|Year : 2018 | Volume
| Issue : 4 | Page : 171-176
Cannabinoids for treating cardiovascular disorders: Putting together a complex puzzle
Basma Ghazi Eid
Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
|Date of Web Publication||22-Oct-2018|
Dr. Basma Ghazi Eid
Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, PO Box 80260, Jeddah 21589
Kingdom of Saudi Arabia
Source of Support: None, Conflict of Interest: None
Cannabinoids have been increasingly gaining attention for their therapeutic potential in treating various cardiovascular disorders. These disorders include myocardial infarction, hypertension, atherosclerosis, arrhythmias, and metabolic disorders. The aim of this review is to cover the main actions of cannabinoids on the cardiovascular system by examining the most recent advances in this field and major literature reviews. It is well recognized that the actions of cannabinoids are mediated by either cannabinoid 1 or cannabinoid 2 receptors (CB2Rs). Endocannabinoids produce a triphasic response on blood pressure, while synthetic cannabinoids show a tissue-specific and species-specific response. Blocking cannabinoid 1 receptors have been shown to be effective against cardiometabolic disorders, although this should be done peripherally. Blocking CB2Rs may be a useful way to treat atherosclerosis by affecting immune cells. The activation of CB2Rs was reported to be useful in animal studies of myocardial infarction and cardiac arrhythmia. Although cannabinoids show promising effects in animal models, this does not always translate into human studies, and therefore, extensive clinical studies are needed to truly establish their utility in treating cardiovascular disease.
Keywords: Cannabinoid 1 receptor, cannabinoid 2 receptor, cannabinoids, cardiovascular, metabolic disorders
|How to cite this article:|
Eid BG. Cannabinoids for treating cardiovascular disorders: Putting together a complex puzzle. J Microsc Ultrastruct 2018;6:171-6
|How to cite this URL:|
Eid BG. Cannabinoids for treating cardiovascular disorders: Putting together a complex puzzle. J Microsc Ultrastruct [serial online] 2018 [cited 2019 Nov 17];6:171-6. Available from: http://www.jmau.org/text.asp?2018/6/4/171/243826
| Introduction|| |
Cannabinoid compounds are being extensively studied for their wide range of therapeutic potentials. Although there is an abundance of information on the role of cannabinoids in the central and peripheral nervous systems, their role in the cardiovascular system seems to be more complex. The aim of this review is to cover the role that cannabinoids play in the treatment or prevention of various cardiovascular diseases including blood pressure, metabolic disorders, atherosclerosis, myocardial infarction, and cardiac arrhythmia. In addition, the most recent advances in this field and the challenges and negative effects of cannabinoids on human participants will be highlighted.
| History of Cannabinoids and Their Mechanism of Action|| |
Cannabinoids have traditionally been known for acting on the central nervous system. tetrahydrocannabinol (THC), which was first extracted from Cannabis sativa by Gaoni and Mechoulam in 1964, has been extensively studied and shown to have psychoactive properties. Since then, it has been shown that cannabis contains over 80 active constituents. In addition to naturally occurring cannabinoids, several endogenous cannabinoid compounds (endocannabinoids), such as N-arachidonoyl ethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG),, have been identified and examined. AEA is inactivated in vivo by fatty acid amidohydrolase whereas 2-AG is inactivated by monoglyceride lipase with other enzymes playing a more minor role in their inactivation. Cannabinoid receptors consist of two main forms, namely cannabinoid 1 receptor (CB1R) and cannabinoid 2 receptor (CB2R). They are both classified as G-protein-coupled receptors. CB1R is present in the central nervous system as well as other peripheral sites such as the cardiovascular, respiratory, reproductive, and digestive systems. CB2R is a peripheral receptor found in immune cells and organs. The behavioral properties of cannabinoids have been shown to be mediated by CB1R,, whereas CB2R is mainly implicated in immunomodulation.
