Abstract
The endocannabinoid system is widely distributed throughout the cardiovascular system. Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders. In shock, endocannabinoids released within blood mediate the associated hypotension through CB1 activation. In hypertension, there is evidence for changes in the expression of CB1, and CB1 antagonism reduces blood pressure in obese hypertensive and diabetic patients. The endocannabinoid system is also upregulated in cardiac pathologies. This is likely to be cardioprotective, via CB2 and CB1 (lesser extent). In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids. Endocannabinoids have positive (CB2) and negative effects (CB1) on the progression of atherosclerosis. However, any negative effects of CB1 may not be consequential, as chronic CB1 antagonism in large scale human trials was not associated with significant reductions in atheroma. In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB1, CB2, TRPV1 and PPARα. Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
1 Introduction
Cannabinoid receptors are widely distributed throughout the cardiovascular system. The CB1 receptor is expressed in myocardium, human coronary artery , endothelial and smooth muscle cells and on pre-synaptic sympathetic nerve terminals innervating the cardiovascular system. CB2 receptors have also been identified in the myocardium and in human coronary endothelial and smooth muscle cells. Endocannabinoids are produced in endothelial and smooth muscle cells and in cardiac tissue, and circulating levels of endocannabinoids are detectable in blood . Despite this, under normal conditions, it is unlikely that the endocannabinoid system plays a major role in the regulation of cardiovascular function. The evidence for this is that animals in whom either CB1 (Mukhopadhyay et al. 2007), CB2 (Batkai et al. 2007) or fatty acid amide hydrolase (FAAH, the main endocannabinoid degradation enzyme) (Pacher et al. 2005) has been knocked down have no major changes in cardiovascular function. However, it is clear that in many pathological conditions of the cardiovascular system, the endocannabinoid system is upregulated and appears to play an important, possibly protective, role. For example, mice in which FAAH has been knocked-out (which will increase endocannabinoid levels due to decreased degradation) have a reduced decline in age-related cardiac dysfunction and increased susceptibility to atherosclerosis (Batkai et al. 2007). Mice in which the CB1 receptor has been knocked-out are more susceptible to chronic heart failure (Liao et al. 2013), and stroke (Batkai et al. 2007). CB2-deficient mice have increased susceptibility to atherosclerosis (Netherland et al. 2010; Hoyer et al. 2011), stroke (Zhang et al. 2008) and cardiomyopathy (Duerr et al. 2014).
In the following article, I will review the role for the endocannabinoid system in cardiovascular function in health and disease, starting from the in vivo haemodynamic (changes in blood pressure and heart rate) effects of endocannabinoids, the role of endocannabinoids in modulating cardiac function, vascular and haematological (blood) function as well as neurovascular function. I will also discuss the evidence for endocannabinoid involvement in hypertension , cardiovascular shock, myocardial infarction (heart attack), atherosclerosis , stroke and traumatic brain injury.
2 In Vivo Haemodynamic Response to Endocannabinoids
2.1 Blood Pressure and Heart Rate
Endocannabinoids have a complex effect on blood pressure and heart rate in animal studies, and the response observed is dependent on whether the animal is anaesthetised or conscious. Differences between anaesthetised and conscious responses may be due to altered basal levels of sympathetic activity observed with anaesthesia (Neukirchen and Kienbaum 2008), as many of the in vivo responses to endocannabinoids are mediated by modulation of the autonomic nervous system, through changes in both vagal and sympathetic activity.
In anaesthetised animals, application of anandamide (AEA) causes a triphasic response; rapid and transient bradycardia (fall in heart rate), a rapid and transient pressor response (increase in blood pressure ) and a prolonged hypotensive phase (see Malinowska et al. 2012 for a detailed review). The initial bradycardic response to AEA is absent in transient receptor potential vanilloid 1 (TRPV1) knockout mice (Pacher et al. 2004) and is brought about by vagal activation (Varga et al. 1995). The mechanisms behind the brief pressor response are more complex and are likely to involve TRPV1, N-methyl-d-aspartate (NMDA) and beta2 (β2) adrenoceptors (Malinowska et al. 2012). The prolonged hypotensive response to AEA in anaesthetised animals has been best characterised. This response is absent in CB1 knockout mice (Jarai et al. 1999), and the location of the CB1 receptors involved is likely to be on nerve terminals of the sympathetic nervous system inhibiting function at the level of the heart and vasculature. Endocannabinoids inhibit noradrenaline release via CB1 activation in arteries (Deutsch et al. 1997) and in the mesenteric arterial bed (Ralevic et al. 2002). 2-arachidonoylglycerol (2-AG) administration to anaesthetised rats also causes a fall in blood pressure, although accompanied by tachycardia. Unlike AEA, the response to 2-AG is CB1-independent and more likely to involve cyclooxygenase-catalysed metabolism to other vasoactive compounds (Jarai et al. 2000).
In contrast to its effects on anaesthetised animals, in conscious rats, AEA causes profound bradycardia, with a transient hypotension followed by a longer lasting pressor effect accompanied by vasoconstriction of the renal and mesenteric vascular beds (Stein et al. 1996; Gardiner et al. 2001, 2002, 2009). This is also accompanied by a hindquarter β2-adrenoceptor-mediated vasodilator response (Gardiner et al. 2002). Gardiner and colleagues (2001, 2002) showed this complex haemodynamic effect results from increased circulating adrenaline acting via β2-adrenoceptors and a CB1-mediated increase in sympathetic activity. In contrast to data obtained from anaesthetised rats, there appears to be no role for TRPV1 activation (Gardiner et al. 2009). Looking at other endocannabinoid agonists in conscious animals, N-arachidonoyl dopamine (NADA) causes a similar triphasic response to that seen in anaesthetised animals but with tachycardia accompanying the hypotensive phase, mediated by TRPV1 (Wang and Wang 2007). Oleamide has no effect on haemodynamics (Huitron-Resendiz et al. 2001).
The endocannabinoid system appears to be involved in the central control of blood pressure via the brainstem baroreceptor complex. The nucleus tractus solitarius is one site of termination of baroreceptor afferent fibres from arterial baroreceptors and cardiac mechanoreceptors. Cannabinoid CB1 receptors are functionally expressed in the nucleus tractus solitarius (Himmi et al. 1998), and microinjection of AEA prolongs reflex inhibition of renal sympathetic nerve activity, suggesting an increase in baroreflex sensitivity, probably due to inhibition of GABAergic tone (Rademacher et al. 2003). AEA concentrations in the nucleus tractus solitarius increase after a phenylephrine-induced rise in blood pressure, supporting the physiological relevance of the endocannabinoid control of baroreflex activity (Seagard et al. 2004). Interestingly, this effect of AEA is blunted in hypertensive rats, possibly contributing to impaired baroreflex sensitivity (Brozoski et al. 2009).
It is worth remembering that animals in whom the CB1, CB2 or FAAH proteins have been knocked out have normal cardiovascular function, suggesting the endocannabinoid system plays a minimal role in the regulation of blood pressure and cardiac function under normal conditions. Similarly antagonists of CB1 or FAAH/monoacylglycerol lipase (MAGL) inhibitors do not affect blood pressure and heart rate in conscious, normotensive animals (later in this review I will discuss how this is different in hypertensive animals), also shedding doubt on the role of the endocannabinoid system in the regulation of haemodynamics. However, recent evidence has pointed to a role for CB1 in modulating sleep–wake cardiorespiratory control (Silvani et al. 2014). Mice lacking the CB1 receptor had a significantly enhanced blood pressure and heart rate response to changes in sleep–wake cycles, and irregular breathing rhythms during sleep, suggesting further research is required to fully understand the role of the endocannabinoid system in all aspects of cardiovascular control.
There is very little evidence for a potential role of the endocannabinoid system in regulating blood pressure in humans in non-pathological situations. To my knowledge, there are no studies that have examined the acute haemodynamic effects of endocannabinoids in humans, although administration of a CB1 receptor antagonist does not affect resting blood pressure in normotensive humans (Ruilope et al. 2008). However, a FAAH gene variant is associated with lower blood pressure in young males, suggesting a potential endocannabinoid role (Sarzani et al. 2008).
2.2 Endocannabinoids and Hypertension
In anaesthetised hypertensive rats, the prolonged hypotensive effect of AEA is enhanced compared to normotensive rats (Lake et al. 1997). CB1 receptor agonists or FAAH inhibition also decreases contractility and normalises blood pressure in anaesthetised hypertensive animals (Bátkai et al. 2004). However, a similar experiment with conscious, freely moving animals showed only a modest response to AEA, although the hypertensive rats had a CB1-mediated bradycardic response to AEA not seen in the normotensive animals (Wheal et al. 2007). Nonetheless, Bátkai and colleagues (2004) also showed that CB1 expression was significantly greater in both cardiac tissue and the aortic endothelium of spontaneously hypertensive rats (SHRs) than in normotensive controls, indicating at least that the expression of the endocannabinoid system is altered in hypertension .
Clinical studies with the CB1 antagonist, Rimonabant, in the Rimonabant in Obesity trials demonstrated minimal effects on blood pressure in normotensive subjects, but much greater reductions in blood pressure in obese hypertensives and patients with type II diabetes (Ruilope et al. 2008) suggesting that excessive endocannabinoid activation of CB1 receptors could underlie the patients’ hypertension . To support this theory, several studies have shown positive correlations between circulating endocannabinoid levels and blood pressure. One study looking at potential correlations between circulating AEA and obstructive sleep apnea found that circulating AEA was a stronger determinant of blood pressure than sleep apnea severity, obesity, insulin resistance or inflammation (Engeli et al. 2012). Another study in females with depression showed that diastolic and mean arterial blood pressures were positively correlated with serum levels of AEA and 2-AG (Ho et al. 2012).
2.3 Endocannabinoids in Shock
Shock is characterised by a reduction in cardiac output, significantly reduced blood pressure and poor tissue perfusion. In 1997, Wagner and colleagues showed that a CB1 receptor antagonist could prevent the fall in blood pressure associated with haemorrhagic shock and that AEA and 2-AG synthesised by monocytes and platelets were responsible for CB1 activation in shock (Wagner et al. 1997). The same group went on to show a similar role for CB1 in endotoxic shock (Varga et al. 1998) and in cardiogenic shock after a myocardial infarction (Wagner et al. 2001). The effects of the CB1 receptor antagonist were not observed when administered centrally, indicating a peripheral mechanism of action. Activation of CB1 on arteries to directly produce vasodilatation (see Sect. 4), as well as inhibition of sympathetic neurotransmitter release (see Malinowska et al. 2008 for a review), brings about vasodilatation and the drop in blood pressure. It is suggested that the release of endocannabinoids may play an important role in mediating cardioprotection in shock (see Sect. 3.1), however, it has also been shown that CB1 antagonists decrease mortality in models of shock (Kadoi et al. 2005).
2.4 Summary on Haemodynamic Effects of Endocannabinoids
Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, with the exception of modulation of baroreflex sensitivity and sleep–wake cardiorespiratory control at a central level. In various forms of shock, there is a clear role for activation of the CB1 receptor by endocannabinoids released within blood in mediating the associated hypotension. In hypertension , there is evidence for both upregulation (cardiac tissue and the aortic endothelium) and downregulation (nucleus tractus solitarius) of the CB1 receptor involved in the maintenance of high blood pressure and reduced baroreflex sensitivity. Human studies have shown that CB1 antagonism reduces blood pressure in obese hypertensive and diabetic patients.
