Category Archives: Cardiovascular Disease

Chronic cannabidiol treatment induces cardiovascular improvement in renovascular hypertensive rats

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“Background: Cannabidiol (CBD) is increasingly studied for its therapeutic potential in neurodegenerative diseases. Previous research on acute CBD administration has demonstrated cardiovascular benefits in hypertensive rats, including reduced mean blood pressure and oxidative stress.

Aim: To investigate the long-term cardiovascular effects of chronic CBD treatment in renovascular hypertension induced by the 2-kidney-1-clip (2K1C) model.

Methods: Male Wistar rats (180-200 g, 8 weeks old) underwent 2K1C or SHAM surgery. Six weeks later, rats received chronic CBD treatment (20 mg/kg, twice daily for 14 days). A combination of ex vivo, in vitro, and in vivo methods was used to assess CBD’s cardiovascular effects in 2K1C hypertensive rats.

Results: Chronic CBD treatment significantly reduced blood pressure and the depressor response to hexamethonium (a ganglionic blocker). It also normalized variability in low-frequency (LF) power and LF/high-frequency (HF) ratio. CBD enhanced vasodilation and reduced vasoconstriction in the mesenteric artery of 2K1C rats, accompanied by decreased expression of aortic reactive oxygen species (ROS).

Conclusion: Our findings suggest that chronic CBD treatment exerts antihypertensive effects by improving baroreflex sensitivity and vascular function while decreasing arterial ROS levels and sympathetic nerve activity. These results underscore CBD’s potential therapeutic role in managing cardiovascular complications associated with renovascular hypertension.”

https://pubmed.ncbi.nlm.nih.gov/39351852/

https://journals.lww.com/jhypertension/abstract/9900/chronic_cannabidiol_treatment_induces.554.aspx

Effect of Cannabistilbene I in Attenuating Angiotensin II-Induced Cardiac Hypertrophy: Insights into Cytochrome P450s and Arachidonic Acid Metabolites Modulation

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“Introduction: This research investigated the impact of Cannabistilbene I on Angiotensin II (Ang II)-induced cardiac hypertrophy and its potential role in cytochrome P450 (CYP) enzymes and arachidonic acid (AA) metabolic pathways. Cardiac hypertrophy, a response to increased stress on the heart, can lead to severe cardiovascular diseases if not managed effectively. CYP enzymes and AA metabolites play critical roles in cardiac function and hypertrophy, making them important targets for therapeutic intervention. 

Methods: Adult human ventricular cardiomyocyte cell line (AC16) was cultured and treated with Cannabistilbene I in the presence and absence of Ang II. The effects on mRNA expression related to cardiac hypertrophic markers and CYP were analyzed using real-time polymerase chain reaction, while CYP protein levels were measured by Western blot analysis. AA metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). 

Results: Results showed that Ang II triggered hypertrophy, as evidenced by the increase in hypertrophic marker expression, and enlarged the cell surface area, effects that were alleviated by Cannabistilbene I. Gene expression analysis indicated that Cannabistilbene I upregulated CYP1A1, leading to increased enzymatic activity, as evidenced by 7-ethoxyresorufin-O-deethylase assay. Furthermore, LC-MS/MS analysis of AA metabolites revealed that Ang II elevated midchain (R/S)-hydroxyeicosatetraenoic acid (HETE) concentrations, which were reduced by Cannabistilbene I. Notably, Cannabistilbene I selectively increased 19(S)-HETE concentration and reversed the Ang II-induced decline in 19(S)-HETE, suggesting a unique protective role. 

Conclusion: This study provides new insights into the potential of Cannabistilbene I in modulating AA metabolites and reducing Ang II-induced cardiac hypertrophy, revealing a new candidate as a therapeutic agent for cardiac hypertrophy.”

https://pubmed.ncbi.nlm.nih.gov/39324890/

https://www.liebertpub.com/doi/10.1089/can.2024.0148

“Cannabistilbene I (CBG-I) is a naturally occurring derivative of the plant cannabis. It is a polyphenol compound found in the resinous glandular trichomes of the cannabis plant. CBG-I is known for its potent antioxidant, anti-inflammatory, and neuroprotective properties, making it a promising area of research in various fields.