Several studies have explored targeting the endocannabinoid system to treat various vascular diseases and disorders such as myocardial and cerebral ischemia, hypertension circulatory shock, atherosclerosis, metabolic syndrome, stroke, arrhythmia, and myocardial infarction. Furthermore, studies have reported positive as well as negative effects of cannabinoids when used to combat cardiac disorders and there seems to be a complicated relationship between the endocannabinoid system, the cardiovascular, and the immune system.
| Effects of Cannabinoids on the Heart, Blood Pressure, and Vasculature|| |
It is well known that acute exposure to cannabis leads to tachycardia, although the effect on blood pressure is less consistent.,, On the contrary, chronic exposure was reported to cause bradycardia and a lowering of blood pressure., The endocannabinoids AEA and 2-AG are present in various parts of the vasculature including red blood cells, platelets, serum and vascular cells, and the myocardium.,, The activation of CB1R in the myocardial tissue produces a negative inotropic response on the heart.,,, Although the expression of CB2R has been demonstrated in cardiac myocytes, and in endothelial and smooth muscle cells of coronary arteries,, their role has been less well characterized and requires further investigation.
The effects of endocannabinoids on blood pressure are not different from those of cannabis. The intravenous administration of AEA and 2-AG has been reported to cause a triphasic response that ultimately causes a lowering of blood pressure in experimental animals. Although it was postulated in the 1970s that modulation of cannabinoid receptors could lead to the development of blood pressure-lowering agents, this was complicated by an overlap in the cardiovascular and neurological effects. In recent years, however, it was shown that cannabinoids have a more profound blood pressure-lowering effect on hypertensive animals when compared to their nondiseased counterparts.,,,, This has led to the rebirth of the hypothesis that cannabinoid ligands may indeed be used to target hypertension. The vasodilatory response of endocannabinoids has been shown to be partially attributed to the blockage of norepinephrine release from perivascular nerves in the sympathetic nervous system, and partially, due to their ability to directly affect endothelial and vascular smooth muscle.
When the effects of synthetic and endocannabinoids were studied on isolated blood vessels, there seemed to be a complex range of responses which proved to be species and tissue dependent. In addition to the CB1R, the involvement in a variety of other receptors, including the transient receptor potential vanilloid 1 receptor (TRPV1), has been shown to mediate the vascular effects of cannabinoids.,, The activation of perivascular TRPV1 receptors by AEA in animal studies causes a cascade of events, whereby calcitonin gene-related peptide and various neuropeptides are produced ultimately activating vascular potassium channels and producing a dilatory response.,, The vasodilatory effect of 2-AG has also been linked to the activation of TRPV4 in the endothelium and which ultimately activates calcium-dependent potassium channels in vascular smooth muscle cells. The endocannabinoids, AEA, and 2-AG were shown to activate peroxisome proliferator-activated receptors (PPAR). These may be exploited when using cannabinoids in treating cardiometabolic conditions since PPAR have widespread use in conditions displaying inflammation and tissue fibrosis. Therefore, the actions of cannabinoids on vascular tone are complex and are mediated by a vast number of receptors which activate a wide range of signaling pathways.
Cannabinoids may also affect local blood flow since they possess autocrine functions. Studies have shown that endocannabinoid release in isolated arteries increases after exposure to vasoconstrictors such as angiotensin II.,, To further support this activity, the presence of enzymes that metabolize cannabinoids in the vasculature has also been shown in a number of studies., It has been demonstrated that endocannabinoids are released in ample amounts by white blood cells and platelets in certain inflammatory diseases.,, These endocannabinoids subsequently exert their actions on the heart and vascular cells leading to vasodilation, lowering of blood pressure, and negative inotropy. Furthermore, various studies suggest that endocannabinoids may even mediate tissue remodeling in certain diseases.,,
| Cannabinoids in the Treatment of Metabolic Syndrome and its Associated Cardiac Complications|| |
The role of the endocannabinoid system in metabolic syndrome has been an area of growing research interest over the past several decades. Furthermore, several animal models and clinical human trials have explored the therapeutic potential of CB1R antagonists, such as rimonabant, for the treatment of metabolic diseases. The expression of the CB1R has been demonstrated in adipose tissue, whereby its activation is believed to cause an augmentation in lipolysis and an attenuation of oxidation of fatty acids. CB1R is also expressed in the liver where it is block counteracts fats and stenosis. There have been reports of improved insulin resistance and glucose tolerance after CB1R blockage in diet-induced and genetic animal obesity studies.
