anandamide and Hypotension

Cannabinoids, the bioactive ingredients of the marijuana plant, are best known for their psychoactive properties, but they also influence other physiological processes, such as cardiovascular variables. Endocannabinoids are recently identified lipid mediators that act as natural ligands at cannabinoid receptors and mimic most of the biological effects, including the cardiovascular actions, of plant-derived cannabinoids. In experimental animals, the most prominent component of the cardiovascular effects of cannabinoids is prolonged hypotension and bradycardia. This review focuses on the possible mechanisms underlying these effects. The emerging evidence suggesting that endocannabinoids may be involved in the peripheral regulation of vascular tone under certain conditions is also discussed.

Topics: Animals; Arachidonic Acids; Biological Factors; Bradycardia; Cannabinoid Receptor Modulators; Cannabinoids; Cardiovascular System; Endocannabinoids; Glycerides; Humans; Hypotension; Polyunsaturated Alkamides; Vasodilator Agents

Acute hypotension, hypoxemia, cardiac arrhythmias, cardiac arrest, (or a combination of these), and sudden death are well-recognized complications of the cemented hip arthroplasty procedure. Collectively, these are known as the bone cement implantation syndrome (BCIS). The endogenous cannabinoids, anandamide (ANA) and 2-arachidonylglycerol (2-AG), are reported to be strong vasodilators and play a role in the hypotension associated with hemorrhagic and septic shock. In the present study, a potential role for the endogenous cannabinoids in influencing hemodynamic variables in BCIS was investigated. Thirty-five patients (35 hips) entered a prospective, randomized clinical trial. The patients were divided into two groups. Group 1 comprised 16 patients who had the component inserted using a conventional cementing technique, whereas group 2 consisted of 19 patients who had the femoral component inserted without cement. Blood samples were taken at six consecutive time points: before anesthesia, after reaming the femur, 2 min after insertion of stems with or without cement into the femur, and 10 min, 20, and 30 min after stem insertion. In group 1 (with cement), the mean levels of ANA and 2-AG significantly increased after stem insertion. In a comparison of each group after stem insertion, mean ANA and 2-AG levels in group 1 also significantly differed from those in group 2. By contrast, in group 2 (without cement) neither ANA nor 2-AG levels exhibited a significant increase or change at any point in time. In conclusion, we have shown for the first time that endogenous cannabinoids are candidates for lipid mediators of BCIS.

Topics: Aged; Arachidonic Acids; Arthroplasty, Replacement, Hip; Blood Pressure; Bone Cements; Cannabinoids; Endocannabinoids; Female; Glycerides; Heart Diseases; Humans; Hypotension; Lipid Metabolism; Male; Models, Biological; Polyunsaturated Alkamides; Prospective Studies; Prosthesis Failure; Shock; Syndrome; Time Factors; Vasodilator Agents

Intravenous injection of the endocannabinoid anandamide induces complex cardiovascular changes via cannabinoid CB(1), CB(2) and vanilloid TRPV1 receptors. Recently, evidence has been accumulating that in vitro, but not in vivo, anandamide relaxes blood vessels, via an as yet unidentified, non-CB(1) vascular cannabinoid receptor, sensitive to O-1918 (1,3-dimethoxy-5-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-benzene). We here examined whether the anandamide-induced hypotension in urethane-anaesthetized rats was also mediated via a non-CB(1) vascular cannabinoid receptor.. Effects of two antagonists (O-1918 and cannabidiol) of the non-CB(1) vascular cannabinoid receptor on anandamide-induced changes in mean, systolic and diastolic blood pressure (MBP, SBP, DBP), mesenteric (MBF) and renal (RBF) blood flow and heart rate (HR) in urethane-anaesthetized rats was examined.. In anaesthetized rats, anandamide (1.5-3 micromol.kg(-1)) and its stable analogue methanandamide (0.5 micromol.kg(-1)) caused a delayed and prolonged decrease in MBP, SBP, DBP, MBF and RBF by about 10-30% of the respective basal values without changing HR. In pithed rats, anandamide (3 micromol.kg(-1)) decreased blood pressure by about 15-20% of the basal value without affecting HR, MBF and RBF. All vascular changes were reduced by about 30-70% by cannabidiol and O-1918 (3 micromol.kg(-1), each).. Non-CB(1) cannabinoid vascular receptors, sensitive to O-1918, contribute to the hypotensive effect of anandamide in anaesthetized rats. Activation of these receptors may be therapeutically important as the endocannabinoid system could be activated as a compensatory mechanism in various forms of hypertension.

