Neuropharmacology 48 (2005) 1130e1138
Blood pressure regulation by endocannabinoids and
Pa´l Pacher), Sa´ndor Ba´tkai, George Kunos)
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse & Alcoholism, National Institutes of Health,
Bethesda, MD 20892-8115, USA
Received 7 September 2004; accepted 10 December 2004
Cannabinoids and their endogenous and synthetic analogs exert powerful hypotensive and cardiodepressor e?ects by complex
mechanisms involving direct and indirect e?ects on myocardium and vasculature. On the one hand, endocannabinoids and
cannabinoid receptors have been implicated in the hypotensive state associated with hemorrhagic, endotoxic and cardiogenic shock,
and advanced liver cirrhosis. On the other hand, there is emerging evidence suggesting that the endocannabinergic system plays an
important role in the cardiovascular regulation in hypertension. This review is aimed to discuss the in vivo hypotensive and
cardiodepressant e?ects of cannabinoids mediated by cannabinoid and TRPV1 receptors, and focuses on the novel therapeutical
strategies o?ered by targeting the endocannabinoid system in the treatment of hypertension.
Published by Elsevier Ltd.
Keywords: Hypertension; Cannabinoids; Hemodynamics; Cardiac contractility
Mechoulam et al., 1998; Kunos et al., 2000). Apart from
their well-known neurobehavioral and immunological
The biological e?ects of marijuana and its main
actions, cannabinoids also elicit potent cardiovascular
e?ects, such as profound hypotension (Lake et al.,
(THC), are mediated by speci?c G protein-coupled
1997a; Hillard, 2000; Kunos et al., 2002; Randall et al.,
cannabinoid (CB) receptors. To date, two such receptors
2002; Ralevic et al., 2002). Although several lines of
have been identi?ed: the CB1 receptor, which is highly
evidence indicate that the cardiovascular depressive
expressed in the brain (Matsuda et al., 1990), but is also
e?ects of cannabinoids are mediated by peripherally
present in heart and vascular tissues (Gebremedhin
localized CB1 receptors, recent studies also suggest the
et al., 1999; Liu et al., 2000; Bonz et al., 2003), and the
existence of as yet unde?ned endothelial and cardiac
CB2 receptor, expressed primarily by haematopoietic
and immune cells (Munro et al., 1993). Arachidonoyl
induced cardiovascular e?ects (Begg et al., 2003; Ja´rai
ethanolamide or anandamide and 2-arachidonoylglycer-
et al., 1999; Ford et al., 2002; Ho and Hiley, 2003; Kunos
ol, the natural ligands of these receptors, are lipid-
et al., 2002; O?erta´ler et al., 2003; O’Sullivan et al.,
like substances called endocannabinoids (reviewed by
2004), however, the discussion of the latter is beyond the
main scope of this summary. It has been established that
the endocannabinergic system plays a pivotal role in
* Corresponding authors. Tel./fax: C1-301-443-2069.
cardiovascular regulation under various pathophysio-
E-mail addresses: firstname.lastname@example.org (P. Pacher), gkunos@
mail.nih.gov (G. Kunos).
logical conditions associated with hypotension including
0028-3908/$ - see front matter Published by Elsevier Ltd.
P. Pacher et al. / Neuropharmacology 48 (2005) 1130e1138
hemorrhagic (Wagner et al., 1997), endotoxic (Varga
tion in isolated blood vessels in vitro (Zygmunt et al.,
et al., 1998) and cardiogenic shock (Wagner et al., 2001a,
1999), which raised the possibility that anandamide
2003), and advanced liver cirrhosis (Ba´tkai et al., 2001;
activation of TRPV1 receptors could contribute to its
Ros et al., 2002). Additional evidence also implicates this
in vivo hypotensive e?ect. In a recent study (Pacher
system in the regulation of blood pressure (Lake et al.,
et al., 2004) we have tested this possibility by analyzing
1997b; Li et al., 2003; Ba´tkai et al., 2004a). The present
the detailed hemodynamic e?ects of anandamide in
review focuses on the in vivo hypotensive and cardiode-
mice. Similar to previous
pressant e?ects of cannabinoids and on the novel
?ndings in the rat (Varga et al., 1995), bolus injections of
therapeutical strategies o?ered by targeting the endo-
anandamide (20 mg/kg i.v.) caused a triphasic e?ect in
cannabinergic system in the treatment of hypertension.