Another beneficial effect of CB1R blockage is the reversal of reduced heart contractility seen in many patients with cardiac diseases., The patients suffering from obesity tend to have reduced heart contractility,, although this is frequently counteracted by excessive sympathetic stimulation in these patients with a net result of a slight elevation of blood pressure, as is commonly seen in metabolic disorders where norepinephrine levels are reported to increase more than two-fold. Rimonabant administration does not cause any change in blood pressure which further supports the idea of opposing mechanisms of action. Although cannabinoid antagonists may have beneficial effects, their use has been largely limited by their neuropsychiatric adverse effects such as depression and anxiety disorders.,,, Therefore, it is imperative that peripheral CB1R antagonists are developed which possess the beneficial effects, yet lack the unwanted adverse effects.
| Cannabinoids for the Treatment of Atherosclerosis|| |
It is still unclear whether cannabinoids can be truly useful for the treatment of atherosclerosis. Although endocannabinoids may have beneficial effects in certain cardiovascular disorders, they actually possess a prothrombic effect. Studies in humans and rats have reported platelet activation by anandamide and 2-AG. Platelets have a well-recognized role in maintaining blood homeostasis and in the formation of thrombi. Furthermore, the platelets possess anti-inflammatory actions and regulate growth. These properties may collectively contribute to the development of atherosclerosis. Endocannabinoids may also be produced by platelets, macrophages, and endothelial cells, when an atherosclerotic plaque is formed. The increased level of endocannabinoids is counteracted by the metabolic properties of platelets, macrophages, and endothelial cells.
CB2R receptors have been proposed to play a role in the development of atherosclerosis. A study in an experimental model of atherosclerosis showed that THC in low doses was beneficial for treating atherosclerotic plaques. The same study showed that the CB2R receptor blocker SR144528 reversed this effect. Both synthetic and endogenous cannabinoids are involved in the mobilization of immune cells by CB2R activation.
| The Role of Endocannabinoids in Myocardial Infarction|| |
Several studies point to the important beneficial effects of endocannabinoids in protecting against myocardial infarction. One of the earliest studies testing this phenomenon looked at the effects on endocannabinoids on ischemic-isolated hearts with induced shock. In that study, the cardioprotection was abolished after administering the CB2R antagonist SR144528. Blocking CB1R had no effect on the cardioprotection. Other studies have reported that endocannabinoids lead to decreased necrosis of the myocardial tissue as well as lowering the risk of arrhythmia in acute myocardial infarction, and they are also involved in remodeling in the chronic stage., The protective effect of endocannabinoids may be attributed to an action on endothelial cells as well as other mechanisms involving CB1R and CB2R., CB2R has been shown to play a key protective role when activated. This has been linked to an attenuation of the inflammatory response and endothelial activation. Studies on knock-out mice also confirm the important role of CB2R activation in protecting against myocardial infarction.,
Intravenous AEA injection was shown to upregulate heat-shock protein 72 in cardiac tissues. This provided cardiac protection against ischemia/reperfusion injuries in rodents. This effect was unaffected by the administration of a CB1R blocker, but abolished after CB2R blockade further supporting the important role of CB2R in myocardial infarction. Other studies looked at the benefits of CB2R agonists in mice suffering from myocardial infarction using a model of ischemia/reperfusion and showed that mitogen-activated protein kinase as well as protein kinase C maybe involved in the CB2R-mediated protection., The effects on leukocyte migration are thought to underlie the cardioprotective effects of cannabinoids, as demonstrated in a study by Di Filippo et al. They showed that the activation of CB2R reduced the myocardial infarction size by half and caused a decline in leukocyte migration. This effect was reversed when a cannabinoid antagonist was administered further supporting their findings.
