Seyed Ali Gaskari1, Hongqun Liu1, Charlotte D'Mello1, George Kunos2, Samuel S Lee3. 1. Liver Unit, University of Calgary, Calgary, Canada. 2. Laboratory of Physiologic Studies, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. 3. Liver Unit, University of Calgary, Calgary, Canada. Electronic address: samlee@ucalgary.ca.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: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: Jie Liu; Sándor Batkai; Pál Pacher; Judith Harvey-White; Jens A Wagner; Benjamin F Cravatt; Bin Gao; George Kunos Journal: J Biol Chem Date: 2003-08-29 Impact factor: 5.157
Authors: Luis M Ruilope; Jean-Pierre Després; André Scheen; Xavier Pi-Sunyer; Guiseppe Mancia; Alberto Zanchetti; Luc Van Gaal Journal: J Hypertens Date: 2008-02 Impact factor: 4.844
Authors: Csaba Matyas; Katalin Erdelyi; Eszter Trojnar; Suxian Zhao; Zoltan V Varga; Janos Paloczi; Partha Mukhopadhyay; Balazs T Nemeth; György Haskó; Resat Cinar; Robim M Rodrigues; Yeni Ait Ahmed; Bin Gao; Pal Pacher Journal: Hepatology Date: 2020-01-24 Impact factor: 17.298