Category Archives: Cardiovascular Disease

Cannabis Constituents and Acetylcholinesterase Interaction: Molecular Docking, In Vitro Studies and Association with CNR1 rs806368 and ACHE rs17228602.

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biomolecules-logo“The study documented here was aimed to find the molecular interactions of some of the cannabinoid constituents of cannabis with acetylcholinesterase (AChE). Molecular docking and LogP determination were performed to predict the AChE inhibitory effect and lipophilicity. AChE enzyme activity was measured in the blood of cannabis addicted human subjects. Further, genetic predisposition to cannabis addiction was investigated by association analysis of cannabinoid receptor 1 (CNR1) single nucleotide polymorphism (SNP) rs806368 and ACHE rs17228602 using restriction fragment length polymorphism (RFLP) method. All the understudied cannabis constituents showed promising binding affinities with AChE and are lipophilic in nature. The AChE activity was observed to be indifferent in cannabis addicted and non-addicted healthy controls. There was no significant association with CNR1 SNP rs806368 and ACHE rs17228602. The study concludes that in silico prediction for individual biomolecules of cannabis is different from in vivo physiological action in human subjects when all are present together. However, for a deeper mechanistic insight into these interactions and association, multi-population studies are suggested. Further studies to explore the inhibitory potential of different cannabis constituents for intended AChE inhibitor-based drug are warranted.”

https://www.ncbi.nlm.nih.gov/pubmed/32414087

https://www.mdpi.com/2218-273X/10/5/758

“Characterization of Lignanamides from Hemp (Cannabis sativa L.) Seed and Their Antioxidant and Acetylcholinesterase Inhibitory Activities.”  https://www.ncbi.nlm.nih.gov/pubmed/26585089

Endocannabinoid system and cardiometabolic risk factors: A comprehensive systematic review insight into the mechanistic effects of omega-3 fatty acids.

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Life Sciences“Increased levels of endocannabinoids, 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA) have a pathophysiological role in the setting of cardiometabolic diseases. This systematic review was carried out to appraise the effect of omega-3 on cardiometabolic risk factors by highlighting the mediating effect of endocannabinoids.

Eleven animal studies and two human studies showed a marked reduction in 2-AG and AEA levels following intake of omega-3 which correlated with decreased adiposity, weight gain and improved glucose homeostasis. Moreover, endocannabinoids were elevated in three studies that replaced omega-3 with omega-6.

Omega-3 showed anti-inflammatory properties due to reduced levels of inflammatory cytokines, regulation of T-cells function and increased levels of eicosapentaenoyl ethanolamide, docosahexaenoyl ethanolamide and oxylipins; however, a limited number of studies examined a correlation between inflammatory cytokines and endocannabinoids following omega-3 administration.

In conclusion, omega-3 modulates endocannabinoid tone, which subsequently attenuates inflammation and cardiometabolic risk factors. However, further randomized clinical trials are needed before any recommendations are made to target the ECS using omega-3 as an alternative therapy to drugs for cardiometabolic disease improvement.”

https://www.ncbi.nlm.nih.gov/pubmed/32184122

“Endocannabinoid system (ECS) may mediate favorable effects of omega-3 fatty acids in cardiometabolic disorders. Omega-3 fatty acids showed anti-inflammatory effects due to increased levels of ethanolamide and oxylipins. Plant-derived omega-3 may be as effective as animal-derived omega-3 in ECS modulation. Omega-3 may have a potential to be an alternative to drugs for cardiometabolic disease improvement.”

https://www.sciencedirect.com/science/article/abs/pii/S0024320520303040?via%3Dihub

The effects of acute and sustained cannabidiol dosing for seven days on the haemodynamics in healthy men: A randomised controlled trial.

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British Journal of Clinical Pharmacology“In vivo studies show that cannabidiol (CBD) acutely reduces blood pressure (BP) in men.

The aim of this study was to assess the effects of repeated CBD dosing on haemodynamics.

RESULTS:

Compared to placebo, CBD significantly reduced resting mean arterial pressure (P = .04, two-way ANOVA, mean difference (MD) -2 mmHg, 95% CI -3.6 to -0.3) after acute dosing, but not after repeated dosing. In response to stress, volunteers who had taken CBD had lower systolic BP after acute (P = .001, two-way ANOVA, MD -6 mmHg, 95% CI -10 to -1) and repeated (P = .02, two-way ANOVA, MD -5.7 mmHg, 95% CI -10 to -1) dosing. Seven days of CBD increased internal carotid artery diameter (MD +0.55 mm, P = .01). Within the CBD group, repeated dosing reduced arterial stiffness by day 7 (pulse wave velocity; MD -0.44 m/s, P = .05) and improved endothelial function (flow mediation dilatation, MD +3.5%, P = .02, n = 6 per group), compared to day 1.

CONCLUSION:

CBD reduces BP at rest after a single dose but the effect is lost after seven days of treatment (tolerance); however, BP reduction during stress persists. The reduction in arterial stiffness and improvements in endothelial function after repeated CBD dosing are findings that warrant further investigation in populations with vascular diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/32128848

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bcp.14225

Cannabidiol protects against high glucose-induced oxidative stress and cytotoxicity in cardiac voltage-gated sodium channels.