Topics: Anesthesia; Animals; Anisoles; Arachidonic Acids; Blood Pressure; Cannabidiol; Cannabinoid Receptor Antagonists; Cyclohexanes; Endocannabinoids; Hypotension; Male; Polyunsaturated Alkamides; Rats; Rats, Wistar; Renal Circulation; Splanchnic Circulation

It is widely assumed that LPS lowers arterial pressure during sepsis by stimulating release of TNF-alpha and other vasoactive mediators from macrophages. However, recent data from this and other laboratories have shown that LPS hypotension can be prevented by inhibiting afferent impulse flow in the vagus nerve, by blocking neuronal activity in the nucleus of the solitary tract, or by blocking alpha-adrenergic receptors in the preoptic area/anterior hypothalamic area (POA). These findings suggest that the inflammatory signal is conveyed from the periphery to the brain via the vagus nerve, and that endotoxic shock is mediated through a central mechanism that requires activation of POA neurons. In the present study, we tested whether central cannabinoid 1 (CB1) receptors participate in the control of arterial pressure during endotoxemia based on evidence that hypothalamic neurons express CB1 receptors and synthesize the endogenous CB anandamide. We found that intracerebroventricular administration of rimonabant, a CB1 receptor antagonist, inhibited the fall in arterial pressure evoked by LPS significantly in both conscious and anesthetized rats. Rimonabant attenuated both the immediate fall in arterial pressure evoked by LPS and the second, delayed hypotensive phase that leads to tissue ischemia and death. Rimonabant also prevented the associated LPS-induced rise in extracellular fluid norepinephrine concentrations in the POA. Furthermore, rimonabant attenuated the associated increase in plasma TNF-alpha concentrations characteristic of the late phase of endotoxic hypotension. These data indicate that central CB1 receptors may play an important role in the initiation of endotoxic hypotension.

Topics: Animals; Anterior Hypothalamic Nucleus; Arachidonic Acids; Blood Pressure; Endocannabinoids; Endotoxins; Hypotension; Lipopolysaccharides; Macrophages; Male; Neurons; Norepinephrine; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Tumor Necrosis Factor-alpha

Anaesthetized and spontaneously breathing rats were used to study the cardio-respiratory effects of intravenous anandamide administration. To investigate the role of particular levels of the afferent pathway in this response rats were challenged with bolus injection of anandamide (1 mg kg(-1)) into the femoral vein while intact, following bilateral superior laryngeal nerves (SLNs) section and after midcervical vagotomy. To test the hypothesis that the activation of the vanilloid receptors (VR1) as well as cannabinoid receptors (CB1) contributes to the anandamide-induced response administrations of anandamide were preceded by nonselective VR1 antagonist ruthenium red or selective CB1 antagonist AM281. Anandamide evoked apnoea of mean duration of 4.84+/-0.75 s in all animals while intact which was shortened by subsequent neurotomies, after SLNs section to 3.3+/-0.57 s (P<0.05) and after midcervical vagi section to 1.99+/-0.24 s (P<0.01). In post-apnoeic breathing tidal volume (V(T)) was reduced in all neural states. Anandamide evoked hypotension in the intact and SLNs neurotomized rats. Midcervical vagotomy reduced this fall in blood pressure. Both antagonists ruthenium red and AM281 eliminated post-anandamide apnoea and hypotension but had no effect on post-apnoeic depression of V(T). Subsequent SLNs and cervical vagi sections did not eliminate but only reduced post-anandamide depression of breathing. Midcervical vagotomy lessened anandamide-induced hypotension. Apnoeic and hypotensive response to anandamide was mediated by both VR1 and CB1 receptors. Post-anandamide decline of V(T) might depend on different type of receptors.