mice (Fig. 1A). The transient ?rst phase
lasted for a few seconds and was characterized by
profound decreases in cardiac contractility and heart
2. Cardiovascular e?ects of cannabinoids in vivo,
rate and an increase in total peripheral resistance (TPR),
role of CB1 and TRPV1 receptors
followed by a brief pressor response (phase II)
associated with increased cardiac contractility. The
The in vivo cardiovascular e?ects of cannabinoids
third, prolonged hypotensive phase (phase III) was
are complex and may comprise direct e?ects on the
characterized by decreased cardiac contractility and
myocardium (Bonz et al., 2003) and vasculature
TPR and it lasted up to 10 min (Fig. 1A). Pretreatment
(Gebremedhin et al., 1999; Ja´rai et al., 1999; Wagner
of the mice with a CB1 receptor antagonist, SR141716
et al., 2001b), as well as modulation of autonomic
(3 mg/kg i.v.), had no e?ect on the ?rst and second
out?ow in the central (Niederho?er and Szabo, 2000)
phases of the response to anandamide, but completely
and the peripheral nervous systems (Ishac et al., 1996;
prevented the subsequent hypotension and the associat-
Malinowska et al., 1997). CB1 receptors are present in the
ed decreases in TPR and cardiac contractility (Fig. 2A).
myocardium where they mediate negative inotropy
mice, the anandamide-induced initial
(Bonz et al., 2003; Pacher et al., 2004) and also in the
component (phase I), present in TRPVC/C
vasculature (Gebremedhin et al., 1999; Liu et al., 2000),
was absent, and the phase II pressor response was also
where they lead to vasodilation (Gebremedhin et al.,
markedly reduced (Fig. 1B). In contrast, the subsequent
1999), and both of these sites are implicated in the
prolonged hypotensive response accompanied by de-
hypotensive e?ect of anandamide (Wagner et al., 2001b;
creased cardiac contractility and TPR was similar to
Pacher et al., 2004). The cardiovascular depressor e?ects
the responses observed in TRPVC/C
mice, and was
of anandamide are devoid of a centrally mediated
component (Varga et al., 1996), although some synthetic
with SR141716 (Fig. 1B and 2B). In TRPVC/C
cannabinoids can cause centrally mediated sympathoex-
mice, capsaicin (10 and 100 mg/kg i.v.)
citatory e?ects (Niederho?er and Szabo, 2000). Pre-
evoked a brief blood pressure response similar to phase I
synaptic CB1 are also present in sympathetic nerve
and phase II responses to anandamide (Pacher et al.,
terminals where their stimulation inhibits norepinephrine
release (Ishac et al., 1996) contributing to the bradycar-
The above results clearly indicate that the prolonged
dic e?ects of anandamide (Wagner et al., 2001b).
hypotensive e?ect of anandamide involves a profound
Intravenous administration of anandamide in anes-
decrease in cardiac contractility in addition to a decrease
thetized rats initiates a triphasic blood pressure response
in TPR, and these e?ects are mediated exclusively by
with a major prolonged hypotensive e?ect (phase III)
1 and not TRPV1
receptors. The role of TRPV1
preceded by a transient, vagally mediated fall in heart
receptors is limited to the transient activation of the
rate and blood pressure (phase I) followed by a brief,
cardiogenic sympathetic re?ex (BezoldeJarisch re?ex)
non-sympathetically mediated pressor response of un-
by the very high initial plasma concentration of
known mechanism (phase II) (Varga et al., 1995).
anandamide achieved after rapid bolus injections
Capsazepine and ruthenium red, antagonists of the
(Pacher et al., 2004).
