The Production of Endocannabinoids by Platelets and Blood Cells
The ability of various blood cells to produce endocannabinoids is well established.
Interest in the role endocannabinoids play in cardiovascular pathophysiology was initiated when it was demonstrated, in a rat model of haemorrhagic shock, that activated macrophages release anandamide which may contribute towards the hypotension. Subsequently it was also found in endotoxic shock that the synthesis of 2-AG in platelets and anandamide in macrophages are increased and that these may contribute towards the associated hypotension.
Further studies have confirmed that circulating cells produce endocannabinoids, for example, macrophages produce and release 2-AG. Platelet-activating factor has also been shown to stimulate both platelets and macrophage cell line to produce 2-AG. So, clearly blood cells represent an important circulating source of endocannabinoids which may participate in pathophysiological responses. Additionally it was reported that lipopolysaccharide, a key component in endotoxic shock, causes a downregulation of FAAH expression in human lymphocytes, and the reduction in the metabolism of anandamide leads to increased levels. This mechanism could lead to further increases in circulating levels of anandamide in endotoxic shock.
Endotoxic shock is associated with disseminated intravascular coagulation (which involves widespread platelet aggregation).
Cannabinoids and Platelets: Reuptake and Metabolism
Not only may platelets be activated by endocannabinoids, although at very high concentrations, but they may also be involved in metabolic conversion.
To date, the precise mechanisms of uptake of endocannabinoids into cells are unclear and the existence of a specific transporter is controversial; indeed the uptake may be a passive process driven by a FAAH-dependent gradient.
It was reported that human platelets convert anandamide via 12-lipoxygenase to 12(S)-hydroxyeicosatetraenoylethanolamide (12(S)-HAEA). This metabolite is pharmacologically active at both _CB1 and CB2 receptors with similar affinities to anandamide. Furthermore, 12(S)-HAEA was shown to be relatively resistant to metabolism by FAAH, and the authors proposed that the platelet-dependent conversion was a means by which the activity of endogenous cannabinoid ligands might be prolonged in the circulation.
Cannabinoids and the Risk of Thromboembolism
Accordingly in patients with atherosclerotic plaques, the risk of myocardial infarction triggered by cannabis smoking might be related to cannabis-induced thromboembolism.
Despite the acute administration of cannabis being associated with an increased risk of myocardial infarction, long-term cannabis smoking was not associated with increased cardiovascular risk. Consistent with an increased acute risk of thromboembolism, recently reported that Δ-9-tetrahydrocannabinol (THC) increased the expression of glycoprotein IIb–IIIa and P-selectin on platelets. In view of the risk of thrombosis posed by THC, this raises questions over the safety of THC as a medicine. Accordingly, it would be prudent to take account of the patient's cardiovascular risk factors when using it as a medicine.
2-arachidonoylglycerol (2-AG) caused activation of human platelets at lower concentrations than reported for anandamide, and that these effects were inhibited by high concentrations of the cannabinoid CB1 and CB2 receptor antagonists. Radioligand studies suggested the expression of a CB-type receptor, but different from the classical CB1 and CB2 classification.
In conclusion, based on these findings, it is clear that high concentrations of endocannabinoids may cause platelet activation and this may be relevant as there is an indication that the endothelium may be a source of endocannabinoids and this may also be relevant to thrombosis. However, there is also evidence that the endothelium may be a site of endocannabinoid metabolism, and this may enable the endothelium to represent an antithrombogenic surface. Accordingly, the balance between the release of thrombogenic endocannabinoids and their endothelium-dependent metabolism will determine the role of endocannabinoids in thrombosis but this may be altered in disease states, including atherosclerosis.
Cannabinoids and Atherosclerosis
There has been little work in this area, but recently it was reportedthat low doses of THC acting via CB2 receptors caused a reduction in the development of atherosclerotic plaques in a murine knockout model of atherogenesis. These effects appeared via suppression of macrophage chemotaxis. Whether endocannabinoids play a role in atherosclerosis remains to be determined, but a recent study has shown that low levels of palmitoylethanolamide (PEA) may protect low-density lipoprotein (LDL) against oxidation, which is a feature of atherogenesis.
Bibliography
Avgeropoulos, N. G., & Batchelor, T. T. (1999). New treatment strategies for malignant gliomas.
Oncologist 4, 209–224.
Bayewitch, M., Avidor-Reiss, T., Levy, R., Barg, J., Mechoulam, R., & Vogel, Z. (1995). The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling.
FEBS Lett 375, 143– 147.
Bisogno, T., Katayama, K., Melck, D., Ueda, N., De Petrocellis, L., Yamamoto, S., & Di Marzo, V. (1998). Biosynthesis and degradation of bioactive fatty acid amides in human breast cancer and rat pheochromocytoma cells. Implications for cell proliferation and differentiation.
Eur J Biochem 254, 634– 642.
Cabral, G. A., & Dove Pettit, D. A. (1998). Drugs and immunity: cannabinoids and their role in decreased resistance to infectious disease.
JNeuroimmunol 83, 116– 123.
Chen, Y., & Buck, J. (2000). Cannabinoids protect cells from oxidative cell death: a receptor independent mechanism.
J Pharmacol Exp Ther 293, 807– 812.
De Petrocellis, L., Melck, D., Palmisano, A., Bisogno, T., Laezza, C.,Bifulco, M., & Di Marzo, V. (1998). The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation.
Proc Natl Acad Sci USA 95, 8375– 8380.
Gallily, R., Yamin, A., Waksmann, Y., Ovadia, H., Weidenfeld, J., Bar- Joseph, A., Biegon, A., Mechoulam, R., & Shohami, E. (1997). Protection against septic shock and supression of tumor necrosis factor a and nitric oxide production by dexanabinol (HU-211), a nonpsychotropic
cannabinoid.
J Pharmacol Exp Ther 283, 918– 924.
Francesco Licciardi e Matteo Manfredi
