A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study.

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“Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid used in multiple sclerosis and intractable epilepsies. Preclinical studies show CBD has numerous cardiovascular benefits, including a reduced blood pressure (BP) response to stress. The aim of this study was to investigate if CBD reduces BP in humans.

CONCLUSIONS:

This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR. These hemodynamic changes should be considered for people taking CBD. Further research is required to establish whether CBD has a role in the treatment of cardiovascular disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/28614793

“Our data show that a single dose of CBD reduces resting blood pressure and the blood pressure response to stress. This may reflect the anxiolytic and analgesic effects of CBD, as well as any potential direct cardiovascular effects. CBD has multiple desirable effects on the cardiovascular system” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470879/

https://insight.jci.org/articles/view/93760

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A Systematic Review and Meta-Analysis of the Haemodynamic Effects of Cannabidiol

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“Cannabidiol (CBD) is the second most abundant phytocannabinoid, after Δ9-tetrahydrocannabinol (THC) and was first isolated from the cannabis extract in 1940.

Given the increasing clinical use of CBD, and the numerous effects of CBD in the cardiovascular system, the aim of the present study was to systematically review and analyse in vivo studies evaluating the effects of CBD on alterations in haemodynamics.

From the limited data available, we conclude that acute and chronic administration of CBD had no effect on BP or HR under control conditions, but reduces BP and HR in stressful conditions, and increases cerebral blood flow (CBF) in mouse models of stroke.

This meta-analysis and systematic review has highlighted the haemodynamic effects of CBD administration in vivo.

The positive effects induced by CBD include maintaining the fall in BP after global hypoxia, reducing the increase in MBP and HR post-stress, and increasing BF in ischaemia-reperfusion models.

It is possible that beneficial effects of CBD on haemodynamics occurs when the cardiovascular system is abnormally altered, suggesting that CBD may be used as a treatment for various cardiovascular disorders, such as hypertension, myocardial infarction and stroke.”

http://journal.frontiersin.org/article/10.3389/fphar.2017.00081/full

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Diuretic effects of cannabinoid agonists in mice

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“Cannabinoids both increase urine output and decrease urinary frequency in human subjects. However, these effects have not been systematically evaluated in intact mice, a species commonly used to evaluate the effects of novel cannabinoids.

The present studies investigated whether cannabinoid agonists reliably produce diuresis in mice at doses comparable to those that produce other cannabinoid effects and, further, identified the receptors that may mediate these effects.

These findings suggest that mice may provide a model for understanding the mixed effects of marijuana on urine output, as described in clinical studies, and aid in the development of targeted cannabinoid based therapies for bladder dysfunction.

Clinical studies have reported beneficial effects of smoked or aerosolized cannabis on bladder dysfunction in patients with multiple sclerosis, primarily by decreasing urinary frequency in these subjects following marijuana use. These reports contrast with the earlier clinical reports demonstrating increase in urine output after cannabis administration.

Our findings in mice demonstrate a dose related increase or decrease in urine output, providing a platform for understanding the mixed effects on urine output observed with marijuana in various clinical studies. As noted earlier in a study with rats, the diuresis induced by THC in mice also is weakly naturetic compared to furosemide and further investigations in this area may yield a new, clinically beneficial diuretic.

In contrast, our data suggest that development of peripherally selective cannabinoid CB1 agonists may be beneficial for patients suffering from bladder dysfunction.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872476/

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Diuretic effects of cannabinoids.

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“These data indicate that cannabinoids have robust diuretic effects in rats that are mediated via CB1 receptor mechanisms.

Overall, our data indicate that diuresis is a CB1-mediated effect that may serve as a reliable and objective physiologic measure of cannabinoid action in rats; the circumstances under which these results represent a potential therapeutic benefit or potential liability of cannabinoids remain to be determined.