TRPV1 receptor, dose-dependently inhibit the phase I
bradycardic response in anesthetized rats, without
a?ecting the phase III hypotension, which was abolished
3. Role of the endocannabinergic system in the
by the cannabinoid CB1 receptor antagonist SR141716
hypotension associated with hemorrhagic,
(Malinowska et al., 2001) and was also absent in CB1
endotoxic, cardiogenic shock and
receptor knockout mice (Ledent et al., 1999; Ja´rai et al.,
advanced liver cirrhosis
Anandamide also activates TRPV1 receptors on
The extreme, long-lasting, yet reversible, hypotension
sensory nerve terminals, triggering the release of
elicited by potent synthetic cannabinoids (Lake et al.,
calcitonin gene-related peptide that elicits vasorelaxa-
1997a) raised the question of whether endocannabinoids
P. Pacher et al. / Neuropharmacology 48 (2005) 1130e1138AAEA+/+lITRPV1) 10010 ming
d -10e3)100re (mmHgressuLV p0020400204002040020402040LV volume (µl)BAEATRPV -/-1) 100lIg10 minH
d -10e3Hg)100ure (mmressLV p020400204002040020402040LV volume (µl)
Fig. 1. Representative recordings of the e?ect of anandamide (20 mg/kg, i.v., AEA) on mean arterial pressure (MAP, top panel) and cardiac
contractility (LVSP and dP/dt; middle panel) and pressure
evolume relations (bottom panel) in anesthetized TRPV1
(A) and TRPV1
The ?ve parts of the middle and bottom panels represent baseline conditions (Bl), phase I, phase II, and phase III of the anandamide response and
conditions 10 min after injection (10 min). The arrows indicate the injection of the drug. Figure is reproduced with permission from Pacher et al.
ASR141716 pretreatedAEAlITRPV +/+1) 100glII10 minH
d -10e3)100re (mmHgressuLV p00204002040020400204002040LV volume (µl)BSR141716 pretreatedAEATRPV -/-1)lI100g10 minH
mBl llII (m
d -10e3Hg)ure (mmressLV p0204002040020400204002040LV volume (µl)
Fig. 2. Representative recordings of the e?ects of anandamide (20 mg/kg i.v., AEA) after pretreatment with SR141716 (3 mg/kg, i.v.) on mean
arterial pressure (MAP, top panel) and cardiac contractility (LVSP and dP/dt; middle panel) and pressureevolume relationship (bottom panel) in
(A) and TRPV1
mice (B). The ?ve parts of the middle and bottom panels represent the same ?ve stages as described in the
legend for Fig. 1. The arrows indicate the injection of the drugs. Figure is reproduced with permission from Pacher et al. (2004).
P. Pacher et al. / Neuropharmacology 48 (2005) 1130e1138
may contribute to the profound hypotension associated
CB1 receptors in hemorrhagic (Wagner et al., 1997) and
with various forms of shock. Indeed, as demonstrated
cardiogenic shock (Wagner et al., 2001a, 2003) increased
by several studies over the last decade macrophage- and
mortality, despite the increase in blood pressure. These
platelet-derived endocannabinoids contribute to the
results suggest that endocannabinoid-mediated cardio-
hypotension associated with hemorrhagic (Wagner
vascular e?ects appear to have survival value. The
et al., 1997), endotoxic (Varga et al., 1998; Liu et al.,
bene?cial e?ects of cannabinoids could involve im-
2003; Ba´tkai et al., 2004; Wang et al., 2001) and
provement of tissue oxygenation by counteracting the
cardiogenic shock (Wagner et al., 2001a, 2003). Fur-
excessive sympathetic vasoconstriction triggered by
thermore, a similar mechanism seems to be involved in
hemorrhage or myocardial infarction and also potent
the vasodilated state associated with advanced liver
anti-in?ammatory e?ects (reviewed in Hiley and Ford,
cirrhosis (Ba´tkai et al., 2001; Ros et al., 2002), which is
2003, 2004; Walter and Stella, 2004).
possibly secondary to the endotoxemia frequently found
in patients with late-stage cirrhosis (Lumsden et al.,
1988). Importantly, in all of the above-mentioned
4. Role of the endocannabinergic system in blood
pathological conditions the hypotension could be re-
pressure regulation in hypertension
versed or inhibited by the CB1 antagonist SR141716.
The involvement of CB1 receptors in many of these
The intriguing possibility of using cannabinoid
conditions was also suggested by the observation that
ligands as antihypertensive agents was ?rst considered
circulating macrophages and platelets from endotoxe-
more than 30 years ago (Archer, 1974; Adams et al.,
mic or cirrhotic animals had elevated levels of endo-
1977; Birmingham, 1973; Crawford and Merritt, 1979;
cannabinoids and, when isolated and injected into
Varma and Goldbaum, 1975; Zaugg and Kyncl, 1983).
normal rats, these cells elicited SR141716-sensitive
However, initial enthusiasm was tempered by the
hypotension. In cirrhosis, the role of CB1 receptors
inability to separate the neurobehavioral and cardio-
was further supported by increase in CB1 receptor
vascular e?ects of cannabinergic ligands and also by
mRNA and binding sites in vascular endothelial cells
a report of the development of rapid tolerance to the
from cirrhotic human livers (Ba´tkai et al., 2001).
