| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
(Received 17 March 2004;
accepted after revision 29 April 2004;
first published online 30 April 2004)
Corresponding author P. Pacher: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA. Email: pacher{at}mail.nih.gov
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
9-tetrahydrocannabinol (THC), are mediated by specific receptors. To date, two cannabinoid (CB) receptors have been identified by molecular cloning: the CB1 receptor, which is highly expressed in the brain (Matsuda et al. 1990), but is also present in peripheral tissues including the heart and vascular tissues (Gebremedhin et al. 1999; Liu et al. 2000; Bonz et al. 2003), and the CB2 receptor, expressed primarily by immune and haematopoietic cells (Munro et al. 1993). The natural ligands of these receptors are lipid-like substances called endocannabinoids, which include arachidonoyl ethanolamide or anandamide and 2-arachidonoylglycerol (reviewed by Mechoulam et al. 1998). Cannabinoids elicit not only neurobehavioural and immunological effects, but also cardiovascular effects such as profound hypotension (Lake et al. 1997a; Hillard, 2000; Kunos et al. 2002; Randall et al. 2002; Ralevic et al. 2002). Anandamide has been implicated in the pathomechanism of hypotension associated with various forms of shock, including haemorrhagic (Wagner et al. 1997), endotoxic (Varga et al. 1998) and cardiogenic shock (Wagner et al. 2001a,), and advanced liver cirrhosis (Bátkai et al. 2001). Increased sensitivity of hypertensive rats to the hypotensive action of anandamide (Lake et al. 1997b) could also suggest a role for endocannabinoids in hypertension. In anaesthetized rats, intravenous administration of anandamide causes a triphasic blood pressure response, in which the major, prolonged hypotensive effect (phase III) is preceded by a transient, vagally mediated fall in heart rate and blood pressure (phase I) followed by a brief, non-sympathetically mediated pressor response of unknown mechanism (phase II) (Varga et al. 1995). Also in anaesthetized rats it has been observed (Malinowska et al. 2001) that the phase I bradycardic response was dose-dependently inhibited by the vanilloid TRPV1 receptor antagonist capsazepine and the non-selective inhibitor ruthenium red. These two inhibitors had no effect on the phase III hypotension, which was abolished by the cannabinoid CB1 receptor antagonist SR141716 (Malinowska et al. 2001) and was also absent in CB1 receptor knockout mice (Ledent et al. 1999; Járai et al. 1999).
At micromolar concentrations, anandamide binds to vanilloid TRPV1 receptors (Zygmunt et al. 1999), and there is evidence that the in vitro vasodilator effect of anandamide in certain vascular beds involves activation of TRPV1 receptors on sensory nerve terminals, causing the release of calcitonin gene-related peptide (CGRP) and the activation of CGRP receptors (Zygmunt et al. 1999). Interplay between the vanilloid and endocannabinoid systems has recently been implicated in blood pressure regulation in hypertension (Li et al. 2003). However, the involvement of TRPV1 receptors in the in vivo hypotensive response to anandamide is uncertain (Szolcsányi, 2000; Ralevic et al. 2002; Kunos et al. 2002) and only based on pharmacological inhibitors whose specificity has been questioned (Ray et al. 2003). Therefore, the aim of this study was to characterize the cardiovascular profile of anaesthetized TRPV1 knockout mice (TRPV1–/–) and their wild-type littermates (TRPV1+/+), and to use them for a detailed analysis of the haemodynamic effects of anandamide, including its effect on myocardial function, using the Millar pressure–volume conductance catheter system (Pacher et al. 2003). The results indicate that the predominant hypotensive effect of anandamide involves a profound decrease in cardiac contractility and is mediated exclusively by cannabinoid CB1 receptors in both TRPV1+/+ and TRPV1–/– mice, but the transient activation of the cardiogenic sympathetic reflex by very high initial concentration of anandamide involves TRPV1 receptors.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Haemodynamic measurements