Topics: Afferent Pathways; Animals; Apnea; Arachidonic Acids; Blood Pressure; Calcium Channel Blockers; Cannabinoid Receptor Modulators; Endocannabinoids; Heart; Hypotension; Injections, Intravenous; Male; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Respiration; Ruthenium Red; TRPV Cation Channels; Vagotomy; Vagus Nerve

We recently demonstrated that activation of the pulmonary sensory neurons plays a critical role in prevention of endotoxin-induced shock by releasing calcitonin gene-related peptide (CGRP) in rats. CGRP increased the endothelial production of prostacyclin (PGI(2)) in the lungs, thereby preventing endotoxin-induced shock response by inhibiting tumor necrosis factor-alpha (TNF-alpha) production. Since antithrombin (AT) enhances sensory neuron activation, we hypothesized that AT might reduce endotoxin-induced hypotension by enhancing the activation of pulmonary sensory neurons in rats. We examined this possibility using a rat model of endotoxin shock. AT-induced effects including reduction of hypotension (n = 5) and inhibition of induction of iNOS (n = 4 or 5) and TNF- alpha (n = 5) in the lungs of endotoxin-treated animals were completely reversed by pretreatment with capsazepine (CPZ) (n = 4 or 5), a vanilloid receptor antagonist, or CGRP(8-37), a CGRP receptor antagonist (n = 4 or 5). AT enhanced endotoxin-induced increases in lung tissue levels of CGRP (n = 4), but this effect of AT was not seen in animals pretreated with CPZ (n = 4). CGRP produced therapeutic effects (n = 5) similar to those induced by AT, and such therapeutic effects were completely abrogated by pretreatment with indomethacin (n = 4). AT increased CGRP release from cultured dorsal root ganglion neurons only in the presence of anandamide (n = 5), and AT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (n = 5). AT markedly increased intracellular levels of cAMP in the presence of anandamide (n = 5). These results strongly suggested that AT might reduce endotoxin-induced hypotension in rats by enhancing activation of sensory neurons via activation of protein kinase A.

Topics: Animals; Antithrombins; Arachidonic Acids; Blood Pressure; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Capsaicin; Carbazoles; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinase Type II; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase Inhibitors; Disease Models, Animal; Endocannabinoids; Endotoxins; Ganglia, Spinal; Gene Expression Regulation; Hypotension; Indoles; Indomethacin; Lung; Male; Neurons, Afferent; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Peptide Fragments; Polyunsaturated Alkamides; Protein Kinase Inhibitors; Pyrroles; Rats; Rats, Wistar; Receptors, Calcitonin Gene-Related Peptide; RNA, Messenger; TRPV Cation Channels; Tumor Necrosis Factor-alpha

Arachidonylethanolamide (anandamide, AEA) is believed to be the endogenous ligand of the cannabinoid CB(1) and CB(2) receptors. CB(1) receptors have been found localized on fibers in the spinal trigeminal tract and spinal trigeminal nucleus caudalis. Known behavioral effects of anandamide are antinociception, catalepsy, hypothermia, and depression of motor activity, similar to Delta(9)-tetrahydocannanbinol, the psychoactive constituent of cannabis. It may be a possible therapeutic target for migraine. In this study, we looked at the possible role of the CB(1) receptor in the trigeminovascular system, using intravital microscopy to study the effects of anandamide against various vasodilator agents. Anandamide was able to inhibit dural blood vessel dilation brought about by electrical stimulation by 50%, calcitonin gene-related peptide (CGRP) by 30%, capsaicin by 45%, and nitric oxide by 40%. CGRP(8-37) was also able to attenuate nitric oxide (NO)-induced dilation by 50%. The anandamide inhibition was reversed by the CB(1) receptor antagonist AM251. Anandamide also reduced the blood pressure changes caused by CGRP injection, this effect was not reversed by AM251. It would seem that anandamide acts both presynaptically, to prevent CGRP release from trigeminal sensory fibers, and postsynaptically to inhibit the CGRP-induced NO release in the smooth muscle of dural arteries. CB(1) receptors seem to be involved in the NO/CGRP relationship that exists in causing headache and dural blood vessel dilation. It also seems that some of the blood pressure changes caused by anandamide are mediated by a noncannabinoid receptor, as AM251 was unable to reverse these effects. It can be suggested that anandamide is tonically released to play some form of modulatory role in the trigeminovascular system.

