(Hypertension. 1997;29:1204-1210.)
© 1997 American Heart Association, Inc.
Articles |
Cardiovascular Effects of Anandamide in Anesthetized and Conscious Normotensive and Hypertensive Rats
From the Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Correspondence to Dr K. Varga, Department of Pharmacology and Toxicology, Virginia Commonwealth University, PO Box 980613, 410 N 12th St, Richmond, VA 23298. E-mail kvarga{at}gems.vcu.edu
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Abstract |
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Abstract We previously showed that in anesthetized rats anandamide elicits bradycardia and a triphasic blood pressure response: transient hypotension secondary to a vagally mediated bradycardia, followed by a brief pressor and prolonged depressor response, the latter two effects being similar to those of
9-tetrahydrocannabinol (THC). The prolonged depressor
but not the pressor response was reduced after 
-adrenergic receptor
blockade or cervical spinal cord transection and was inhibited by the
cannabinoid type 1 (CB1) receptor antagonist
SR141716A, suggesting CB1 receptor–mediated
sympathoinhibition as the underlying mechanism. Here we examined the
relationship between sympathetic tone and the
cardiovascular effects of anandamide by testing these
effects in both conscious and anesthetized, normotensive and
spontaneously hypertensive rats. In urethane-anesthetized
normotensive rats, SR141716A inhibited the prolonged depressor and
bradycardic effects of anandamide and THC with similar potency, whereas
it did not affect the pressor response to either agent. Anandamide
caused similar hypotension in spontaneously breathing and in paralyzed,
mechanically ventilated rats, suggesting that the hypotension is not
secondary to respiratory effects. In conscious normotensive rats,
anandamide elicited transient vagal activation and a brief pressor
response, but the prolonged hypotensive component was absent. SR141716A
potentiated and prolonged the brief pressor response to anandamide,
suggesting that the depressor response may have been masked by an
increased pressor response. All three phases of the anandamide response
were present in both anesthetized and conscious
spontaneously hypertensive rats, and the hypotensive component,
inhibited by SR141716A in both, was more prolonged in the absence (>50
minutes) than the presence (10 to 15 minutes) of
anesthesia. We conclude that anandamide causes a
non–CB1 receptor–mediated pressor and a CB1
receptor–mediated prolonged depressor response. The depressor response
can be elicited in both conscious and anesthetized animals, but
its magnitude depends on preexisting sympathetic tone.
Key Words: hypotension • cannabinoids • blood pressure • heart rate
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Introduction |
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Marijuana is a popular recreational drug of abuse because of its psychoactive properties. The major active constituent of marijuana is THC. In experimental animals, THC elicits a tetrad of neurobehavioral effects as well as cardiovascular effects. In conscious humans, an acute dose of THC elicits dose-related tachycardia without altering BP,1 whereas administered orally over a 3-week period, THC induces supine hypotension and bradycardia.2 In anesthetized animals, THC elicits a transient pressor response followed by gradual hypotension and a parallel decrease in HR.3 4 5 6 7 In rats with genetic or surgically induced hypertension, THC significantly lowers BP to normotensive levels.6 8 9 THC has also been shown to prevent immobilization stress–induced hypertension.10
Cannabinoid receptors have been identified in the rat by radioligand binding and autoradiography.11 12 Subsequently, two cannabinoid receptors have been cloned: the CB1 receptor, located in the brain and testes,13 14 and the CB2 receptor, identified in macrophages.15 Additionally, a splice variant of the CB1 receptor (CB1A) has also been described.16 CB1 receptor mRNA has been identified in rat17 and human18 brain tissue by in situ hybridization histochemistry. In 1992, a putative endogenous cannabinoid receptor ligand, anandamide (arachidonyl-2-ethanolamide), was isolated from porcine brain.19 Like THC, anandamide binds to cannabinoid receptors,19 20 inhibits adenylate cyclase via an inhibitory G protein,20 and inhibits voltage-gated N-type calcium channels.21 In neurobehavioral assays, anandamide has been shown to mimic THC in terms of catalepsy, hypomotility, hypothermia, and analgesia.22 23