Male TRPV1–/– and TRPV1+/+ mice weighing 25–30 g were used for the study. Heterozygote breeding pairs were kindly provided by Dr David Julius, University of California at San Francisco, and additional mice were purchased from the Jackson Laboratory, Bar Harbour, ME, USA. Mice were anaesthetized with pentobarbital sodium (80 mg kg–1I.P.) and tracheotomized to facilitate breathing. Animals were placed on controlled heating pads, and core temperature measured via a rectal probe was maintained at 37°C. A microtip pressure–volume catheter (SPR-839; Millar Instruments, Houston, TX, USA) was inserted into the right carotid artery and advanced into the left ventricle (LV) as described (Pacher et al. 2002a,b,c, 2003). Polyethylene cannulae (P10) were inserted into the right femoral artery and vein for measurement of mean arterial pressure (MAP) and administration of drugs, respectively. After stabilization for 20 min, the signals were continuously recorded at a sampling rate of 1000 s–1 using an ARIA pressure–volume conductance system (Millar Instruments) coupled to a Powerlab/4SP A/D converter (AD Instruments, Mountain View, CA, USA), and then stored and displayed on a computer. All pressure–volume loop data were analysed with a cardiac pressure–volume analysis program (PVAN3.2; Millar Instruments), and the heart rate (HR), maximal left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), MAP, maximal slope of systolic pressure increment (+dP/dt) and diastolic decrement (–dP/dt), ejection fraction (EF), stroke volume (SV), arterial elastance (Ea; end-systolic pressure/stroke volume), cardiac output (CO) and stroke work (SW) were computed. The relaxation time constant (
), an index of diastolic function, was also calculated by two different methods (Weiss method: regression of log[pressure]versus time; Glantz method: regression of dP/dtversus pressure) using PVAN3.2. Total peripheral resistance (TPR) was calculated by the equation: TPR = MAP/CO.
In six additional TRPV1+/+ and six TRPV1–/– mice, haemodynamic parameters were determined under conditions of changing preload, elicited by transiently compressing the inferior vena cava (IVC) using a cotton swab, inserted through a small, transverse, upper abdominal incision. This technique yields very reproducible occlusions in mice without opening the chest cavity. Since +dP/dt may be preload-dependent (Kass et al. 1987), in these animals pressure–volume (PV) loops recorded at different preloads were used to derive other useful systolic function indices that may be less influenced by loading conditions and cardiac mass. These measures include the dP/dt–end diastolic volume (EDV) relation (dP/d –EDV) (Kass et al. 1987), the preload-recruitable stroke work (PRSW), which represents the slope of the relation between stroke work and EDV and is independent of chamber size and mass (Kass et al. 1987), and the end-systolic pressure–volume relation (ESPVR, Emax) (Nakano et al. 1990). The slope of the end diastolic pressure–volume relation (EDPVR), an index of LV stiffness, was also calculated from PV relations using PVAN 3.2. (see Table 1 and Fig. 1). At the end of the experiments, animals were killed by an overdose of anaesthetic (sodium pentobarbital).
|
|
The volume calibration of this conductance system was performed as previously described (Pacher et al. 2003). Briefly, seven cylindrical holes in a block 1 cm deep and with known diameters ranging from 1.4 to 5 mm were filled with fresh heparinized whole murine blood. An interelectrode distance of 4.5 mm was used to calculate the absolute volume in each cylinder. In this calibration, the linear regression between the absolute volume in each cylinder versus the raw signal acquired by the conductance catheter was used as the volume calibration formula. At the end of each experiment, 10 µl of 15% saline was injected I.V. and from the shift of pressure–volume relation, parallel conductance volume (Vp) was calculated by PVAN 3.2 and used for correction for the cardiac mass volume as previously described (Pacher et al. 2003).
Drugs
Anandamide was from Tocris (Baldwin, MO, USA); SR141716 was from the National Institute on Drug Abuse Drug Supply Program (Research Triangle Park, NC, USA). Capsaicin was from Sigma Chemicals (St Louis, MO, USA). Anandamide and SR141716 were emulsified in corn oil: water (1: 4); capsaicin was dissolved in ethanol: Tween80: saline 1: 1: 8, as described (Malinowska et al. 2001).