| Cannabinoids for Treating Cardiac Arrhythmia|| |
Since most of the patients that suffer from a myocardial infarction tend to develop arrhythmia as a complication, it is also important to explore the role that the cannabinoid system plays in controlling this detrimental complication. Endocannabinoids have been shown to decrease the risk of developing cardiac arrhythmia, an effect which is mediated mainly by CB2R.,,, A study looking at the effects of AEA in an arrhythmia model induced by ischemia found that it led to a significant decrease in the arrhythmia events. This effect of AEA disappeared if the CB2R antagonist SR144528 was given, but not after administration of the CB1R antagonist rimonabant. The CB2R agonist, HU-210, showed nearly a complete reversal of the arrhythmia observed in both an ischemia model and epinephrine-induced and aconitine-induced model.,, All these studies highlighted the important role that CB2R receptors play over CB1R in the antiarrhythmia effects of cannabinoids. Furthermore, a study of cannabidiol in rats with cardiac injury showed that it caused a significant reduction in the ischemia-induced arrhythmias an effect which was later shown to be mediated by potassium channels.
| Negative Effects of Cannabinoids on the Cardiovascular System in Humans|| |
Although several animal studies have provided a promising role for both endocannabinoids and synthetic cannabinoids in treating and preventing certain cardiovascular disorders, this unfortunately does not always translate well in human trials. In fact, a large body of research has shown that the signaling of CB1R can have detrimental effects on the cardiovascular system. Drop in blood pressure, tachycardia, increased heart rate and higher incidence of a heart attack were all reported in otherwise healthy young cannabis users. Furthermore, it has been demonstrated that the synthetic cannabinoid K2 may cause healthy young children to suffer from myocardial infarction. Another study by Heath et al. reported that adolescents suffered from an increase in heart rate, unconsciousness, and pain.
It is postulated that the mediation of CB1R leads to unwanted cardiac effects whereas CB2R has more protective and anti-inflammatory action., Other than affecting the cardiovascular system, the endocannabinoid system was reported to play a key role in various body functions including the gastrointestinal tract. Endocannabinoids have also been reported to mediate the activities of cyclooxygenase enzyme, which is activated in certain gastric inhibitory responses to THC as well as in the hindbrain to mediate the inhibitory cardiac effects.
| Conclusion|| |
Cannabinoids are increasingly being recognized for their wide range of therapeutic effects both in the cardiovascular system and on other systems in the human body. Both endocannabinoids and synthetic cannabinoid compounds have been widely studied and proven to be useful in treating a large number of cardiac disorders. However, there still seems to be a dimension of complexity that accompanies these compounds which exert effects on CB1R, CB2R as well as other noncannabinoid receptors. Although several rodent models have shown promising actions of cannabinoids on the cardiovascular system, indeed we are a long way from seeing these compounds on the market. It is, therefore, required that the cannabinoid compounds with promising effects in animal studies be taken to the next stage and studied in humans. These clinical studies will shed light on the true therapeutic potential of cannabinoids in the cardiovascular system.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Mechoulam R, Gaoni Y. Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. Tetrahedron 1965;21:1223-9.
Mechoulam R, Hanuš LO, Pertwee R, Howlett AC. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci 2014;15:757-64.
Devane WA, Breuer A, Sheskin T, Järbe TU, Eisen MS, Mechoulam R. A novel probe for the cannabinoid receptor. J Med Chem 1992;35:2065-9.
Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al.
Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 1995;50:83-90.
Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, et al.
2-arachidonoylglycerol: A possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 1995;215:89-97.
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB, et al.
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 1996;384:83-7.
Blankman JL, Simon GM, Cravatt BF. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 2007;14:1347-56.
Howlett AC. The cannabinoid receptors. Prostaglandins Other Lipid Mediat 2002;68-69:619-31.
