Anandamide and endocannabinoid system: an attractive therapeutic approach for cardiovascular disease.

SAGE Journals

“Cardiovascular disease is currently not adequately managed and has become one of the main causes of morbidity and mortality worldwide. Current therapies are inadequate in terms of preventing its progression. There are several limitations, such as poor oral bioavailability, side effects, low adherence to treatment, and high dosage frequency of formulations due to the short half-life of the active ingredients used, among others.

This review aims to highlight the most relevant aspects of the relationship between the cardiovascular system and the endocannabinoid system, with special attention to the possible translational effect of the use of anandamide in cardiovascular health. The deep and detailed knowledge of this interaction, not always beneficial, and that for years has gone unnoticed, is essential for the development of new therapies.

We discuss the most recent and representative results obtained in the field of basic research, referring to the aforementioned subject, emphasizing fundamentally the main role of nitric oxide, renal physiology and its deregulation in pathological processes.”

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Relation of Cannabis Use and Atrial Fibrillation Among Patients Hospitalized for Heart Failure.

 The American Journal of Cardiology

“Left ventricular dysfunction triggers the activation of the sympathetic nervous system, providing inotropic support to the failing heart and concomitantly increasing the risk of atrial fibrillation (AF). The cardiovascular effects of cannabis have been characterized as biphasic on the autonomic nervous system with an increased sympathetic effect at low doses and an inhibitory sympathetic activity at higher doses. It is unknown if the autonomic effect of cannabis impacts the occurrence of AF in patients with heart failure (HF).

We used data from the Healthcare Cost and Utilization Project-National Inpatient Sample for patients admitted with a diagnosis of HF in 2014. The outcome variable was the diagnosis of AF, with the main exposure being cannabis use. We identified a cannabis user group and a 1:1 propensity-matched non-cannabis user group, each having 3,548 patients. We then estimated the odds of AF diagnosis in cannabis users. An estimated 3,950,392 patients were admitted with a diagnosis of HF in the United States in 2014. Among these, there were 17,755 (0.45%) cannabis users. In the matched cohort, cannabis users were less likely to have AF (19.08% vs 21.39%; AOR 0.87 [0.77 to 0.98]).

In conclusion, cannabis users have lower odds of AF when compared with nonusers, which was not explained by co-morbid conditions, age, insurance type, and socioeconomic status.”

https://www.ncbi.nlm.nih.gov/pubmed/29685570

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The Endocannabinoid System and Heart Disease: The Role of Cannabinoid Receptor Type 2.

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“Decades of research has provided evidence for the role of the endocannabinoid system in human health and disease. This versatile system, consisting of two receptors (CB1 and CB2), their endogenous ligands (endocannabinoids), and metabolic enzymes has been implicated in a wide variety of disease states, ranging from neurological disorders to cancer.

CB2 has gained much interest for its beneficial immunomodulatory role that can be obtained without eliciting psychotropic effects through CB1. Recent studies have shed light on a protective role of CB2 in cardiovascular disease, an ailment which currently takes more lives each year in Western countries than any other disease or injury.

By use of CB2 knockout mice and CB2-selective ligands, knowledge of how CB2 signaling affects atherosclerosis and ischemia has been acquired, providing a major stepping stone between basic science and translational clinical research.

Here, we summarize the current understanding of the endocannabinoid system in human pathologies and provide a review of the results from preclinical studies examining its function in cardiovascular disease, with a particular emphasis on possible CB2-targeted therapeutic interventions to alleviate atherosclerosis.”

https://www.ncbi.nlm.nih.gov/pubmed/29412125

“Researchers suggest that THC and other cannabinoids, which are active at CB2, the cannabinoid receptor expressed on immune cells, may be valuable in treating atherosclerosis.” https://www.medscape.com/viewarticle/787468

“Cardiovascular disease: New use for cannabinoids”  https://www.nature.com/articles/nrd1733

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Cholesterol-induced stimulation of platelet aggregation is prevented by a hempseed-enriched diet.

Canadian Journal of Physiology and Pharmacology

“Hypercholesterolemia indirectly increases the risk for myocardial infarction by enhancing the ability of platelets to aggregate.

