Category Archives: Cardiovascular Disease

An ultra-low dose of tetrahydrocannabinol provides cardioprotection.

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“Tetrahydrocannabinol (THC), the major psychoactive component of marijuana, is a cannabinoid agonist that exerts its effects by activating at least two specific receptors (CB1 and CB2) that belong to the seven transmembrane G-protein coupled receptor (GPCR) family.

Both CB1 and CB2 mRNA and proteins are present in the heart.

THC treatment was beneficial against hypoxia in neonatal cardiomyocytes in vitro.

We also observed a neuroprotective effect of an ultra low dose of THC when applied to mice before brain insults.

The present study was aimed to test and characterize the cardioprotective effects of a very low dose of THC…

All protocols of THC administration were found to be beneficial.

CONCLUSION:

A single ultra low dose of THC before ischemia is a safe and effective treatment that reduces myocardial ischemic damage.”

http://www.ncbi.nlm.nih.gov/pubmed/23537701

Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production.

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“Delta-9-tetrahydrocannabinol (THC), the major active component of marijuana, has a beneficial effect on the cardiovascular system during stress conditions…

The present study was designed to investigate the central (CB1) and the peripheral (CB2)cannabinoid receptor expression in neonatal cardiomyoctes and possible function in the cardioprotection of THC from hypoxia.

The antagonist for the CB2, but not CB1 receptor antagonist abolished the protective effect of THC.

In agreement with these results using RT-PCR, it was shown that neonatal cardiac cells express CB2, but not CB1 receptors.

Involvement of NO in the signal transduction pathway activated by THC through CB2 was examined. It was found that THC induces nitric oxide (NO) production by induction of NO synthase (iNOS) via CB2 receptors.

L-NAME (NOS inhibitor, 100 microM) prevented the cardioprotection provided by THC.

Taken together, our findings suggest that THC protects cardiac cells against hypoxia via CB2 receptor activation by induction of NO production.

An NO mechanism occurs also in the classical pre-conditioning process; therefore, THC probably pre-trains the cardiomyocytes to hypoxic conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/16444588

Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury

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Heart and Circulatory Physiology

“CANNABINOIDS ARE NATURAL and synthetic compounds structurally or pharmacologically related to the constituents of the plant Cannabis sativa or to the endogenous agonists (endocannabinoids) of the cannabinoid CB1 and CB2 receptors.

Cannabidiol (CBD) is a major cannabinoid constituent of Cannabis.

In contrast to tetrahydrocannabinol, CBD binds very weakly to CB1 and CB2 receptors. Contrary to most cannabinoids, CBD does not induce psychoactive or cognitive effects.

CBD has been shown to have anti-inflammatory properties. CBD (together with tetrahydrocannabinol) has been successfully tested in a few preliminary human trials related to autoimmune diseases…

Cannabidiol (CBD) is a major, nonpsychoactive Cannabis constituent with anti-inflammatory activity mediated by enhancing adenosine signaling.

Inasmuch as adenosine receptors are promising pharmaceutical targets for ischemic heart diseases, we tested the effect of CBD on ischemic rat hearts.

Our study shows that CBD induces a substantial in vivo cardioprotective effect from ischemia that is not observed ex vivo.

Inasmuch as CBD has previously been administered to humans without causing side effects, it may represent a promising novel treatment for myocardial ischemia.”

http://ajpheart.physiology.org/content/293/6/H3602

Effect of dietary hempseed intake on cardiac ischemia-reperfusion injury.

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Regulatory, Integrative and Comparative Physiology

“Polyunsaturated fatty acids (PUFAs) have significant, cardioprotective effects against ischemia.

Hempseed contains a high proportion of the PUFAs linoleic acid (LA) and alpha-linolenic acid (ALA),

Hearts from rats fed a hempseed-supplemented diet exhibited significantly better postischemic recovery of maximal contractile function and enhanced rates of tension development and relaxation during reperfusion than hearts from the other groups.