Zubrzycki M, Liebold A, Janecka A, Zubrzycka M. A new face of endocannabinoids in pharmacotherapy. Part II: Role of endocannabinoids in inflammation-derived cardiovaascular diseases. J Physiol Pharmacol 2014;65:183-91.
Pandey R, Mousawy K, Nagarkatti M, Nagarkatti P. Endocannabinoids and immune regulation. Pharmacol Res 2009;60:85-92.
Hillard CJ. The endocannabinoid signaling system in the CNS: A primer. Int Rev Neurobiol 2015;125:1-47.
Ishac EJ, Jiang L, Lake KD, Varga K, Abood ME, Kunos G, et al.
Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. Br J Pharmacol 1996;118:2023-8.
Rom S, Persidsky Y. Cannabinoid receptor 2: Potential role in immunomodulation and neuroinflammation. J Neuroimmune Pharmacol 2013;8:608-20.
Varga K, Wagner JA, Bridgen DT, Kunos G. Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J 1998;12:1035-44.
Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006;58:389-462.
Ashton JC, Smith PF. Cannabinoids and cardiovascular disease: The outlook for clinical treatments. Curr Vasc Pharmacol 2007;5:175-85.
Pacher P, Mukhopadhyay P, Mohanraj R, Godlewski G, Bátkai S, Kunos G, et al.
Modulation of the endocannabinoid system in cardiovascular disease: Therapeutic potential and limitations. Hypertension 2008;52:601-7.
Goyal H, Awad HH, Ghali JK. Role of cannabis in cardiovascular disorders. J Thorac Dis 2017;9:2079-92.
Pacher P, Steffens S. The emerging role of the endocannabinoid system in cardiovascular disease. Semin Immunopathol 2009;31:63-77.
Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Huestis MA, et al.
The cannabinoid CB1 receptor antagonist rimonabant attenuates the hypotensive effect of smoked marijuana in male smokers. Am Heart J 2006;151:754.e1-5.
Jones RT. Cardiovascular system effects of marijuana. J Clin Pharmacol 2002;42:58S-63S.
Ho WS, Kelly ME. Cannabinoids in the cardiovascular system. Adv Pharmacol 2017;80:329-66.
Randall MD, Harris D, Kendall DA, Ralevic V. Cardiovascular effects of cannabinoids. Pharmacol Ther 2002;95:191-202.
Hillard CJ, Shi L, Tuniki VR, Falck JR, Campbell WB. Studies of anandamide accumulation inhibitors in cerebellar granule neurons: Comparison to inhibition of fatty acid amide hydrolase. J Mol Neurosci 2007;33:18-24.
Ho WS, Barrett DA, Randall MD. 'Entourage' effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors. Br J Pharmacol 2008;155:837-46.
Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR, Kunos G. Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature 1997;390:518-21.
Bonz A, Laser M, Küllmer S, Kniesch S, Babin-Ebell J, Popp V, et al.
Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle. J Cardiovasc Pharmacol 2003;41:657-64.
Bátkai S, Pacher P, Osei-Hyiaman D, Radaeva S, Liu J, Harvey-White J, et al.
Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation 2004;110:1996-2002.
Pacher P, Bátkai S, Kunos G. Haemodynamic profile and responsiveness to anandamide of TRPV1 receptor knock-out mice. J Physiol 2004;558:647-57.
Mukhopadhyay P, Bátkai S, Rajesh M, Czifra N, Harvey-White J, Haskó G, et al.
Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J Am Coll Cardiol 2007;50:528-36.
Bouchard JF, Lépicier P, Lamontagne D. Contribution of endocannabinoids in the endothelial protection afforded by ischemic preconditioning in the isolated rat heart. Life Sci 2003;72:1859-70.
Rajesh M, Mukhopadhyay P, Bátkai S, Haskó G, Liaudet L, Huffman JW, et al.
CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol 2007;293:H2210-8.