Diets enriched with polyunsaturated fatty acids (PUFAs) have been shown to reduce the detrimental effects of cholesterol on platelet aggregation.

This study investigated whether dietary hempseed, a rich source of PUFAs, inhibits platelet aggregation under normal and hypercholesterolemic conditions.

The results of this study demonstrate that when hempseed is added to a cholesterol-enriched diet, cholesterol-induced platelet aggregation returns to control levels.”

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Cannabidiol Limits T Cell–Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation

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“Cannabidiol (CBD) is a nonpsychoactive ingredient of marijuana (Cannabis sativa).

Collectively, our study demonstrates that CBD treatment markedly attenuates autoimmune myocarditis and improves myocardial dysfunction and heart failure primarily by its antiinflammatory and antifibrotic effects.

These results, coupled with the proven safety of CBD in human clinical trials and its current orphan drug approval by the FDA for different neurological disorders, suggest that it has tremendous therapeutic potential in the therapy of myocarditis with different etiologies and various autoimmune disorders. The latter is also supported by beneficial effects of CBD in preventing graft versus host disease after allogeneic hematopoietic cell transplantation in a recent phase II human study, as well as in mice with arthritis. Attenuation of the T cell–mediated injury by CBD also suggests that it may have therapeutic utility in management of organ transplantation/rejection.

In conclusion, CBD may represent a promising novel treatment for managing autoimmune myocarditis and possibly other autoimmune disorders and organ transplantation.”

https://www.ncbi.nlm.nih.gov/pubmed/26772776

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004721/

http://static.smallworldlabs.com/molmedcommunity/content/pdfstore/16_007_Lee.pdf

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Prospects for the Use of Cannabinoid Receptor Ligands for the Treatment of Metabolic Syndrome and Atherosclerosis: Analysis of Experimental and Clinical Data.

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“An antagonist of central cannabinoid CB1 receptors rimonabant causes weight loss in patients with obesity and metabolic syndrome, improves blood lipid parameters, increases the adiponectin level, decreases the rate of glucose and glycosylated hemoglobin in patients with diabetes mellitus type-2. However, rimonabant adverse effects include depression, anxiety, nausea, and dizziness which are apparently due to the blockade of central CB1 receptors.

In mice with a high-calorie diet, we defined that the blockade of peripheral CB1 receptors prevents obesity, steatosis of the liver, improves lipid and carbohydrate metabolism. Experimental studies suggest that peripheral CB2 receptor agonists have antiatherogenic effect. To validate the expediency of clinical research of CB2 receptor agonists in patients with atherosclerosis the comparative analysis of antiatherogenic properties of cannabinoids should be performed. In addition, experiments are needed on the combination use of cannabinoids with well-known antiatherogenic agents, such as statins.”

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Abnormal cannabidiol confers cardioprotection in diabetic rats independent of glycemic control.

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“Chronic GPR18 activation by its agonist abnormal cannabidiol (trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; abn-cbd) improves myocardial redox status and function in healthy rats.

Here, we investigated the ability of abn-cbd to alleviate diabetes-evoked cardiovascular pathology and the contribution of GPR18 to this effect.

Collectively, the current findings present evidence for abn-cbd alleviation of diabetes-evoked cardiovascular anomalies likely via GPR18 dependent restoration of cardiac adiponectin-Akt-eNOS signaling and the diminution of myocardial oxidative stress.”

https://www.ncbi.nlm.nih.gov/pubmed/29274332

http://www.sciencedirect.com/science/article/pii/S0014299917308336

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The endocannabinoid system in cardiovascular function: novel insights and clinical implications.

Clinical Autonomic Research

“Cardiovascular disease is now recognized as the number one cause of death in the world, and the size of the population at risk continues to increase rapidly. The dysregulation of the endocannabinoid (eCB) system plays a central role in a wide variety of conditions including cardiovascular disorders. Cannabinoid receptors, their endogenous ligands, as well as enzymes conferring their synthesis and degradation, exhibit overlapping distributions in the cardiovascular system. Furthermore, the pharmacological manipulation of the eCB system has effects on blood pressure, cardiac contractility, and endothelial vasomotor control. Growing evidence from animal studies supports the significance of the eCB system in cardiovascular disorders.