In urethane-anesthetized rats, anandamide elicits complex yet
reproducible cardiovascular effects: transient vagal
bradycardia with secondary hypotension, followed by a brief pressor and
more prolonged depressor response, the latter two components being
similar to the effects of THC.24 The prolonged depressor
but not the brief pressor effect was inhibited by cervical transection
of the spinal cord, -adrenergic receptor blockade, or the
CB1 receptor antagonist SR141716A. These
observations suggested that the prolonged hypotensive response to
anandamide and THC is mediated by a CB1-like receptor via
suppression of sympathetic tone.24 Additional findings
indicate that the sympathoinhibitory effect of anandamide
is due to activation of presynaptic CB1 receptors on
sympathetic nerve terminals that inhibit exocytotic
norepinephrine release.25 26
It is well known that anesthesia has a profound influence on the cardiovascular system, particularly on cardiovascular drug effects due to changes in sympathetic tone.27 It is also known that the hypotensive effect of sympathoinhibitory agents is greater in hypertension than under normotensive conditions. Therefore, in the present study, we examined the cardiovascular effects of anandamide in conscious and anesthetized normotensive rats and SHR to assess the importance of sympathetic tone in these cardiovascular effects.
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Methods |
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Animals
Adult male SD rats or SHR weighing 280 to 400 g were obtained from Harlan Sprague Dawley, Inc (Indianapolis, Ind) and were housed in suspension cages with food and water ad libitum. A total of 100 SD rats and 15 SHR were used. The rats were maintained at 24° to 26°C under a 14:10-hour light/dark cycle and were allowed to acclimate for at least 1 week before surgery.
Surgical Preparation
Anesthesia was induced with ethyl ether, and a
femoral vein was cannulated for intravenous drug
administration. Ether anesthesia was then discontinued and
urethane was administered (0.7 g/kg IV plus 0.3 g/kg IP). Urethane
administered according to this protocol was found to produce stable and
long-lasting anesthesia without causing significant
hypotension or inhibition of cardiovascular
reflexes.28 The femoral artery was cannulated and the
catheter connected to a pressure transducer (Abbott Laboratories) for
continuous monitoring of arterial BP with a physiograph
(Astromed). HR was monitored by a tachograph preamplifier driven by the
pressure wave. The trachea was cannulated with PE-160 tubing to
maintain an open airway. For experiments in awake animals, the rats
were anesthetized with sodium pentobarbital (40 mg/kg IP). With
the use of aseptic techniques, the right femoral vein and artery were
cannulated with PE-50 tubing or micro-renothane (MRE-033, Braintree
Scientific, Inc), which was tunneled under the skin and externalized at
the base of the neck. Both catheters were filled with heparinized
saline, and the ends of the tubing were melted to form a leak-proof
seal. The externalized catheters were protected by a wire spring
attached to a body harness secured to the rat. Each rat was
individually housed, with the spring attached to a swivel mounted above
the cage top. The rats were allowed 2 days to recover from surgery. On
the study day, the ends of the cannulas were clipped and connected to a
pressure transducer (arterial cannula) or drug-filled
syringe (venous cannula). The rats were not handled at any time during
the assay.
Mechanical Ventilation
A group of urethane-anesthetized SD rats were paralyzed
and mechanically ventilated to eliminate the possible confounding
effects of anandamide-induced respiratory changes on
cardiovascular parameters. The trachea was
cannulated and connected to a small-animal respirator (Harvard
Apparatus). After the rat was paralyzed by administration
of 1 mg/kg tubocurarine IV, respiration was maintained on room air at
60 cycles per minute at a tidal volume of 1.8 mL.
Drugs
Anandamide (arachidonyl-2-ethanolamide) was synthesized by Dr
Raj Razdan (Organix Inc). SR141716A
[N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide
HCl] was provided by Dr John Lowe at Pfizer Central Research as the
free base. THC was obtained from the National Institute on Drug Abuse.