3 Endocannabinoids and Cardiac Function
The endocannabinoid system is expressed throughout the myocardium, and endocannabinoids are detected in cardiac tissue (see Tuma and Steffens 2012 for a review), playing roles in various aspects of cardiac function including contractility and regulation of coronary tone. AEA decreases contractile performance in human atrial muscle via CB1 receptors (Bonz et al. 2003). This may be related to the finding that CB1 activation in the heart decreases noradrenaline release, so less β1 receptors will then be activated (Molderings et al. 1999). It is also related to the fact that AEA inhibits the function of voltage-dependent Na+ and L-type Ca2+ channels in rat ventricular myocytes (Al Kury et al. 2014). AEA causes endothelium-dependent vasorelaxation of rat or sheep coronary arteries via CB1 activation, with no role for endocannabinoid metabolites, CB2 or TRPV1 (White et al. 2001; Ford et al. 2002; Grainger and Boachie-Ansah 2001). In contrast, palmitoylethanolamide (PEA) did not relax precontracted rat coronary arteries (White et al. 2001).
3.1 Cardioprotective Effects of Endocannabinoids
In cardiac pathologies, the endocannabinoid system is altered, and the majority of evidence suggests the increases in endocannabinoid levels in cardiac disorders are protective. AEA levels are transiently increased during ischaemia/reperfusion (Duerr et al. 2014). Patients with aortic stenosis have higher concentrations of AEA (Duerr et al. 2013). Chronic heart failure patients have elevated AEA and 2-AG levels (Weis et al. 2010). Cardiac levels of 2-AG, but not AEA, are increased in preconditioning (Wagner et al. 2006). However, acute stress was recently shown to decrease cardiac endocannabinoid levels (Holman et al. 2014), which might indicate that an upregulation of the endocannabinoid system in the heart is a chronic effect. Upregulation of cannabinoid receptors has been shown in cardiac pathologies, particularly CB2, which is upregulated in chronic heart failure (Weis et al. 2010), in aortic stenosis (Duerr et al. 2013) and in ischaemia/reperfusion (Duerr et al. 2014). CB2 expression is under the control of microRNA-665 (miR-665), whose expression is increased in heart failure (Mohnle et al. 2014).
The hypothesis that endocannabinoids are protective in cardiac dysfunction comes from multiple pieces of evidence. Exogenous application of 2-AG (Wagner et al. 2006), PEA (Lepicier et al. 2003) or AEA (Underdown et al. 2005; Hydock et al. 2009; Li et al. 2013a) confers cardiac protection after various stressors in animal models. The majority of studies suggest that this is a CB2 receptor-mediated event, although AEA has been shown to also have cardioprotective actions through CB1. The importance of CB2 in cardioprotection was highlighted in a recent paper which found that CB2-deficient mice showed greater damage in response to repetitive periods of ischaemia/reperfusion leading to cardiomyopathy (Duerr et al. 2014). This was because the hearts of the CB2 knockout mice had increased inflammatory responses, adverse remodelling, increased rates of apoptosis and an inability to turn on anti-oxidative enzymes (Duerr et al. 2014). CB1 knockout mice are also more susceptible to a chronic heart failure model (Liao et al. 2013). Similarly, mice in whom FAAH has been knocked-out have reduced age-related cardiac dysfunction, indicating a cardioprotective role for locally produced endogenous cannabinoids (Batkai et al. 2007). In humans, a polymorphism of FAAH is associated with an increased risk of a myocardial infarction (Chmelikova et al. 2014).
In the heart, mild stress confers protection leading to a reduction in infarct size in response to subsequent stressors. This is known as preconditioning. A role for the endocannabinoid system has been well established in mediating cardiac preconditioning. Endotoxin preconditioning (Lagneux and Lamontagne 2001) and heat stress preconditioning (Joyeux et al. 2002) are attenuated by CB2 receptor blockade, suggesting a protective role for locally produced endocannabinoids. Delayed preconditioning is also sensitive to CB1 receptor blockade (Wagner et al. 2006).
Cardiac protection is conferred not only by endocannabinoids locally synthesised in the heart but also by circulating endocannabinoids. Remote ischaemic preconditioning is defined as transient brief episodes of ischaemia at a remote site before a subsequent prolonged ischaemia/reperfusion injury of the target organ. In the heart, remote ischaemic preconditioning reduces subsequent infarct volume, and this was inhibited by a CB2, but not CB1, antagonist, implicating a role for circulating endocannabinoids (Hajrasouliha et al. 2008).
The mechanisms by which endocannabinoids are cardioprotective include decreased neutrophil infiltration, decreased inflammation, decreased oxidative stress and increased activation of cardioprotective signalling pathways, through activation of CB1 and CB2 (Tuma and Steffens 2012). The cardioprotective effects of AEA involve the induction of heat shock protein 72 through the PI3K/Akt signalling pathway via CB2 (Li et al. 2013a). CB2 activation also inhibits mitochondria-mediated apoptosis via PI3K/Akt signalling in the myocardium after ischaemia/reperfusion injury (Li et al. 2013b).
3.2 Cardiodeleterious Effects of Endocannabinoids
There are also studies suggesting CB1 receptor activation has negative effects on cardiac function. For example, CB1 receptor antagonism reduces, and AEA enhances, the cardiotoxic effects of the chemotherapy drug doxorubicin in human cardiomyocytes (Mukhopadhyay et al. 2010). CB1 activation by AEA in human coronary artery endothelial cells activates cell death (Rajesh et al. 2010). Daily treatment with the CB1 antagonist Rimonabant has also been shown to reduce infarct size, and this effect was absent in CB1 −/− mice (Lim et al. 2009). Daily treatment with Rimonabant also improves systolic and diastolic heart function after permanent ligation of the left coronary artery (Slavic et al. 2013).
3.3 Endocannabinoids and Arrhythmias
CB2 receptor activation reduces the incidence of ventricular arrhythmias during coronary occlusion (Krylatov et al. 2001). AEA also reduces epinephrine-induced arrhythmias, although this was CB1 and CB2 independent (Ugdyzhekova et al. 2001). However, more recently, neither AEA nor 2-AG were found to affect ischaemia-induced ventricular fibrillation, although a CB1 antagonist (but not CB2 antagonist) alone did have some positive effects during the later stage of acute ischaemia (Andrag and Curtis 2013). In isolated sinoatrial node samples from rabbits, AEA shortens the action potential duration and amplitude via CB1 (Zhang et al. 2013). A similar effect of AEA, that resulted from an inhibitory effect on the functioning of voltage-dependent Na+ and L-type Ca2+ channels, has been observed on the action potential of rat ventricular myocytes, although in these cells, the effect was independent of CB1 and CB2 receptors (Al Kury et al. 2014).
3.4 Summary of Cardiac Effects of Endocannabinoids
There is much evidence that the endocannabinoid system is upregulated in cardiac pathologies. The majority of evidence indicates this is likely to be cardioprotective, mainly through CB2 activation, but with a role also for CB1 activation. However, the role of CB1 is controversial because in some situations, CB1 activation may be detrimental in the heart.
4 Endocannabinoids and the Vasculature
CB1 and CB2 are widely distributed in the vasculature, observed in vascular smooth muscle and endothelial cells (Sugiura et al. 1998; Liu et al. 2000; Rajesh et al. 2007; Rajesh et al. 2008). The first in vitro report of endocannabinoid-induced vasorelaxation of isolated arteries and arterial beds came from Ellis and colleagues (1995) who showed that AEA and Δ9-tetrahydrocannabinol (THC) cause vasorelaxation of rabbit cerebral arteries, associated with an increase in vasoactive prostanoids. Many studies have since shown acute vasorelaxant responses (within minutes of application) to other endocannabinoid and endocannabinoid-like compounds including 2-AG, NADA, oleoylethanolamine (OEA), PEA, N-arachidonoyl-L-serine (ARA-S), N-arachidonoyl glycine and oleamide in a range of different arterial beds from different species (see Stanley and O’Sullivan 2014a). The mechanisms underlying these responses involve the activation of some, but not necessarily all, of the following targets/actions: CB1, TRPV1, a site on the endothelium and modulation of ion channels. Some endocannabinoids also cause a time-dependent (over hours) vasorelaxant effect mediated by peroxisome proliferator-activated receptors (PPARs; O’Sullivan et al. 2009; Romano and Lograno 2012). The evidence for each of the pathways involved will now be discussed.
4.1 Role for CB1
A potential role for CB1 activation is one of the most commonly investigated mechanisms of action for the vascular effects of cannabinoids, and we know this underpins the hypotensive effects of endocannabinoids in shock. Vasorelaxation to AEA is inhibited by CB1 receptor antagonism in renal arterioles (Deutsch et al. 1997; Koura et al. 2004), rat mesenteric arteries (White and Hiley 1998; O’Sullivan et al. 2004a), the perfused mesenteric bed (Wagner et al. 1999), bovine ophthalmic arteries (Romano and Lograno 2006), cat cerebral arteries (Gebremedhin et al. 1999) and the rabbit aorta (Mukhopadhyay et al. 2002). However, other studies have shown that CB1 antagonism does not affect AEA-induced vasorelaxation in rat mesenteric arteries (Plane et al. 1997), the rat mesenteric bed (Peroni et al. 2004), rat hepatic arteries or guinea pig basilar arteries (Zygmunt et al. 1999) or the rat aorta (O’Sullivan et al. 2005). AEA is also capable of causing vasorelaxation of the same magnitude in the mesenteric bed of CB1 −/− as CB1 +/+ mice (Jarai et al. 1999), suggesting other pathways can compensate when CB1 is blocked or absent. Vasorelaxation induced by NADA, OEA and oleamide are all at least partly mediated by CB1 (see Stanley and O’Sullivan 2014a). The mechanism by which CB1 activation brings about relaxation is likely to involve numerous pathways. Gebremedhin et al. (1999) showed that AEA decreases Ca2+ currents via CB1 in smooth muscles cells from cat cerebral microvasculature. Other studies have shown that CB1 activation in the vasculature is coupled to nitric oxide (NO) release (Deutsch et al. 1997; Poblete et al. 2005).
In humans, AEA-induced vasorelaxation of isolated mesenteric arteries is inhibited by CB1 antagonism (Stanley and O’Sullivan 2012). However, in the same arteries, the vasorelaxant effect of 2-AG was not CB1 mediated (Stanley and O’Sullivan 2014b). AEA and virodhamine-induced vasorelaxation of the human pulmonary artery is also not dependent on CB1 (Kozlowska et al. 2007; Kozlowska et al. 2008; Baranowska-Kuczko et al. 2014).
4.2 Role for CB2
Most studies have found that there is no involvement of CB2 in mediating the vascular responses to endocannabinoids in animals or humans (see Stanley and O’Sullivan 2014a). However, there are a couple of exceptions to this. AlSuleimani and Hiley (2013) showed a role for CB2 in OEA-induced vasorelaxation of small resistance arteries of the mesenteric bed. AEA also causes vasorelaxation of rat coronary arteries that is inhibited by CB2 antagonism (Mair et al. 2010). It is more likely that CB2 plays a role in other functions of the endothelium such as the regulation of adhesion molecules, monocyte adhesion and endothelial permeability (see Sect. 4.10).
