Vanilloid receptor vasorelaxation

Anandamide has been shown to act via the release of endothelium-derived nitric oxide in the rat kidney (Dentsch et al., 1997). A range of human blood vessels and the right atrium have also been shown to release nitric oxide in response to anandamide (Bilfinger et al., 1998). However, in many instances (see Randall etal., 1996 White and Ehley, 1997 Jarai etal., 1999), vasorelaxant responses to anandamide are insensitive to inhibition of nitric oxide synthase. In HUVECs, Maccarrone et al. (2000) reported that anandamide and the CB agonist, HU210, both cause an upregulation of the expression and activity of the inducible nitric oxide synthase. Mukhopadhyay et al. (2002) demonstrated that the endothelium-dependent component was G protein coupled and mediated via nitric oxide, whereas the endothehum-independent component was due to activation of vanilloid receptors, at least in rabbit aortic rings. 

Endocannabinoids exert potmt and complex cardiovascular effects. The findings in isolated arterial vessels overwhelmingly support the view that endocannabinoids are vasorelaxants and act via several diffCTent mechanisms. These include release of vasorelaxant neurotransmitters from sensory nerves via vanilloid receptor activation, the release of EDHF coupled to the activation of a novel endothehal caimabinoid receptor, and actions at classical caimabinoid receptors. The cardiovascular effects of endocannabinoids in vivo are, however, complex, as the in vitro vasorelaxant actions do not translate into simple responses. Indeed, the responses observed appear depmdent on the prevailing conditions, e.g., the absence or presence of anesthetic. Roles are emerging for endocannabinoids in pathophysiological conditions, where the release may be involved in some of the circulatory changes and adaptive responses there is the possibility that endocannabinoids may lead to cardioproteetion in ischemia. 

Finally, Zygmunt et al. (1999) described an unusual indirect pathway. They demonstrated that anandamide induces vasorelaxation in rat mesenteric and hepatic arteries, and in guinea pig basilary artery through the activation of TRPVl receptors on sensory neurons, causing the release of the vasodilatory peptide calcitonin gene-related peptide (CGRP) (see also Sect. 4 below, Role of Vanilloid TRPVl Receptors in the Cardiovascular Effects of Cannabinoids ). 

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