British Journal of Pharmacology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Application of cannabinoids and endocannabinoids to perfused vascular beds or individual isolated arteries results in changes in vascular resistance. In most cases, the result is vasorelaxation, although vasoconstrictor responses are also observed. Cannabinoids also modulate the actions of vasoactive compounds including acetylcholine, methoxamine, angiotensin II and U46619 (thromboxane mimetic). Numerous mechanisms of action have been proposed including receptor activation, potassium channel activation, calcium channel inhibition and the production of vasoactive mediators such as calcitonin gene-related peptide, prostanoids, nitric oxide, endothelial-derived hyperpolarising factor and hydrogen peroxide. The purpose of this review is to examine the evidence for the range of receptors now known to be activated by cannabinoids. Direct activation by cannabinoids of CB₁, CB_e, TRPV1 (and potentially other TRP channels) and PPARs in the vasculature has been observed. A potential role for CB_2, GPR55 and 5HT1A has also been identified in some studies. Indirectly, activation of prostanoid receptors (TP, IP, EP₁ and EP₄) and the CGRP receptor are involved in the vascular responses to cannabinoids. The majority of this evidence has been obtained through animal research, but recent work has confirmed some of these targets in human arteries. Vascular responses to cannabinoids are enhanced in hypertension and cirrhosis, but are reduced in obesity and diabetes, both due to changes in the target sites of action. Much further work is required to establish the extent of vascular actions of cannabinoids and the application of this research in physiological and pathophysiological situations.