title: Blunted cardiac response to hemorrhage in cirrhotic rats is mediated by local macrophage-released endocannabinoids.
abstract: OBJECTIVE
  Cirrhosis is associated with blunted cardiovascular response to stimuli such as hemorrhage, but the mechanism remains unclear. We aimed to clarify the role of endocannabinoids in blunted hemorrhage response in cirrhotic rats.
  
  
  METHODS
  Cirrhosis was induced by bile duct ligation (BDL). Hemodynamics were measured. Cannabinoid receptor-1 (CB1) antagonist, AM251, and macrophage inhibitor gadolinium chloride (GdCl3) were administered. Myocardial levels of anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) were measured and resident monocytes and macrophages quantified by immunohistochemistry. Isolated cardiomyocyte contractility was measured before and after incubation with monocytes from BDL and sham controls.
  
  
  RESULTS
  Hemorrhage significantly decreased arterial pressure and left ventricular dP/dT. After hemorrhage, these changes quickly reversed in controls, but were severely prolonged in BDL rats. Chronic AM251 treatment restored this impaired response. AEA and 2-AG levels were increased in BDL hearts and further increased after hemorrhage. Sham hearts showed virtually no monocytes or macrophages before or after hemorrhage, whereas BDL hearts had significantly more white blood cells which further increased after hemorrhage. GdCl3 treatment significantly reduced cardiac endocannabinoid levels both at baseline and after hemorrhage. This treatment also restored cardiovascular response to hemorrhage in BDL rats but did not affect sham controls. Monocytes isolated from BDL rats more potently inhibited cardiomyocyte contractility than sham control monocytes.
  
  
  CONCLUSIONS
  The cirrhotic heart showed increased monocyte recruitment and endocannabinoid levels. CB1 blockade or GdCl3 treatment restored blunted cardiovascular response to hemorrhage. Endocannabinoids released by monocytes blunt cardiac response to hemorrhage. Preventing monocyte recruitment or blocking endocannabinoid signaling may improve cardiovascular homeostasis in cirrhosis.
authors: Liver Unit, University of Calgary, Calgary, Canada.
authors: Seyed Ali
authors: SA
authors: Gaskari
authors: Liver Unit, University of Calgary, Calgary, Canada.
authors: Hongqun
authors: H
authors: Liu
authors: Liver Unit, University of Calgary, Calgary, Canada.
authors: Charlotte
authors: C
authors: D'Mello
authors: Laboratory of Physiologic Studies, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors: George
authors: G
authors: Kunos
authors: Liver Unit, University of Calgary, Calgary, Canada. Electronic address: samlee@ucalgary.ca.
authors: Samuel S
authors: SS
authors: Lee
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D063388:Endocannabinoids / Q000378:metabolism / Q000502:physiology*; D005682:Gadolinium / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism; D006470:Hemorrhage / Q000150:complications / Q000503:physiopathology*; D008103:Liver Cirrhosis / Q000150:complications / Q000503:physiopathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C094503:glyceryl 2-arachidonate; D005682:Gadolinium; C038958:gadolinium chloride; C078814:anandamide
keywords: AM251; CB-1; Cardiomyopathy; Cirrhosis; Endocannabinoids; Hemorrhage; Macrophages; Monocytes
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