Our data demonstrate that dietary hempseed can provide significant cardioprotective effects during postischemic reperfusion. This appears to be due to its highly enriched PUFA content.”  http://www.ncbi.nlm.nih.gov/pubmed/17122327

“Polyunsaturated fatty acids (PUFAs) have received special research attention because of their antiarrhythmic and cardioprotective effects in hearts challenged by an ischemia-reperfusion insult. There are two major types of PUFAs: omega-3 and omega-6. Linoleic acid (LA) and α-linolenic acid (ALA) are common examples of an omega-6 and an omega-3 fatty acid, respectively… We have demonstrated for the first time in this study that dietary hempseed represents an effective, unique method to significantly alter the levels of ALA in the heart. We have also demonstrated for the first time that dietary hempseed will confer beneficial cardioprotective effects in hearts subjected to ischemia-reperfusion challenge.”  http://ajpregu.physiology.org/content/292/3/R1198

CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion.

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“Preventive treatment with cannabinoid agonists has been reported to reduce the infarct size in a mouse model of myocardial ischemia/reperfusion.

Here we investigated the possible cardioprotective effect of selective CB(2) cannabinoid receptor activation during ischemia.

Our data suggest that administration during ischemia reduces the infarct size in a mouse model of myocardial ischemia/reperfusion through a direct cardioprotective activity on cardiomyocytes and neutrophils.”

http://www.ncbi.nlm.nih.gov/pubmed/19162037

The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy

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“Post-myocardial infarction (MI) heart failure is a major public health problem in Western countries and results from ischemia/reperfusion (IR)-induced cell death, remodeling, and contractile dysfunction.

Ex vivo studies have demonstrated the cardioprotective anti-inflammatory effect of the cannabinoid type 2 (CB2) receptor agonists within hours after IR.

Herein, we evaluated the in vivo effect of CB2 receptors on IR-induced cell death, fibrosis, and cardiac dysfunction and investigated the target role of cardiac myocytes and fibroblasts… CB2 receptor activation may protect against post-IR heart failure through direct inhibition of cardiac myocyte and fibroblast death and prevention of myofibroblast activation…

In conclusion, modulation of the endocannabinoid system is emerging as a novel approach for the therapy of various inflammatory, metabolic, cardiovascular, hepatic, and neurodegenerative disorders.

CB1 receptors exert cardioprotective effects in cirrhotic rats and against doxorubicin toxicity. Pharmacological inhibition of the endocannabinoid degradative pathway, fatty acid aminohydrolase, represents a novel protective strategy against chronic inflammation, oxidative and nitrative stresses, and apoptosis associated with cardiovascular aging and atherosclerosis.

CB2 receptor activation is thought to be anti-inflammatory and involved in protective mechanisms during atherosclerosis. In addition, selective CB2 agonists protect against cerebral and hepatic IR injuries.

We demonstrated a highly protective role of CB2 receptors in post-IR cardiac remodeling, potentially related to activation of antiapoptotic, prosurvival, and antifibrogenic pathways.

Our results infer that CB2 agonists may be useful in preventing reperfusion injury in acute coronary syndrome and provide novel evidence for the pivotal role of CB2 receptors in post-IR-induced cardiomyopathy.”

http://www.fasebj.org/content/23/7/2120.long

Cannabinoid system as a potential target for drug development in the treatment of cardiovascular disease.

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“Although cannabinoids have been recreationally employed for thousands of years, it was not until the discovery of their specific receptors, in the early nineties, that the molecular basis of cannabinoid activity have began to be understood.

Growing research in this field has demonstrated not only that the action of cannabinoids in mammals is mainly receptor-mediated, but also that endogenous cannabinoids, such as anandamide, are produced, metabolized, and taken up across the cell membrane through a facilitated uptake process.

The exogenous administration of cannabinoids, as well as the manipulation of their endogenous levels have been related to a variety of effects, such as analgesia, (temporary) impairment of cognition and learning, appetite enhancement and peripheral vasodilation.

Hence, the endocannabinoid system, including the CB1 and CB2 receptors, the metabolizing enzyme fatty acid amide hydrolase and the anandamide transporter, is a potential target for the development of novel therapeutic drugs in the treatment of various conditions, such as pain, feeding disorders and vascular disease among others.

Although most of the research in the field of cannabinoids has been focused on their effects in the central nervous system, a growing line of evidence indicates that cannabinoids can also play a major role in the control of physiopathological functions in the cardiovascular system.

In this context, endocannabinoids have been proposed as novel possible hypotensive agents, and have been involved in the hypotension observed in septic shock, acute myocardial infarction and cirrhosis. In addition, a protective role for endocannabinoids has been described in ischemia.”

http://www.ncbi.nlm.nih.gov/pubmed/15320476

[Cardiovascular effects of cannabinoids].

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“The psychoactive properties of cannabinoids, the biologically active constituents of the marijuana plant, have long been recognized. Recent research has revealed that cannabinoids elicit not only neurobehavioral, and immunological, but also profound cardiovascular effects.

Similar effects can be elicited by the endogenous ligand arachidonyl ethanolamine (anandamide) and 2-arachidonoyl-glycerol.

The biological effects of cannabinoids are mediated by specific receptors.

Two cannabinoid receptors have been identified so far: CB1-receptors are expressed by different cells of the brain and in peripheral tissues, while CB2-receptors were found almost exclusively in immune cells.

Through the use of a selective CB1 receptor antagonist and CB1 receptor-knockout mice the hypotensive and bradycardic effects of cannabinoids in rodents could be attributed to activation of peripheral CB1 receptors. In hemodynamic studies using the radioactive microsphere technique in anesthetized rats, cannabinoids were found to be potent CB1-receptor dependent vasodilators in the coronary and cerebrovascular beds.

Recent findings implicate the endogenous cannabinoid system in the pathomechanism of haemorrhagic, endotoxic and cardiogenic shock.

Finally, there is evidence that the extreme mesenteric vasodilation, portal hypertension and systemic hypotension present in advanced liver cirrhosis are also mediated by the endocannabinoid system.

These exciting, recent research developments indicate that the endogenous cannabinoid system plays an important role in cardiovascular regulation, and pharmacological manipulation of this system may offer novel therapeutic approaches in a variety of pathological conditions.”

Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling.

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“Cannabinoids include not only plant-derived compounds (of which delta9-tetrahydrocannabinol is the primary psychoactive ingredient of cannabis), but also synthetic agents and endogenous substances termed endocannabinoids which include anandamide (2-arachidonoylethanolamide) and 2-arachidonoylglycerol.

Cannabinoids act on specific, G-protein-coupled, receptors which are currently divided into two types, CB1 and CB2. Relatively selective agonists and antagonists for these receptors have been developed, although one agent (SR141716A) widely used as an antagonist at CB1 receptors has non-cannabinoid receptor-mediated effects at concentrations which are often used to define the presence of the CB1 receptor.

Both cannabinoid receptors are primarily coupled to Gi/o proteins and act to inhibit adenylyl cyclase. Stimulation of CB1 receptors also modulates the activity of K+ and Ca2+ channels and of protein kinase pathways including protein kinase B (Akt) which might mediate effects on apoptosis. CB, receptors may activate the extracellular signal-regulated kinase cascade through ceramide signalling.

Cannabinoid actions on the cardiovascular system have been widely interpreted as being mediated by CB1 receptors although there are a growing number of observations, particularly in isolated heart and blood vessel preparations, that suggest that other cannabinoid receptors may exist.

Interestingly, the currently identified cannabinoid receptors appear to be related to a wider family of lipid receptor, those for the lysophospholipids, which are also linked to Gi/o protein signalling.

Anandamide also activates vanilloid VR1 receptors on sensory nerves and releases the vasoactive peptide, calcitonin gene-related peptide (CGRP), which brings about vasodilatation through its action on CGRP receptors.

Current evidence suggests that endocannabinoids have important protective roles in pathophysiological conditions such as shock and myocardial infarction.

Therefore, their cardiovascular effects and the receptors mediating them are the subject of increasing investigative interest.”

http://www.ncbi.nlm.nih.gov/pubmed/15005177