Statistical analyses
In each phase, at least 10 PV loops were examined to generate an average. Time-dependent variables were analysed by ANOVA followed by Dunnett's post hoc test. In other cases, Student's t test was used, as appropriate. Values with P < 0.05 were considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Baseline cardiovascular characteristics (MAP, LVSP, LVEDP, Ea, +dP/dt, –dP/dt, HR, EF, , SV, SW, CO and TPR) were not significantly different in TRPV1–/– and TRPV1+/+ mice (Table 1). Figure 1 illustrates typical PV loops obtained after inferior vena cava occlusions in both strains. Note that the slopes of systolic and diastolic pressure volume relations (ESPVR and EDPVR) are similar in TRPV1–/– and TRPV1+/+ mice (Fig. 1). The load-independent indices of contractility and left ventricular stiffness (Emax, dP/dt–EDV, PRSW, EDPVR) were also similar in both strains and are summarized in Table 1.
Haemodynamic effects of anandamide in TRPV1+/+ mice
Bolus injections of anandamide (20 mg kg–1I.V.) caused a triphasic effect in TRPV1+/+ mice (Figs 2, 3 and 5). The transient first phase, which lasted a few seconds, was characterized by profound decreases in cardiac contractility and heart rate and an increase in TPR, followed by a brief pressor response (phase II) associated with increased cardiac contractility. The third, prolonged hypotensive phase was characterized by decreased cardiac contractility and TPR and it lasted up to 10 min (Figs 2, 3 and 5). Pretreatment of the mice with a CB1 receptor antagonist, SR141716 (3 mg kg–1I.V.), had no effect on the first and second phases of the response to anandamide, but completely prevented the subsequent hypotension and the associated decreases in TPR and cardiac contractility (Figs 4 and 5).
|
|
|
|
In TRPV1–/– mice, the anandamide-induced initial component (phase I), present in TRPV1+/+ littermates, was absent, and the phase II pressor response was also markedly reduced (Figs 4 and 5). In contrast, the subsequent prolonged hypotensive response accompanied by decreased cardiac contractility and TPR were similar to the responses observed in TRPV1+/+ mice, and were similarly completely antagonized by pretreatment with SR141716 (Figs 4 and 5).
Effect of capsaicin on MAP in TRPV1–/– and TRPV1+/+ mice
In TRPV1+/+ mice, capsaicin (10 and 100 µg kg–1I.V.) evoked a brief blood pressure response similar to phase I and II responses to anandamide (Fig. 6). This response was completely absent in TRPV1–/– mice.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The in vivo cardiovascular effects of cannabinoids are complex and may involve modulation of the autonomic outflow in both the central (Niederhoffer & Szabo, 2000) and the peripheral nervous systems (Ishac et al. 1996), as well as direct effects on the myocardium (Bonz et al. 2003) and vasculature (Gebremedhin et al. 1999; Járai et al. 1999; Wagner et al. 2001b). CB1 receptors are present in both the vasculature (Gebremedhin et al. 1999; Liu et al. 2000), where they mediate vasodilatation (Gebremedhin et al. 1999), and in the myocardium where they mediate negative inotropy (Bonz et al. 2003), and both of these sites may be implicated in the hypotensive effect of anandamide (Wagner et al. 2001). Although some synthetic cannabinoids can cause centrally mediated sympathoexcitatory effects (Niederhoffer & Szabo, 2000), the cardiovascular depressor effects of anandamide do not have a centrally mediated component (Varga et al. 1996). Additionally, presynaptic CB1 are present in sympathetic nerve terminals where their stimulation inhibits noradrenaline (norepinephrine) release (Ishac et al. 1996), and such receptors are likely to mediate the bradycardic effects of anandamide (Wagner et al. 2001b).