Rajesh M, Mukhopadhyay P, Haskó G, Huffman JW, Mackie K, Pacher P. CB2 cannabinoid receptor agonists attenuate TNF-alpha-induced human vascular smooth muscle cell proliferation and migration. Br J Pharmacol 2008;153:347-57.
Varga K, Lake K, Martin BR, Kunos G. Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide. Eur J Pharmacol 1995;278:279-83.
Wheal AJ, Bennett T, Randall MD, Gardiner SM. Cardiovascular effects of cannabinoids in conscious spontaneously hypertensive rats. Br J Pharmacol 2007;152:717-24.
Lake KD, Martin BR, Kunos G, Varga K. Cardiovascular effects of anandamide in anesthetized and conscious normotensive and hypertensive rats. Hypertension 1997;29:1204-10.
Li J, Kaminski NE, Wang DH. Anandamide-induced depressor effect in spontaneously hypertensive rats: Role of the vanilloid receptor. Hypertension 2003;41:757-62.
Schultheiss T, Flau K, Kathmann M, Göthert M, Schlicker E. Cannabinoid CB1 receptor-mediated inhibition of noradrenaline release in guinea-pig vessels, but not in rat and mouse aorta. Naunyn Schmiedebergs Arch Pharmacol 2005;372:139-46.
Hillard CJ, Jarrahian A. The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes. Chem Phys Lipids 2000;108:123-34.
Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, et al.
Evidence for novel cannabinoid receptors. Pharmacol Ther 2005;106:133-45.
Varga K, Lake KD, Huangfu D, Guyenet PG, Kunos G. Mechanism of the hypotensive action of anandamide in anesthetized rats. Hypertension 1996;28:682-6.
White R, Ho WS, Bottrill FE, Ford WR, Hiley CR. Mechanisms of anandamide-induced vasorelaxation in rat isolated coronary arteries. Br J Pharmacol 2001;134:921-9.
Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sørgård M, Di Marzo V, et al.
Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999;400:452-7.
Ho WS, Zheng X, Zhang DX. Role of endothelial TRPV4 channels in vascular actions of the endocannabinoid, 2-arachidonoylglycerol. Br J Pharmacol 2015;172:5251-64.
O'Sullivan SE. An update on PPAR activation by cannabinoids. Br J Pharmacol 2016;173:1899-910.
Calkin AC, Thomas MC. PPAR agonists and cardiovascular disease in diabetes. PPAR Res 2008;2008:245410.
El-Bassossy HM, El-Maraghy NN, El-Fayoumi HM, Watson ML. Haem oxygenase-1 induction protects against tumour necrosis factor alpha impairment of endothelial-dependent relaxation in rat isolated pulmonary artery. Br J Pharmacol 2009;158:1527-35.
Rademacher DJ, Patel S, Ho WS, Savoie AM, Rusch NJ, Gauthier KM, et al.
U-46619 but not serotonin increases endocannabinoid content in middle cerebral artery: Evidence for functional relevance. Am J Physiol Heart Circ Physiol 2005;288:H2694-701.
Szekeres M, Nádasy GL, Turu G, Soltész-Katona E, Benyó Z, Offermanns S, et al.
Endocannabinoid-mediated modulation of gq/11 protein-coupled receptor signaling-induced vasoconstriction and hypertension. Mol Cell Endocrinol 2015;403:46-56.
Bátkai S, Járai Z, Wagner JA, Goparaju SK, Varga K, Liu J, et al.
Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 2001;7:827-32.
Hydock DS, Lien CY, Hayward R. Anandamide preserves cardiac function and geometry in an acute doxorubicin cardiotoxicity rat model. J Cardiovasc Pharmacol Ther 2009;14:59-67.
Mukhopadhyay B, Cinar R, Yin S, Liu J, Tam J, Godlewski G, et al.
Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB1) receptors in the regenerating liver. Proc Natl Acad Sci U S A 2011;108:6323-8.
Wenzel D, Matthey M, Bindila L, Lerner R, Lutz B, Zimmer A, et al.
Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction. Proc Natl Acad Sci U S A 2013;110:18710-5.
Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M, et al.
The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 2003;112:423-31.
Gary-Bobo M, Elachouri G, Gallas JF, Janiak P, Marini P, Ravinet-Trillou C, et al.
Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese zucker Fa/Fa rats. Hepatology 2007;46:122-9.
Poirier B, Bidouard JP, Cadrouvele C, Marniquet X, Staels B, O'Connor SE, et al.
The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab 2005;7:65-72.
Chinali M, de Simone G, Roman MJ, Lee ET, Best LG, Howard BV, et al.
Impact of obesity on cardiac geometry and function in a population of adolescents: The strong heart study. J Am Coll Cardiol 2006;47:2267-73.
Garavaglia GE, Messerli FH, Nunez BD, Schmieder RE, Grossman E. Myocardial contractility and left ventricular function in obese patients with essential hypertension. Am J Cardiol 1988;62:594-7.
Rumantir MS, Vaz M, Jennings GL, Collier G, Kaye DM, Seals DR, et al.
Neural mechanisms in human obesity-related hypertension. J Hypertens 1999;17:1125-33.
Després JP, Golay A, Sjöström L; Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N
Engl J Med 2005;353:2121-34.
Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S; RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005;365:1389-97.
Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF; RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: A randomised controlled study. Lancet 2006;368:1660-72.
Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J; RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: A randomized controlled trial. JAMA 2006;295:761-75.
Cunha P, Romão AM, Mascarenhas-Melo F, Teixeira HM, Reis F. Endocannabinoid system in cardiovascular disorders-new pharmacotherapeutic opportunities. J Pharm Bioallied Sci 2011;3:350-60.
Leite CE, Mocelin CA, Petersen GO, Leal MB, Thiesen FV. Rimonabant: An antagonist drug of the endocannabinoid system for the treatment of obesity. Pharmacol Rep 2009;61:217-24.
Braunersreuther V, Mach F. Leukocyte recruitment in atherosclerosis: Potential targets for therapeutic approaches? Cell Mol Life Sci 2006;63:2079-88.
Lagneux C, Lamontagne D. Involvement of cannabinoids in the cardioprotection induced by lipopolysaccharide. Br J Pharmacol 2001;132:793-6.
Liao Y, Bin J, Luo T, Zhao H, Ledent C, Asakura M, et al.
CB1 cannabinoid receptor deficiency promotes cardiac remodeling induced by pressure overload in mice. Int J Cardiol 2013;167:1936-44.
Wagner JA, Hu K, Karcher J, Bauersachs J, Schäfer A, Laser M, et al.
CB(1) cannabinoid receptor antagonism promotes remodeling and cannabinoid treatment prevents endothelial dysfunction and hypotension in rats with myocardial infarction. Br J Pharmacol 2003;138:1251-8.
Hajrasouliha AR, Tavakoli S, Ghasemi M, Jabehdar-Maralani P, Sadeghipour H, Ebrahimi F, et al.
Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart. Eur J Pharmacol 2008;579:246-52.
Pacher P, Haskó G. Endocannabinoids and cannabinoid receptors in ischaemia-reperfusion injury and preconditioning. Br J Pharmacol 2008;153:252-62.
Li Q, Shi M, Li B. Anandamide enhances expression of heat shock protein 72 to protect against ischemia-reperfusion injury in rat heart. J Physiol Sci 2013;63:47-53.
Defer N, Wan J, Souktani R, Escoubet B, Perier M, Caramelle P, et al.
The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy. FASEB J 2009;23:2120-30.
Montecucco F, Lenglet S, Braunersreuther V, Burger F, Pelli G, Bertolotto M, et al.
CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol 2009;46:612-20.
Di Filippo C, Rossi F, Rossi S, D'Amico M. Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia-reperfusion injury: Involvement of cytokine/chemokines and PMN. J Leukoc Biol 2004;75:453-9.
