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Using cannabinoids as therapeutic agents in the cardiovascular system and how it may be overcome

Marijuana usage is traditionally associated with a laid back, low blood pressure lifestyle so the potential for cannabinoid to be used as antihypertensives has been increasingly explored since the original suggestions more than 30 years ago (Pacher, Batkai & Kunos 2005).  However research into the cardiovascular effects of cannabinoids has only taken off properly since the discovery of endogenous ligands and the identification of specific receptors.  Unfortunately there are currently many disadvantages to the use of cannabinoids as therapeutic agents in the cardiovascular system, as will be discussed in the context of the pharmacology and cardiovascular effects of cannabinoids below.

Pharmacology of cannabinoids and the cannabinoid receptor

The 7 transmembrane G-protein linked cannabinoid receptor (Gebremedhin et al. 1999)was first characterised in 1988, and subsequent research has elucidated at least 2 subtypes of receptor - the (predominantly) central CB1 and peripheral CB2 subtypes (Di Marzo et al. 1998).  CB1 are localised mainly in brain tissues, but have also been found in vascular smooth muscle cells (Gebremedhin et al. 1999) and CB2 are found in immune cells (Mendizabal, Adler-Graschinsky 2003). 

The central actions of cannabinoids are mediated by action on CB1 receptors; indicated by correlations between CB1 affinity and potency of central actions, as well as effective inhibition by the CB1 antagonist SR 141716A of central actions (Mendizabal, Adler-Graschinsky 2003).  Cannabinoids are lipophilic so easily cross the blood brain barrier in order to exert effects on the central nervous system (Mendizabal, Adler-Graschinsky 2003).
Endogenous cannabinoids such as anandamide are believed to be formed only as necessary and near their site of action, as physiological levels are low and preclude a hormonal role (Mendizabal, Adler-Graschinsky 2003). 

The biologically active component of marijuana (9-tetrahydrocannabinol - 9-THC) (for structure see figure 1), attains it effects via partial agonism of the CB1 cannabinoid receptor in the human body (Hillard 2000). 
Figure 1. The structure of 9-tetrahydrocannabinol (Hiley, Ford 2004)
 
Whilst there is till debate about the exact function of cannabinoid receptors research into the endogenous CB1 partial agonist anandamide (see figure 2 for structure) has found that it mediates a downregulation of the autonomic nervous system, leading to hypotension and smooth muscle relaxation (Di Marzo et al. 1998). 
Figure 2. The structure of the endogenous cannabinoid anandamide (N-arachidonylethanolamine) (Di Marzo et al. 1998)
 
It had been noted that both endogenous and administered cannabinoids have actions that cannot be explained by activity on cannabinoid receptors alone (Mendizabal, Adler-Graschinsky 2003).  Indeed it has now been found that the endogenous cannabinoid anandamide is also active at the V1 capsaicin receptor (Di Marzo, Bisogno & De Petrocellis 2001, Hogestatt, Zygmunt 2002) which, whilst primarily involved in nociception, is also believed to have a role in the modulation of cardiovascular function (Ralevic et al. 2002). 

It is likely that the vasoactive neurotransmitter calcitonin gene-related peptide is primarily responsible for the V1 mediated vasorelaxation (Hogestatt, Zygmunt 2002) and indeed it has been suggested that the vasoactive effects of anandamide could not exist without its activity on V1 receptors. 
Intracellular 2nd messengers involved in the VR¬1¬ mediated activity include nitric oxide and substance P (Ralevic et al. 2002).  Figure 3 below summarises these proposed sites of action of anandamide.
Figure 3. The possible sites of vasodilator actions of anandamide (adapted from Kunos et al. 2000)
 

Endogenous cannabinoids undergo very rapid metabolism.  Anandamide is an eicosanoids (Gebremedhin et al. 1999) and is metabolised via carrier uptake into cells and hydrolysis to arachidonic acid and ethanolamide (Mendizabal, Adler-Graschinsky 2003).  Indeed it was initially suggested that some of the endogenous effects of cannabinoids were mediated via the activity of prostanoids derived from arachadonic acid (Di Marzo et al. 1998) but later evidence using anandamide analogues such as R-methanandamide indicated that this was not actually the case (Kunos et al. 2000).  However it is known that the duration of action of endocanabinnoids is short lived due to their rapid degradation.

The argument for clinical use of cannabinoids

It has been suggested that endocannabinoids have a role in the normal regulation of (lowering) blood pressure, thus this does indicate a potential role for therapeutic application.  In addition essential hypertension in humans could be treated using a CB1 agonist to bring about a reduction in noradrenaline thus a reduction in the (excessive) sympathetic outflow (Hillard 2000).