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Publication cover image“Cardiovascular complications are the major cause of mortality in diabetic patients. However, the molecular mechanisms underlying diabetes-associated arrhythmias are unclear.

We hypothesized that high glucose, could adversely affect Nav1.5, the major cardiac sodium channel isoform of the heart, at least partially via oxidative stress.

We further hypothesized that cannabidiol (CBD), one of the main constituents of Cannabis sativa, through its effects on Nav1.5, could protect against high glucose elicited oxidative stress and cytotoxicity.

KEY RESULTS:

High glucose evoked cell death associated with elevation in reactive oxygen species, right shifted the voltage dependence of conductance and steady state fast inactivation and increased persistent current leading to computational prolongation of action potential (hyperexcitability) which could result in long QT3 arrhythmia. CBD mitigated all the deleterious effects provoked by high glucose. Perfusion with Lidocaine (a well-known sodium channels inhibitor with anti-oxidant effects), or co-incubation of Tempol (a well-known anti-oxidant) elicited protection, comparable to CBD, against the deleterious effects of high glucose.

CONCLUSIONS AND IMPLICATIONS:

These findings suggest that, through its favourable anti-oxidant and sodium channel inhibitory effects, CBD may protect against high-glucose induced arrhythmia and cytotoxicity.”

https://www.ncbi.nlm.nih.gov/pubmed/32077098

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15020

Targeting GPCRs Against Cardiotoxicity Induced by Anticancer Treatments.

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Image result for frontiers in cardiovascular medicine“Novel anticancer medicines, including targeted therapies and immune checkpoint inhibitors, have greatly improved the management of cancers. However, both conventional and new anticancer treatments induce cardiac adverse effects, which remain a critical issue in clinic.

Cardiotoxicity induced by anti-cancer treatments compromise vasospastic and thromboembolic ischemia, dysrhythmia, hypertension, myocarditis, and cardiac dysfunction that can result in heart failure. Importantly, none of the strategies to prevent cardiotoxicity from anticancer therapies is completely safe and satisfactory.

Certain clinically used cardioprotective drugs can even contribute to cancer induction. Since G protein coupled receptors (GPCRs) are target of forty percent of clinically used drugs, here we discuss the newly identified cardioprotective agents that bind GPCRs of adrenalin, adenosine, melatonin, ghrelin, galanin, apelin, prokineticin and cannabidiol.

We hope to provoke further drug development studies considering these GPCRs as potential targets to be translated to treatment of human heart failure induced by anticancer drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/32039239

https://www.frontiersin.org/articles/10.3389/fcvm.2019.00194/full

“Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.”  https://www.ncbi.nlm.nih.gov/pubmed/25569804

Marijuana use and coronary artery disease in young adults.

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Image result for plos one“This study aims to determine the frequency of coronary artery disease among young to middle aged adults presenting with chest pain who currently use marijuana as compared to nonusers.

Only 6.8% of the 146 marijuana users had evidence of coronary artery disease on coronary CT angiography. In comparison, the rate was 15.0% among the 1,274 marijuana nonusers.

A majority of marijuana users were younger than nonusers and had a lower frequency of hypertension and diabetes than nonusers.

There was no statistical difference in lipid panel values between the two groups.

CONCLUSION:

Among younger patients being evaluated for chest pain, self-reported cannabis use conferred no additional risk of coronary artery disease as detected on coronary CT angiography.”

https://www.ncbi.nlm.nih.gov/pubmed/31995626

“There is no association between marijuana use and the presence of coronary artery disease on coronary CT angiography in young to middle aged patients presenting with chest pain.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228326

Activation of Cannabinoid Receptors Attenuates Endothelin-1-induced Mitochondrial Dysfunction in Rat Ventricular Myocytes.

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Image result for Journal of Cardiovascular Pharmacology.“Evidence suggests that activation of the endocannabinoid system offers cardioprotection.

Aberrant energy production by impaired mitochondria purportedly contributes to various aspects of cardiovascular disease. We investigated whether cannabinoid (CB) receptor activation would attenuate mitochondrial dysfunction induced by endothelin-1 (ET1).

Acute exposure to ET1 (4 h) in the presence of palmitate as primary energy substrate induced mitochondrial membrane depolarization, and decreased mitochondrial bioenergetics and expression of genes related to fatty acid oxidation (i.e. peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, a driver of mitochondrial biogenesis, and carnitine palmitoyltransferase (CPT)-1β, facilitator of fatty acid uptake).

A CB1/CB2 dual agonist with limited brain penetration, CB-13, corrected these parameters. AMP-activated protein kinase (AMPK), an important regulator of energy homeostasis, mediated the ability of CB-13 to rescue mitochondrial function. In fact, the ability of CB-13 to rescue fatty acid oxidation-related bioenergetics, as well as expression of PGC-1α and CPT-1β, was abolished by pharmacological inhibition of AMPK using compound C and shRNA knockdown of AMPKα1/α2, respectively.

