Vascular cannabinoid receptors

The ability of cannabinoids to cause vascular effects implies that the vasculature contains a molecular target. Evidence to date suggests that there may be vascular cannabinoid receptors, which may either fall into the classical CBj/CBj classification or represent a new subtype. As stated above, the biphasic hypotension in response to anandamide is absent in CBi receptor knockout mice (Ledent et al., 1999). This clearly points to the involvement of the CBj receptor. However, it should be noted that this does not conclusively identify the cannabinoid receptors as being on the vascular smooth muscle or associated with neuronal tissue. The sensitivity of vasorelaxant responses to CB receptor antagonists has been controversial, with some studies indicating that the responses are... 

Mouse vas deferens (MVD) seems to express CB1 and at least one CB2-like cannabinoid receptor type, as is demonstrated by the presence of CB1 and CB2-like mRNA as well as by data collected from experiments with cannabinoid receptor selective agonists and antagonists (Pertwee, 1999). Furthermore, evidence indicates that a CBl-like receptor exists in vascular endothelium, which upon activation produces significant hypotension (Wagner, 1999). This receptor differs from CB1 in its pharmacological response to some well-characterized cannabimimetics. 

Liu J, Gao B, Mirshahi F, Sanyal AJ, Khanolkar AD, Makriyannis A, Kunos G (2000) Functional CBI cannabinoid receptors in human vascular endothelial cells. Biochem J 346 835-840... 

Extensive studies on the endocannabinoid system have revealed a number of cannabinergic proteins involved in the inactivation and biosynthesis of endocannabinoids. These include fatty acid amide hydrolase (FAAH) (Di Marzo et al. 1994 Gaetani et al. 2003 Piomelli et al. 1999), monoglyceride lipase (MAG) (Dinh et al. 2002), and the anandamide transporter (ANT) (Beltramo et al. 1997 Di Marzo et al. 1994 Fegley et al. 2004 Hillard et al. 1997). The above three proteins and the two cannabinoid receptors have received considerable attention and show great promise as potential targets for the development of novel medications for various conditions, including pain, immunosuppression, peripheral vascular disease, appetite enhancement or suppression, and motor disorders. 

Stefano GB, Bilfinger TV, Rialas CM, Deutsch DG (2000) 2-Arachidonyl-glycerol stimulates nitric oxide release from human immune and vascular tissues and invertebrate immunocytes by cannabinoid receptor 1. Pharmacol Res 42 317-322... 

Collectively, the above-mentioned results indicate that the synthetic cannabinoid ligands abn-cbd and 0-1918 act as a selective agonist and silent antagonist, respectively, of a novel vascular endothelial receptor distinct from CBi and CB2 that mediates mesenteric vasodilation, and is coupled to a phosphoinositide (PI)3-kinase/Akt-dependent pathway through Gi/Go. 

Cannabinoids, the active components of Cannabis sativa and their derivatives, act in organisms by mimicking endogenous substances—the endocannabinoids anandamide and 2-arachidonoylglycerol—that bind to and activate specific cannabinoid receptors. So far, two cannabinoid-specific Gj/o protein-coupled receptors, CBl (Matsuda et al. 1990) and CB2 (Munro et al. 1993), have been cloned and characterised from mammalian tissues. Most of the effects of cannabinoids rely on CBi receptor activation. This receptor is particularly abundant in discrete areas of the brain, but is also expressed in peripheral nerve terminals and various extra-neural sites such as testis, eye, vascular endothelium and spleen. In contrast, the CB2 receptor is almost exclusively present in the immune system (Howlett et al. 2002). 

Not only do endocannabinoids affect vascular function, but they may also have direct cardiac actions. Ford et al. (2002) reported in the rat isolated heart that anandamide had a negative inotropic effect and reduced left ventricular pressure. This action appeared to be due to action at a novel cannabinoid receptor. In human atrial muscle, anandamide has also been shown to exert negative inotropic effects but, in this case, via the activation of CB, receptors (Bonz et al., 2003). 

Kunos G, Batkai S, Offertaler L, Mo F, Liu J, Karcher J, Harvey-White J. 2002. The quest for a vascular endothelial cannabinoid receptor. Chem Phys Lipids 121 45-56. 

The existence of cannabinoid receptors was confirmed when it was observed that cannabinoids decreased cAMP levels in neuroblastoma cell cultures (Howlett, 1984). This finding was followed by the determination and characterization of a cannabinoid receptor in rat brain (Devane et al., 1988). Shortly after, the stmcture of this CBj receptor and functional expression of the cloned cDNA was reported (Matsuda et al, 1990). The CBj receptor is found in the central nervous system as well as in several peripheral tissues, including testis, small intestine, vascular endothelium, utems and vas deferens (Herkenham et al., 1990). The distribution and localization of CBj receptor in the brain correlates well with the known effects of cannabinoids on memory, perception and the control of movement. CBj receptors are highly expressed in the hippocampus, association cortex, cerebellum and basal ganglia. 

Sugiura T, Kodaka T, Nakane S, Kishimoto S, Kondo S, Waku K (1998) Detection of an endogenous cannabimimetic molecule, 2-arachidonoylglycerol, and cannabinoid CBI receptor mRNA in human vascular cells is 2-arachidonoylglycerol a possible vasomod-ulator Biochem Biophys Res Commun 243 838-843... 

Keywords Cannabinoid - Anandamide CB, receptor Blood pressure Cardiac function Vascular Ischemia... 

Cannabinoids and their synthetic and endogenous analogs are best known for their prominent psychoactive properties, but their cardiovascular effects were also recognized as early as the 1960s. The most important component of these effects is a profound decrease in arterial blood pressure, cardiac contractility, and heart rate (Lake et al. 1997a,b Hillard 2000 Kunos et al. 2000,2002 Randall et al. 2002 Ralevic et al. 2002 Hiley and Ford 2004). Although several lines of evidence indicate that the cardiovascular depressive effects of cannabinoids are mediated by peripherally localized CBi receptors, cannabinoids can also elicit vascular and cardiac effects, which are independent of CBi and CB2 receptors, as discussed in detail later in this chapter. 

In contrast to the growing knowledge on the vascular effects of cannabinoids, little is known about cannabinoid-induced direct cardiac effects. The endocannabinoid anandamide (Felder et al. 1996), anandamide amidohydrolase (Bilfinger et al. 1998), and traces of the message for the CBi receptor (Galiegue et al. 1995) have all been detected in the human heart. In a more recent study, the existence of CBi receptors was confirmed in human atrial myocytes by immunoblotting and immunohistochemistry (Bonz et al. 2003). In the same study, it was demonstrated... 

Functional CBi receptors are present in vascular tissue as well as the myocardium, and cannabinoid agonists and endocannahinoids exert major hypotensive and cardiodepressor effects in vivo through the stimulation of CB receptors. There is evidence for the existence of an as-yet-undefined endothelial and cardiac receptor or receptors that mediate certain endocannabinoid-induced cardiovascular effects. Vanilloid TRPVl receptors can be activated by anandamide, but the role of these receptor in in vivo hemodynamic effects appears to be limited to the transient activation of the Bezold-Jarisch reflex by very high initial plasma concentrations of anandamide. 

Cannabinoid CB, receptors have also been localized to cat cerebral arterial smooth muscle (Gebremedhin et al., 1999). In this smdy, it was demonstrated that feline vascular smooth muscle contained CB, receptors together with cDNA, showing very close homology to that associated with neuronal CB, receptors. 

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