RESULTS:

Drugs targeting CB1R, CB2R, TRPV1 and PPARs are proven effective in animal models mimicking cardiovascular disorders such as hypertension, atherosclerosis and myocardial infarction. Despite the setback of two clinical trials that exhibited unexpected harmful side-effects, preclinical studies are accelerating the development of more selective drugs with promising results devoid of adverse effects.

CONCLUSION:

Over the last years, increasing evidence from basic and clinical research supports the role of the eCB system in cardiovascular function. Whereas new discoveries are paving the way for the identification of novel drugs and therapeutic targets, the close cooperation of researchers, clinicians and pharmaceutical companies is needed to achieve successful outcomes.”

https://www.ncbi.nlm.nih.gov/pubmed/29222605

https://link.springer.com/article/10.1007%2Fs10286-017-0488-5

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Δ9-Tetrahydrocannabinol Prevents Cardiovascular Dysfunction in STZ-Diabetic Wistar-Kyoto Rats.

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“The aim of this study was to determine if chronic, low-dose administration of a nonspecific cannabinoid receptor agonist could provide cardioprotective effects in a model of type I diabetes mellitus.

Δ9-Tetrahydrocannabinol administration to diabetic animals significantly reduced blood glucose concentrations and attenuated pathological changes in serum markers of oxidative stress and lipid peroxidation. Positive changes to biochemical indices in diabetic animals conferred improvements in myocardial and vascular function.

This study demonstrates that chronic, low-dose administration of Δ9-tetrahydrocannabinol can elicit antihyperglycaemic and antioxidant effects in diabetic animals, leading to improvements in end organ function of the cardiovascular system. Implications from this study suggest that cannabinoid receptors may be a potential new target for the treatment of diabetes-induced cardiovascular disease.”   https://www.ncbi.nlm.nih.gov/pubmed/29181404

“The aim of this study was to determine if a nonspecific cannabinoid receptor agonist could provide cardioprotective effects in a model of type I diabetes mellitus. Outcomes from this study indicate that THC administration to STZ improved functional parameters of cardiovascular health by reducing oxidative stress, lipid peroxidation, and blood glucose levels. These results indicate that activation of cannabinoid receptors may be a viable experimental target for the prevention of oxidative stress-induced complications in type I diabetes mellitus.”  https://www.hindawi.com/journals/bmri/2017/7974149/

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Effects of chronic Δ9-tetrahydrocannabinol treatment on Rho/Rho-kinase signalization pathway in mouse brain.

Saudi Pharmaceutical Journal

“Δ9-Tetrahydrocannabinol (Δ9-THC) shows its effects by activating cannabinoid receptors which are on some tissues and neurons. Cannabinoid systems have role on cell proliferation and development of neurons. Furthermore, it is interesting that cannabinoidsystem and rho/rho-kinase signalization pathway, which have important role on cell development and proliferation, may have role on neuron proliferation and development together. Thus, a study is planned to investigate rhoA and rho-kinase enzyme expressions and their activities in the brain of chronic Δ9-THC treated mice. One group of mice are treated with Δ9-THC once to see effects of acute treatment. Another group of mice are treated with Δ9-THC three times per day for one month. After this period, rhoA and rho-kinase enzyme expressions and their activities in mice brains are analyzed by ELISA method. Chronic administration of Δ9-THC decreased the expression of rhoA while acute treatment has no meaningful effect on it. Administration of Δ9-THC did not affect expression of rho-kinase on both chronic and acute treatment. Administration of Δ9-THC increased rho-kinase activity on both chronic and acute treatment, however, chronic treatment decreased its activity with respect to acute treatment. This study showed that chronic Δ9-THC treatment down-regulated rhoA expression and did not change the expression level of rho-kinase which is downstream effector of rhoA. However, it elevated the rho-kinase activity. Δ9-THC induced down-regulation of rhoA may cause elevation of cypin expression and may have benefit on cypin related diseases. Furthermore, use of rho-kinase inhibitors and Δ9-THC together can be useful on rho-kinase related diseases.”

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