The implications of these findings currently are poorly understood, although a better understanding of mechanisms and sites of action by which cannabinoids increase urine loss may lead to the rational development of novel cannabinergic medications.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533417/

“Diuretics are medicines that help reduce the amount of water in the body. Diuretics are used to treat the buildup of excess fluid in the body that occurs with some medical conditions such ascongestive heart failure, liver disease, and kidney disease. Some diuretics are also prescribed to treat high bloodpressure. These drugs act on the kidneys to increase urine output. This reduces the amount of fluid in the bloodstream,which in turn lowers blood pressure.” http://medical-dictionary.thefreedictionary.com/diuretics
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The endogenous lipid N-arachidonoyl glycine is hypotensive and nitric oxide-cGMP-dependent vasorelaxant.

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“N-arachidonoyl glycine (NAGLY), is the endogenous lipid that activates the G protein-couple receptor 18 (GPR18) with vasodilatory activity in resistance arteries. This study investigates its hemodynamic effects and mechanisms of vasorelaxation.

NAGLY is an endothelium-dependent vasodilator and hypotensive lipid. The vasorelaxation is predominantly via activation of nitric oxide-cGMP pathway and NCX and probably mediated by the “endothelial anandamide” receptor, while the hypotensive effect of NAGLY appears not to involve the anandamide receptor. NAGLY also potentiates carbachol-induced vasorelaxation, the mechanism of which might involve stimulation of NO release.”

https://www.ncbi.nlm.nih.gov/pubmed/27890711

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Overactivation of cannabinoid receptor type 1 in rostral ventrolateral medulla promotes cardiovascular responses in spontaneously hypertensive rats.

 

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“Stimulation of cannabinoid type 1 (CB1) receptor in the rostral ventrolateral medulla (RVLM) increases renal sympathetic nerve activity (RSNA) and blood pressure (BP) in rats.

Thus, we hypothesized that abnormal expression of CB1 receptor in the RVLM may play a critical role in the pathogenesis of essential hypertension.

Taken together, our results suggested that alterations of CB1 receptor desensitization in the RVLM may play a role in the pathogenesis of essential hypertension.”

https://www.ncbi.nlm.nih.gov/pubmed/27861247

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The Effect of Chronic Activation of the Novel Endocannabinoid Receptor GPR18 on Myocardial Function and Blood Pressure in Conscious Rats.

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“While acute activation of the novel endocannabinoid receptor GPR18 causes hypotension, there are no reports on GPR18 expression in the heart or its chronic modulation of cardiovascular function. In this study, after demonstrating GPR18 expression in the heart, we show that chronic (2 weeks) GPR18 activation with its agonist abnormal cannabidiol (abn-cbd; 100 µg/kg/day; i.p) produced hypotension, suppressed the cardiac sympathetic dominance, and improved left ventricular (LV) function (increased the contractility index dp/dtmax, and reduced LV end diastolic pressure, LVEDP) in conscious rats. Ex vivo studies revealed increased: (i) cardiac and plasma adiponectin (ADN) levels; (ii) vascular (aortic) endothelial nitric oxide synthase (eNOS) expression, (iii) vascular and serum nitric oxide (NO) levels; (iv) myocardial and plasma cyclic guanosine monophosphate (cGMP) levels; (v) phosphorylation of myocardial protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) along with reduced myocardial reactive oxygen species (ROS) in abn-cbd treated rats. These biochemical responses contributed to the hemodynamic responses and were GPR18-mediated because concurrent treatment with the competitive GPR18 antagonist (O-1918) abrogated the abn-cbd evoked hemodynamic and biochemical responses. The current findings present new evidence for a salutary cardiovascular role for GPR18, mediated, at least partly, via elevation in the levels of ADN.”

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Heterologous Regulation of the Cannabinoid Type 1 Receptor by Angiotensin II in Astrocytes of Spontaneously Hypertensive Rats.

“Brainstem and cerebellar astrocytes have critical roles to play in hypertension and attention deficit hyperactivity disorder (ADHD), respectively. Angiotensin (Ang) II, via the astroglial Ang Type 1 receptor (AT1R), has been demonstrated to elevate pro-inflammatory mediators in the brainstem and the cerebellum.

The activation of astroglial Cannabinoid Type 1 Receptor (CB1R), a master regulator of homeostasis, has been shown to neutralize inflammatory states.

