Central cannabinoid 1 receptor antagonist administration prevents endotoxic hypotension affecting norepinephrine release in the preoptic anterior hypothalamic area

Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York 12208, USA.
Shock (Augusta, Ga.) (Impact Factor: 3.05). 04/2009; 32(6):614-20. DOI: 10.1097/SHK.0b013e3181a4fd8f
Source: PubMed


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.

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Available from: Loren H Parsons, Sep 23, 2014
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    • "Saline administration did not affect extracellular fluid NE concentrations in the POA significantly (Fig. 1). These data show that 15 mg/kg LPS elevates extracellular NE in the POA as shown previously for a lower dose of LPS (Villanueva et al., 2009). "
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    ABSTRACT: This study tested the hypothesis that lipopolysaccharide (LPS) lowers arterial pressure through two different mechanisms depending on the dose. Previously, we found that a low hypotensive dose of LPS (1mg/kg) lowers arterial pressure by activating vagus nerve afferents. Here we report that hypotension evoked by high dose LPS (15mg/kg) can be prevented by injecting lidocaine into the OVLT but not by vagotomy or inactivation of the NTS. The hypotension produced by both LPS doses was correlated with elevated extracellular norepinephrine concentrations in the POA and prevented by blocking alpha-adrenergic receptors. Thus, initiation of endotoxic hypotension is dose-related, mechanistically. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Neuroimmunology 05/2015; 285. DOI:10.1016/j.jneuroim.2015.05.023 · 2.47 Impact Factor
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    • "Binding of LPS to specific receptors in brain endothelial cells triggers a series of signaling events leading to the increase of cytokine production [28]. These cytokines participate in the disruption of BBB integrity and induce brain vessel dilation [21,29]. TNF-α is a major mediator in septic encephalopathy, as mice deficient in TNF-receptor 1 are more resistant to LPS-induced changes [30]. "
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    ABSTRACT: The phytocannabinoid cannabidiol (CBD) exhibits antioxidant and antiinflammatory properties. The present study was designed to explore its effects in a mouse model of sepsis-related encephalitis by intravenous administration of lipopolysaccharide (LPS). Vascular responses of pial vessels were analyzed by intravital microscopy and inflammatory parameters measured by qRT-PCR. CBD prevented LPS-induced arteriolar and venular vasodilation as well as leukocyte margination. In addition, CBD abolished LPS-induced increases in tumor necrosis factor-alpha and cyclooxygenase-2 expression as measured by quantitative real time PCR. The expression of the inducible-nitric oxide synthase was also reduced by CBD. Finally, preservation of Blood Brain Barrier integrity was also associated to the treatment with CBD. These data highlight the antiinflammatory and vascular-stabilizing effects of CBD in endotoxic shock and suggest a possible beneficial effect of this natural cannabinoid.
    Journal of Neuroinflammation 01/2011; 8(1):5. DOI:10.1186/1742-2094-8-5 · 5.41 Impact Factor
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    • "Recent studies indeed have suggested that CB 1 receptor antagonists may exert protective effects in multiple preclinical disease models ranging from hepatic steatosis [48], ischemic–reperfusion injury [49], and endotoxin shock [50] [51] to atherosclerosis [9] [10] [16] and cardiomyopathy [7]. Chronic rimonabant treatment decreases the elevated serum/plasma levels of TNF-α, RANTES (regulated on activation, normal T cell expressed, and secreted), and MCP-1; restores plasma levels of the anti-inflammatory hormone adiponectin in obese Zucker fa/fa rats [52]; and decreases NF-κB activation and consequent iNOS expression in mitogen-stimulated human peripheral blood mononuclear cells [53]. "
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    ABSTRACT: Previous studies have suggested that increased levels of endocannabinoids in various cardiovascular disorders (e.g., various forms of shock, cardiomyopathies, atherosclerosis) through the activation of CB(1) cannabinoid receptors may promote cardiovascular dysfunction and tissue injury. We have investigated the role of the main endocannabinoid anandamide-metabolizing enzyme (fatty acid amide hydrolase; FAAH) in myocardial injury induced by an important chemotherapeutic drug, doxorubicin (DOX; known for its cardiotoxicity mediated by increased reactive oxygen and nitrogen species generation), using well-established acute and chronic cardiomyopathy models in mice. The DOX-induced myocardial oxidative/nitrative stress (increased 4-hydroxynonenal, protein carbonyl, and nitrotyrosine levels and decreased glutathione content) correlated with multiple cell death markers, which were enhanced in FAAH knockout mice exhibiting significantly increased DOX-induced mortality and cardiac dysfunction compared to their wild type. The effects of DOX in FAAH knockouts were attenuated by CB(1) receptor antagonists. Furthermore, anandamide induced enhanced cell death in human cardiomyocytes pretreated with FAAH inhibitor and enhanced sensitivity to ROS generation in inflammatory cells of FAAH knockouts. These results suggest that in pathological conditions associated with acute oxidative/nitrative stress FAAH plays a key role in controlling the tissue injury that is, at least in part, mediated by the activation of CB(1) receptors by endocannabinoids.
    Free Radical Biology and Medicine 11/2010; 50(1):179-95. DOI:10.1016/j.freeradbiomed.2010.11.002 · 5.74 Impact Factor
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