All three drugs were dissolved in emulphor/ethanol/saline (1:1:18).
Emulphor (EL-620, a polyoxyethylated vegetable oil, GAF Corp) is
currently available as Alkmulphor. d-Tubocurarine chloride
was from Sigma Chemical Co and was dissolved in saline. All drugs were
injected as an intravenous bolus over 10 to 15
seconds.
Data Analysis
Mean arterial pressure was calculated as
1/3(Systolic BP-Diastolic
BP)+Diastolic BP. Time-dependent, anandamide-induced
changes in BP and HR in the absence or presence of SR141716A were
compared with ANOVA followed by Tukey's post hoc test. In
dose-response studies of SR141716A for antagonizing the hypotensive and
bradycardic effects of anandamide or THC, peak changes in BP and HR in
response to an agonist dose of 4 mg/kg IV were determined in the
absence or presence of SR141716A, and the percent inhibition was
calculated for each antagonist dose. The
antagonist dose causing 50% inhibition (AD50)
of SR141716A was estimated with the ALLFIT sigmoidal curve-fitting
program.29
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Effects of Anandamide and THC in Anesthetized SD Rats
Intravenous bolus administration of 0.2 to 20 mg/kg anandamide produced triphasic and dose-dependent changes in BP as well as an acute decrease in HR (Fig 1
). The initial
pronounced bradycardia and transient decrease in BP were followed by a
brief pressor response that lasted for 30 to 60 seconds, followed by a
delayed hypotensive response that lasted less than 10 minutes for any
dose. Similar administration of the vehicle had no effect on BP or HR.
The responses to anandamide were highly reproducible when repeated in
the same rat up to four times, at 20-minute intervals, indicating the
lack of tachyphylaxis (not shown). This justified the analysis
of the inhibition of CB1 receptors by comparing the effects
of anandamide obtained before and after SR141716A administration in the
same rat.
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) or anandamide at
doses of 0.2 (
), 4 (
), or 20 (
) mg/kg were injected
as an intravenous bolus. Points represent means
from four to eight experiments. *Significant difference from
corresponding vehicle value (P<.05).
When tested at doses of 4 mg/kg or higher, anandamide induced
noticeable apnea. Since respiratory changes can indirectly affect BP
and HR, the cardiovascular effects of 4 mg/kg
anandamide were retested after the rats were paralyzed and mechanically
ventilated. As illustrated in Fig 2, the pattern of the
cardiovascular response to anandamide was not
significantly altered during mechanical ventilation (compare Fig 2A and 2B).
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In agreement with the results of numerous earlier studies,3 4 5 6 7 THC elicited a brief (30- to 45-second) pressor response followed by dose-dependent (0.01 to 4 mg/kg IV) hypotension and concomitant bradycardia (not shown). In six anesthetized SD rats, THC (4 mg/kg IV) elicited a brief pressor response (peak: +28±4 mm Hg) followed by hypotension (maximum: -39±6 mm Hg) and bradycardia (maximum: -88±25 beats per minute), which peaked at 20 to 25 minutes and lasted for more than 60 minutes.