hypotensive and bradycardic e?ects of THC (Adams
It should be emphasized, however, that SR141716
et al., 1976). Even though a subsequent study in
may also inhibit endothelial and/or myocardial recep-
spontaneously hypertensive rats (SHR) found no
tor(s) distinct from conventional CB1 or CB2 (Ja´rai
evidence for tolerance to the same e?ects during a 10-
et al., 1999; Ford et al., 2002; Ho and Hiley, 2003;
day treatment period (Kosersky, 1978), interest in this
O’Sullivan et al., 2004). Indeed, in a detailed hemody-
issue waned over the next 20 years.
namic study in anesthetized rats (Ba´tkai et al., 2004b),
The cloning of CB1 receptor in 1990, the introduction
the acute hypotensive e?ect of LPS could be attributed
of selective CB receptor antagonists in the mid 1990s
to decreased cardiac contractility rather than decreased
and the development of receptor knockout mice
TPR, and it could be inhibited by SR141716, but not by
rekindled the interest in the cardiovascular regulatory
AM251, an antagonist equipotent with SR141716 at
e?ects of cannabinoids. Treatment of normotensive rats
CB1 receptors (Gatley et al., 1997) but lacking inhibitory
or mice with CB1 antagonists alone was found not to
potency at SR141716-sensitive endothelial and myocar-
a?ect blood pressure (Lake et al., 1997a; Varga et al.,
dial receptors (Fig. 3) (Ford et al., 2002; Ho and Hiley,
1995), and baseline blood pressure was similar in CB1
2003; O’Sullivan et al., 2004). In the same study we have
knockout mice and their wild-type littermates (Ja´rai
demonstrated that LPS elicited similar, SR141716-
et al., 1999; Ledent et al., 1999). Further studies dem-
sensitive hypotension in wild-type mice and in mice
onstrated that a relatively modest hypotensive e?ect of
de?cient in CB1 or both CB1 and CB2 receptors (Ba´tkai
anandamide was present in anesthetized (Lake et al.,
et al., 2004b). Taken together, these ?ndings imply that
1997a; Varga et al., 1995) but not in conscious
receptors distinct from CB1 or CB2 are primarily
normotensive rats (Stein et al., 1996; Lake et al.,
responsible for the acute, SR141716-sensitive cardiode-
1997b), and a lack of signi?cant hypotension following
pressive e?ects of LPS, which are responsible for the
inhibition of anandamide transport (Calignano et al.,
hypotension. Anandamide is a ligand for such recep-
1997). All of these ?ndings indicate the absence of an
tor(s) and LPS increases the synthesis of anandamide
endocannabinergic ‘tone’ in the maintenance of normal
(Liu et al., 2003) in macrophages. The existence of
blood pressure. In contrast, both anandamide (Lake
additional putative endogenous ligands for such recep-
et al., 1997b; Ba´tkai et al., 2004a) and THC (Kosersky,
tors needs to be explored.
1978) evoke larger and longer lasting hypotension in
Treatment with the cannabinoid agonists THC or
SHR than in normotensive rats, and the e?ect in the
HU-210 improved endothelial function and increased
former does not depend on the absence or presence of
survival in cardiogenic (Wagner et al., 2001a, 2003) and
anesthesia (Lake et al., 1997b). Consistent with these
endotoxic shock (Varga et al., 1998), while blockade of
observations, THC inhalation was found to result in
P. Pacher et al. / Neuropharmacology 48 (2005) 1130e1138
Fig. 3. LPS-induced hypotension is inhibited by SR141716 but not by AM251 in anesthetized rats. (A) Representative tracings of the e?ects of LPS
on MAP in a rat pretreated with vehicle (left), SR141716 (3 mg/kg i.v.; center), and AM251 (3 mg/kg i.v.; right). (B) Mean G SE DMAP from similar
experiments from 4 to 5 animals. *Signi?cant di?erence from values in vehicle C LPS-treated rats (P ! 0.05). Figure is reproduced with permission
from Ba´tkai et al. (2004b).
