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.
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