Factors that drive disease physiology, are known to alter the expression of CB1Rs.

In the current study, we investigated the role of Ang II in regulating CB1R protein and mRNA expression in astrocytes isolated from the brainstem and the cerebellum of Spontaneously Hypertensive Rats (SHRs).

The results were then compared with the normotensive counterpart, Wistar rats. Not only was the basal expression of CB1R protein and mRNA significantly lower in SHR brainstem astrocytes, but treatment with Ang II resulted in lowering it further in the initial 12 hours. In the case of cerebellum, Ang II upregulated the CB1R protein and mRNA in SHR astrocytes. While the effect of Ang II on CB1R protein was predominantly mediated via the AT1R in SHR brainstem; both AT1R and AT2R mediated Ang II’s effect in the SHR cerebellum.

This data is strongly indicative of a potential new mode of cross talk between components of the renin angiotensin system and the endocannabinoid system in astrocytes. The consequence of such a crosstalk could be a potential reduced endocannabinoid tone in brainstem in hypertensive states, but not in the cerebellum under the same conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/27529509

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Blood pressure regulation by endocannabinoids and their receptors

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“Cannabinoids and their endogenous and synthetic analogs exert powerful hypotensive and cardiodepressor effects by complex mechanisms involving direct and indirect effects on myocardium and vasculature.

On the one hand, endocannabinoids and cannabinoid receptors have been implicated in the hypotensive state associated with hemorrhagic, endotoxic and cardiogenic shock, and advanced liver cirrhosis.

On the other hand, there is emerging evidence suggesting that the endocannabinergic system plays an important role in the cardiovascular regulation in hypertension.

This review is aimed to discuss the in vivo hypotensive and cardiodepressant effects of cannabinoids mediated by cannabinoid and TRPV1 receptors, and focuses on the novel therapeutical strategies offered by targeting the endocannabinoid system in the treatment of hypertension.

The endocannabinergic system plays an important cardiovascular regulatory role not only in pathophysiological conditions associated with excessive hypotension but also in hypertension.

Thus, the pharmacological manipulation of this system may offer novel therapeutic approaches in a variety of cardiovascular disorders.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2225528/

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Researcher explores effects of cannabinoids on blood pressure

Andrei Derbenev, associate professor of physiology, Tulane School of Medicine

“Hypertension — or high blood pressure — is a long-term, high-risk condition for millions of people worldwide.

At the moment, synthetic beta-blockers are one of the most common drugs prescribed to treat hypertension.

But what if a natural drug, marijuana, which has been known for 5,000 years, could be used in the treatment of high blood pressure?

Andrei Derbenev, associate professor of physiology in the Tulane University School of Medicine, recently received a four-year, $1.5 million research grant from the National Institutes of Health to study how cannabinoids — the compounds of cannabis (another name for marijuana) — affect a brain stem area involved in blood pressure control.

His research may have important clinical applications for the treatment of hypertension.

He is identifying the cells in the sympathetic nervous system linked to the kidneys, a key organ in hypertension. (The sympathetic nervous system is the part of the autonomic nervous system that stimulates the body’s “fight or flight” response. Overactivity of the sympathetic nervous system is a cause of high blood pressure.)

He and his research team are studying the effect of exogenous cannabinoids — from the marijuana plant — and endogenous cannabinoids —those naturally produced within the body.

Cannabis “has lots of different chemicals inside. Some of them are painkillers. Some of them, we don’t know what they are doing.”

People ask Derbenev all the time: Is marijuana good? Is it bad? But the debate, he says, should be, instead, “Which works? Which does not work?”

About a decade ago, Derbenev led a study about the effect of cannabinoids on the parasympathetic nervous system, the part of the autonomic nervous system that stimulates the body to “rest and digest.” In that investigation, his team showed the mechanism by which cannabis can reduce digestive spasms and thus decrease vomiting. It’s a finding of great interest to cancer patients experiencing nausea while undergoing chemotherapy.”

https://news.tulane.edu/news/researcher-explores-effects-cannabinoids-blood-pressure

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