The recent introduction of SR141716A has made it possible to explore
the involvement of CB1 receptors in cannabinoid
effects.30 At a dose of 10 mg/kg, SR141716A blocked the
prolonged depressor response to anandamide without influencing the
first two phases of the response.24 We examined the dose
dependence of the inhibition by SR141716A against both anandamide and
THC. Both agonists were used at a dose of 4 mg/kg, which produces
near-maximal hypotension. Earlier experiments have demonstrated that
the maximal inhibitory effect of SR141716A is achieved
within 10 minutes of its intravenous administration and the
receptor blockade persists unchanged for at least 1
hour.24 Anandamide was tested before and then 20 minutes
after SR141716A administration, and the degree of inhibition was
determined in each rat as the percent reduction of the control
hypotensive response to anandamide. Because of the long duration of its
hypotensive effect, THC was tested only once in each rat 20 minutes
after administration of either SR141716A or vehicle. No rat was tested
with more than one dose of SR141716A. As summarized in Fig 3, SR141716A dose dependently antagonized the
hypotensive response to both anandamide and THC. Computerized
curve-fitting analysis (ALLFIT) yielded AD50
values of 0.29±0.14 and 0.08±0.01 mg/kg IV for anandamide and THC,
respectively (P>.2). The prolonged bradycardic responses to
anandamide and THC were also inhibited, with AD50 values of
0.08±0.10 and 0.33±0.08 mg/kg, respectively (P>.1). The
brief pressor response to anandamide or THC and the initial vagal
bradycardia and secondary hypotension observed only after anandamide
were unaffected by any of the SR141716A doses tested (not shown).
SR141716A alone caused no changes in basal BP at doses up to and
including 3 mg/kg, whereas at 5 and 10 mg/kg, it reduced BP by 8±2
(P<.05) and 15±5 mm Hg (P<.05),
respectively. The inhibition of the hypotensive but not the first two
phases of the anandamide response by 3 mg/kg SR141716A is illustrated
in Fig 4.
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) hypotension.
Inhibition was defined as percent reduction in maximal hypotensive
response to 4 mg/kg anandamide or THC. Points and vertical bars are
mean±SE from four to six separate experiments. Dose-response curve was
derived by computerized curve-fitting with the ALLFIT program (see
text).
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) and 20 minutes after (
Effects of Anandamide in Conscious SD Rats
To test whether anesthesia may modify the
cardiovascular effects of anandamide, we tested
anandamide (4 mg/kg IV) in conscious, chronically cannulated SD rats.
As illustrated in Fig 5, anandamide elicited the initial
vagally mediated bradycardia and hypotension and the subsequent brief
pressor response, but the prolonged depressor response present in
anesthetized rats (see Fig 4
) was absent. That this difference
was in fact due to the absence or presence of anesthesia
and not to individual variability of the depressor effect of anandamide
was verified in some chronically cannulated rats in which 4 mg/kg
anandamide was first tested with rats in the conscious state and then
after the induction of anesthesia by urethane. In these
rats, anandamide produced a strong depressor response after but not
before the induction of anesthesia. When anandamide was
retested in the conscious rats after administration of 4 mg/kg
SR141716A IV, the pressor component of the response was increased as
well as slightly prolonged compared with the control response. The
anandamide-induced BP increase was analyzed by measuring the
area under the mean arterial pressure curve between 0.5 and
6 minutes, which was 87±5% greater after than before SR141716A
(P<.02). This could suggest that the depressor component is
not completely absent in conscious rats but that it is counteracted by
an enhanced pressor response to anandamide.
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Effects of Anandamide in Anesthetized SHR
Since resting sympathetic tone is higher in SHR than SD rats, we
tested the effects of anandamide in conscious and anesthetized
SHR. In four urethane-anesthetized SHR, anandamide (4 mg/kg IV)
elicited triphasic BP changes and bradycardia similar to those in
anesthetized SD rats, except that the prolonged hypotensive
phase lasted somewhat longer (Fig 6). In the same rats,
pretreatment with SR141716A (3 mg/kg IV) blocked the prolonged
hypotension and concomitant moderate bradycardia and in fact unmasked a
moderate and prolonged tachycardic response (Fig 6). As in conscious SD
rats, SR141716A significantly enhanced the brief pressor response to
anandamide.
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Effects of Anandamide in Conscious SHR
In six conscious, chronically cannulated SHR, anandamide (4 mg/kg
IV) caused a triphasic BP change and bradycardia similar to those in
anesthetized SHR, except that the prolonged hypotension
developed more slowly and lasted up to 60 minutes (Fig 7). When the same rats were pretreated with SR141716A (3
mg/kg IV), the prolonged hypotension and concomitant moderate
bradycardia were completely blocked, whereas the brief pressor response
remained unchanged.