There is also a potential use in cerebrovascular disease, and specifically the immediate treatment of stroke victims.  However a recently completed clinical trial into the use of the non-psychotropic synthetic cannabinoid dexanabinol in the treatment of ischaemic brain injury found that there was no improvement to intracranical pressure or cerebral perfusion pressure.  So, whilst mortality rates were better than in controls, the vascular effects of dexanabinol were not proven in this instance (Maas et al. 2006).
Endocannabinoids have also been implicated in the haemodynamic changes accompanying shock.  Specifically cardiogenic shock has been found to be associated with raised levels of anandamide, implying a role for cannabinoid antagonists in the treatment of myocardial infarction (Mendizabal, Adler-Graschinsky 2003). 
Disadvantages to overcome in using cannabinoids as therapeutic agents in cardiovascular disease
Significant listed side effects with cannabinoids include sedation, cognitive dysfunction, tachycardia, postural hypotension, dry mouth, ataxia, immunosuppressant effects as well as psychotropic effects (Mendizabal, Adler-Graschinsky 2003).
Effects on isolated blood vessels appears to differ significantly from effects on blood vessels in anaesthetised and conscious animals (Randall, Kendall & O'Sullivan 2004). 
The response to anandamide is known to increase in conditions of noxious heat and acidosis (Ralevic et al. 2002) which may cause significant drug interactions.
It should also be noted that chronic cannabinoid use is associated with toxicity including impaired immune response and amotivational syndrome (Mendizabal, Adler-Graschinsky 2003) so their use in long term conditions is unlikely at present. 

Cardiovascular effects of cannabinoids

9-THC is known to cause peripheral dilation and tachycardia leading to increased cardiac output and peripheral blood flow (Hillard 2000).  Experimental CB1 ligands have been shown to mediate vasorelaxation in vascular smooth muscle cells via activity on L-type calcium channels, leading to a reduced calcium influx (Gebremedhin et al. 1999).  

Anandamide has a triphasic activity in vivo, with an initial bradycardic effect rapidly followed by a secondary pressor effect (possibly due to a reflexive action), both believed to be caused by vagal nerve activity (Ralevic et al. 2002, Randall, Kendall & O'Sullivan 2004).  In the majority of studies these effects have been followed by a long lasting hypotension, believed to result from reduced presynaptic sympathetic activity (Randall, Kendall & O'Sullivan 2004).  This hypotensive effect is obviously the ideal and desired therapeutic effect.

However, the vasorelaxant effects of anandamide differ greatly depending on the regional location of the blood vessel.  Relaxation varies from as little as 20% in the aorta to 100% in mesenteric arteries, with a suggested reason being the density of the CB1 and V1 receptors (Randall, Kendall & O'Sullivan 2004).  Likewise it has been shown that anandamide is selective to the part of the vessel wall it affects in order to cause vadodilation (Taddei 2005).  Finally the effects on humans differ greatly to those in animals (Hiley, Ford 2004), possibly causing some of the confusion about therapeutic benefits. 
Systemic administration of cannabinoids causes hypotension via a reduction in sympathetic activity (Randall et al. 2002).  In fact the presence of a background sympathetic tone is viewed to be crucial to the effects of cannabinoids such as anandamide (Randall, Kendall & O'Sullivan 2004).   This may explain the differing and apparently conflicting results observed in isolated and in vivo studies of the cardiovascular effects of cannabinoids.  In has also been noted that there is a minimum dose required for the pressor effect to arise (Mendizabal, Adler-Graschinsky 2003). 

The fact that the biologically active 9-THC achieves its activity via partial agonism of the CB1 receptor may also be relevant to the differing actions of cannabinoids in the vasculature.  It is entirely possible that the degree of agonism varies between receptors in different locales, thus the resulting activity could also vary.  Given that other receptor families such as the adrenergic and glutamatergic have both expanded numerically since the discovery of their first isolated receptor; and have had further physiological effects elucidated; it is also possible that a similar thing will happen to the cannabinoid in time. 

The ideal cannabinoid drug

As with all drugs the development of highly specific ligands for a specific receptor subtype will prevent the incidence of side effects that are caused by interaction of the drug at other receptors.  In the case of cannabinoids the desired therapeutic effects would relate to peripheral CB1 receptors so a ligand that is able to bind to peripheral CB1 receptors, ideally in vascular smooth muscle, would be desired.  In addition, it would help if the ligand was lipophilic as then it would not be able to cross the blood brain barrier in order to affect CB1 receptors located within the CNS.

It is also important to be clear exactly what is required of a cardiovascular drug.  For instance is there only a requirement to lower blood pressure (possibly at any cost) or is it more important to be more prophylactic in preventing the damage to endothelial cells and resistance vessels that leads to atherosclerosis and hypertension? (Mendizabal, Adler-Graschinsky 2003).  Indeed some researchers have discounted any protective role for cannabinoids due to (as yet) uncharacterised actions on damaging effects including oxidative stress and endothelial dysfunction. However it should be noted that this conclusion is based on the evidence to date and it is fair to say that research into cannabinoids and their receptors has only just begun to scratch the surface in the decade or so of research thus far.  Indeed a recent study indicates that the synthetic cannabinoid dexanabinol does target pathophysiological mechanisms such as oxidative stress, and is also neuroprotective (Maas et al. 2006).
Further it was found that endocannabinoids exerted a regulatory effect on the cardiovascular system, and were involved in cardioprotection via activity on CB2 receptors and associated inflammatory responses, possibly related to nitric oxide (Lagneux, Lamontagne 2001).  However, it is unclear how significant this is in terms of the overall cardiovascular response to cannabinoids. 

Conclusion

Due to the activity of cannabinoids such as anandamide on non-cannabinoid receptors, including the capsaicin V1 receptor, and other neuronal targets, their use as therapeutic agents would be complicated.  The activity of cannabinoids remains poorly understood and, whilst there is now more understanding about the effects that arise from cannabinoids administration, the receptors mediating these effects are not certain. 
If the dose dependent cardiovascular activity in humans could be pinpointed more accurately then their potential could be exploited more fruitfully.

References