular capsaicin-sensitive CGRPergic nerve–mediated vasodilatation.
Mechanisms involved in oleamide-induced vasorelaxation in rat mesenteric resistance arteries
2009, European Journal of Pharmacology
Fatty acid amides are a new class of signaling lipids that have been implicated in diverse physiological and pathological conditions. Oleamide is a fatty acid amide that induces vasorelaxation. Here, we investigated the mechanisms behind the vasorelaxation effect of oleamide in rat mesenteric resistance arteries. Oleamide-induced concentration dependent (0.01 µM–10 µM) vasorelaxation in mesenteric resistance arteries. This relaxation was unaffected by the presence of the fatty acid amide hydrolase (FAAH) inhibitors. The cannabinoid type 1 (CB₁) receptor antagonist, AM251 and the non-CB₁/CB₂ cannabinoid receptor antagonist, O-1918, attenuated the oleamide vasodilatory response, however the cannabinoid CB₂ receptor antagonist, AM630, did not affect the vascular response. Moreover, inhibition of the transient receptor potential vanilloid (TRPV) 1 receptor with capsazepine shifted the oleamide-induced vasorelaxation response to the right. In agreement with the vascular functional data, the cannabinoid CB₁ and TRPV1 receptor proteins were expressed in mesenteric resistance arteries but cannabinoid CB₂ receptors and the FAAH enzyme were not. In endothelium-denuded arteries, the oleamide-mediated vasorelaxation was attenuated and cannabinoid CB₁ or non-CB₁/CB₂ cannabinoid receptor blockade did not further reduce the dilatory response whereas TRPV1 antagonism further decreased the response. These findings indicate that cannabinoid receptors on the endothelium and endothelium-independent TRPV1 receptors contribute to the oleamide vasodilatory response. Taken together, these results demonstrate that the oleamide-induced vasorelaxation is mediated, in part, by cannabinoid CB₁ receptors, non-CB₁/CB₂ cannabinoid receptors, and TRPV1 receptors in rat mesenteric resistance arteries. These mechanisms are overlapping in respect to oleamide-induced mesenteric resistance artery dilation.
Functional characterization of nonadrenergic noncholinergic neurotransmitter release via endocannabinoids: An in vitro study in rabbit corpus cavernosum
2009, Journal of Sexual Medicine
Citation Excerpt :
This result has demonstrated that endocannabinoids did not enhance EFS-induced relaxation responses by releasing agents like NO and prostaglandins from corpus cavernosum endothelia. Randall et al. demonstrated that anandamide is a potent endothelium-derived vasorelaxant in the mesentery, acting via a hyperpolarizing mechanism that could involve endothelium-derived hyperpolarizing factor (EDHF) [43]. However, in the rat hepatic artery, it was demonstrated that anandamide induces hyperpolarization by an inhibitory action at Ca+2 stores and is not the same entity as EDHF [33].
Corporal smooth muscle relaxation is mediated mainly but not completely by nitric oxide. Endocannabinoids modulate the various neurotransmitter systems.
In the present study, a possible role of endocannabinoids on non-nitrergic nonadrenergic noncholinergic (NANC)-mediated relaxations was investigated.
In precontracted tissues, control electrical field stimulation (EFS)-induced NANC relaxation responses were obtained using varying frequencies of stimulation in the presence of L-arginine methyl ester (L-NAME), guanethidine, and atropine. To investigate the effects of cannabinoids on EFS-evoked non-nitrergic NANC relaxation responses, a similar experimental procedure was applied in the presence of cannabinoid receptor antagonists AM251 or AM630; vanilloid receptor antagonist capsazepine; or cannabinoid receptor agonists anandamide, arachidonyl-2-chloroethylamide (ACEA), or JHW015.
Effects of cannabinoid receptor antagonists and agonists on EFS-evoked non-nitrergic NANC relaxation responses.
L-NAME abolished EFS-induced relaxation responses at lower frequencies (2–4 Hz) and inhibited the relaxation responses at higher frequencies (8–32 Hz). AM251 and AM630 either together or separately inhibited, whereas anandamide, ACEA, and JHW015 enhanced non-nitrergic NANC relaxation responses. Anandamide did not alter EFS-induced non-nitrergic NANC relaxations in the presence of AM251 and AM630. Capsazepine enhanced non-nitrergic NANC relaxation responses.
These results suggest that non-nitrergic NANC relaxations may be mediated partially by cannabinoid-like neuronal factors acting at both cannabinoid CB₁ and cannabinoid CB₂ receptors. Vural IM, Ozturk GS, and Sarioglu Y. Functional characterization of nonadrenergic noncholinergic neurotransmitter release via endocannabinoids: An in vitro study in rabbit corpus cavernosum. J Sex Med 2009;6:717–729.
Pharmacognosy and Effects of Cannabinoids in the Vascular System
2022, ACS Pharmacology and Translational Science

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Regular ArticleAn Endogenous Cannabinoid as an Endothelium-Derived Vasorelaxant

Abstract

Regular Article
An Endogenous Cannabinoid as an Endothelium-Derived Vasorelaxant