Structural similarities between anandamide and vanilloid compounds such as capsaicin (Di Marzo et al. 1998) raised the possibility of interplay between these two systems. Indeed, Zygmunt et al. (1999) demonstrated that in rat mesenteric arteries, the endothelium-independent vasodilator effect of anandamide is inhibited by the TRPV1 receptor antagonist capsazepine or by a calcitonin gene-related peptide (CGRP) receptor antagonist. They further demonstrated that anandamide binds to the cloned TRPV1 receptor with micromolar affinity, and at nanomolar concentrations it releases immunoreactive CGRP from sensory nerve terminals located in the vascular adventitia (Zygmunt et al. 1999). A similar involvement of TRPV1 receptors in the mesenteric vasodilator action of methanandamide has also been proposed (Ralevic et al. 2000). These observations support the hypothesis that anandamide acts at TRPV1 receptors in sensory nerves to release the potent vasodilator peptide CGRP.
The above results do not implicate the endothelium in the vasodilator effect of anandamide. In two other studies in which the vasodilatation induced by anandamide was found to have both endothelium-dependent and -independent components, the role of TRPV1 receptors was confirmed for the endothelium-independent component only (Járai et al. 1999; Mukhopadhyay et al. 2002). The endothelium-dependent vasodilator effect of anandamide is unaffected by capsazepine in rabbit aortic rings (Mukhopadhyay et al. 2002). Interestingly, sensory nerve terminals also appear to have CB1 receptors, stimulation of which by very low doses of anandamide or by the synthetic cannabinoid HU-210, neither of which interacts with TRPV1 receptors, inhibits sensory neurotransmission (reviewed in Ralevic et al. 2002). Furthermore, a recent study by Zygmunt et al. (2002) indicates that THC and cannabinol, but not other psychotropic cannabinoids, can elicit CGRP release from periarterial sensory nerves by a mechanism that is independent of not only CB1 and CB2 receptors, but also of vanilloid TRPV1 receptors. Thus, the sensory nerve-dependent effects of cannabinoids are complex, as interactions with CB1 and TRPV1 receptors appear to have opposite functional consequences and there may be additional actions independent of both of these receptors. TRPV1 receptors do not appear to be involved in the dilatation of isolated coronary arteries by anandamide either in the sheep, where the effect is endothelium dependent (Grainger & Boachie-Ansah, 2001), or in the rat, where it is endothelium independent (White et al. 2001). Furthermore, in the rat mesenteric arterial bed, the role of sensory nerves and vanilloid receptors in the dilator effect of anandamide was found to be conditional on the presence of nitric oxide (Harris et al. 2002).
TRPV1-containing afferent nerve fibres are present on the epicardial surface of the heart and the activation of these receptors by epicardially injected capsaicin evokes a sympathoexcitatory response with a brief increase in blood pressure (Zahner et al. 2003). Capsaicin infusion also induces a moderate pressor effect in pigs (Kapoor et al. 2003). In the present experiments, I.V. injection of 10 µg kg–1 capsaicin evoked only a brief pressor response, while at the much higher dose of 100 µg kg–1 its effect had both a depressor and a pressor component (Fig. 6). The finding that capsaicin elicited no change in blood pressure in TRPV1–/– mice (Fig. 6) suggests that TRPV1 receptors mediate the cardiogenic sympathetic or Bezold-Jarisch reflex in mice, which is in agreement with recent findings in rats (Zahner et al. 2003).