4.3 Role for CBe
Early indications of an endothelial cannabinoid receptor that is distinct from CB1 and CB2 came from the works of Jarai and colleagues (1999) who showed that AEA was able to cause endothelium-dependent vasorelaxation of the mesenteric vasculature equally in CB1/CB2 knockouts as in wild-type mice, suggesting the involvement of receptors other than CB1 or CB2 located on the endothelium. This has become known as the endothelial cannabinoid receptor, or CBe. Activation of this receptor by AEA has been confirmed in numerous studies. In rabbit aortic rings, AEA causes vasorelaxation through a pertussis toxin (PTX)-sensitive endothelial receptor (Mukhopadhyay et al. 2002), and in the rat aorta, AEA-induced relaxation is sensitive to endothelium denudation, PTX and O-1918 (a proposed antagonist of CBe that has no affinity for CB1 or CB2 receptors), but not to CB1 or CB2 antagonism (Herradon et al. 2007). Similar results have been obtained in rat resistance mesenteric arteries (O’Sullivan et al. 2004a). Other endocannabinoids or endocannabinoid-like compounds suggested to activate CBe include NADA in rat mesenteric arteries (O’Sullivan et al. 2004b), OEA in rat mesenteric arteries and the aorta (Wheal et al. 2010; AlSuleimani and Hiley 2013), oleamide in rat mesenteric resistance arteries (Hoi and Hiley 2006) and ARA-S (Milman et al. 2006) and N-arachidonoyl glycine (Parmar and Ho 2010) in rat mesenteric arteries. However, there is no role for CBe in the vasorelaxant effects of 2-AG (Kagota et al. 2001) or PEA (White and Hiley 1998). Vasorelaxation induced by the activation of CBe may involve the release of endothelium-derived hyperpolarising factor (Jarai et al. 1999; O’Sullivan et al. 2004b), BKca channel modulation (Hoi and Hiley 2006) and NO production (Mukhopadhyay et al. 2002; Herradon et al. 2007; McCollum et al. 2007).
In human pulmonary and mesenteric arteries, AEA causes endothelium-dependent vasorelaxation that can be inhibited using the proposed CBe antagonist O-1918 (Stanley and O’Sullivan 2012; Baranowska-Kuczko et al. 2014). Similarly, in the human pulmonary artery , the vasorelaxant effects of virodhamine are inhibited by O-1918 (Kozlowska et al. 2007, 2008). This suggests that this proposed endothelial target site for endocannabinoids is also present and functional in human vasculature.
4.4 Role for Other Uncloned CB Receptors
Some pharmacological evidence suggests there may be other cannabinoid receptors in the vasculature that remain to be identified. For example, 2-AG-induced vasorelaxation of the rabbit mesenteric arteries is inhibited by 3 μM but not 1 μM Rimonabant and is not affected by removal of the endothelium. This is not consistent with a role for either CB1 or CBe and suggests that another target for 2-AG may exist on the vascular smooth muscle (Kagota et al. 2001). ARA-S-induced vasorelaxation of rat mesenteric arteries is inhibited by O-1918 (even in denuded arteries) but not PTX (Milman et al. 2006), which casts doubt on the specificity of action of O-1918 at CBe if it inhibits responses in endothelial-denuded arteries. In the rat aorta, vasorelaxation by AEA or NADA is inhibited by PTX, but not by antagonism of either CB1 or CB2 or removal of the endothelium (O’Sullivan et al. 2005), again suggesting another receptor for these endocannabinoids is located on vascular smooth muscle. Similarly, vasorelaxation of the rat aorta by ARA-S is inhibited by PTX but not O-1918, or CB1 or CB2 antagonism (Milman et al. 2006). Together, these studies suggest that further sites of action for endocannabinoids may exist on vascular smooth muscle.
4.5 Role for TRPV1
Zygmunt and colleagues (1999) were the first to show that the vasorelaxant effects of AEA, but not 2-AG or PEA, could be blocked by capsaicin pre-treatment (to deplete sensory neurotransmitters) or inhibited by a TRPV1 antagonist. They showed this involves the release of calcitonin gene-related peptide (CGRP) causing vasorelaxation through activation of CGRP receptors (Zygmunt et al. 1999). AEA induced vasorelaxation though TRPV1 is also reported to be linked to NO production in the rat mesenteric vascular bed (Poblete et al. 2005). Many studies have confirmed the role of TRPV1 in AEA-induced vasorelaxation (Harris et al. 2002; Ho and Hiley 2003; O’Sullivan et al. 2004b; Peroni et al. 2004). Other endocannabinoids or endocannabinoid-like compounds that cause vasorelaxation through TRPV1 activation include NADA (O’Sullivan et al. 2004a) and OEA (Ho et al. 2008; Wheal et al. 2010; AlSuleimani and Hiley 2013). However, in rat coronary arteries and rat pulmonary arteries, AEA-induced vasorelaxation is not affected by incubation with capsaicin or a TRPV1 antagonist (White et al. 2001; Baranowska-Kuczko et al. 2012), which may reflect differences in sensory innervations or TRP expression between vascular beds. In isolated human mesenteric arteries and pulmonary arteries, capsaicin pre-treatment does not inhibit AEA-, 2-AG- or virodhamine-induced vasorelaxation (Kozlowska et al. 2008; Stanley and O’Sullivan 2014b; Baranowska-Kuczko et al. 2014), possibly suggesting species differences in the role or expression of TRP channels in the vasculature or the ability of endocannabinoids to activate these sites.
4.6 Role for PPARs
In addition to the acute vascular responses to endocannabinoids, a time-dependent (over hours) vasorelaxant response can be seen after a single application of AEA and NADA, but not PEA (O’Sullivan et al. 2009). This effect was mediated by PPARγ. Romano and Lograno (2012) showed a similar time-dependent vasorelaxant response to AEA and PEA in the bovine ophthalmic artery that could be inhibited by a PPARα (but not PPARγ) antagonist. As PPAR activation in the vasculature mediates other effects such as anti-inflammatory and anti-atherosclerotic actions, the possibility exists that the endocannabinoid system and production of endocannabinoids, in endothelial or smooth muscle cells, could bring about some of these effects through PPAR activation.
4.7 Metabolic Products of Cannabinoids
Some of the vascular effects of endocannabinoids are mediated by their metabolic products. This is evidenced by the fact that the vasorelaxant effects of AEA and 2-AG can be inhibited by FAAH, MAGL, cyclooxygenase (COX) and cytochrome P450 inhibition (Ellis et al. 1995; Fleming et al. 1999; Gauthier et al. 2005; Herradon et al. 2007; Awumey et al. 2008; Czikora et al. 2012; Stanley and O’Sullivan 2014b). The metabolites produced include arachidonic acid, prostaglandins and epoxyeicosatrienoic acids (Pratt et al. 1998; Stanke-Labesque et al. 2004), which can themselves have direct vascular effects, or be further metabolised into vasoactive substances. For example, metabolic products of AEA metabolism activate the prostacyclin receptor in the rat and human pulmonary artery (Baranowska-Kuczko et al. 2012, 2014). It is likely that for some endocannabinoids, their vascular responses are brought about by a combination of effects of the compounds themselves (through CB1, TRPV or PPAR activation) and vascular effects of their metabolites. Some of these metabolites formed from endocannabinoids or endocannabinoid-like compounds can also have vasoconstrictor effects. For example, metabolites of AEA can induce vasoconstriction in the rabbit lung via the prostanoid EP1 receptor (Wahn et al. 2005), and metabolites of 2-AG (Stanke-Labesque et al. 2004) and OEA (Wheal et al. 2010) cause vasoconstriction via the thromboxane receptor. Therefore, it is worth considering that the vascular effects of endocannabinoids might be altered in pathologies where the expression of enzymes involved (FAAH, MAGL or COX) and of the receptors activated might be altered.
4.8 Vascular Responses to Endocannabinoids in Disease Situations
The vascular responses to endocannabinoids are altered in some disease situations. Wheal et al. (2007) showed an enhanced vasorelaxant response to AEA in perfused mesenteric beds of rats made hypertensive by chronic NO synthase inhibition. A subsequent study with this model showed this was abolished by capsaicin pre-treatment, suggesting an increased sensory nerve involvement (Wheal and Randall 2009). However, in the SHR, the vasorelaxant effects of AEA were reduced in the perfused mesenteric bed and were enhanced in aortic rings (Wheal and Randall 2009). The enhanced response in SHR aortae was endothelium-dependent (Wheal and Randall 2009). Hopps et al. (2012) also showed that the vasorelaxant response to oleamide was enhanced in the aorta of SHRs, and that this could be abolished by capsaicin pre-treatment, again suggesting an increased role for sensory nerve activation by endocannabinoids in hypertension . In contrast, the COX-sensitive component of the response to oleamide was lost in SHRs (Hopps et al. 2012).
Domenicali and colleagues (2005) showed that the vasorelaxant response to AEA was enhanced in cirrhotic rats, and that this was associated with an increase in CB1 and TPRV1 receptor expression. Similarly, Moezi et al. (2006) showed that AEA increases mesenteric arteriole diameter in cirrhotic rats but not control rats, and that this was blocked by a CB1 antagonist and associated with increased CB1 and TPRV1 receptor protein. By contrast, the vasorelaxant responses to AEA are reduced in mesenteric arteries from young obese Zucker rats, and this is associated with decreased CB1 and CB2 expression (Lobato et al. 2013). We have also shown that the responses to AEA and 2-AG are reduced in the Zucker diabetic model, which appears to be brought about by enhanced metabolism of these endocannabinoids, including the production of vasoconstrictor metabolites acting at the thromboxane receptor (Wheal et al. 2012).
4.9 Endocannabinoids and Veins
Despite the wealth of literature on the direct effects of endocannabinoids on arteries, there are few studies on the effects of endocannabinoids in veins. Although many authors have used human umbilical vein endothelial cells, this has been as a model of endothelial cell function, rather than to examine the effects of endocannabinoid on venous function. Only two studies have looked at this. Stefano et al. (1998) showed that acute treatment with AEA increased NO release in human saphenous vein, and this was associated with decreased monocyte adherence. However, chronic treatment of human saphenous veins with AEA led to increased monocyte adherence because of a desensitisation to AEA-induced NO release (Stefano et al. 1998). In isolated rings of human umbilical vein (Pelorosso et al. 2009), 150 min (but not 15 min) exposure to AEA decreases the contractile response to bradykinin via the CB1 receptor and not the CB2 receptor.
4.10 Endocannabinoids and Atherosclerosis
Many studies have investigated the role of the endocannabinoid system in atherosclerosis (see Steffens and Pacher 2015; Carbone et al. 2014 for reviews). Increased expression of CB1 has been observed in human coronary atherectomy samples and CB1 expression was greater in lipid-rich atheromatous plaques than in fibrous plaques (Sugamura et al. 2009). Increased levels of 2-AG have also been observed in the aorta of a mouse model of atherosclerosis (Montecucco et al. 2009). Plasma levels of AEA and 2-AG are raised in patients with coronary artery disease (Sugamura et al. 2009). As in cardiac pathologies, the assumption is that upregulation of the endocannabinoid system in atherosclerosis is protective. Accordingly, FAAH knockout mice show increased monocyte adhesion to endothelial cells (Batkai et al. 2007), and genetic deletion of CB2 worsens atherogenesis in hyperlipidic mice (Hoyer et al. 2011).
Given the anti-inflammatory effects of CB2 activation, it is not surprising that many studies have indicated a protective role of CB2 agonists/activation in vivo in animal models of atherosclerosis . The effects of CB2 activation in vivo include decreased plaque development, decreased vascular smooth muscle cell proliferation, improved endothelial function, decreased expression of adhesion molecules, decreased oxidative stress, and decreased macrophage infiltration (Steffens et al. 2005; Zhao et al. 2010; Hoyer et al. 2011). In endothelial cell studies, AEA and CB2 agonists decrease TNFα and adhesion molecules, and chemotaxis and neutrophil adhesion (Rajesh et al. 2007). CB2 agonists also decrease the proliferation and migration of human vascular smooth muscle cells (Rajesh et al. 2008).