Topics: Animals; Arachidonic Acids; Blood Pressure; Calcitonin Gene-Related Peptide; Capsaicin; Electric Stimulation; Endocannabinoids; Hypotension; Male; Neurons; Nitroprusside; Pain; Peptide Fragments; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Trigeminal Caudal Nucleus; Vasodilation

The endocannabinoid anandamide and cannabinoid (CB) receptors have been implicated in the hypotension in various forms of shock and in advanced liver cirrhosis. Anandamide also activates vanilloid TRPV(1) receptors on sensory nerve terminals, triggering the release of calcitonin gene-related peptide which elicits vasorelaxation in isolated blood vessels in vitro. However, the contribution of TRPV(1) receptors to the in vivo hypotensive effect of anandamide is equivocal. We compared the cardiac performance of anaesthetized TRPV(1) knockout (TRPV(1)(-/-)) mice and their wild-type (TRPV(1)(+/+)) littermates and analysed in detail the haemodynamic effects of anandamide using the Millar pressure-volume conductance catheter system. Baseline cardiovascular parameters and systolic and diastolic function at different preloads were similar in TRPV(1)(-/-) and TRPV(1)(+/+) mice. The predominant hypotensive response to bolus intravenous injections of anandamide and the associated decrease in cardiac contractility and total peripheral resistance (TPR) were similar in TRPV(1)(+/+) and TRPV(1)(-/-) mice, as was the ability of the CB(1) receptor antagonist SR141716 to completely block these effects. In TRPV(1)(+/+) mice, this hypotensive response was preceded by a transient, profound drop in cardiac contractility and heart rate and an increase in TPR, followed by a brief pressor response, effects which were unaffected by SR141716 and were absent in TRPV(1)(-/-) mice. These results indicate that mice lacking TRPV(1) receptors have a normal cardiovascular profile and their predominant cardiovascular depressor response to anandamide is mediated through CB(1) receptors. The role of TRPV(1) receptors is limited to the transient activation of the Bezold-Jarisch reflex by very high initial plasma concentrations of anandamide.

Topics: Animals; Arachidonic Acids; Blood Pressure; Cannabinoid Receptor Modulators; Capsaicin; Endocannabinoids; Hypotension; Ion Channels; Male; Mice; Mice, Knockout; Neurons, Afferent; Polyunsaturated Alkamides; Reflex; Sympathetic Nervous System; TRPV Cation Channels; Ventricular Pressure

The results of vasorespiratory studies in rats anaesthetised with pentobarbital show that (+/-) cannabidiol, a cannabinoid that lacks psychotropic actions and is inactive at cannabinoid (CB) receptors, does not affect respiration or blood pressure when injected (1-2000 microg; 3.2-6360 nmol i.a.). Cannabidiol in doses up to 2 mg (6360 nmol) i.a. or i.v. did not affect the fall in mean blood pressure or the increase in ventilation (respiratory minute volume) caused by capsaicin and high doses of anandamide, responses that are mediated by activation of vanilloid VR1 (TRPV1) receptors in this species. Similar results were obtained with (-) cannabidiol (30-100 microg i.a.; 95-318 nmol). It has previously been shown using human embryonic kidney (HEK) cells over-expressing vanilloid human VR1 (hVR1) receptors that cannabidiol is a full agonist at vanilloid VR1 receptors in vitro. However, in the intact rat cannabidiol lacked vanilloid VR1 receptor agonist effects. We conclude that there are substantial functional differences between human and rat vanilloid VR1 receptors with respect to the actions of cannabidiol as an agonist at vanilloid VR1 receptors. Studies in vivo show that cannabidiol lacks any significant effect on mean blood pressure or respiratory minute volume when injected i.a. or i.v., and that this cannabinoid does not modulate the vanilloid VR1 receptor-mediated cardiovascular and ventilatory changes reflexly evoked by capsaicin or anandamide in rats anaesthetised with pentobarbital.