Cannabistilbene I was first isolated and identified in 1975 by scientists from the University of Mississippi. It is a distinct compound from other cannabinoids and is found in different cannabis varieties. CBG-I is the precursor to THC, CBD, and other cannabinoids, which makes it essential in the biosynthesis of these compounds.”

https://www.smolecule.com/products/s579399


Pharmacology of Non-Psychoactive Phytocannabinoids and Their Potential for Treatment of Cardiometabolic Disease

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“The use of Cannabis sativa by humans dates back to the third millennium BC, and it has been utilized in many forms for multiple purposes, including production of fibre and rope, as food and medicine, and (perhaps most notably) for its psychoactive properties for recreational use. The discovery of Δ9-tetrahydrocannabinol (Δ9-THC) as the main psychoactive phytocannabinoid contained in cannabis by Gaoni and Mechoulam in 1964 (J Am Chem Soc 86, 1646-1647), was the first major step in cannabis research; since then the identification of the chemicals (phytocannabinoids) present in cannabis, the classification of the pharmacological targets of these compounds and the discovery that the body has its own endocannabinoid system (ECS) have highlighted the potential value of cannabis-derived compounds in the treatment of many diseases, such as neurological disorders and cancers. Although the use of Δ9-THC as a therapeutic agent is constrained by its psychoactive properties, there is growing evidence that non-psychoactive phytocannabinoids, derived from both Cannabis sativa and other plant species, as well as non-cannabinoid compounds found in Cannabis sativa, have real potential as therapeutics. This chapter will focus on the possibilities for using these compounds in the prevention and treatment of cardiovascular disease and related metabolic disturbances.”

https://pubmed.ncbi.nlm.nih.gov/39235486/

https://link.springer.com/chapter/10.1007/164_2024_731

Beneficial Consequences of One-Month Oral Treatment with Cannabis Oil on Cardiac Hypertrophy and the Mitochondrial Pool in Spontaneously Hypertensive Rats

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“Introduction: It has been demonstrated the dysregulation of the cardiac endocannabinoid system in cardiovascular diseases. Thus, the modulation of this system through the administration of phytocannabinoids present in medicinal cannabis oil (CO) emerges as a promising therapeutic approach. Furthermore, phytocannabinoids exhibit potent antioxidant properties, making them highly desirable in the treatment of cardiac pathologies, such as hypertension-induced cardiac hypertrophy (CH). 

Objective: To evaluate the effect of CO treatment on hypertrophy and mitochondrial status in spontaneously hypertensive rat (SHR) hearts. 

Methods: Three-month-old male SHR were randomly assigned to CO or olive oil (vehicle) oral treatment for 1 month. We evaluated cardiac mass and histology, mitochondrial dynamics, membrane potential, area and density, myocardial reactive oxygen species (ROS) production, superoxide dismutase (SOD), and citrate synthase (CS) activity and expression. Data are presented as mean ± SEM (n) and compared by t-test, or two-way ANOVA and Bonferroni post hoc test were used as appropriate. p < 0.05 was considered statistically significant. 

Results: CH was reduced by CO treatment, as indicated by the left ventricular weight/tibia length ratio, left ventricular mass index, myocyte cross-sectional area, and left ventricle collagen volume fraction. The ejection fraction was preserved in the CO-treated group despite the persistence of elevated systolic blood pressure and the reduction in CH. Mitochondrial membrane potential was improved and mitochondrial biogenesis, dynamics, area, and density were all increased by treatment. Moreover, the activity and expression of the CS were enhanced by treatment, whereas ROS production was decreased and the antioxidant activity of SOD increased by CO administration. 

Conclusion: Based on the mentioned results, we propose that 1-month oral treatment with CO is effective to reduce hypertrophy, improve the mitochondrial pool and increase the antioxidant capacity in SHR hearts.”

https://pubmed.ncbi.nlm.nih.gov/39137344/

https://www.liebertpub.com/doi/10.1089/can.2024.0066

β-Caryophyllene Confers Cardioprotection by Scavenging Radicals and Blocking Ferroptosis

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“Ferroptosis is a form of regulated cell death triggered by iron-dependent lipid peroxidation and has been associated with heart diseases. However, there are currently no approved drugs that specifically inhibit ferroptosis in clinical practice, which largely limits the translational potential of this novel target.

Here, we demonstrated that β-caryophyllene (BCP; 150 μM), a natural dietary cannabinoid, protects cardiomyocytes against ferroptotic cell death induced by cysteine deprivation or glutathione peroxidase 4 (GPX4) inactivation. Moreover, BCP preserved the mitochondrial morphology and function during ferroptosis induction. Unexpectedly, BCP supported ferroptosis resistance independent of canonical antiferroptotic pathways.

Our results further suggested that BCP may terminate radical chain reactions through interactions with molecular oxygen, which also explains why its oxidation derivative failed to suppress ferroptosis. Finally, oral BCP administration (50 mg/kg, daily) significantly alleviated doxorubicin (15 mg/kg, single i.p. injection)-induced cardiac ferroptosis and cardiomyopathy in mice.

In conclusion, our data revealed the role of BCP as a natural antiferroptotic compound and suggest pharmacological modification based on BCP as a promising therapeutic strategy for treating ferroptosis-associated heart disorders.”

https://pubmed.ncbi.nlm.nih.gov/39088660/

https://pubs.acs.org/doi/10.1021/acs.jafc.4c03239

“Beta-caryophyllene is a dietary cannabinoid.” https://www.ncbi.nlm.nih.gov/pubmed/18574142

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934


Unmasking the cannabis paradox: in-hospital outcomes of cannabis users admitted with acute myocardial infarction over a 20-year period in the United States

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“Introduction: Cannabis is increasingly becoming a socially acceptable substance, with multiple countries having legalised its consumption. Epidemiological studies have demonstrated an association between cannabis use and an increased risk of developing coronary artery disease. However, there is a lack of studies about the influence of cannabis consumption on the outcomes following acute myocardial infarction (AMI).

Material and methods: We retrospectively analysed hospitalised patients with a primary diagnosis of AMI from the 2001 to 2020 National Inpatient Sample (NIS). Pearson’s χ2 tests were applied to categorical variables, and t-tests for continuous variables. We conducted a 1:1 propensity score matching (PSM). Multivariate regression models were deployed on the PSM sample to estimate the differences in several events and all-cause mortality.

Results: A total of 9,930,007 AMI patients were studied, of whom 117,641 (1.2%) reported cannabis use. Cannabis users had lower odds of atrial fibrillation (aOR = 0.902, p < 0.01), ventricular fibrillation (aOR = 0.919, p < 0.01), cardiogenic shock (aOR = 0.730, p < 0.01), acute ischaemic stroke (aOR = 0.825, p < 0.01), cardiac arrest (aOR = 0.936, p = 0.010), undergoing PCI (aOR = 0.826, p < 0.01), using IABP (aOR = 0.835, p < 0.01), and all-cause mortality (aOR = 0.640, p < 0.01), but with higher odds of supraventricular tachycardia (aOR = 1.104, p < 0.01), ventricular tachycardia (aOR = 1.054, p < 0.01), CABG use (aOR = 1.040, p = 0.010), and acute kidney injury (aOR = 1.103, p < 0.01).

Conclusions: Among patients aged 18-80 years admitted to hospital with AMI between 2001 and 2020 in the United States, cannabis use was associated with lower risks of cardiogenic shock, acute ischaemic stroke, cardiac arrest, PCI use, and in-hospital mortality.”

https://pubmed.ncbi.nlm.nih.gov/39086618/

https://amsad.termedia.pl/Unmasking-the-cannabis-paradox-in-hospital-outcomes-of-cannabis-users-admitted-with,189731,0,2.html

The prophylactic and therapeutic effects of cannabidiol on lung injury secondary to cardiac ischemia model in rats via PERK/NRF2/CHOP/BCL2 pathway

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“Background: Inflammation and oxidative stress are key players in lung injury stemming from cardiac ischemia (LISCI). Cannabidiol (CBD) demonstrates tissue-protective properties through its antioxidant, anti-inflammatory, and anti-apoptotic characteristics. This study aims to assess the preventive (p-CBD) and therapeutic (t-CBD) effects of CBD on LISCI.

Methods: Forty male Wistar Albino rats were divided into four groups: control (CON), LISCI, p-CBD, and t-CBD. The left anterior descending coronary artery was ligated for 30 minutes of ischemia followed by 30 minutes of reperfusion. Lung tissues were then extracted for histopathological, immunohistochemical, genetic, and biochemical analyses.

Results: Histopathologically, marked hyperemia, increased septal tissue thickness, and inflammatory cell infiltrations were observed in the lung tissues of the LISCI group. Spectrophotometrically, total oxidant status and oxidative stress index levels were elevated, while total antioxidant status levels were decreased. Immunohistochemically, expressions of cyclooxygenase-1 (COX1), granulocyte colony-stimulating factor (GCSF), interleukin-6 (IL6) were increased. In genetic analyses, PERK and CHOP expressions were increased, whereas Nuclear factor erythroid 2-related factor 2 (NRF2) and B-cell leukemia/lymphoma 2 protein (BCL2) expressions were decreased. These parameters were alleviated by both prophylactic and therapeutic CBD treatment protocols.