In the absence of anandamide-induced hypotension in CB1 knockout mice, the physiological relevance of the interaction of anandamide with TRPV1 receptors has been questioned (Szolcsányi, 2000). In the present study we have attempted to resolve this issue. We previously reported that anandamide causes a triphasic blood pressure response where the predominant hypotensive effect is preceded by a transient, vagally mediated drop in heart rate and blood pressure followed by a brief pressor response (Varga et al. 1995). Here we show that this initial component is missing in TRPV1–/– mice and is unaffected by the CB1 antagonist SR141716 in wild-type mice. Bolus intravenous injections of anandamide may reach high enough plasma concentrations for a few seconds to activate TRPV1 receptors, which may explain the above findings. Indeed, the phase I transient hypotension and bradycardia do not appear when anandamide is injected slowly to limit its peak plasma concentration (Kunos G, Bátkai S. & Pacher P, unpublished observations). In contrast, the prolonged hypotensive phase of the anandamide response is characterized by decreased cardiac contractility and TPR, which were similar in TRPV1+/+ and TRPV1–/– mice and were completely antagonized by SR141716, implicating CB1 receptors. In agreement with this observation, the sustained hypotensive and bradycardic effects of cannabinoids are totally absent in mice lacking the CB1 receptor (Ledent et al. 1999; Járai et al. 1999). Thus, TRPV1 receptors are not involved in the sustained cardiovascular response to anandamide, but may become transiently activated in response to pharmacological concentrations achieved after bolus I.V. injections. These findings are in agreement with a recent report by Malinowska et al. (2001), who found that in anaesthetized rats the transient vagal activation to a bolus injection of anandamide was partially blocked by the TRPV1 antagonists capsazepine or ruthenium red, whereas the CB1-mediated prolonged hypotension remained unaffected.
In conclusion, our results demonstrate that the sustained hypotensive effect of anandamide involves a marked cardiodepressor component in addition to a decrease in TPR, and these effects are mediated by CB1 but not TRPV1 receptors. We also demonstrate that TRPV1–/– mice have normal cardiac performance and blood pressure, and that TRPV1 receptors mediate the cardiogenic sympathetic reflex.
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
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, 657–664.[CrossRef][Medline]
Di Marzo V, Bisogno T, Melck D, Ross R, Brockie H, Stevenson L, Pertwee R & De Petrocellis L (1998). Interactions between synthetic vanilloids and the endogenous cannabinoids system. FEBS Lett 436, 449–454.[CrossRef][Medline]
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 266, H2085–H2093.
Grainger J & Boachie-Ansah G (2001). Anandamide-induced relaxation of sheep coronary arteries: the role of the vascular endothelium, arachidonic acid metabolites and potassium channels. Br J Pharmacol 134, 1003–1012.[CrossRef][Medline]
Harris D, McCulloch AI, Kendall DA & Randall MD (2002). Characterization of vasorelaxant responses to anandamide in the rat mesenteric arterial bed. J Physiol 539, 893–902.
Hillard CJ (2000). Endocannabinoids and vascular function. J Pharmacol Exp Ther 294, 27–32.
Ishac EJ, Jiang L, Lake KD, Varga K, Abood ME & Kunos G (1996). Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. Br J Pharmacol 118, 2023–2028.[Medline]
Járai 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, 14136–14141.
Kapoor K, Arulmani U, Heiligers JP, Garrelds IM, Willems EW, Doods H, Villalon CM & Saxena PR (2003). Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Br J Pharmacol 140, 329–338.[CrossRef][Medline]
Kass DA, Maughan WL, Guo ZM, Kono A, Sunagawa K & Sagawa K (1987). Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships. Circulation 76, 1422–1436.
Kunos G, Batkai S, Offertaler L, Mo F, Liu J, Karcher J & Harvey-White J (2002). The quest for a vascular endothelial cannabinoids receptor. Chem Physics Lipids 121, 45–56.[CrossRef][Medline]
Lake KD, Compton DR, Varga K, Martin BR & Kunos G (1997a). Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors. J Pharmacol Exp Ther 281, 1030–1037.
Lake KD, Martin BR, Kunos G & Varga K (1997b). Cardiovascular effects of anandamide in anesthetized and conscious normotensive and hypertensive rats. Hypertension 29, 1204–1210.
Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, Bohme GA, Imperato A, Pedrazzini T, Roques BP, Vassart G, Fratta W & Parmentier M (1999). Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283, 401–404.
Li J, Kaminski NE & Wang DH (2003). Anandamide-induced depressor effect in spontaneously hypertensive rats: role of the vanilloid receptor. Hypertension 41, 757–762.