The role of CB1 in atherosclerosis is more controversial, with evidence suggesting both a pro- and anti-atherosclerotic effect of receptor activation. Rimonabant has been shown to reduce atherosclerotic lesions and decrease cytokine release in a mouse model (Dol-Gleizes et al. 2009), and cell studies have shown that CB1 blockade decreases inflammatory cytokines in macrophages (Sugamura et al. 2009; Han et al. 2009). Also, CB1 activation causes endothelial cell injury (Rajesh et al. 2007). In contrast to these studies, the STRADIVARIUS trial studying the effect of Rimonabant on atherosclerosis progression in patients with abdominal obesity and coronary artery disease did not see a significant difference in their primary outcome measure, atheroma volume (Nissen et al. 2008). Similarly, the AUDITOR study (Atherosclerosis Underlying Development assessed by Intima-media Thickness in patients On Rimonabant) saw no difference in atherosclerosis progression in patients receiving Rimonabant for 30 months (O’Leary et al. 2011), casting doubt on a contributory role for CB1 activation in atherosclerosis. Furthermore, a screening of 2411 patients looking at 19 different polymorphisms of the gene encoding CB1 did not reveal any association with coronary heart disease (de Miguel-Yanes et al. 2011). However, the G1359A polymorphism of CNR1 (the gene encoding CB1) does contribute to the genetic risk of coronary artery disease in a Chinese Han population with type 2 diabetes (Wang et al. 2012).
4.11 Summary of Vascular Effects of Endocannabinoids
Endocannabinoids cause acute and time-dependent vasorelaxation of arteries in animal and human studies through activation of CB1, CBe, TRPV and PPARs, coupled to inhibition of calcium channels, activation of potassium channels, NO and vasoactive metabolite production and the release of other vasoactive substances such as CGRP. Changes in the expression of any of these components alters the vascular effects of endocannabinoids, with both enhancement and reductions in the response to endocannabinoids observed in hypertension , cirrhosis, obesity and diabetes. Endocannabinoids can have positive and negative effects on the progression of atherosclerosis . Most evidence suggests a protective role for CB2 activation and a negative effect of CB1 activation. However, any negative CB1-mediated effects may not be consequential, as chronic CB1 antagonism in large scale human trials was not associated with significant reductions in atheroma volume.
5 Endocannabinoids and Blood
Circulating levels of endocannabinoids are altered in a multitude of disorders including (but not limited to) obesity (Blüher et al. 2006), diabetes and insulin resistance (Cote et al. 2007; Abdulnour et al. 2014), obstructive sleep apnea (Engeli et al. 2012) and post-traumatic stress (Hauer et al. 2013). In many studies, it has been shown that plasma levels of AEA and 2-AG are correlated with metabolic and cardiovascular risks (Weis et al. 2010; Quercioli et al. 2011), although it is not clear whether there is a causal link between these factors. It is also not clear what the source of circulating endocannabinoids are, although in situations like cardiogenic shock, it is likely that endocannabinoids are derived from platelets and macrophages (Varga et al. 1998), while in obesity, it is suggested that they might arise from adipose tissue.
Looking first at the effects of endocannabinoids and endocannabinoid-like compounds on the formation of blood cellular components, AEA, 2-AG and PEA have been shown to stimulate mouse haematopoietic cell growth and differentiation into granulocyte, erythrocyte, macrophage and megakaryocyte colonies (Valk et al. 1997; Patinkin et al. 2008) through activation of the CB2 receptor (Valk et al. 1997). 2-AG can also increase the formation and maturation of platelets from human megakaryoblasts (Gasperi et al. 2014).
AEA can easily pass through the cell membrane of red blood cells (erythrocytes) (Bojesen and Hansen 2005), and in red blood cells, AEA increases cytosolic Ca2+ activity, leading to cell shrinkage and cell membrane scrambling of mature erythrocytes, and this was inhibited by cyclooxygenase inhibitors (Bentzen and Lang 2007). This ability of AEA to stimulate red blood cell death is beneficial in infections in which erythrocytes get infected, and inducing cell death maintains a healthy red blood cell population (Bobbala et al. 2010).
Both AEA (Maccarrone et al. 1999) and 2-AG (Maccarrone et al. 2001) activate platelets, albeit at very high concentrations. However, the platelet levels of endocannabinoids may also be very high, suggesting this activation is likely to be physiologically relevant. Activation of platelets by endocannabinoids has been ascribed to their metabolism to arachidonic acid (Braud et al. 2000) or to cannabinoid receptor activation (Maccarrone et al. 2001). Interestingly, CB1 and CB2 have been detected in human platelets, within the cell membrane (Catani et al. 2010a). More recently, virodhamine and 2-AG, but not AEA, were shown to share the ability of arachidonic acid to induce human platelet aggregation (Brantl et al. 2014). This could be blocked by inhibitors of their metabolism by MAGL or COX, and was not mimicked by CB1 or CB2 agonists, suggesting it is metabolites of virodhamine and 2-AG that mediate their effects. 2-AG can also increase platelet formation and maturation (Gasperi et al. 2014). Similarly, AEA can extend platelet survival through CB1-dependent Akt signalling (Catani et al. 2010b), indicating that there are many aspects of platelet function that can be modulated by endocannabinoids.
In human peripheral blood mononuclear cells (lymphocytes, monocytes and macrophages), endocannabinoids decrease cytokine production and regulate many aspects of white blood cell function and immunity. Immune system modulation by endocannabinoids is discussed in detail in this volume in Cabral et al., “Endocannabinoids and the immune system in health and disease”.
6 Endocannabinoids and Neurovascular Function
Endocannabinoids are neuroprotective, an effect brought about by decreased excitotoxicity, decreased oxidative stress, anti-inflammatory actions and the induction of hypothermia (see Fernández-Ruiz et al., “Endocannabinoids and neurodegenerative disorders: Parkinson’s disease, Huntington’s chorea, Alzheimer’s disease, and others” in this volume). As well as these neurological actions, endocannabinoids also affect vascular function in the brain. As in other arteries, endocannabinoids cause vasorelaxation of cerebral arteries through the production of vasoactive prostanoids (Ellis et al. 1995). Activation of the CB1 receptor in cat cerebral vascular smooth muscle cells inhibits the influx of Ca2+ through L-type Ca2+ channels, helping to bring about vasorelaxation (Gebremedhin et al. 1999). 2-AG reduces the effects of endothelin-1 and thus reduces cerebral vasoconstriction in human cerebral endothelial cells, mediated by CB1 (Chen et al. 2000). AEA also inhibits the vasoconstrictor effects of endothelin-1 in rabbit basilar arteries (Dogulu et al. 2003). There appears to be a relationship between endocannabinoids and cerebral vasoconstriction, as another study showed that the thromboxane mimetic, U-46619, significantly increased AEA and 2-AG content of the middle cerebral artery , whereas serotonin decreased AEA and 2-AG content (Rademacher et al. 2005). U46619-induced contractions of the rat middle cerebral artery could also be enhanced by antagonism of the CB1 receptor. This may help to explain the potential beneficial effects of endocannabinoids in migraine (see Greco et al. 2010 for a review).
The blood –brain barrier (BBB) is formed by brain endothelial cells that line the cerebral microvasculature, capillary basement membranes and astrocyte end feet, which surround 99 % of the BBB endothelia and play an important role in maintaining BBB integrity. Increased BBB permeability associated with multiple sclerosis is decreased by AEA (Mestre et al. 2011). We recently investigated the effects of various endocannabinoids and endocannabinoid-like compounds on BBB permeability using an in vitro model in which human brain microvascular endothelial cells and human astrocytes were co-cultured (Hind et al. 2015). We found that only AEA and OEA affected BBB permeability in control conditions and that they both decreased BBB permeability (i.e. increased resistance). This was mediated by CB2, TRPV1 and CGRP receptors (for AEA) and PPARα (for OEA). In contrast, oleamide has been shown to inhibit gap junction coupling in pig brain microvascular endothelial cells, thus increasing barrier permeability in vitro (Nagasawa et al. 2006). However, we saw no effect of oleamide on BBB permeability in our human in vitro model (Hind et al. 2015).
Given the knowledge that endocannabinoids are neuroprotective, cause cerebral vasorelaxation and reduce BBB permeability, it is not surprising that they have been shown to be protective in neurovascular disorders such as traumatic brain injury (TBI) and cerebral ischaemia/reperfusion injury (stroke).
6.1 Endocannabinoids and Traumatic Brain Injury
TBI occurs when an external force traumatically injures the brain. This type of brain injury has been shown to increase 2-AG levels up to tenfold within hours and to last for at least 24 h post-injury (Panikashvili et al. 2001). The hypothesis that this increase in 2-AG might be protective was proven when it was found that administration of 2-AG enhanced the recovery from TBI, associated with a decrease in infarct volume, neuronal loss and inflammation (Panikashvili et al. 2001). TBI is known to disrupt the BBB, and in this study, 2-AG limited the increase in BBB permeability, and thus reduced the associated oedema. The effect of 2-AG was inhibited by CB1 receptor antagonism and absent in CB1 knockout mice. The effects of TBI are worse in CB1 knockout mice, suggesting a CB1-mediated protective role for endogenous endocannabinoid production in TBI. However, there is probably also a contribution of the CB2 receptor, as a synthetic CB2-selective agonist can also ameliorate TBI outcomes, which can be inhibited by CB2 antagonism (Elliott et al. 2011). The endocannabinoid-like substance N-arachidonoyl-L-serine also improves TBI outcomes, and for this compound, the effects were inhibited by antagonists of CB2 and TRPV1, but not CB1 (Cohen-Yeshurun et al. 2013). More recently, PEA has been shown to have a beneficial effect in reducing oedema and infarct size in TBI (mechanisms of action not probed) (Ahmad et al. 2012a).
6.2 Endocannabinoids and Cerebral Ischaemia/Stroke
The expression of cannabinoid receptors is upregulated in the rat brain following cerebral ischaemia (stroke), indicating that the endocannabinoid system may play an important role in the endogenous response to stroke (see Hillard 2008; Tuma and Steffens 2012). Human and animal in vivo data have shown increases in neurological and circulating plasma levels of AEA, 2-AG, OEA and PEA after stroke (Schabitz et al. 2002; Hillard 2008; Naccarato et al. 2010). As in other cardiovascular disorders, the hypothesis is that upregulation of the endocannabinoid system is protective in stroke, and this is supported by numerous studies showing that 2-AG (Wang et al. 2009), AEA (Wang et al. 2009) as well as the endocannabinoid-like compounds, OEA (Sun et al. 2007; Zhou et al. 2012) and PEA (Schomacher et al. 2008; Garg et al. 2010; Ahmad et al. 2012b), offer protection against ischaemic/reperfusion injury. N-acylethanolamine compounds such as lauroylethanolamide and linoleoylethanolamide have also been shown to be protective against stroke (Garg et al. 2011). In a recent systematic review and meta-analysis, we reported that endocannabinoids significantly reduced infarct volume in several models of experimental stroke (England et al. 2015).
