Recent evidence indicates that activation of peripheral CB1 cannabinoid receptors by macrophage derived anandamide contributes to hemorrhagic hypotension. Rat platelets contain the endogenous cannabinoid 2 arachidonyl glyceride (2 AG), and in vitro exposure of platelets to LPS (200 microg/ml) markedly increases 2 AG levels. [Varga K; Wagner JA; Bridgen DT; Kunos G. Platelet and macrophage derived endogenous cannabinoids are involved in endotoxin induced hypotension. FASEB J 1998 Aug;12(11):1035 44. ]

     LPS stimulated, but not control, macrophages contain anandamide, which is undetectable in either control or LPS stimulated platelets. Prolonged hypotension and tachycardia are elicited in urethane anesthetized rats treated 1) with LPS (15 mg/kg i.v.); 2) with macrophages plus platelets isolated from 3 ml of blood from an LPS treated donor rat; or 3) with rat macrophages or 4) platelets preincubated in vitro with LPS (200 microg/ml). In all four cases, the hypotension but not the tachycardia is prevented by pretreatment of the recipient rat with the CB1 receptor antagonist SR141716A (3 mg/kg i.v.), which also inhibits the hypotensive response to anandamide or 2 AG. The hypotension elicited by LPS treated macrophages or platelets remains unchanged in the absence of sympathetic tone or after blockade of nitric oxide synthase. These findings indicate that platelets and macrophages generate different endogenous cannabinoids, and that both 2 AG and anandamide may be paracrine mediators of endotoxin induced hypotension via activation of vascular CB1 receptors. Oxygenation of the endocannabinoid, 2 arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase 2 Kozak KR; Rowlinson SW; Marnett LJ.Source: JOURNAL OF BIOLOGICAL CHEMISTRY 2000, Vol 275, Iss 43, pp 33744 33749.

     Cyclooxygenases (COX) play an important role in lipid signaling by oxygenating arachidonic acid to endoperoxide precursors of prostaglandins and thromboxane. Two cyclooxygenases exist which differ in tissue distribution and regulation but otherwise carry out identical chemical functions. The neutral arachidonate derivative, 2 arachidonylglycerol (2 AG), is one of two described endocannabinoids and appears to be a ligand for both the central (CB1) and peripheral (CB2) cannabinoid receptors. Here we report that 2 AG is a substrate for COX 2 and that it is metabolized as effectively as arachidonic acid. COX 2 mediated 2 AG oxygenation provides the novel lipid, prostaglandin H 2 glycerol ester (PGH(2) G), in vitro and in cultured macrophages. PGH(2) G produced by macrophages is a substrate for cellular PGD synthase, affording PGD(2) G. Pharmacological studies reveal that macrophage production of PGD(2) G from endogenous sources of 2 AG is calcium dependent and mediated by diacylglycerol Lipase and COX 2. These results identify a distinct function for COX 2 in endocannabinoid metabolism and in the generation of a new family of prostaglandins derived from diacylglycerol and 2 AG. Kozak KR; Rowlinson SW; Marnett LJ. Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2 J. Biol. Chem 2000, 275: 33744-33749.