a greater and longer lasting decrease of arterial blood
sion that limits the elevation of blood pressure and
pressure in hypertensive as compared to normotensive
cardiac contractile performance through tonic activa-
individuals (Crawford and Merritt, 1979). Although the
tion of cardiac and probably vascular CB1. Indeed, we
mechanisms behind this increased sensitivity require
have found increased expression of cardiac and vascular
further clari?cation, it strongly suggests a role for the
CB1 in SHR as compared to their normotensive controls
endocannabinergic system in cardiovascular regulation
(Ba´tkai et al., 2004a). Consistent with previous results,
anandamide induced more pronounced and prolonged
To explore this possibility, we employed a sophisti-
hypotension in SHR but also in AII-induced hyperten-
cated pressureevolume (PV) analysis system (Pacher
sive rats (Fig. 4A) than in the corresponding normo-
et al., 2003) to determine the hemodynamic e?ects of
tensive controls, and the e?ect of anandamide was
cannabinoid agonists and antagonists in three di?erent
primarily mediated by decreased cardiac contractility
models of experimental hypertension (Ba´tkai et al.,
and only to a lesser extent by a reduction in TPR
(Ba´tkai et al., 2004a). The e?ect of the synthetic CB
Wistar Kyoto rats (WKY), i.v. injection of the CB1
agonist HU-210 was similarly potentiated in SHR
antagonists SR141716 and AM251, as already men-
compared to WKY rats. Importantly, the hypotensive
tioned above, had no e?ect on blood pressure and
and cardiodepressive e?ects of anandamide in hyper-
cardiac contractility. On the contrary, in SHR the same
tensive rats were fully prevented or reversed by CB1
two antagonists, but not a CB2 antagonist, evoked
antagonists, but were una?ected by capsazepine, an
marked and sustained further increase in blood pressure
antagonist of TRPV1 receptor (Ba´tkai et al., 2004a).
and cardiac contractility without changing the heart rate
Next, we examined whether the e?ects of endogenous
(Ba´tkai et al., 2004a). A similar pressor response to CB1
anandamide are similarly potentiated in hypertension,
blockade was also evident in angiotensin II-induced and
by testing the hemodynamic e?ects of a potent inhibitor
Dahl salt-sensitive hypertensive rats, but not in their
of fatty acid amidohydrolase (FAAH), the enzyme
corresponding normotensive controls (Ba´tkai et al.,
responsible for the degradation of anandamide in vivo.
2004a). The most likely explanation of these ?ndings is
The hemodynamic e?ects of the FAAH inhibitor,
the existence of an endocannabinergic tone in hyperten-
URB597 (10 mg/kg i.v.) (Kathuria et al., 2003), were
P. Pacher et al. / Neuropharmacology 48 (2005) 1130e1138A300AEAAEA)
H 200m (m
H 200m (m
H 200200m (m
Fig. 4. Representative recordings of the e?ects of anandamide (10 mg/kg i.v., AEA; panel A) and the FAAH antagonist URB597 (10 mg/kg i.v.;
panel B) on blood pressure in normotensive (left column) and in angiotensine II-induced hypertensive (right column) anesthetized rats, and reversal
(panel B left) or prevention (panel C) of the hypotensive e?ects of URB597 in hypertensive rats by the CB1 antagonist AM251. The arrows indicate
the injection of the drugs.
remarkably similar to those of exogenous anandamide
degradation may not have the same potential for abuse
(Fig. 4B) (Ba´tkai et al., 2004a). In hypertensive rats,
(Kathuria et al., 2003). Further studies are in progress to
URB597 decreased arterial pressure to near-normoten-
test the antihypertensive e?cacy of FAAH inhibitors in
sive values by decreasing cardiac contractility and TPR,
awake hypertensive animals.
while in normotensive rats it had no detectable
hemodynamic e?ects (Fig. 4B). URB597 raised the
concentration of anandamide in the myocardium, and
its hemodynamic e?ects were completely prevented
(Fig. 4C) or reversed (Fig. 4B) by the CB1 antagonist
The endocannabinergic system plays an important
AM251 but not by the TRPV1 antagonist capsazepine.
cardiovascular regulatory role not only in pathophysi-
This indicates that the action of URB597 is fully
ological conditions associated with excessive hypoten-
accounted for by the endocannabinoid-mediated stimu-
sion but also in hypertension. Thus, the pharmacological
lation of CB1. Treatment with the anandamide transport
manipulation of this system may o?er novel therapeutic
inhibitors AM404 (10 mg/kg i.v.) or OMDM-2 (5 mg/kg
approaches in a variety of cardiovascular disorders.
i.v.), which increase anandamide levels at the receptors
by blocking its cellular uptake, also induced greater
blood pressure reduction in hypertensive animals than in
normotensive controls (Ba´tkai et al., 2004a).
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