Anandamide-induced vasorelaxation in rabbit aortic rings  has two components: G protein dependent and independent

Mukhopadhyay, Somnath; Chapnick, B. M.; Howlett, A­llyn C.

doi:10.1152/ajpheart.00497.2001

Cited by 88 publications

(127 citation statements)

References 42 publications

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“…Vascular endothelial cells express CB 1 receptors (28,34,40) as well as SR141716-sensitive receptors distinct from CB 1 or CB 2 (10,41,42). The involvement of these latter receptors is suggested by our observation 2 that the SR141716-sensitive hypotensive response to LPS remains unchanged in CB 1 knockout or CB 1 /CB 2 double knockout mice.…”

Section: Lps-treated Macrophages Elicitmentioning

confidence: 75%

Lipopolysaccharide Induces Anandamide Synthesis in Macrophages via CD14/MAPK/Phosphoinositide 3-Kinase/NF-κB Independently of Platelet-activating Factor

Liu

Bátkai

Pacher

et al. 2003

Journal of Biological Chemistry

221

185

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Macrophage-derived endocannabinoids have been implicated in endotoxin (lipopolysaccharide (LPS))-induced hypotension, but the endocannabinoid involved and the mechanism of its regulation by LPS are unknown. In RAW264.7 mouse macrophages, LPS (10 ng/ ml) increases anandamide (AEA) levels >10-fold via CD14-, NF-B-, and p44/42-dependent, platelet-activating factor-independent activation of the AEA biosynthetic enzymes, N-acyltransferase and phospholipase D. LPS also induces the AEA-degrading enzyme fatty acid amidohydrolase (FAAH), and inhibition of FAAH activity potentiates, whereas actinomycin D or cycloheximide blocks the LPS-induced increase in AEA levels and N-acyltransferase and phospholipase D activities. In contrast, cellular levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) are unaffected by LPS but increased by platelet-activating factor. LPS similarly induces AEA, but not 2-AG, in mouse peritoneal macrophages where basal AEA levels are higher, and the LPS-stimulated increase in AEA is potentiated in cells from FAAH ؊/؊ as compared with FAAH ؉/؉ mice. Intravenous administration of 10 7 LPS-treated mouse macrophages to anesthetized rats elicits hypotension, which is much greater in response to FAAH ؊/؊ than FAAH ؉/؉ cells and is susceptible to inhibition by SR141716, a cannabinoid CB 1 receptor antagonist. We conclude that AEA and 2-AG synthesis are differentially regulated in macrophages, and AEA rather than 2-AG is a major contributor to LPS-induced hypotension.Anandamide (arachidonylethanolamide, AEA) 1 and 2-arachidonoylglycerol (2-AG), recently discovered endogenous ligands of cannabinoid receptors (1), are synthesized by neurons (2) as well as macrophages (3-5) in a calcium-dependent manner. The effects of AEA at the receptor are terminated by its rapid uptake through a high affinity membrane transporter (6) and subsequent intracellular degradation by fatty acid amidohydrolase (FAAH) (7). Although 2-AG is also a substrate for FAAH in vitro, it is metabolized in vivo by a monoglyceride lipase (8). AEA and 2-AG display many of the pharmacological properties of ⌬ 9 -tetrahydrocannabinol, including the ability to elicit hypotension mediated by peripheral CB 1 receptors (9, 10), and macrophage-derived endocannabinoids have been shown to contribute to the hypotension in various forms of shock (4, 5, 11).Lipopolysaccharide (LPS), an integral part of the outer membrane of Gram-negative bacteria, is a major pathogenic factor in septic shock. Macrophages are the primary target of LPS, which interacts with the CD14 protein/toll-like receptor-4 complex (12, 13) to activate multiple signaling pathways (14), which, in turn, activate a variety of transcription factors that regulate gene expression (15). LPS induces the expression of the cytokines TNF␣, interleukin-1 (IL-1), IL-6, and IL-8, which have been implicated in the pathomechanism of septic shock (12). LPS also induces the production of lipid mediators in macrophages, such as prostaglandins (16), leukotrienes (17), and platelet-activating factor (P...

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Section: Lps-treated Macrophages Elicitmentioning

confidence: 75%

Lipopolysaccharide Induces Anandamide Synthesis in Macrophages via CD14/MAPK/Phosphoinositide 3-Kinase/NF-κB Independently of Platelet-activating Factor

Liu

Bátkai

Pacher

et al. 2003

Journal of Biological Chemistry

221

185

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“…Anandamide can elicit vasodilation 13,[32][33][34] and decreased cardiac contractility 35 through an additional G i /G o -coupled receptor distinct from CB 1 or CB 2 , which is inhibited by SR141716 13 but not by other CB 1 antagonists such as AM251. 35,36 In the present experiments, AM251 and SR141716 were equally effective in eliciting pressor and cardiostimulatory responses and in blocking the depressor effects of URB597 in hypertensive rats.…”

Section: Discussionmentioning

confidence: 99%

Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension

et al. 2004

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Background-Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension. Methods and Results-In spontaneously hypertensive rats (SHR), cannabinoid-1 receptor (CB 1 ) antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility, and vascular resistance to levels in normotensive rats, and these effects are prevented by CB 1 antagonists. Similar changes are observed in 2 additional models of hypertension, whereas in normotensive control rats, the same parameters remain unaffected by any of these treatments. CB 1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB 1 is increased in heart and aortic endothelium of SHR compared with Wistar-Kyoto rats. Conclusions-We conclude that endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB 1 -mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension.

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“…Abn-cbd elicits endothelium-dependent vasodilation in the isolated mesenteric arterial bed of the rat and mouse, including mice lacking both CB 1 and CB 2 receptors (10). More recently, a study of the responses of isolated segments of rat mesenteric arteries indicated that the endothelium dependent vasorelaxing effect of both anandamide and abd-cbd could be inhibited by another structural analog of cannabidiol, O-1918 (13), as well as by pertussis toxin (13,14), and a similar site has been identified in the rabbit aortic endothelium (15). Vanilloid VR1 receptors, which mediate the endothelium-independent component of the vasodilator effect of anandamide (15,16), do not have a role in this endotheliumdependent vasodilator response (10,(13)(14)(15).…”

mentioning

confidence: 93%

“…More recently, a study of the responses of isolated segments of rat mesenteric arteries indicated that the endothelium dependent vasorelaxing effect of both anandamide and abd-cbd could be inhibited by another structural analog of cannabidiol, O-1918 (13), as well as by pertussis toxin (13,14), and a similar site has been identified in the rabbit aortic endothelium (15). Vanilloid VR1 receptors, which mediate the endothelium-independent component of the vasodilator effect of anandamide (15,16), do not have a role in this endotheliumdependent vasodilator response (10,(13)(14)(15). This has led us to postulate the existence of a novel, endothelial cannabinoid receptor coupled to G i /G o , for which abn-cbd is a selective agonist and O-1918 is a silent antagonist (13).…”

mentioning

confidence: 95%

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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Anandamide-induced vasorelaxation in rabbit aortic rings has two components: G protein dependent and independent

Cited by 88 publications

References 42 publications

Lipopolysaccharide Induces Anandamide Synthesis in Macrophages via CD14/MAPK/Phosphoinositide 3-Kinase/NF-κB Independently of Platelet-activating Factor

Lipopolysaccharide Induces Anandamide Synthesis in Macrophages via CD14/MAPK/Phosphoinositide 3-Kinase/NF-κB Independently of Platelet-activating Factor

Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension

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

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