Interventions that target CB/AMPK signaling might represent a novel therapeutic approach to address the multi-factorial problem of cardiovascular disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31815823

https://insights.ovid.com/crossref?an=00005344-900000000-98463

The effect of high maternal linoleic acid on endocannabinoid signalling in rodent hearts.

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Image result for journal of developmental origins of health and disease “The endocannabinoid system (ECS), modulated by metabolites of linoleic acid (LA), is important in regulating cardiovascular function.

In pregnancy, LA is vital for foetal development.

Data indicate that a high LA diet alters cell viability and CB2 expression, potentially influencing cardiac function during pregnancy and development of the offspring’s heart.”

https://www.ncbi.nlm.nih.gov/pubmed/31814560

https://www.cambridge.org/core/journals/journal-of-developmental-origins-of-health-and-disease/article/effect-of-high-maternal-linoleic-acid-on-endocannabinoid-signalling-in-rodent-hearts/C92E2C1126249B7CF9D8A929F0E52FA2

“A number of previous studies have shown that polyunsaturated fatty acids (PUFAs) and phytosterols are critically important for human health. Hempseed is a rich source of plant oil, which contains more than 80% PUFAs. The fatty acids in hempseed oil include a variety of essential fatty acids, including linoleic acid ”

https://link.springer.com/article/10.1007%2Fs10059-011-0042-6

Vasodilatory effects of cannabidiol in human pulmonary and rat small mesenteric arteries: modification by hypertension and the potential pharmacological opportunities.

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 Image result for ovid journal“Cannabidiol (CBD) has been suggested as a potential antihypertensive drug.

The aim of our study was to investigate its vasodilatory effect in isolated human pulmonary arteries (hPAs) and rat small mesenteric arteries (sMAs).

METHODS:

Vascular effects of CBD were examined in hPAs obtained from patients during resection of lung carcinoma and sMAs isolated from spontaneously hypertensive (SHR); 11-deoxycorticosterone acetate (DOCA-salt) hypertensive rats or their appropriate normotensive controls using organ bath and wire myography, respectively.

RESULTS:

CBD induced almost full concentration-dependent vasorelaxation in hPAs and rat sMAs. In hPAs, it was insensitive to antagonists of CB1 (AM251) and CB2 (AM630) receptors but it was reduced by endothelium denudation, cyclooxygenase inhibitors (indomethacin and nimesulide), antagonists of prostanoid EP4 (L161982), IP (Cay10441), vanilloid TRPV1 (capsazepine) receptors and was less potent under KCl-induced tone and calcium-activated potassium channel (KCa) inhibitors (iberiotoxin, UCL1684 and TRAM-34) and in hypertensive, overweight and hypercholesteremic patients. The time-dependent effect of CBD was sensitive to the PPARγ receptor antagonist GW9662. In rats, the CBD potency was enhanced in DOCA-salt and attenuated in SHR. The CBD-induced relaxation was inhibited in SHR and DOCA-salt by AM251 and only in DOCA-salt by AM630 and endothelium denudation.

CONCLUSION:

The CBD-induced relaxation in hPAs that was reduced in hypertensive, obese and hypercholesteremic patients was endothelium-dependent and mediated via KCa and IP, EP4, TRPV1 receptors. The CBD effect in rats was CB1-sensitive and dependent on the hypertension model. Thus, modification of CBD-mediated responses in disease should be considered when CBD is used for therapeutic purposes.”

https://www.ncbi.nlm.nih.gov/pubmed/31800399

https://insights.ovid.com/crossref?an=00004872-900000000-97067

Alcohol Binge-Induced Cardiovascular Dysfunction Involves Endocannabinoid-CB1-R Signaling.

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 JACC: Basic to Translational Science“Excessive binge alcohol drinking may adversely affect cardiovascular function. In this study we characterize the detailed hemodynamic effects of an acute alcohol binge in mice using multiple approaches and investigate the role of the endocannabinoid-cannabinoid 1 receptor (CB1-R) signaling in these effects. Acute alcohol binge was associated with elevated levels of cardiac endocannabinoid anandamide and profound cardiovascular dysfunction lasting for several hours and redistribution of circulation. These changes were attenuated by CB1-R antagonist or in CB1-R knockout mice. Our results suggest that a single alcohol binge has profound effects on the cardiovascular system, which involve endocannabinoid-CB1-R signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/31768478

“Alcohol is one of the most frequently used intoxicants in the United States. Binge alcohol drinking is a major contributor of emergency department visits. Binge alcohol drinking may adversely affect cardiovascular function. Here we show that acute alcohol intoxication is associated with elevated levels of cardiac endocannabinoid anandamide and profound cardiovascular dysfunction and blood redistribution lasting for several hours. The adverse cardiovascular effects of acute alcohol intoxication are attenuated by CB1-R antagonist or in CB1-R knockout mice. A single alcohol binge has profound effect on the cardiovascular system, which involves endocannabinoid-CB1-R signaling.”

https://www.sciencedirect.com/science/article/pii/S2452302X19301755?via%3Dihub