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, 835–840.[CrossRef][Medline]
Malinowska B, Kwolek G & Gothert M (2001). Anandamide and methanandamide induce both vanilloid VR1- and cannabinoids CB1 receptor-mediated changes in heart rate and blood pressure in anaesthetized rats. Naunyn Schmiedebergs Arch Pharmacol 364, 562–569.[CrossRef][Medline]
Matsuda LA, Lolait SJ, Brownstein MJ, Young CA & Bonner TI (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564.[CrossRef][Medline]
Mechoulam R, Fride E & Di Marzo V (1998). Endocannabionoids. Eur J Pharmacol 359, 1–18.[CrossRef][Medline]
Mukhopadhyay S, Chapnick BM & Howlett AC (2002). Anandamide-induced vasorelaxation in rabbit aortic rings has two components: G protein dependent and independent. Am J Physiol 282, H2046–H2054.
Munro S, Thomas KL & Abu-Shaar M (1993). Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65.[CrossRef][Medline]
Nakano K, Sugawara M, Ishihara K, Kanazawa S, Corin WJ, Denslow S, Biederman RW & Carabello BA (1990). Myocardial stiffness derived from end-systolic wall stress and logarithm of reciprocal of wall thickness. Contractility index independent of ventricular size. Circulation 82, 1352–1361.
Niederhoffer N & Szabo B (2000). Cannabinoids cause central sympathoexcitation and bradycardia in rabbits. J Pharmacol Exp Ther 294, 707–713.
Pacher P, Liaudet L, Bai P, Mabley JG, Kaminski PM, Virag L, Deb A, Szabo E, Ungvari Z, Wolin MS, Groves JT & Szabo C (2003). Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation 107, 896–904.
Pacher P, Liaudet L, Bai P, Virag L, Mabley JG, Hasko G & Szabo C (2002a). Activation of poly (ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure. J Pharmacol Exp Ther 300, 862–867.
Pacher P, Liaudet L, Mabley J, Komjati K & Szabo C (2002b). Pharmacologic inhibition of poly (adenosine diphosphate-ribose) polymerase may represent a novel therapeutic approach in chronic heart failure. J Am Coll Cardiol 40, 1006–1016.
Pacher P, Liaudet L, Soriano FG, Mabley JG, Szabo E & Szabo C (2002c). The role of poly (ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes. Diabetes 51, 514–521.
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, 2577–2594.[CrossRef][Medline]
Ralevic V, Kendall DA, Randall MD, Zygmunt PM, Movahed P & Hogestatt ED (2000). Vanilloid receptors on capsaicin-sensitive sensory nerves mediate relaxation to methanandamide in the rat isolated mesenteric arterial bed and small mesenteric arteries. Br J Pharmacol 130, 1483–1488.[CrossRef][Medline]
Randall MD, Harris D, Kendall DA & Ralevic V (2002). Cardiovascular effects of cannabinoids. Pharmacol Ther 95, 191–202.[CrossRef][Medline]
Ray AM, Benham CD, Roberts JC, Gill CH, Lanneau C, Gitterman DP, Harries M, Davis JB & Davies CH (2003). Capsazepine protects against neuronal injury caused by oxygen glucosae deprivation by inhibiting I(h). J Neurosci 23, 10146–10153.
Szolcsányi J (2000). Are cannabinoids endogenous ligands for the VR1 capsaicin receptor?Trends Pharmacol Sci 21, 41–42.[CrossRef][Medline]
Varga K, Lake KD, Huangfu D, Guyenet PG & Kunos G (1996). Mechanism of the hypotensive action of anandamide in anesthetized rats. Hypertension 28, 682–686.
Varga K, Lake K, Martin BR & Kunos G (1995). Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide. Eur J Pharmacol 278, 279–283.[CrossRef][Medline]
Varga K, Wagner JA, Bridgen DT & Kunos G (1998). Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J 12, 1035–1044.
Wagner JA, Hu K, Bauersachs J, Karcher J, Wiesler M, Goparaju SK, Kunos G & Ertl G (2001a). Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J Am Coll Cardiol 38, 2048–2054.
