Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats

Toxicol Appl Pharmacol. 2016 Jun 15;301:31-41. doi: 10.1016/j.taap.2016.04.006. Epub 2016 Apr 13.

Abstract

Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB1 receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB1 receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis.

Keywords: Endocannabinoid system; Hypertension; Liver; Oxidative stress; URB597.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Animals
  • Benzamides / pharmacology*
  • Carbamates / pharmacology*
  • Catalase / metabolism
  • Desoxycorticosterone Acetate
  • Endocannabinoids / metabolism*
  • Glutathione / metabolism
  • Glutathione Disulfide / metabolism
  • Glutathione Peroxidase / metabolism
  • Glutathione Transferase / metabolism
  • Hypertension / chemically induced
  • Hypertension / metabolism*
  • Liver / drug effects*
  • Male
  • Monoacylglycerol Lipases / metabolism
  • Phospholipases A2 / metabolism
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Receptor, Cannabinoid, CB1 / metabolism
  • Superoxide Dismutase / metabolism

Substances

  • Benzamides
  • Carbamates
  • Endocannabinoids
  • Reactive Oxygen Species
  • Receptor, Cannabinoid, CB1
  • cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
  • Desoxycorticosterone Acetate
  • Catalase
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • Glutathione Transferase
  • Monoacylglycerol Lipases
  • Phospholipases A2
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • Glutathione
  • Glutathione Disulfide