Pharmacological Actions of Cannabinoids 334.1.5ReceptorsforAbnormal-Cannabidiol
Cardiovascular System
There is evidence, mainly from in vitro experiments with rat or mouse phenyl-
ephrine- or methoxamine-precontracted buffer-perfused isolated mesenteric arte-
rial beds or isolated mesenteric arterial segments, for the presence in these tissues
of non-CB 1 , non-CB 2 receptors with which anandamide and methanandamide can
interact to induce a relaxant effect (reviewed in Howlett et al. 2002; Pertwee 2004a;
Wiley and Martin 2002). There are several reasons for believing that these are not
CB 1 or CB 2 receptors. First, relaxation is not induced in rat precontracted mesen-
teric arterial beds by 2-arachidonoyl glycerol or by established non-eicosanoid
cannabinoid receptor agonists such as∆^9 -THC orR-(+)-WIN55212 (Wagner et
al. 1999) but is induced in rat and mouse precontracted mesenteric arterial beds
or rat precontracted mesenteric arterial segments by two cannabidiol analogues,
abnormal-cannabidiol and O-1602 (Fig. 12), neither of which exhibits signifi-
cant affinity for CB 1 receptors (Ho and Hiley 2003; Járai et al. 1999; Offertáler
et al. 2003; Showalter et al. 1996). Second, anandamide, methanandamide and
abnormal-cannabidiol also relax precontracted buffer-perfused mesenteric arte-
rial beds of CB 1 –/–knockout or CB 1 –/–/CB 2 –/–double-knockout C57BL6J mice
(Járai et al. 1999). Third, the CB 1 -selective antagonist AM281 (1 μM) and the
CB 2 -selective antagonist AM630 (10 μM) do not attenuate abnormal-cannabidiol-
induced relaxations of rat precontracted mesenteric arterial segments (Ho and
Hiley 2003). Although SR141716A has been found to oppose the vasorelaxant ef-
fects of abnormal-cannabidiol, methanandamide and anandamide in rat or mouse
precontracted mesenteric arterial beds or segments, this is generally with a po-
tency lower than expected from its affinity for CB 1 receptors (Ho and Hiley 2003;
Járai et al. 1999). Negative results obtained with capsaicin and capsazepine also
make it unlikely that the putative “abnormal-cannabidiol” receptor is a TRPV1
receptor (Ho and Hiley 2003; Járai et al. 1999; Offertáler et al. 2003).
Fig. 12.The structures of abnormal cannabidiol, O-1602 and O-1918