Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling

Abstract

Cannabinoids include not only plant-derived compounds (of which Δ⁹-tetrahydrocannabinol is the primary psychoactive ingredient of cannabis), but also synthetic agents and endogenous substances termed endocannabinoids which include anandamide (2-arachidonoylethanolamide) and 2-arachidonoylglycerol. Cannabinoids act on specific, G-protein-coupled, receptors which are currently divided into two types, CB₁ and CB₂. Relatively selective agonists and antagonists for these receptors have been developed, although one agent (SR141716A) widely used as an antagonist at CB₁ receptors has non-cannabinoid receptor-mediated effects at concentrations which are often used to define the presence of the CB₁ receptor. Both cannabinoid receptors are primarily coupled to G_i/o proteins and act to inhibit adenylyl cyclase. Stimulation of CB₁ receptors also modulates the activity of K⁺ and Ca²⁺ channels and of protein kinase pathways including protein kinase B (Akt) which might mediate effects on apoptosis. CB₁ receptors may activate the extracellular signal-regulated kinase cascade through ceramide signalling. Cannabinoid actions on the cardiovascular system have been widely interpreted as being mediated by CB₁ receptors although there are a growing number of observations, particularly in isolated heart and blood vessel preparations, that suggest that other cannabinoid receptors may exist. Interestingly, the currently identified cannabinoid receptors appear to be related to a wider family of lipid receptor, those for the lysophospholipids, which are also linked to G_i/o protein signalling. Anandamide also activates vanilloid VR1 receptors on sensory nerves and releases the vasoactive peptide, calcitonin gene-related peptide (CGRP), which brings about vasodilatation through its action on CGRP receptors. Current evidence suggests that endocannabinoids have important protective roles in pathophysiological conditions such as shock and myocardial infarction. Therefore, their cardiovascular effects and the receptors mediating them are the subject of increasing investigative interest.