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Discussion |
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Previous observations in urethane-anesthetized rats have demonstrated that the endogenous cannabinoid anandamide elicits a brief pressor effect followed by a more prolonged hypotensive response similar to the effects of THC.24 Additionally, anandamide but not THC elicits an initial, transient drop in BP secondary to a brief, vagally mediated bradycardia.24 We have now extended these observations by characterizing the cardiovascular effects of anandamide in the presence and absence of anesthesia as well as in normotensive rats and SHR.
Of the various components of the effects of THC and anandamide, the prolonged depressor phase is the most interesting, as it has raised the possible therapeutic use of certain cannabinoid analogues in hypertension.31 32 33 This depressor effect was found to be inhibited by SR141716A, which suggested the involvement of a CB1-like receptor.24 The present findings indicate that in urethane-anesthetized rats, SR141716A inhibits the depressor response to THC and anandamide with similar potency, confirming the notion that anandamide and plant-derived cannabinoids interact with the same receptor. Although the onset of hypotension is more rapid and its duration shorter for anandamide than THC, the neurobehavioral effects of anandamide are also shorter lasting than those of THC34 ; the basis for this difference is not yet clear. It is also noteworthy that the potencies of SR141716A determined for the hypotensive compared with the neurobehavioral effects of THC and anandamide30 are also similar. Although this could be interpreted as evidence for the involvement of the same receptor, it is possible that different cannabinoid receptor subtypes with similar affinities for SR141716A are involved. This latter possibility is suggested by the existence of certain cannabinoid analogues, such as abnormal cannabidiol, that have been reported to cause hypotension but be devoid of neurobehavioral effects,32 33 an observation we have been able to confirm in anesthetized mice (K.D.L. et al, unpublished observations, 1997). A possible candidate for an alternative receptor is the recently identified CB1A receptor, which is a splice variant of the CB1 receptor,16 the pharmacological properties of which have not yet been characterized. CB2 receptors are unlikely to play a role in the hypotensive response in view of their low affinity for SR141716A.30
In the course of our experiments in anesthetized rats, it was observed that anandamide at doses of 4 mg/kg or higher elicited apnea; THC is known to cause similar effects.5 35 Since changes in respiration can indirectly affect BP and HR, we evaluated the effects of anandamide in paralyzed, mechanically ventilated rats. None of the three phases of the anandamide response was significantly affected, although a slight enhancement of the prolonged hypotensive phase was observed in the paralyzed, mechanically ventilated state. Thus, the respiratory depressant action of anandamide cannot account for the hypotension. If anything, it may counteract it, probably by hypoxic stimulation of sympathetic outflow. A similar observation has been reported for THC in anesthetized dogs.36
-Adrenergic receptor blockade and cervical spinal cord transection
were found to strongly inhibit the prolonged depressor response to
anandamide despite maintained responsiveness to the direct vasodilator
sodium nitroprusside.24 These findings implicated
inhibition of sympathetic tone as the underlying
mechanism,24 and a similar mechanism has been proposed to
account for the hypotensive effect of THC.7 36 We have
subsequently found that in urethane-anesthetized rats,
anandamide does not reduce the activity of sympathetic premotor neurons
in the rostral ventrolateral medulla or the activity of preganglionic
or postganglionic sympathetic neurons.26 Furthermore, the
pressor response to rostral ventrolateral medulla stimulation in
barodenervated rats was blunted by anandamide, whereas the pressor
response to intravenous phenylephrine was
unchanged. Together, these observations strongly suggest a presynaptic
site of action of anandamide on postganglionic sympathetic nerves
innervating the heart and vasculature.26 In agreement with
such a possibility, we documented a CB1 receptor–mediated
suppression of exocytotic norepinephrine release in rat
isolated atria and vasa deferentia and demonstrated the presence of
