The endogenous cardiac cannabinoid system: a new protective mechanism against myocardial ischemia.

“The pharmacological (and recreational) effects of cannabis have been known for centuries. However, it is only recently that one has identified two subtypes of G-protein-coupled receptors, namely CB1 and CB2-receptors, which mediate the numerous effects of delta9-tetrahydrocannabinol and other cannabinoids.

Logically, the existence of cannabinoid-receptors implies that endogenous ligands for these receptors (endocannabinoids) exist and exert a physiological role. Hence, arachidonoylethanolamide (anandamide) and sn-2 arachidonoylglycerol, the first two endocannabinoids identified, are formed from plasma membrane phospholipids and act as CB1 and/or CB2 agonists.

The presence of both CB1 and CB2-receptors in the rat heart is noteworthy.

This endogenous cardiac cannabinoid system is involved in several phenomena associated with cardioprotective effects.

The reduction in infarct size following myocardial ischemia, observed in rats exposed to either LPS or heat stress 24 hours before, is abolished in the presence of a CB2-receptor antagonist.

Endocannabinoids and synthetic cannabinoids, the latter through either CB1 or CB2-receptors, exert direct cardioprotective effects in rat isolated hearts.

The ability of cannabinoids to reduce infarct size has been confirmed in vivo in anesthetized mice and rats. This latter effect appears to be mediated through CB2-receptors.

Thus, the endogenous cardiac cannabinoid system, through activation of CB2-receptors, appears to be an important mechanism of protection against myocardial ischemia.”

https://pubmed.ncbi.nlm.nih.gov/16618028

An ultra-low dose of tetrahydrocannabinol provides cardioprotection.

“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.

“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

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.

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

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

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

“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

Minor oxygenated cannabinoids from high potency Cannabis sativa L.

“Nine oxygenated cannabinoids were isolated from a high potency Cannabis sativa L. variety. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR, HRMS and GC-MS.

These minor compounds include four hexahydrocannabinols, four tetrahydrocannabinols, and one hydroxylated cannabinol, namely 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexa-hydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol, Δ9-THC aldehyde A, 8-oxo-Δ9-THC, 10aα-hydroxy-10-oxo-Δ8-THC, 9α-hydroxy-10-oxo-Δ6a,10a-THC, and 1’S-hydroxycannabinol, respectively.

The latter compound showed moderate anti-MRSa (IC50 10.0μg/mL), moderate antileishmanial (IC50 14.0μg/mL) and mild antimalarial activity against Plasmodium falciparum (D6 clone) and P. falciparum (W2 clone) with IC50values of 3.4 and 2.3μg/mL, respectively.”

http://www.ncbi.nlm.nih.gov/pubmed/26093324

No smoke, no fire: What the initial literature suggests regarding vapourized cannabis and respiratory risk

“Given current limitations in developing an inhalant alternative for delivering cannabis medication, smoked marijuana remains the most readily accessible form of cannabis among medicinal users…

Cannabis actually served as an asthma treatment in the 1800s and, perhaps, in ancient times…

Informed health care professionals may consider making recommendations to their medicinal cannabis patients for vapourization of the plant, particularly for those who want the rapid relief that oral administration fails to provide.

It is not our intention to encourage inappropriate use of the plant, but to increase safety for those who choose to use it.

Vapourization of cannabis is likely less harmful than smoking.

Preliminary findings do support the idea that vapourization is an improvement over smoking.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456813/

Cannabis Use and Reduced Risk of Insulin Resistance in HIV-HCV Infected Patients: A Longitudinal Analysis (ANRS CO13 HEPAVIH).

“Diabetes and insulin resistance (IR) is common in human immunodeficiency virus-hepatitis C virus (HIV-HCV)-coinfected patients…

Cannabis has been associated with reduced IR risk in some population-based surveys.

We determined whether cannabis use was consistently associated with reduced IR risk in HEPAVIH, a French nationwide cohort of HIV-HCV-coinfected patients…

Cannabis use is associated with a lower IR risk in HIV-HCV-coinfected patients.

The benefits of cannabis-based pharmacotherapies for patients concerned with increased risk of IR and diabetes need to be evaluated in clinical research and practice.”

http://www.ncbi.nlm.nih.gov/pubmed/25778750