There are multiple target sites at which endocannabinoids may act in this regard. Mice that are lacking the CB1 receptor are more susceptible to stroke (Parmentier-Batteur et al. 2002), and CB1 has been shown to mediate the protective effects of AEA and 2-AG (Wang et al. 2009). CB1 activation increases neurotrophic factors, reduces excitotoxicity, reduces oxidative stress and causes the induction of hypothermia (see Tuma and Steffens 2012 for a review). CB2 activation is also important in cerebral ischaemic injury by decreasing the release of pro-inflammatory cytokines, decreasing neutrophil recruitment, decreasing leukocyte adhesion to cerebral vessels and increasing brain-derived neurotrophic factor (Choi et al. 2013). Mice that lack the CB2 receptor are also more susceptible to stroke (Zhang et al. 2008). In addition, the protective effects of OEA have been shown to be mediated by PPARα (Sun et al. 2007), while the protective effects of PEA are independent of CB1 or TRPV1 (Garg et al. 2010). We have found that OEA and PEA decreased ischaemia/reperfusion-induced increases in BBB permeability in vitro and that this was PPARα mediated (Hind et al. 2015). The vasodilatory effects of endocannabinoids in the cerebral vasculature may also play a role in maintaining and restoring blood flow after a stroke.
6.3 Summary
In neurovascular disorders such as TBI and stroke, endocannabinoids are produced and the endocannabinoid system is upregulated in a protective manner, as shown by the ability of various endocannabinoid agonists to reduce damage in TBI and stroke. This protection involves CB1, CB2, TRPV1 and PPARα activation, and both vascular tissue (vasorelaxation, inhibition of vasoconstriction and reductions of BBB permeability and oedema) and neuronal tissue.
7 Conclusions and Closing Comments
It is clear that the endocannabinoid system has important roles in the cardiovascular system, particularly in cardiovascular pathologies. However, although much research has been carried out with AEA and 2-AG, comparatively little is known about the role and effect of other endocannabinoids and endocannabinoid-like compounds in the cardiovascular system and cardiovascular pathologies. When probing possible mechanisms of action, many studies have focussed on the potential role of CB1 and CB2 activation, and less is therefore known about the impact on cardiovascular pathologies of the activation by endocannabinoids of other targets, such as CBe, and the vascular receptors, PPARs, GPR55 and 5HT1A. Furthermore, the majority of work in this area has been carried out in animals, and more research is required in humans to establish the importance of the endocannabinoid system (including as yet unidentified targets on the endothelium and vascular smooth muscle), especially in cardioprotection and atherosclerosis , both areas of unmet medical needs. Despite this, is seems likely from the evidence presented in this review that greater understanding of the role and effects of the endocannabinoid system in cardiovascular regulation in humans will lead to new target sites of action for drug discovery.
Abbreviations
- 2-AG:
-
2-Arachidonoylglycerol
- AEA:
-
Anandamide
- ARA-S:
-
N-arachidonoyl-L-serine
- BBB:
-
Blood–brain barrier
- CB1 :
-
Cannabinoid receptor 1
- CB2 :
-
Cannabinoid receptor 2
- COX:
-
Cyclooxygenase
- eNOS:
-
Endothelial nitric oxide synthase
- FAAH:
-
Fatty acid amide hydrolase
- MAGL:
-
Monoacylglycerol lipase
- NADA:
-
N-arachidonoyl dopamine
- NO:
-
Nitric oxide
- OEA:
-
Oleoylethanolamide
- PEA:
-
Palmitoylethanolamide
- PPAR:
-
Peroxisome proliferator-activated receptors
- PTX:
-
Pertussis toxin
- SHR:
-
Spontaneously hypertensive rat
- TBI:
-
Traumatic brain injury
- THC:
-
Delta-9-tetrahydrocannabinol
- TRPV1:
-
Transient receptor potential vanilloid 1
References
Abdulnour J, Yasari S, Rabasa-Lhoret R, Faraj M, Petrosino S, Piscitelli F, Prud’ Homme D, Di Marzo V (2014) Circulating endocannabinoids in insulin sensitive vs. insulin resistant obese postmenopausal women. A MONET group study. Obesity (Silver Spring) 22(1):211–216. doi:10.1002/oby.20498
Ahmad A, Crupi R, Impellizzeri D, Campolo M, Marino A, Esposito E, Cuzzocrea S (2012a) Administration of palmitoylethanolamide (PEA) protects the neurovascular unit and reduces secondary injury after traumatic brain injury in mice. Brain Behav Immun 26(8):1310–1321
Ahmad A, Genovese T, Impellizzeri D, Crupi R, Velardi E, Marino A, Esposito E, Cuzzocrea S (2012b) Reduction of ischemic brain injury by administration of palmitoylethanolamide after transient middle cerebral artery occlusion in rats. Brain Res 1477:45–58
Al Kury LT, Voitychuk OI, Yang KH, Thayyullathil FT, Doroshenko P, Ramez AM, Shuba YM, Galadari S, Howarth FC, Oz M (2014) Effects of the endogenous cannabinoid AEA on voltage-dependent sodium and calcium channels in rat ventricular myocytes. Br J Pharmacol 171(14):3485–3498
AlSuleimani YM, Hiley CR (2013) Mechanisms of vasorelaxation induced by oleoylethanolamide in the rat small mesenteric artery. Eur J Pharmacol 702(1–3):1–11. doi:10.1016/j.ejphar.2013.01.006, Epub 2013 Jan 20
Andrag E, Curtis MJ (2013) Feasibility of targeting ischaemia-related ventricular arrhythmias by mimicry of endogenous protection by endocannabinoids. Br J Pharmacol 169(8):1840–1848
Awumey EM, Hill SK, Diz DI, Bukoski RD (2008) Cytochrome P-450 metabolites of 2-arachidonoylglycerol play a role in Ca2+-induced relaxation of rat mesenteric arteries. Am J Physiol Heart Circ Physiol 294(5):H2363–H2370
Baranowska-Kuczko M, MacLean MR, Kozlowska H, Malinowska B (2012) Endothelium-dependent mechanisms of the vasodilatory effect of the endocannabinoid, AEA, in the rat pulmonary artery. Pharmacol Res 66(3):251–259
Baranowska-Kuczko M, Kozłowska H, Kozłowski M, Schlicker E, Kloza M, Surażyński A, Grzęda E, Malinowska B (2014) Mechanisms of endothelium-dependent relaxation evoked by anandamide in isolated human pulmonary arteries. Naunyn Schmiedebergs Arch Pharmacol 387(5):477–486. doi:10.1007/s00210-014-0961-9, Epub 2014 Feb 28
Bátkai S, Pacher P, Osei-Hyiaman D, Radaeva S, Liu J, Harvey-White J, Offertáler L, Mackie K, Rudd MA, Bukoski RD, Kunos G (2004) Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation 110(14):1996–2002, Epub 2004 Sept 27
Batkai S, Rajesh M, Mukhopadhyay P, Hasko G, Liaudet L, Cravatt BF, Csiszar A, Ungvari Z, Pacher P (2007) Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase. Am J Physiol Heart Circ Physiol 293(2):H909–H918
Bentzen PJ, Lang F (2007) Effect of AEA on erythrocyte survival. Cell Physiol Biochem 20(6):1033–1042
Blüher M, Engeli S, Klöting N, Berndt J, Fasshauer M, Bátkai S, Pacher P, Schön MR, Jordan J, Stumvoll M (2006) Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 55(11):3053–3060
Bobbala D, Alesutan I, Foller M, Huber SM, Lang F (2010) Effect of AEA in Plasmodium berghei-infected mice. Cell Physiol Biochem 26(3):355–362
Bojesen IN, Hansen HS (2005) Membrane transport of AEA through resealed human red blood cell membranes. J Lipid Res 46(8):1652–1659
Bonz A, Laser M, Kullmer S, Kniesch S, Babin-Ebell J, Popp V, Ertl G, Wagner JA (2003) Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle. J Cardiovasc Pharmacol 41(4):657–664
Brantl SA, Khandoga AL, Siess W (2014) Activation of platelets by the endocannabinoids 2-arachidonoylglycerol and virodhamine is mediated by their conversion to arachidonic acid and thromboxane A2, not by activation of cannabinoid receptors. Platelets 25(6):465–466
Braud S, Bon C, Touqui L, Mounier C (2000) Activation of rabbit blood platelets by AEA through its cleavage into arachidonic acid. FEBS Lett 471(1):12–16
Brozoski DT, Dean C, Hopp FA, Hillard CJ, Seagard JL (2009) Differential endocannabinoid regulation of baroreflex-evoked sympathoinhibition in normotensive versus hypertensive rats. Auton Neurosci 150(1–2):82–93
Carbone F, Mach F, Vuilleumier N, Montecucco F (2014) Cannabinoid receptor type 2 activation in atherosclerosis and acute cardiovascular diseases. Curr Med Chem 21(35):4046–4058
Catani MV, Gasperi V, Catanzaro G, Baldassarri S, Bertoni A, Sinigaglia F, Avigliano L, Maccarrone M (2010a) Human platelets express authentic CB(1) and CB(2) receptors. Curr Neurovasc Res 7(4):311–318
Catani MV, Gasperi V, Evangelista D, Finazzi Agro A, Avigliano L, Maccarrone M (2010b) AEA extends platelets survival through CB(1)-dependent Akt signaling. Cell Mol Life Sci 67(4):601–610
Chen Y, McCarron RM, Ohara Y, Bembry J, Azzam N, Lenz FA, Shohami E, Mechoulam R, Spatz M (2000) Human brain capillary endothelium: 2-arachidonoglycerol (endocannabinoid) interacts with endothelin-1. Circ Res 87(4):323–327
Chmelikova M, Pacal L, Spinarova L, Vasku A (2014) Association of polymorphisms in the endocannabinoid system genes with myocardial infarction and plasma cholesterol levels. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. doi:10.5507/bp.2014.043
Choi IY, Ju C, Anthony Jalin AM, da Lee I, Prather PL, Kim WK (2013) Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. Am J Pathol 182(3):928–939
Cohen-Yeshurun A, Willner D, Trembovler V, Alexandrovich A, Mechoulam R, Shohami E, Leker RR (2013) N-arachidonoyl-L-serine (AraS) possesses proneurogenic properties in vitro and in vivo after traumatic brain injury. J Cereb Blood Flow Metab 33(8):1242–1250
Cote M, Matias I, Lemieux I, Petrosino S, Almeras N, Despres JP, Di Marzo V (2007) Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes (Lond) 31(4):692–699
Czikora A, Lizanecz E, Boczan J, Darago A, Papp Z, Edes I, Toth A (2012) Vascular metabolism of AEA to arachidonic acid affects myogenic constriction in response to intraluminal pressure elevation. Life Sci 90(11–12):407–415
de Miguel-Yanes JM, Manning AK, Shrader P, McAteer JB, Goel A, Hamsten A, Fox CS, Florez JC, Dupuis J, Meigs JB (2011) Variants at the endocannabinoid receptor CB1 gene (CNR1) and insulin sensitivity, type 2 diabetes, and coronary heart disease. Obesity (Silver Spring) 19(10):2031–2037
