Ischemia and Cannabinoids
Use of cannabis appears very rarely to trigger heart attacks the initial increase in risk might be related to the acute effects of the drug to increase heart rate in humans.
Since this effect is largely mediated through actions on the central nervous system, then the potential beneficial effects of cannabinoids on the cardiovascular system might be harnessed through use of compounds which do not penetrate the blood–brain barrier or alternatively producing a compound with suitable selectivity.
As a counterweight to the possible adverse effects of marijuana, there is mounting evidence that endocannabinoids may play important roles in limiting damage to the heart and circulation in shock and in myocardial infarction.
New evidence shows that cannabinoids reduce infarct size associated with ischaemia/reperfusion in rat isolated hearts and the effect is sensitive to either SR141716A or SR144528.
As noted above, endogenous release of cannabinoids has been implicated in survival after coronary artery occlusion in rats but in this case the CB1 receptor was implicated.
The origins of the endogenous cannabinoids mediating cardioprotection have not yet been identified. Possible cardiovascular sources of endocannabinoids have been discussed, they would include activated circulating leukocytes.
In isolated hearts a likely origin is the vascular endothelial cells, though cardiac nerves are another possible source as well as any macrophages present in the tissue.
Even if we have many evidence of cannabinoids role in the heart quantitative studies show that this molecules are rare in myocardium.
Nevertheless, it needs to be borne in mind that these studies apply to healthy hearts and that
there may be considerable changes in enzyme activity after ischaemia; for many years it was thought that N-acyl ethanolamines and their lipid precursors were formed only after tissue injury.
Mechanism of cannabinoid action
The known effects of cannabinoids on cellular function, such as the signalling through Akt are likely to reduce cell death through apoptosis and thereby bring myocardial salvage after interruption of coronary blood flow. They might also act to reduce the second wave of cell death induced during the inflammatory phase of myocardial infarction through their effects on the CB2 receptors of white blood cells.
Is interesting that both the CB1 and the CB2 seams to be envolved. CB1-receptors have been observed mainly on endothelial cells, and require NO to exert a cardioprotective effect. On the other hand, CB2-receptors appeared mostly on cardiomyocytes and exert NO-independent cardioprotective effects. The signalling pathway involved in the cardioprotective effect of CB2-receptors has been studied earlier and includes PKC, p38 MAPK, and ERK1/2.
The NO-synthase inhibitor, NNLA, blocked the cardioprotective effect of the CB1-agonist without affecting that of the CB2-agonist. This result, along with the endothelial localization of CB1-receptors, suggests a possible implication of the endothelial isoform of NOS (eNOS) in this NO-mediated effect. The induction of iNOS by the CB1-agonist suggests a contribution of this isoform as well. On the other hand, the absence of CB1-receptors on vascular smooth muscle cells tends to exclude the implication of the nNOS, constitutively present in these cells
Shock and Cannabinoids
Endocannabinoids may also be involved in the mechanisms by which bacterial lipopolysaccharide endotoxin limits infarct size. Comparing the effects of a period of 90 min of low-flow ischaemia on hearts from rats given an intravenous injection of Escherichia coli endotoxin and those from rats treated with saline endotoxin pretreatment reduced infarct size and enhanced functional recovery on reperfusion.
However, unlike in shock, the beneficial effects were blocked by the CB2 receptor antagonist SR144528. A similar sensitivity to the cannabinoid receptor antagonists was found in heat stress preconditioning suggesting that a different receptor type may be involved in the beneficial effects of endocannabinoids.
Other authors suspect that there are others mechanism of action apart from CB2 activation.
Furthermore, chronic treatment with the cannabinoid agonist HU-210 enhanced contractile function after myocardial infarction, but at the cost of elevated left ventricular end-diastolic pressure. Despite the enhanced cardiac contractility, the effects on LVEDP would be considered likely to lead to an increase in mortality.
If it is hypothesised that enhancing peripheral levels of endocannabinoids is beneficial to cardiovascular function, then it is interesting to note that estrogens, at physiological concentrations, activate phospholipase D in human cultured endothelial cells.
FAAH is inhibited by the treatment and the result is an increase in release of anandamide which
is able to decrease the pro-aggregatory release of 5-hydroxytryptamine from activated platelets.
This might be one means by which estrogens, either naturally occurring or those in hormone replacement therapy, have a beneficial effect to reduce cardiovascular events in women.
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Francesco Licciardi e Matteo Manfredi