Topics: Anesthesia; Animals; Arachidonic Acids; Blood Pressure; Cannabidiol; Capsaicin; Dose-Response Relationship, Drug; Endocannabinoids; Hyperventilation; Hypotension; Male; Polyunsaturated Alkamides; Pulmonary Ventilation; Rats; Rats, Wistar; Receptors, Drug

Macrophage-derived endocannabinoids have been implicated in endotoxin (lipopolysaccharide (LPS))-induced hypotension, but the endocannabinoid involved and the mechanism of its regulation by LPS are unknown. In RAW264.7 mouse macrophages, LPS (10 ng/ml) increases anandamide (AEA) levels >10-fold via CD14-, NF-kappaB-, and p44/42-dependent, platelet-activating factor-independent activation of the AEA biosynthetic enzymes, N-acyltransferase and phospholipase D. LPS also induces the AEA-degrading enzyme fatty acid amidohydrolase (FAAH), and inhibition of FAAH activity potentiates, whereas actinomycin D or cycloheximide blocks the LPS-induced increase in AEA levels and N-acyltransferase and phospholipase D activities. In contrast, cellular levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) are unaffected by LPS but increased by platelet-activating factor. LPS similarly induces AEA, but not 2-AG, in mouse peritoneal macrophages where basal AEA levels are higher, and the LPS-stimulated increase in AEA is potentiated in cells from FAAH-/- as compared with FAAH+/+ mice. Intravenous administration of 107 LPS-treated mouse macrophages to anesthetized rats elicits hypotension, which is much greater in response to FAAH-/- than FAAH+/+ cells and is susceptible to inhibition by SR141716, a cannabinoid CB1 receptor antagonist. We conclude that AEA and 2-AG synthesis are differentially regulated in macrophages, and AEA rather than 2-AG is a major contributor to LPS-induced hypotension.

Topics: Acyltransferases; Amidohydrolases; Animals; Arachidonic Acids; Cell Line; Endocannabinoids; Glycerides; Hypotension; Kinetics; Lipopolysaccharide Receptors; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphatidylethanolamines; Phosphatidylinositol 3-Kinases; Phospholipase D; Platelet Activating Factor; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley

Advanced cirrhosis is associated with generalized vasodilation of unknown origin, which contributes to mortality. Cirrhotic patients are endotoxemic, and activation of vascular cannabinoid CB1 receptors has been implicated in endotoxin-induced hypotension. Here we show that rats with biliary cirrhosis have low blood pressure, which is elevated by the CB1 receptor antagonist SR141716A. The low blood pressure of rats with CCl4-induced cirrhosis was similarly reversed by SR141716A, which also reduced the elevated mesenteric blood flow and portal pressure. Monocytes from cirrhotic but not control patients or rats elicited SR141716A-sensitive hypotension in normal recipient rats and showed significantly elevated levels of anandamide. Compared with non-cirrhotic controls, in cirrhotic human livers there was a three-fold increase in CB1 receptors on isolated vascular endothelial cells. These results implicate anandamide and vascular CB1 receptors in the vasodilated state in advanced cirrhosis and indicate a novel approach for its management.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Chromatography, High Pressure Liquid; Endocannabinoids; Endothelium, Vascular; Hypotension; Liver Cirrhosis; Male; Mass Spectrometry; Monocytes; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Vasodilation