CB1 receptor mRNA in a sympathetic
ganglion.25
Anesthesia is known to influence
cardiovascular drug effects, particularly those
mediated through changes in sympathetic tone. For instance, clonidine
elicits centrally mediated hypotension and bradycardia in
urethane-anesthetized normotensive rats,37 whereas
in conscious normotensive rats, a centrally mediated pressor response
is prominent.38 Opioid peptides have also been shown to
cause qualitatively different effects in anesthetized versus
conscious rats.27 In conscious SD rats, the initial vagal
activation and brief pressor effect of anandamide were present, but
the subsequent hypotension was not observed (Fig 5). Resting
sympathetic tone is known to be higher in urethane-anesthetized
rats than in unstressed, conscious rats.39 Since the
hypotensive action of anandamide has been attributed to inhibition of
sympathetic tone, it is plausible that under conditions of low basal
sympathetic tone, the hypotensive response is blunted. In the conscious
SD rats, SR141716A enhanced and prolonged the brief pressor response to
anandamide, suggesting that a residual depressor response to anandamide
may have been offset by an increased and more prolonged pressor
response. The experiments in SHR, which are known to have elevated
sympathetic tone,40 support this hypothesis. In both
conscious and urethane-anesthetized SHR, anandamide elicited
the characteristic triphasic BP response and bradycardia, which is
compatible with the dependence of the prolonged hypotension on the
preexisting sympathetic tone. The hypotensive effect of anandamide was
somewhat prolonged in anesthetized SHR and markedly prolonged
in the conscious SHR model compared with SD rats, and in both cases,
SR141716A blocked these effects as well as the accompanying moderate
bradycardia. Although the mechanism responsible for the prolongation of
the hypotensive response to anandamide in SHR is not clear, this may be
a useful feature regarding the search for therapeutically useful
antihypertensive cannabinoids.
In anesthetized rats, anandamide and THC were found to elicit a
similar brief pressor response, which was not inhibited but rather
enhanced after -adrenergic receptor blockade by phentolamine
or after acute surgical transection of the spinal cord.24
These findings were interpreted to indicate that the pressor effect is
not sympathetically mediated.24 In the present
experiments, this pressor effect was evident in all four rat models
studied, and its resistance to inhibition by the selective
CB1 receptor antagonist SR141716A demonstrates
the lack of involvement of CB1 receptors (see Figs 4 through 7). The actual enhancement of the pressor response after
pretreatment with SR141716A may result from the removal of the
partially overlapping hypotensive phase, which may limit as well as
shorten the duration of the pressor component. The pressor effect is
likely to be of vascular origin, as HR is decreased rather than
increased by both anandamide and THC, and there is evidence that THC
decreases cardiac contractility.9 41 These
findings suggest that anandamide and THC cause vasoconstriction either
via a receptor other than CB1 or by a nonreceptor mechanism
such as a direct effect on smooth muscle
contractility.
In conclusion, anandamide and THC are similar in that they produce a transient increase in BP followed by a prolonged hypotensive phase in anesthetized rats. The depressor phase is mediated by a CB1-like receptor and is due to decreased sympathetic tone to the heart and vasculature. The pressor response is most likely due to a direct vasoconstrictor action of the cannabinoids that does not involve CB1 receptors. The prolonged depressor response to anandamide is present in both conscious and anesthetized normotensive as well as hypertensive rats, but in the conscious normotensive rats, it is masked by an enhanced pressor response.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by National Institutes of Health (NIH) grants HL-49938 to G.K., DA-09789 to B.R.M., and DA-08677 to Dr Raj Razdan as well as American Heart Association, Virginia Affiliate, grant VA-96-GS7 to K.V. K.D.L. was supported by NIH training grant DA-07027. We thank Dr Raj Razdan for the synthesis of anandamide, Dr John Lowe for SR141716A, and Dr David R. Compton for helpful discussions.
Received September 20, 1996; first decision November 5, 1996; accepted November 14, 1996.
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