Deutsch DG, Goligorsky MS, Schmid PC, Krebsbach RJ, Schmid HH, Das SK, Dey SK, Arreaza G, Thorup C, Stefano G, Moore LC (1997) Production and physiological actions of AEA in the vasculature of the rat kidney. J Clin Invest 100(6):1538–1546
Dogulu FH, Ozogul C, Akpek S, Kurt G, Emmez H, Ercan S, Baykaner MK (2003) Intra-arterial simultaneous administration of AEA attenuates endothelin-1 induced vasospasm in rabbit basilar arteries. Acta Neurochir 145(7):579–582
Dol-Gleizes F, Paumelle R, Visentin V, Mares AM, Desitter P, Hennuyer N, Gilde A, Staels B, Schaeffer P, Bono F (2009) Rimonabant, a selective cannabinoid CB1 receptor antagonist, inhibits atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 29(1):12–18
Domenicali M, Ros J, Fernandez-Varo G, Cejudo-Martin P, Crespo M, Morales-Ruiz M, Briones AM, Campistol JM, Arroyo V, Vila E, Rodes J, Jimenez W (2005) Increased AEA induced relaxation in mesenteric arteries of cirrhotic rats: role of cannabinoid and vanilloid receptors. Gut 54(4):522–527
Duerr GD, Heinemann JC, Dunkel S, Zimmer A, Lutz B, Lerner R, Roell W, Mellert F, Probst C, Esmailzadeh B, Welz A, Dewald O (2013) Myocardial hypertrophy is associated with inflammation and activation of endocannabinoid system in patients with aortic valve stenosis. Life Sci 92(20–21):976–983
Duerr GD, Heinemann JC, Suchan G, Kolobara E, Wenzel D, Geisen C, Matthey M, Passe-Tietjen K, Mahmud W, Ghanem A, Tiemann K, Alferink J, Burgdorf S, Buchalla R, Zimmer A, Lutz B, Welz A, Fleischmann BK, Dewald O (2014) The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy. Basic Res Cardiol 109(4):425
Elliott MB, Tuma RF, Amenta PS, Barbe MF, Jallo JI (2011) Acute effects of a selective cannabinoid-2 receptor agonist on neuroinflammation in a model of traumatic brain injury. J Neurotrauma 28(6):973–981
Ellis EF, Moore SF, Willoughby KA (1995) AEA and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin. Am J Physiol 269(6 Pt 2):H1859–H1864
Engeli S, Bluher M, Jumpertz R, Wiesner T, Wirtz H, Bosse-Henck A, Stumvoll M, Batkai S, Pacher P, Harvey-White J, Kunos G, Jordan J (2012) Circulating AEA and blood pressure in patients with obstructive sleep apnea. J Hypertens 30(12):2345–2351
England TJ, Hind WH, Rasid NA, O’Sullivan SE (2015) Cannabinoids in experimental stroke: a systematic review and meta-analysis. J Cereb Blood Flow Metab 35(3):348–358. doi:10.1038/jcbfm.2014.218
Fleming I, Schermer B, Popp R, Busse R (1999) Inhibition of the production of endothelium-derived hyperpolarizing factor by cannabinoid receptor agonists. Br J Pharmacol 126(4):949–960
Ford WR, Honan SA, White R, Hiley CR (2002) Evidence of a novel site mediating AEA-induced negative inotropic and coronary vasodilatator responses in rat isolated hearts. Br J Pharmacol 135(5):1191–1198
Gardiner SM, March JE, Kemp PA, Bennett T (2001) Regional haemodynamic responses to the cannabinoid agonist, WIN 55212-2, in conscious, normotensive rats, and in hypertensive, transgenic rats. Br J Pharmacol 133(3):445–453
Gardiner SM, March JE, Kemp PA, Bennett T (2002) Complex regional haemodynamic effects of AEA in conscious rats. Br J Pharmacol 135(8):1889–1896
Gardiner SM, March JE, Kemp PA, Bennett T (2009) Factors influencing the regional haemodynamic responses to methAEA and AEA in conscious rats. Br J Pharmacol 158(4):1143–1152
Garg P, Duncan RS, Kaja S, Koulen P (2010) Intracellular mechanisms of N-acylethanolamine-mediated neuroprotection in a rat model of stroke. Neuroscience 166(1):252–262
Garg P, Duncan RS, Kaja S, Zabaneh A, Chapman KD, Koulen P (2011) Lauroylethanolamide and linoleoylethanolamide improve functional outcome in a rodent model for stroke. Neurosci Lett 492(3):134–138
Gasperi V, Avigliano L, Evangelista D, Oddi S, Chiurchiu V, Lanuti M, Maccarrone M, Valeria Catani M (2014) 2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts. Cell Cycle 13(24):3938–3947
Gauthier KM, Baewer DV, Hittner S, Hillard CJ, Nithipatikom K, Reddy DS, Falck JR, Campbell WB (2005) Endothelium-derived 2-arachidonylglycerol: an intermediate in vasodilatory eicosanoid release in bovine coronary arteries. Am J Physiol Heart Circ Physiol 288(3):H1344–H1351
Gebremedhin D, Lange AR, Campbell WB, Hillard CJ, Harder DR (1999) Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am J Physiol 276(6 Pt 2):H2085–H2093
Grainger J, Boachie-Ansah G (2001) AEA-induced relaxation of sheep coronary arteries: the role of the vascular endothelium, arachidonic acid metabolites and potassium channels. Br J Pharmacol 134(5):1003–1012
Greco R, Gasperi V, Maccarrone M, Tassorelli C (2010) The endocannabinoid system and migraine. Exp Neurol 224(1):85–91
Hajrasouliha AR, Tavakoli S, Ghasemi M, Jabehdar-Maralani P, Sadeghipour H, Ebrahimi F, Dehpour AR (2008) Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart. Eur J Pharmacol 579(1–3):246–252
Han KH, Lim S, Ryu J, Lee CW, Kim Y, Kang JH, Kang SS, Ahn YK, Park CS, Kim JJ (2009) CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. Cardiovasc Res 84(3):378–386
Harris D, McCulloch AI, Kendall DA, Randall MD (2002) Characterization of vasorelaxant responses to AEA in the rat mesenteric arterial bed. J Physiol 539(Pt 3):893–902
Hauer D, Schelling G, Gola H, Campolongo P, Morath J, Roozendaal B, Hamuni G, Karabatsiakis A, Atsak P, Vogeser M, Kolassa IT (2013) Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder. PLoS One 8(5), e62741
Herradon E, Martin MI, Lopez-Miranda V (2007) Characterization of the vasorelaxant mechanisms of the endocannabinoid AEA in rat aorta. Br J Pharmacol 152(5):699–708
Hillard CJ (2008) Role of cannabinoids and endocannabinoids in cerebral ischemia. Curr Pharm Des 14(23):2347–2361
Himmi T, Perrin J, El Ouazzani T, Orsini JC (1998) Neuronal responses to cannabinoid receptor ligands in the solitary tract nucleus. Eur J Pharmacol 359(1):49–54
Hind WH, Tufarelli C, Neophytou M, Anderson SI, England TJ, O’Sullivan SE (2015) Endocannabinoids modulate human blood-brain barrier permeability in vitro. Br J Pharmacol 172(12):3015–3027. doi:10.1111/bph.13106
Ho WS, Hiley CR (2003) Endothelium-independent relaxation to cannabinoids in rat-isolated mesenteric artery and role of Ca2+ influx. Br J Pharmacol 139(3):585–597
Ho WS, Barrett DA, Randall MD (2008) ‘Entourage’ effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors. Br J Pharmacol 155(6):837–846. doi:10.1038/bjp.2008.324, Epub 2008 Aug 11
Ho WS, Hill MN, Miller GE, Gorzalka BB, Hillard CJ (2012) Serum contents of endocannabinoids are correlated with blood pressure in depressed women. Lipids Health Dis 11:32
Hoi PM, Hiley CR (2006) Vasorelaxant effects of oleamide in rat small mesenteric artery indicate action at a novel cannabinoid receptor. Br J Pharmacol 147(5):560–568
Holman EA, Guijarro A, Lim J, Piomelli D (2014) Effects of acute stress on cardiac endocannabinoids, lipogenesis, and inflammation in rats. Psychosom Med 76(1):20–28. doi:10.1097/PSY.0000000000000025
Hopps JJ, Dunn WR, Randall MD (2012) Enhanced vasorelaxant effects of the endocannabinoid-like mediator, oleamide, in hypertension. Eur J Pharmacol 684(1–3):102–107
Hoyer FF, Steinmetz M, Zimmer S, Becker A, Lutjohann D, Buchalla R, Zimmer A, Nickenig G (2011) Atheroprotection via cannabinoid receptor-2 is mediated by circulating and vascular cells in vivo. J Mol Cell Cardiol 51(6):1007–1014
Huitron-Resendiz S, Gombart L, Cravatt BF, Henriksen SJ (2001) Effect of oleamide on sleep and its relationship to blood pressure, body temperature, and locomotor activity in rats. Exp Neurol 172(1):235–243
Hydock DS, Lien CY, Hayward R (2009) AEA preserves cardiac function and geometry in an acute doxorubicin cardiotoxicity rat model. J Cardiovasc Pharmacol Ther 14(1):59–67
Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, Razdan RK, Zimmer A, Kunos G (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A 96(24):14136–14141
Jarai Z, Wagner JA, Goparaju SK, Wang L, Razdan RK, Sugiura T, Zimmer AM, Bonner TI, Zimmer A, Kunos G (2000) Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice. Hypertension 35(2):679–684
Joyeux M, Arnaud C, Godin-Ribuot D, Demenge P, Lamontagne D, Ribuot C (2002) Endocannabinoids are implicated in the infarct size-reducing effect conferred by heat stress preconditioning in isolated rat hearts. Cardiovasc Res 55(3):619–625
Kadoi Y, Hinohara H, Kunimoto F, Kuwano H, Saito S, Goto F (2005) Effects of AM281, a cannabinoid antagonist, on systemic haemodynamics, internal carotid artery blood flow and mortality in septic shock in rats. Br J Anaesth 94(5):563–568. doi:10.1093/bja/aei106
Kagota S, Yamaguchi Y, Nakamura K, Sugiura T, Waku K, Kunitomo M (2001) 2-Arachidonoylglycerol, a candidate of endothelium-derived hyperpolarizing factor. Eur J Pharmacol 415(2–3):233–238
Koura Y, Ichihara A, Tada Y, Kaneshiro Y, Okada H, Temm CJ, Hayashi M, Saruta T (2004) AEA decreases glomerular filtration rate through predominant vasodilation of efferent arterioles in rat kidneys. J Am Soc Nephrol 15(6):1488–1494
Kozlowska H, Baranowska M, Schlicker E, Kozlowski M, Laudanski J, Malinowska B (2007) Identification of the vasodilatory endothelial cannabinoid receptor in the human pulmonary artery. J Hypertens 25(11):2240–2248
Kozlowska H, Baranowska M, Schlicker E, Kozlowski M, Laudanski J, Malinowska B (2008) Virodhamine relaxes the human pulmonary artery through the endothelial cannabinoid receptor and indirectly through a COX product. Br J Pharmacol 155(7):1034–1042
Krylatov AV, Ugdyzhekova DS, Bernatskaya NA, Maslov LN, Mekhoulam R, Pertwee RG, Stephano GB (2001) Activation of type II cannabinoid receptors improves myocardial tolerance to arrhythmogenic effects of coronary occlusion and reperfusion. Bull Exp Biol Med 131(6):523–525
Lagneux C, Lamontagne D (2001) Involvement of cannabinoids in the cardioprotection induced by lipopolysaccharide. Br J Pharmacol 132(4):793–796
Lake KD, Martin BR, Kunos G, Varga K (1997) Cardiovascular effects of AEA in anesthetized and conscious normotensive and hypertensive rats. Hypertension 29(5):1204–1210