We sought to determine whether endocannabinoids influence hemodynamic variables in experimental models of acute myocardial infarction (MI).. Hypotension and cardiogenic shock are common complications in acute MI. Cannabinoids are strong vasodilators, and endocannabinoids are involved in hypotension in hemorrhagic and septic shock.. The early effect of left coronary artery ligation on hemodynamic variables was measured in rats pretreated with the selective cannabinoid(1) receptor (CB(1)) antagonist SR141716A (herein referred to as SR, 6.45 micromol/kg body weight intravenously) or vehicle. Endocannabinoids produced in monocytes and platelets were quantified by liquid chromatography/mass spectrometry (LC/MS), and their effects on blood pressure and vascular reactivity were determined.. After MI, mean arterial pressure (MAP) dropped from 126 +/- 2 mm Hg to 76 +/- 3 mm Hg in control rats, whereas the decline in blood pressure was smaller (from 121 +/- 3 mm Hg to 108 +/- 7 mm Hg, p < 0.01) in rats pretreated with SR. SR increased the tachycardia that follows MI (change [Delta] in heart rate [HR] = 107 +/- 21 beats/min vs. 49 +/- 9 beats/min in control rats, p < 0.05). The MI sizes were the same in control rats and SR-treated rats. Circulating monocytes and platelets isolated 30 min after MI only decreased MAP when injected into untreated rats (DeltaMAP = -20 +/- 5 mm Hg), but not in SR-pretreated rats. The endocannabinoids anandamide and 2-arachidonyl glycerol were detected in monocytes and platelets isolated after MI, but not in cells from sham rats. Survival rates at 2 h after MI were 70% for control rats and 36% for SR-treated rats (p < 0.05). Endothelium-dependent arterial relaxation was attenuated in SR-treated rats (maximal relaxation: 44 +/- 3% [p < 0.01] vs. 70 +/- 3% in control rats) and further depressed by SR treatment (24 +/- 5%, p < 0.01 vs. MI placebo).. Cannabinoids generated in monocytes and platelets contribute to hypotension in acute MI. Cannabinoid(1) receptor blockade restores MAP but increases 2-h mortality, possibly by impairing endothelial function.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Endocannabinoids; Female; Glycerides; Hypotension; Myocardial Infarction; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Shock, Cardiogenic; Vasodilation

Anandamide (ANA), an endogenous cannabinoid, can be generated by activated macrophages during endotoxin shock and is thought to be a paracrine contributor to hypotension. We discovered that ANA in saline/ethanol solution and in serum was efficiently adsorbed in a polymyxin B (PMB)-immobilized beads column and eluted with ethanol. We confirmed the direct binding of PMB to ANA by using surface plasmon resonance. The adsorption of ANA by PMB may abolish the diverse effects of ANA such as hypotension, immunosuppression, and cytotoxicity, and may suggest a new therapeutic strategy for endotoxin shock.

Topics: Adsorption; Animals; Arachidonic Acids; Blood Proteins; Cannabinoids; Cell Death; Chromatography, Affinity; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Endocannabinoids; Humans; Hypotension; Lipopolysaccharides; Microspheres; PC12 Cells; Polymyxin B; Polyunsaturated Alkamides; Protein Binding; Rats; Shock, Septic; Surface Plasmon Resonance

Macrophages are the primary cellular targets of bacterial lipopolysaccharide (LPS), but the role of macrophage-derived cytokines in LPS-induced septic shock is uncertain. Recent evidence indicates that activation of peripheral CB1 cannabinoid receptors contributes to hemorrhagic hypotension and that macrophage-derived anandamide as well as unidentified platelet-derived substances may be contributing factors. Here we demonstrate that rat platelets contain the endogenous cannabinoid 2-arachidonyl glyceride (2-AG), as identified by reverse phase high-performance liquid chromatography, gas chromatography, and mass spectrometry, and that in vitro exposure of platelets to LPS (200 microg/ml) markedly increases 2-AG levels. LPS-stimulated, but not control, macrophages contain anandamide, which is undetectable in either control or LPS-stimulated platelets. Prolonged hypotension and tachycardia are elicited in urethane-anesthetized rats treated 1) with LPS (15 mg/kg i.v.); 2) with macrophages plus platelets isolated from 3 ml of blood from an LPS-treated donor rat; or 3) with rat macrophages or 4) platelets preincubated in vitro with LPS (200 microg/ml). In all four cases, the hypotension but not the tachycardia is prevented by pretreatment of the recipient rat with the CB1 receptor antagonist SR141716A (3 mg/kg i.v.), which also inhibits the hypotensive response to anandamide or 2-AG. The hypotension elicited by LPS-treated macrophages or platelets remains unchanged in the absence of sympathetic tone or after blockade of nitric oxide synthase. These findings indicate that platelets and macrophages generate different endogenous cannabinoids, and that both 2-AG and anandamide may be paracrine mediators of endotoxin-induced hypotension via activation of vascular CB1 receptors.

Topics: Animals; Arachidonic Acids; Blood Platelets; Cannabinoids; Cells, Cultured; Dronabinol; Endocannabinoids; Glycerides; Hypotension; Lipopolysaccharides; Macrophages; Male; Nitric Oxide; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant