Cannabidiol Improves Antioxidant Capacity and Reduces Inflammation in the Lungs of Rats with Monocrotaline-Induced Pulmonary Hypertension

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“Cannabidiol (CBD) is a plant-derived compound with antioxidant and anti-inflammatory properties. Pulmonary hypertension (PH) is still an incurable disease. CBD has been suggested to ameliorate monocrotaline (MCT)-induced PH, including reduction in right ventricular systolic pressure (RVSP), a vasorelaxant effect on pulmonary arteries and a decrease in the white blood cell count. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on the parameters of oxidative stress and inflammation in the lungs of rats with MCT-induced PH. In MCT-induced PH, we found a decrease in total antioxidant capacity (TAC) and glutathione level (GSH), an increase in inflammatory parameters, e.g., tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), nuclear factor kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), and cluster of differentiation 68 (CD68), and the overexpression of cannabinoid receptors type 1 and 2 (CB1-Rs, CB2-Rs). Administration of CBD increased TAC and GSH concentrations, glutathione reductase (GSR) activity, and decreased CB1-Rs expression and levels of inflammatory mediators such as TNF-α, IL -1β, NF-κB, MCP-1 and CD68. In conclusion, CBD has antioxidant and anti-inflammatory effects in MCT-induced PH. CBD may act as an adjuvant therapy for PH, but further detailed preclinical and clinical studies are recommended to confirm our promising results.”

https://pubmed.ncbi.nlm.nih.gov/35630804/

https://www.mdpi.com/1420-3049/27/10/3327


Acute Cannabigerol Administration Lowers Blood Pressure in Mice

“Cannabigerol (CBG) is a cannabinoid compound that is synthesized from Cannabis sativa L. and acts as a substrate for both Δ9-tetraydrocannabinol (Δ9-THC) and cannabidiol (CBD) formation. Given that it does not exhibit psychoactive effects, emerging research has focused on CBG as a potential therapeutic for health conditions including algesia, epilepsy, anxiety, and cancer. While CBG can bind to cannabinoid receptors CB1 and CB2, it has also been described as an agonist at α2-adrenoreceptors (A2-AR), which when activated inhibit the release of norepinephrine from α-adrenergic neurons. This raises the concern that CBG could act at A2-AR to reduce norepinephrine release to cardiovascular end organs, such as the heart and kidneys, causing a reduction in blood pressure. Despite this possibility, there are no reports examining cardiovascular effects of CBG. In this study, we tested the hypothesis that acute CBG administration can lower blood pressure. To test this, six male C57BL/6J mice underwent surgery at 8-10 weeks of age to implant a radiotelemetry probe, which allows for continuous measurement of blood pressure, heart rate and locomotor activity in conscious, freely moving mice. Following 10 days of recovery, baseline measurements were obtained and then mice were randomized to receive intraperitoneal injections of CBG (3.3, 5.6, and 10 mg/kg) and vehicle in a crossover design, with at least one-week washout between treatments. Changes in blood pressure, heart rate, and locomotor activity were measured for two hours post-injection. We found that acute CBG significantly lowered blood pressure compared with vehicle (-12±5 mmHg vehicle vs. -28±2 mmHg at 10 mg/kg CBG; p=0.018), with no apparent dose responsiveness at the doses used in this study (-22±2 mmHg at 3.3 mg/kg CBG; -28±4 at 5.6 mg/kg CBG). The greatest blood pressure reduction was seen at 90-minutes post-CBG administration, which is consistent with reports for peak plasma concentrations of this compound in rodents. The blood pressure lowering effects of CBG occurred in the absence of changes in heart rate or locomotor activity. These overall findings suggest acute CBG may lower blood pressure in phenotypically normal young adult male mice, which may provide caution for the potential of hypotension as an adverse effect of CBG administration. Additional studies are needed to determine if the blood pressure lowering effects of CBG are via an A2-AR mechanism.”

https://pubmed.ncbi.nlm.nih.gov/35555999/

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.0R576

Vasoprotective Endothelial Effects of Chronic Cannabidiol Treatment and Its Influence on the Endocannabinoid System in Rats with Primary and Secondary Hypertension

“Our study aimed to examine the endothelium (vascular)-protecting effects of chronic cannabidiol (CBD) administration (10 mg/kg once daily for 2 weeks) in aortas and small mesenteric (G3) arteries isolated from deoxycorticosterone-induced hypertensive (DOCA-salt) rats and spontaneously hypertensive rats (SHR). CBD reduced hypertrophy and improved the endothelium-dependent vasodilation in response to acetylcholine in the aortas and G3 of DOCA-salt rats and SHR. The enhancement of vasorelaxation was prevented by the inhibition of nitric oxide (NO) with L-NAME and/or the inhibition of cyclooxygenase (COX) with indomethacin in the aortas and G3 of DOCA-salt and SHR, respectively. The mechanism of the CBD-mediated improvement of endothelial function in hypertensive vessels depends on the vessel diameter and may be associated with its NO-, the intermediate-conductance calcium-activated potassium channel- or NO-, COX-, the intermediate and the small-conductance calcium-activated potassium channels-dependent effect in aortas and G3, respectively. CBD increased the vascular expression of the cannabinoid CB1 and CB2 receptors and aortic levels of endocannabinoids with vasorelaxant properties e.g., anandamide, 2-arachidonoylglycerol and palmitoyl ethanolamide in aortas of DOCA-salt and/or SHR. In conclusion, CBD treatment has vasoprotective effects in hypertensive rats, in a vessel-size- and hypertension-model-independent manner, at least partly via inducing local vascular changes in the endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/34832902/

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”

https://pubmed.ncbi.nlm.nih.gov/34502379/

https://www.mdpi.com/1422-0067/22/17/9472

 

“Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830475/

Antioxidant and Angiotensin I-Converting Enzyme (ACE) Inhibitory Peptides Obtained from Alcalase Protein Hydrolysate Fractions of Hemp ( Cannabis sativa L.) Bran

Go to Journal of Agricultural and Food Chemistry “Proteins from hemp bran (HPB), a byproduct of the hemp seed food-processing chain, were chemically extracted, hydrolyzed by Alcalase, and separated by membrane ultrafiltration into four fractions (MW <1, 1-3, 3-5, and >5 kDa).

The antioxidant and antihypertensive properties of the initial extract and the fractions were evaluated by in vitro assays for their ability to scavenge radical species, bind with metal ions, reduce ferric ions, and inhibit angiotensin-converting enzyme (ACE) activity.

The hydrolysate was strongly antioxidant and ACE-inhibiting; the most bioactive peptides were further concentrated by ultrafiltration. Of the 239 peptides identified, 47 (12 antioxidant and 35 ACE-inhibitory) exhibited structural features correlated with the specific bioactivity.

These results highlight the promise of hydrolysate and size-based HPB fractions as natural functional ingredients for the food or pharmaceutical industry.”

https://pubmed.ncbi.nlm.nih.gov/34353019/

“In conclusion, this study highlights the potential use of HPB hydrolysate and fractions as multifunctional ingredients for the development of new healthy foods or for the pharmaceutical industry. ”

https://pubs.acs.org/doi/10.1021/acs.jafc.1c01487

Cannabis is associated with blood pressure reduction in older adults – A 24-hours ambulatory blood pressure monitoring study

Patient–physician distance - European Journal of Internal Medicine“Background: Medical cannabis use is increasing rapidly in the past several years, with older adults being the fastest growing group. Nevertheless, the evidence for cardiovascular safety of cannabis use is scarce. The aim of this study was to assess the effect of cannabis on blood pressure, heart rate, and metabolic parameters in older adults with hypertension.

Results: Twenty-six patients with a mean age of 70.42 ± 5.37 years, 53.8% females completed the study. At 3 months follow-up, the mean 24-hours systolic and diastolic blood pressures were reduced by 5.0 mmHg and 4.5 mmHg, respectively (p<0.001 for both). The nadir for the blood pressure and heart rate was achieved at 3 hours post-administration. The proportion of normal dippers changed from 27.3% before treatment to 45.5% afterward. No significant changes were seen in the different metabolic parameters assessed by blood tests, anthropometric measurements, or ECG exam.

Conclusion: amongst older adults with hypertension, cannabis treatment for 3 months was associated with a reduction in 24-hours systolic and diastolic blood pressure values with a nadir at 3 hours after cannabis administration.”

https://pubmed.ncbi.nlm.nih.gov/33483174/

https://www.ejinme.com/article/S0953-6205(21)00005-4/fulltext

Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

ijms-logo“Cannabidiol (CBD) is known for its vasorelaxant (including in the human pulmonary artery), anti-proliferative and anti-inflammatory properties. The aim of our study was to examine the potential preventive effect of chronic CBD administration (10 mg/kg/day for three weeks) on monocrotaline (MCT)-induced pulmonary hypertension (PH) rats.

PH was connected with elevation of right ventricular systolic pressure; right ventricle hypertrophy; lung edema; pulmonary artery remodeling; enhancement of the vasoconstrictor and decreasing vasodilatory responses; increases in plasma concentrations of tissue plasminogen activator, plasminogen activator inhibitor type 1 and leukocyte count; and a decrease in blood oxygen saturation.

CBD improved all abovementioned changes induced by PH except right ventricle hypertrophy and lung edema. In addition, CBD increased lung levels of some endocannabinoids (anandamide, N-arachidonoyl glycine, linolenoyl ethanolamide, palmitoleoyl ethanolamide and eicosapentaenoyl ethanolamide but not 2-arachidonoylglycerol). CBD did not affect the cardiopulmonary system of control rats or other parameters of blood morphology in PH.

Our data suggest that CBD ameliorates MCT-induced PH in rats by improving endothelial efficiency and function, normalization of hemostatic alterations and reduction of enhanced leukocyte count determined in PH. In conclusion, CBD may be a safe, promising therapeutic or adjuvant therapy agent for the treatment of human pulmonary artery hypertension.”

https://pubmed.ncbi.nlm.nih.gov/32992900/

https://www.mdpi.com/1422-0067/21/19/7077

Cannabinoid type 2 receptor agonist JWH133 decreases blood pressure of spontaneously hypertensive rats through relieving inflammation in the rostral ventrolateral medulla of the brain.

Journal of Hypertension | The International Society of Hypertension“Neuroinflammation in the rostral ventrolateral medulla (RVLM) has been reported to be associated with hypertension. The upregulation and activation of the cannabinoid type 2 (CB2) receptor may be part of the active process of limiting or downregulating the inflammatory process.

This study was designed to determine the role of the CB2 receptor in blood pressure (BP) through relieving neuroinflammation in the RVLM in spontaneously hypertensive rats (SHRs).

CONCLUSION:

Taken together, our results suggest that exciting the CB2 receptor relieves proinflammatory cytokine levels in the RVLM to decrease the BP, HR and RSNA in SHRs.”

https://www.ncbi.nlm.nih.gov/pubmed/32238784

https://journals.lww.com/jhypertension/Abstract/2020/05000/Cannabinoid_type_2_receptor_agonist_JWH133.15.aspx

Stimulation of brain cannabinoid CB1 receptors can ameliorate hypertension in spontaneously hypertensive rats.

Clinical and Experimental Pharmacology and Physiology“Excessive activation of the sympatho-adrenomedullary system plays a pathogenic role in triggering and sustaining essential hypertension. We previously reported that, in normotensive rats, intracerebroventricularly (i.c.v.) administered neuropeptides, corticotropin-releasing factor and bombesin induced activation of the sympatho-adrenomedullary system, and that brain cannabinoid CB1 receptors negatively regulated this activation.

In this study, we investigated the effects of brain CB1 receptor stimulation on blood pressure and the sympatho-adrenomedullary outflow in spontaneously hypertensive rats (SHRs), commonly used animal models of essential hypertension, and in Wistar-Kyoto (WKY) rats, normotensive controls of SHRs.

These results suggest that stimulation of brain CB1 receptors can ameliorate hypertension accompanied by enhanced sympathetic outflow without affecting blood pressure under normotensive conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/32141630

https://onlinelibrary.wiley.com/doi/abs/10.1111/1440-1681.13297

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

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