Lepicier P, Bouchard JF, Lagneux C, Lamontagne D (2003) Endocannabinoids protect the rat isolated heart against ischaemia. Br J Pharmacol 139(4):805–815
Li Q, Shi M, Li B (2013a) AEA enhances expression of heat shock protein 72 to protect against ischemia-reperfusion injury in rat heart. J Physiol Sci 63(1):47–53. doi:10.1007/s12576-012-0228-5
Li Q, Wang F, Zhang YM, Zhou JJ, Zhang Y (2013b) Activation of cannabinoid type 2 receptor by JWH133 protects heart against ischemia/reperfusion-induced apoptosis. Cell Physiol Biochem 31(4–5):693–702. doi:10.1159/000350088
Liao Y, Bin J, Luo T, Zhao H, Ledent C, Asakura M, Xu D, Takashima S, Kitakaze M (2013) CB1 cannabinoid receptor deficiency promotes cardiac remodeling induced by pressure overload in mice. Int J Cardiol 167(5):1936–1944
Lim SY, Davidson SM, Yellon DM, Smith CC (2009) The cannabinoid CB1 receptor antagonist, rimonabant, protects against acute myocardial infarction. Basic Res Cardiol 104(6):781–792
Liu J, Gao B, Mirshahi F, Sanyal AJ, Khanolkar AD, Makriyannis A, Kunos G (2000) Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 346(Pt 3):835–840
Lobato NS, Filgueira FP, Prakash R, Giachini FR, Ergul A, Carvalho MH, Webb RC, Tostes RC, Fortes ZB (2013) Reduced endothelium-dependent relaxation to AEA in mesenteric arteries from young obese Zucker rats. PLoS One 8(5), e63449
Maccarrone M, Bari M, Menichelli A, Del Principe D, Agro AF (1999) AEA activates human platelets through a pathway independent of the arachidonate cascade. FEBS Lett 447(2–3):277–282
MacCarrone M, Bari M, Menichelli A, Giuliani E, Del Principe D, Finazzi-Agro A (2001) Human platelets bind and degrade 2-arachidonoylglycerol, which activates these cells through a cannabinoid receptor. Eur J Biochem 268(3):819–825
Mair KM, Robinson E, Kane KA, Pyne S, Brett RR, Pyne NJ, Kennedy S (2010) Interaction between AEA and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery. Br J Pharmacol 161(1):176–192
Malinowska B, Lupinski S, Godlewski G, Baranowska U, Schlicker E (2008) Role of endocannabinoids in cardiovascular shock. J Physiol Pharmacol 59(Suppl 8):91–107
Malinowska B, Baranowska-Kuczko M, Schlicker E (2012) Triphasic blood pressure responses to cannabinoids: do we understand the mechanism? Br J Pharmacol 165(7):2073–2088
McCollum L, Howlett AC, Mukhopadhyay S (2007) AEA-mediated CB1/CB2 cannabinoid receptor–independent nitric oxide production in rabbit aortic endothelial cells. J Pharmacol Exp Ther 321(3):930–937
Mestre L, Inigo PM, Mecha M, Correa FG, Hernangomez-Herrero M, Loria F, Docagne F, Borrell J, Guaza C (2011) AEA inhibits Theiler’s virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB(1) receptors. J Neuroinflammation 8:102
Milman G, Maor Y, Abu-Lafi S, Horowitz M, Gallily R, Batkai S, Mo FM, Offertaler L, Pacher P, Kunos G, Mechoulam R (2006) N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties. Proc Natl Acad Sci U S A 103(7):2428–2433
Moezi L, Gaskari SA, Liu H, Baik SK, Dehpour AR, Lee SS (2006) AEA mediates hyperdynamic circulation in cirrhotic rats via CB(1) and VR(1) receptors. Br J Pharmacol 149(7):898–908
Mohnle P, Schutz SV, Schmidt M, Hinske C, Hubner M, Heyn J, Beiras-Fernandez A, Kreth S (2014) MicroRNA-665 is involved in the regulation of the expression of the cardioprotective cannabinoid receptor CB2 in patients with severe heart failure. Biochem Biophys Res Commun 451(4):516–521
Molderings GJ, Likungu J, Gothert M (1999) Presynaptic cannabinoid and imidazoline receptors in the human heart and their potential relationship. Naunyn Schmiedebergs Arch Pharmacol 360(2):157–164
Montecucco F, Matias I, Lenglet S, Petrosino S, Burger F, Pelli G, Braunersreuther V, Mach F, Steffens S, Di Marzo V (2009) Regulation and possible role of endocannabinoids and related mediators in hypercholesterolemic mice with atherosclerosis. Atherosclerosis 205(2):433–441
Mukhopadhyay S, Chapnick BM, Howlett AC (2002) AEA-induced vasorelaxation in rabbit aortic rings has two components: G protein dependent and independent. Am J Physiol Heart Circ Physiol 282(6):H2046–H2054
Mukhopadhyay P, Batkai S, Rajesh M, Czifra N, Harvey-White J, Hasko G, Zsengeller Z, Gerard NP, Liaudet L, Kunos G, Pacher P (2007) Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J Am Coll Cardiol 50(6):528–536
Mukhopadhyay P, Rajesh M, Batkai S, Patel V, Kashiwaya Y, Liaudet L, Evgenov OV, Mackie K, Hasko G, Pacher P (2010) CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovasc Res 85(4):773–784
Naccarato M, Pizzuti D, Petrosino S, Simonetto M, Ferigo L, Grandi FC, Pizzolato G, Di Marzo V (2010) Possible AEA and palmitoylethanolamide involvement in human stroke. Lipids Health Dis 9:47
Nagasawa K, Chiba H, Fujita H, Kojima T, Saito T, Endo T, Sawada N (2006) Possible involvement of gap junctions in the barrier function of tight junctions of brain and lung endothelial cells. J Cell Physiol 208(1):123–132
Netherland CD, Pickle TG, Bales A, Thewke DP (2010) Cannabinoid receptor type 2 (CB2) deficiency alters atherosclerotic lesion formation in hyperlipidemic Ldlr-null mice. Atherosclerosis 213(1):102–108
Neukirchen M, Kienbaum P (2008) Sympathetic nervous system: evaluation and importance for clinical general anesthesia. Anesthesiology 109(6):1113–1131
Nissen SE, Nicholls SJ, Wolski K, Rodes-Cabau J, Cannon CP, Deanfield JE, Despres JP, Kastelein JJ, Steinhubl SR, Kapadia S, Yasin M, Ruzyllo W, Gaudin C, Job B, Hu B, Bhatt DL, Lincoff AM, Tuzcu EM (2008) Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 299(13):1547–1560
O’Leary DH, Reuwer AQ, Nissen SE, Despres JP, Deanfield JE, Brown MW, Zhou R, Zabbatino SM, Job B, Kastelein JJ, Visseren FL (2011) Effect of rimonabant on carotid intima-media thickness (CIMT) progression in patients with abdominal obesity and metabolic syndrome: the AUDITOR Trial. Heart 97(14):1143–1150
O’Sullivan SE, Kendall DA, Randall MD (2004a) Characterisation of the vasorelaxant properties of the novel endocannabinoid N-arachidonoyl-dopamine (NADA). Br J Pharmacol 141(5):803–812
O’Sullivan SE, Kendall DA, Randall MD (2004b) Heterogeneity in the mechanisms of vasorelaxation to AEA in resistance and conduit rat mesenteric arteries. Br J Pharmacol 142(3):435–442
O’Sullivan SE, Kendall DA, Randall MD (2005) Vascular effects of delta 9-tetrahydrocannabinol (THC), AEA and N-arachidonoyldopamine (NADA) in the rat isolated aorta. Eur J Pharmacol 507(1–3):211–221
O’Sullivan SE, Kendall DA, Randall MD (2009) Time-dependent vascular effects of Endocannabinoids mediated by peroxisome proliferator-activated receptor gamma (PPARgamma). PPAR Res 2009:425289
Pacher P, Batkai S, Kunos G (2004) Haemodynamic profile and responsiveness to AEA of TRPV1 receptor knock-out mice. J Physiol 558(Pt 2):647–657
Pacher P, Batkai S, Osei-Hyiaman D, Offertaler L, Liu J, Harvey-White J, Brassai A, Jarai Z, Cravatt BF, Kunos G (2005) Hemodynamic profile, responsiveness to AEA, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase. Am J Physiol Heart Circ Physiol 289(2):H533–H541
Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413:527–531
Parmar N, Ho WS (2010) N-arachidonoyl glycine, an endogenous lipid that acts as a vasorelaxant via nitric oxide and large conductance calcium-activated potassium channels. Br J Pharmacol 160(3):594–603
Parmentier-Batteur S, Jin K, Mao XO, Xie L, Greenberg DA (2002) Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J Neurosci 22(22):9771–9775
Patinkin D, Milman G, Breuer A, Fride E, Mechoulam R (2008) Endocannabinoids as positive or negative factors in hematopoietic cell migration and differentiation. Eur J Pharmacol 595(1–3):1–6. doi:10.1016/j.ejphar.2008.05.002
Pelorosso FG, Gago JE, Del Rey G, Menendez SD, Errasti AE, Rothlin RP (2009) The endocannabinoid AEA inhibits kinin B1 receptor sensitization through cannabinoid CB1 receptor stimulation in human umbilical vein. Eur J Pharmacol 602(1):176–179
Peroni RN, Orliac ML, Becu-Villalobos D, Huidobro-Toro JP, Adler-Graschinsky E, Celuch SM (2004) Sex-linked differences in the vasorelaxant effects of AEA in vascular mesenteric beds: role of oestrogens. Eur J Pharmacol 493(1–3):151–160
Plane F, Holland M, Waldron GJ, Garland CJ, Boyle JP (1997) Evidence that AEA and EDHF act via different mechanisms in rat isolated mesenteric arteries. Br J Pharmacol 121(8):1509–1511
Poblete IM, Orliac ML, Briones R, Adler-Graschinsky E, Huidobro-Toro JP (2005) AEA elicits an acute release of nitric oxide through endothelial TRPV1 receptor activation in the rat arterial mesenteric bed. J Physiol 568(Pt 2):539–551
Pratt PF, Hillard CJ, Edgemond WS, Campbell WB (1998) N-arachidonylethanolamide relaxation of bovine coronary artery is not mediated by CB1 cannabinoid receptor. Am J Physiol 274(1 Pt 2):H375–H381
Quercioli A, Pataky Z, Vincenti G, Makoundou V, Di Marzo V, Montecucco F, Carballo S, Thomas A, Staub C, Steffens S, Seimbille Y, Golay A, Ratib O, Harsch E, Mach F, Schindler TH (2011) Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur Heart J 32(11):1369–1378
Rademacher DJ, Patel S, Hopp FA, Dean C, Hillard CJ, Seagard JL (2003) Microinjection of a cannabinoid receptor antagonist into the NTS increases baroreflex duration in dogs. Am J Physiol Heart Circ Physiol 284(5):H1570–H1576
Rademacher DJ, Patel S, Ho WS, Savoie AM, Rusch NJ, Gauthier KM, Hillard CJ (2005) U-46619 but not serotonin increases endocannabinoid content in middle cerebral artery: evidence for functional relevance. Am J Physiol Heart Circ Physiol 288(6):H2694–H2701
Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Pacher P (2007) CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol 293(4):H2210–H2218
Rajesh M, Mukhopadhyay P, Hasko G, Huffman JW, Mackie K, Pacher P (2008) CB2 cannabinoid receptor agonists attenuate TNF-alpha-induced human vascular smooth muscle cell proliferation and migration. Br J Pharmacol 153(2):347–357