Krylatov AV, Ugdyzhekova DS, Bernatskaya NA, Maslov LN, Mekhoulam R, Pertwee RG, et al.
Activation of type II cannabinoid receptors improves myocardial tolerance to arrhythmogenic effects of coronary occlusion and reperfusion. Bull Exp Biol Med 2001;131:523-5.
Krylatov AV, Uzhachenko RV, Maslov LN, Bernatskaya NA, Makriyannis A, Mechoulam R, et al.
Endogenous cannabinoids improve myocardial resistance to arrhythmogenic effects of coronary occlusion and reperfusion: A possible mechanism. Bull Exp Biol Med 2002;133:122-4.
Krylatov AV, Uzhachenko RV, Maslov LN, Ugdyzhekova DS, Bernatskaia NA, Pertwee R, et al.
Anandamide and R-(+)-methanandamide prevent development of ischemic and reperfusion arrhythmia in rats by stimulation of CB2-receptors. Eksp Klin Farmakol 2002;65:6-9.
Krylatov AV, Bernatskaia NA, Maslov LN, Pertwee RG, Mechoulam R, Stefano GB, et al.
Increase of the heart arrhythmogenic resistance and decrease of the myocardial necrosis zone during activation of cannabinoid receptors. Ross Fiziol Zh Im I M Sechenova 2002;88:560-7.
Ugdyzhekova DS, Davydova YG, Maimeskulova LA, Mechoulam R. Involvement of central and peripheral cannabinoid receptors in the regulation of heart resistance to arrhythmogenic effects of epinephrine. Bull Exp Biol Med 2000;130:1087-9.
Ugdyzhekova DS, Bernatskaya NA, Stefano JB, Graier VF, Tam SW, Mekhoulam R. Endogenous cannabinoid anandamide increases heart resistance to arrhythmogenic effects of epinephrine: Role of CB(1) and CB(2) receptors. Bull Exp Biol Med 2001;131:251-3.
Walsh SK, Hepburn CY, Kane KA, Wainwright CL. Acute administration of cannabidiol in vivo
suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion. Br J Pharmacol 2010;160:1234-42.
Amorós I, Barana A, Caballero R, Gómez R, Osuna L, Lillo MP, et al.
Endocannabinoids and cannabinoid analogues block human cardiac kv4.3 channels in a receptor-independent manner. J Mol Cell Cardiol 2010;48:201-10.
Gorelick DA, Goodwin RS, Schwilke E, Schwope DM, Darwin WD, Kelly DL, et al.
Tolerance to effects of high-dose oral δ9-tetrahydrocannabinol and plasma cannabinoid concentrations in male daily cannabis smokers. J Anal Toxicol 2013;37:11-6.
Schmid K, Schönlebe J, Drexler H, Mueck-Weymann M. The effects of cannabis on heart rate variability and well-being in young men. Pharmacopsychiatry 2010;43:147-50.
Pratap B, Korniyenko A. Toxic effects of marijuana on the cardiovascular system. Cardiovasc Toxicol 2012;12:143-8.
Mir A, Obafemi A, Young A, Kane C. Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics 2011;128:e1622-7.
Heath TS, Burroughs Z, Thompson AJ, Tecklenburg FW. Acute intoxication caused by a synthetic cannabinoid in two adolescents. J Pediatr Pharmacol Ther 2012;17:177-81.
Steffens S, Pacher P. Targeting cannabinoid receptor CB(2) in cardiovascular disorders: Promises and controversies. Br J Pharmacol 2012;167:313-23.
Warzecha Z, Dembinski A, Ceranowicz P, Dembinski M, Cieszkowski J, Kownacki P, et al.
Role of sensory nerves in gastroprotective effect of anandamide in rats. J Physiol Pharmacol 2011;62:207-17.
Krowicki ZK. Involvement of hindbrain and peripheral prostanoids in gastric motor and cardiovascular responses to delta-9-tetrahydrocannabinol in the rat. J Physiol Pharmacol 2012;63:581-8.