Conclusion: In LISCI-induced damage, both endoplasmic reticulum and mitochondrial stress, along with oxidative and inflammatory markers, were triggered, resulting in lung cell damage. However, both p-CBD and t-CBD treatments effectively reversed these mechanisms, normalizing all histopathological, biochemical, and PCR parameters.”

https://pubmed.ncbi.nlm.nih.gov/39048516/

https://www.tandfonline.com/doi/full/10.1080/08923973.2024.2384904

Cannabidiol ameliorates lipopolysaccharide-induced cardiovascular toxicity by its antioxidant and anti-inflammatory activity via regulating IL-6, Hif1α, STAT3, eNOS pathway

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“Background: Systemic inflammation causes several organ damage by activating the intracellular signaling mechanisms. Heart and aorta tissues are the structures mostly affected by this situation. By examining underlying processes, this study sought to determine whether cannabidiol (CBD) may have protective effects against the cardiovascular damage brought on by lipopolysaccharide (LPS).

Materials and methods: A total of 32 female rats were randomly allocated to one of four groups: control, lipopolysaccharide (LPS) (5 mg/kg, i.p., single dose), LPS + CBD (5 mg/kg, i.p., single dose), and CBD groups. The rats were killed six hours after receiving LPS, and tissues from the heart and aorta were taken. Histopathological and immunohistochemical analyzes were performed. Oxidative stress was evaluated biochemically by spectrophotometric method. Expression levels of genes were studied by RT-qPCR method.

Results: Histopathological analysis of the LPS group showed moderate hyperemia, hemorrhages, edema, inflammation, and myocardial cell damage. There was a slight to moderate increase in Cox-1, G-CSF, and IL-3 immunoexpressions, along with enhanced expressions of IL-6, Hif1α, and STAT3 genes, and decreased expressions of eNOS genes. Additionally, there were increased levels of TOS and decreased TAS levels observed biochemically. CBD treatment effectively reversed and improved all of these observed changes.

Conclusions: CBD protects the heart and aorta against systemic inflammation through its antioxidant and anti-inflammatory activity via regulating IL-6, Hif1α, STAT3, and eNOS intracellular pathways.”

https://pubmed.ncbi.nlm.nih.gov/39023749/

https://link.springer.com/article/10.1007/s11033-024-09772-3

Cannabidiol reduces lung and heart fibrosis in rats with monocrotaline-induced pulmonary hypertension

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European Respiratory Society

“Pulmonary hypertension (PH) is a severe and incurable disease that may lead to right ventricular (RV) failure and consequently, death. The remodeling of small pulmonary vessels, perivascular lung tissue and RV plays a key role in the PH development.

Cannabidiol (CBD) is a non-intoxicating compound of Cannabis and has a multidirectional beneficial properties, including antiproliferative.

The aim of the study was to investigate if CBD possess the antifibrotic potential in the lung and RV of rats with monocrotaline (MCT)-induced PH.

The studies were carried out on rats with (MCT; 60 mg/kg, subcutaneously (s.c.)) and without PH (control group). CBD (10 mg/kg) or its vehicle were administered once daily, intraperitoneally (i.p.), for 3 weeks after administration of MCT or its vehicle. Western blot and immunohistochemistry methods were used.

In the lung and RV of the rats with MCT-induced PH, an increase of galectin-3, the growth transforming factor beta 1 (TGF-β1), collagen I expression and a greater number of mast cells, which are the cells responsible for lung remodeling were observed. CBD reduced the expression of above-mentioned profibrotic parameters and the number of mast cells in the lungs and/or RV of rats with MCT-induced PH.

In conclusion, CBD has potential property to inhibit lung and RV remodeling, possibly by inhibiting the TGF-β1-dependent pathway and may be considered as an adjuvant therapy in the treatment of PH.”

https://erj.ersjournals.com/content/60/suppl_66/4477

Cannabinoids in arterial, pulmonary and portal hypertension – mechanisms of action and potential therapeutic significance

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“The endocannabinoid system is overactivated in arterial, pulmonary and portal hypertension. In this paper, we present limited clinical data concerning the role of cannabinoids in human hypertension including polymorphism of endocannabinoid system components. We underline differences between the acute cannabinoid administration and their potential hypotensive effect after chronic application in experimental hypertension. We discuss pleiotropic effects of cannabinoids on the cardiovascular system mediated via numerous neuronal and non-neuronal mechanisms both in normotension and in hypertension. The final results are dependent on the model of hypertension, age, sex, the cannabinoid ligands used or the action via endocannabinoid metabolites. More experimental and clinical studies are needed to clarify the role of endocannabinoids in hypertension, not only in the search for new therapeutic strategies but also in the context of cardiovascular effects of cannabinoids and the steadily increasing legalization of cannabis use for recreational and medical purposes.”

https://pubmed.ncbi.nlm.nih.gov/29455452/

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.14168