Rajesh M, Mukhopadhyay P, Hasko G, Liaudet L, Mackie K, Pacher P (2010) Cannabinoid-1 receptor activation induces reactive oxygen species-dependent and -independent mitogen-activated protein kinase activation and cell death in human coronary artery endothelial cells. Br J Pharmacol 160(3):688–700
Ralevic V, Kendall DA, Randall MD, Smart D (2002) Cannabinoid modulation of sensory neurotransmission via cannabinoid and vanilloid receptors: roles in regulation of cardiovascular function. Life Sci 71(22):2577–2594
Romano MR, Lograno MD (2006) Cannabinoid agonists induce relaxation in the bovine ophthalmic artery: evidences for CB1 receptors, nitric oxide and potassium channels. Br J Pharmacol 147(8):917–925
Romano MR, Lograno MD (2012) Involvement of the peroxisome proliferator-activated receptor (PPAR) alpha in vascular response of endocannabinoids in the bovine ophthalmic artery. Eur J Pharmacol 683(1–3):197–203
Ruilope LM, Despres JP, Scheen A, Pi-Sunyer X, Mancia G, Zanchetti A, Van Gaal L (2008) Effect of rimonabant on blood pressure in overweight/obese patients with/without co-morbidities: analysis of pooled RIO study results. J Hypertens 26(2):357–367
Sarzani R, Bordicchia M, Salvi F, Cola G, Franchi E, Battistoni I, Mancinelli L, Giovagnoli A, Dessi-Fulgheri P, Rappelli A (2008) A human fatty acid amide hydrolase (FAAH) functional gene variant is associated with lower blood pressure in young males. Am J Hypertens 21(8):960–963
Schabitz WR, Giuffrida A, Berger C, Aschoff A, Schwaninger M, Schwab S, Piomelli D (2002) Release of fatty acid amides in a patient with hemispheric stroke: a microdialysis study. Stroke 33(8):2112–2114
Schomacher M, Muller HD, Sommer C, Schwab S, Schabitz WR (2008) Endocannabinoids mediate neuroprotection after transient focal cerebral ischemia. Brain Res 1240:213–220
Seagard JL, Dean C, Patel S, Rademacher DJ, Hopp FA, Schmeling WT, Hillard CJ (2004) AEA content and interaction of endocannabinoid/GABA modulatory effects in the NTS on baroreflex-evoked sympathoinhibition. Am J Physiol Heart Circ Physiol 286(3):H992–H1000
Silvani A, Berteotti C, Bastianini S, Cohen G, Lo Martire V, Mazza R, Pagotto U, Quarta C, Zoccoli G (2014) Cardiorespiratory anomalies in mice lacking CB1 cannabinoid receptors. PLoS One 9(6), e100536
Slavic S, Lauer D, Sommerfeld M, Kemnitz UR, Grzesiak A, Trappiel M, Thone-Reineke C, Baulmann J, Paulis L, Kappert K, Kintscher U, Unger T, Kaschina E (2013) Cannabinoid receptor 1 inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome. J Mol Med (Berl) 91(7):811–823
Stanke-Labesque F, Mallaret M, Lefebvre B, Hardy G, Caron F, Bessard G (2004) 2-Arachidonoyl glycerol induces contraction of isolated rat aorta: role of cyclooxygenase-derived products. Cardiovasc Res 63(1):155–160
Stanley CP, O’Sullivan SE (2012) The vasorelaxant effects of anandamide in the human mesenteric artery. In: Proceedings of the British Pharmacological Society
Stanley C, O’Sullivan SE (2014a) Vascular targets for cannabinoids: animal and human studies. Br J Pharmacol 171(6):1361–1378
Stanley CP, O’Sullivan SE (2014b) Cyclooxygenase metabolism mediates vasorelaxation to 2-arachidonoylglycerol (2-AG) in human mesenteric arteries. Pharmacol Res 81:74–82
Stefano GB, Salzet M, Bilfinger TV (1998) Long-term exposure of human blood vessels to HIV gp120, morphine, and AEA increases endothelial adhesion of monocytes: uncoupling of nitric oxide release. J Cardiovasc Pharmacol 31(6):862–868
Steffens S, Pacher P (2015) The activated endocannabinoid system in atherosclerosis: driving force or protective mechanism? Curr drug Targets 16:334–41
Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard JL, Mach F (2005) Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434(7034):782–786
Stein EA, Fuller SA, Edgemond WS, Campbell WB (1996) Physiological and behavioural effects of the endogenous cannabinoid, arachidonylethanolamide (AEA), in the rat. Br J Pharmacol 119(1):107–114
Sugamura K, Sugiyama S, Nozaki T, Matsuzawa Y, Izumiya Y, Miyata K, Nakayama M, Kaikita K, Obata T, Takeya M, Ogawa H (2009) Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages. Circulation 119(1):28–36
Sugiura T, Kodaka T, Nakane S, Kishimoto S, Kondo S, Waku K (1998) Detection of an endogenous cannabimimetic molecule, 2-arachidonoylglycerol, and cannabinoid CB1 receptor mRNA in human vascular cells: is 2-arachidonoylglycerol a possible vasomodulator? Biochem Biophys Res Commun 243(3):838–843
Sun Y, Alexander SP, Garle MJ, Gibson CL, Hewitt K, Murphy SP, Kendall DA, Bennett AJ (2007) Cannabinoid activation of PPAR alpha; a novel neuroprotective mechanism. Br J Pharmacol 152(5):734–743
Tuma RF, Steffens S (2012) Targeting the endocannabinod system to limit myocardial and cerebral ischemic and reperfusion injury. Curr Pharm Biotechnol 13(1):46–58
Ugdyzhekova DS, Bernatskaya NA, Stefano JB, Graier VF, Tam SW, Mekhoulam R (2001) Endogenous cannabinoid AEA increases heart resistance to arrhythmogenic effects of epinephrine: role of CB(1) and CB(2) receptors. Bull Exp Biol Med 131(3):251–253
Underdown NJ, Hiley CR, Ford WR (2005) AEA reduces infarct size in rat isolated hearts subjected to ischaemia-reperfusion by a novel cannabinoid mechanism. Br J Pharmacol 146(6):809–816
Valk P, Verbakel S, Vankan Y, Hol S, Mancham S, Ploemacher R, Mayen A, Lowenberg B, Delwel R (1997) AEA, a natural ligand for the peripheral cannabinoid receptor is a novel synergistic growth factor for hematopoietic cells. Blood 90(4):1448–1457
Varga K, Lake K, Martin BR, Kunos G (1995) Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of AEA. Eur J Pharmacol 278(3):279–283
Varga K, Wagner JA, Bridgen DT, Kunos G (1998) Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J 12(11):1035–1044
Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR, Kunos G (1997) Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature 390(6659):518–521
Wagner JA, Varga K, Jarai Z, Kunos G (1999) Mesenteric vasodilation mediated by endothelial AEA receptors. Hypertension 33(1 Pt 2):429–434
Wagner JA, Hu K, Bauersachs J, Karcher J, Wiesler M, Goparaju SK, Kunos G, Ertl G (2001) Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J Am Coll Cardiol 38(7):2048–2054
Wagner JA, Abesser M, Harvey-White J, Ertl G (2006) 2-Arachidonylglycerol acting on CB1 cannabinoid receptors mediates delayed cardioprotection induced by nitric oxide in rat isolated hearts. J Cardiovasc Pharmacol 47(5):650–655
Wahn H, Wolf J, Kram F, Frantz S, Wagner JA (2005) The endocannabinoid arachidonyl ethanolamide (AEA) increases pulmonary arterial pressure via cyclooxygenase-2 products in isolated rabbit lungs. Am J Physiol Heart Circ Physiol 289(6):H2491–H2496
Wang Y, Wang DH (2007) Increased depressor response to N-arachidonoyl-dopamine during high salt intake: role of the TRPV1 receptor. J Hypertens 25(12):2426–2433
Wang Q, Peng Y, Chen S, Gou X, Hu B, Du J, Lu Y, Xiong L (2009) Pretreatment with electroacupuncture induces rapid tolerance to focal cerebral ischemia through regulation of endocannabinoid system. Stroke 40(6):2157–2164
Wang R, Hu W, Qiang L (2012) G1359A polymorphism in the cannabinoid receptor-1 gene is associated with the presence of coronary artery disease in patients with type 2 diabetes. J Investig Med 60(1):44–48
Weis F, Beiras-Fernandez A, Sodian R, Kaczmarek I, Reichart B, Beiras A, Schelling G, Kreth S (2010) Substantially altered expression pattern of cannabinoid receptor 2 and activated endocannabinoid system in patients with severe heart failure. J Mol Cell Cardiol 48(6):1187–1193
Wheal AJ, Randall MD (2009) Effects of hypertension on vasorelaxation to endocannabinoids in vitro. Eur J Pharmacol 603(1–3):79–85. doi:10.1016/j.ejphar.2008.11.061
Wheal AJ, Bennett T, Randall MD, Gardiner SM (2007) Cardiovascular effects of cannabinoids in conscious spontaneously hypertensive rats. Br J Pharmacol 152(5):717–724
Wheal AJ, Alexander SP, Randall MD (2010) Vasorelaxation to N-oleoylethanolamine in rat isolated arteries: mechanisms of action and modulation via cyclooxygenase activity. Br J Pharmacol 160(3):701–711
White R, Hiley CR (1998) The actions of some cannabinoid receptor ligands in the rat isolated mesenteric artery. Br J Pharmacol 125(3):533–541
Wheal A, O’Sullivan SE, Randall M (2012) Acute vascular effects of endocannabinoids in thoracic aortae from zucker diabetic rats. In: Proceedings of the International Cannabinoid Research Society
White R, Ho WS, Bottrill FE, Ford WR, Hiley CR (2001) Mechanisms of AEA-induced vasorelaxation in rat isolated coronary arteries. Br J Pharmacol 134(4):921–929
Zhang M, Martin BR, Adler MW, Razdan RK, Ganea D, Tuma RF (2008) Modulation of the balance between cannabinoid CB(1) and CB(2) receptor activation during cerebral ischemic/reperfusion injury. Neuroscience 152(3):753–760
Zhang J, Wang SY, Zhou JJ, Wei Y, Li Q, Yang J, Zhang Y (2013) Inhibitory effects of endocannabinoid on the action potential of pacemaker cells in sinoatrial nodes of rabbits. Sheng Li Xue Bao 65(2):129–134
Zhao Y, Yuan Z, Liu Y, Xue J, Tian Y, Liu W, Zhang W, Shen Y, Xu W, Liang X, Chen T (2010) Activation of cannabinoid CB2 receptor ameliorates atherosclerosis associated with suppression of adhesion molecules. J Cardiovasc Pharmacol 55(3):292–298
Zhou Y, Yang L, Ma A, Zhang X, Li W, Yang W, Chen C, Jin X (2012) Orally administered oleoylethanolamide protects mice from focal cerebral ischemic injury by activating peroxisome proliferator-activated receptor alpha. Neuropharmacology 63(2):242–249
Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of AEA. Nature 400(6743):452–457
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
O’Sullivan, S.E. (2015). Endocannabinoids and the Cardiovascular System in Health and Disease. In: Pertwee, R. (eds) Endocannabinoids. Handbook of Experimental Pharmacology, vol 231. Springer, Cham. https://doi.org/10.1007/978-3-319-20825-1_14
Download citation
DOI: https://doi.org/10.1007/978-3-319-20825-1_14
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-20824-4
Online ISBN: 978-3-319-20825-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)