Pharmacognosy and Effects of Cannabinoids in the Vascular System

Abstract

Understanding the pharmacodynamics of cannabinoids is an essential subject due to the recent increasing global acceptance of cannabis and its derivation for recreational and therapeutic purposes. Elucidating the interaction between cannabinoids and the vascular system is critical to exploring cannabinoids as a prospective therapeutic agent for treating vascular-associated clinical conditions. This review aims to examine the effect of cannabinoids on the vascular system and further discuss the fundamental pharmacological properties and mechanisms of action of cannabinoids in the vascular system. Data from literature revealed a substantial interaction between endocannabinoids, phytocannabinoids, and synthetic cannabinoids within the vasculature of both humans and animal models. However, the mechanisms and the ensuing functional response is blood vessels and species-dependent. The current understanding of classical cannabinoid receptor subtypes and the recently discovered atypical cannabinoid receptors and the development of new synthetic analogs have further enhanced the pharmacological characterization of the vascular cannabinoid receptors. Compelling evidence also suggest that cannabinoids represent a formidable therapeutic candidate for vascular-associated conditions. Nonetheless, explanations of the mechanisms underlining these processes are complex and paradoxical based on the heterogeneity of receptors and signaling pathways. Further insight from studies that uncover the mechanisms underlining the therapeutic effect of cannabinoids in the treatment of vascular-associated conditions is required to determine whether the known benefits of cannabinoids thus currently outweigh the known/unknown risks.

Figure 1

Endocannabinoid anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are formed from arachidonic acid-containing phospholipids. AEA is formed from a two-step catalysis of phospholipids to form N-arachidonoylphosphatidylethanolamine (NAPE). NAPE is cleaved by phospholipase D (PLD) to form AEA. AEA is metabolized by the enzyme fatty acid amide hydrolase (FAAH) and by N-acylethanolamine-hydrolyzing acid amidase (NAAA) to form arachidonic acid or by COX to form prostaglandin ethanolamide (prostamides). 2-AG is synthesized from diacylglycerol (formed from phosphoinositides by the action of phospholipase C) by the action of diacylglycerol lipase (DAGL). 2-AG is metabolized either via COX to form prostaglandin glycerol esters or by both monoacylglycerol lipase (MAG-L) and α,β-hydrolase domain-containing 6 (ABHD6) to form arachidonic acid. Additionally, arachidonic acid can be synthesized directly from phospholipids by phospholipase A2 (PLA₂) which is further metabolized by lipoxygenase (LOX) to produce leukotrienes (LTs), cyclooxygenase (COX) to form prostaglandin glycerol esters, and cytochrome P450 (CYP) enzymes to form eicosanoids. EETs: epoxyeicosatrienoic acids; HETEs: hydroxyeicosatetraenoic acids.

Figure 2

(A) Binary switch model of GPCRs, where upon stimulation, the GPCR activates heterotrimeric G-proteins causing its dissociation and subsequent formation of effector second messengers and cellular responses with the GRK-β-arrestin pathway serving as a negative feedback loop maintaining homeostasis by desensitization of GPCR interactions with G-proteins. (B) Balanced signaling system: β-arrestin is coupled to numerous signaling mediators aside acting as a negative feedback regulator of GPCR-G-protein signaling, and these two signaling pathways are independent of each other. Biased signaling is when a ligand-receptor-effector complex results in conformations using distinct pathways relative to other pathways. CB receptor signaling can be mediated through β-arrestins and G-proteins suggesting biased signaling. Abbreviations: GRK, G protein-coupled receptor kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; and EGFR, epidermal growth factor receptor.