Wagner JA, Járai Z, Bátkai S & Kunos G (2001b). Haemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB(1) receptors. Eur J Pharmacol 423, 203–210.[CrossRef][Medline]
Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR & Kunos G (1997). Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature 390, 518–521.[CrossRef][Medline]
White R, Ho WS, Bottrill FE, Ford WR & Hiley CR (2001). Mechanisms of anandamide-induced vasorelaxation in rat isolated coronary arteries. Br J Pharmacol 134, 921–929.[CrossRef][Medline]
Zahner MR, Li DP, Chen SR & Pan HL (2003). Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats. J Physiol 551, 515–523.
Zygmunt PM, Andersson DA & Högestätt ED (2002). Delta 9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism. J Neurosci 22, 4720–4727.
Zygmunt PM, Petersson J, Andersson DA, Chuang H-H, Sorgard M, Di Marzo V, Julius D & Högestätt ED (1999). Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457.[CrossRef][Medline]
|
Acknowledgements |
|---|
This article has been cited by other articles:
|
|
 |
|
  M. A. Williams, S. A. Smith, D. E. O'Brien, J. H. Mitchell, and M. G. Garry The group IV afferent neuron expresses multiple receptor alterations in cardiomyopathyic rats: evidence at the cannabinoid CB1 receptor J. Physiol., February 1, 2008; 586(3): 835 - 845. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Telek, T. Biro, E. Bodo, B. I. Toth, I. Borbiro, G. Kunos, and R. Paus Inhibition of human hair follicle growth by endo- and exocannabinoids FASEB J, November 1, 2007; 21(13): 3534 - 3541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Shioura, D. L. Geenen, and P. H. Goldspink Assessment of cardiac function with the pressure-volume conductance system following myocardial infarction in mice Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2870 - H2877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Deng, J.-P. Huang, L.-S. Lu, and L.-M. Hung Impairment of cardiac insulin signaling and myocardial contractile performance in high-cholesterol/fructose-fed rats Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H978 - H987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Batkai, M. Rajesh, P. Mukhopadhyay, G. Hasko, L. Liaudet, B. F. Cravatt, A. Csiszar, Z. Ungvari, and P. Pacher 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, August 1, 2007; 293(2): H909 - H918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Batkai, D. Osei-Hyiaman, H. Pan, O. El-Assal, M. Rajesh, P. Mukhopadhyay, F. Hong, J. Harvey-White, A. Jafri, G. Hasko, et al. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury FASEB J, June 1, 2007; 21(8): 1788 - 1800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Akerman, P. R. Holland, and P. J. Goadsby Cannabinoid (CB1) Receptor Activation Inhibits Trigeminovascular Neurons J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 64 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pacher, S. Batkai, and G. Kunos The Endocannabinoid System as an Emerging Target of Pharmacotherapy Pharmacol. Rev., September 1, 2006; 58(3): 389 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Inoue, L. J. Jensen, J. Shi, H. Morita, M. Nishida, A. Honda, and Y. Ito Transient Receptor Potential Channels in Cardiovascular Function and Disease Circ. Res., July 21, 2006; 99(2): 119 - 131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Milman, Y. Maor, S. Abu-Lafi, M. Horowitz, R. Gallily, S. Batkai, F.-M. Mo, L. Offertaler, P. Pacher, G. Kunos, et al. N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties PNAS, February 14, 2006; 103(7): 2428 - 2433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Pacher, S. Batkai, D. Osei-Hyiaman, L. Offertaler, J. Liu, J. Harvey-White, A. Brassai, Z. Jarai, B. F. Cravatt, and G. Kunos Hemodynamic profile, responsiveness to anandamide, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H533 - H541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Gardiner, T. Bennett, G. Kunos, S. Batkai, P. Pacher, J. A. Wagner, and Z. Jarai Cannabinoids and Endotoxemia Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H451 - H451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Batkai, P. Pacher, D. Osei-Hyiaman, S. Radaeva, J. Liu, J. Harvey-White, L. Offertaler, K. Mackie, M. A. Rudd, R. D. Bukoski, et al. Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension Circulation, October 5, 2004; 110(14): 1996 - 2002. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
)
P < 0.05, TRPV1+/+versus TRPV1–/–. Arrow indicates anandamide injection (0 min).
