PP22 - Liver antioxidant defense after FAAH inhibitor - URB-597 administration to DOCA-salt-induced hypertension in rats

Abstract

Oxidative stress is involved in progression of hypertension therefore the influence on endocannabinoids level may be useful in pharmacotherapy. The increase in the main endocannabinoid - anandamide level may be attained by inhibition of FAAH –enzyme responsible for anandamide degradation. Therefore the aim of this study was to exam complex dependencies between endocannabinoid system and oxidative stress formation as well as consequences of observed changes in the liver of hypertensive rats [DOCA-salt] receiving URB597 - FAAH inhibitor. 4-5 weeks old rats after nephrectomy have been receiving DOCA twice weekly and replacement of drinking water with 1% NaCl solution for 6 weeks. One group of these rats was injected i.p. with URB597 (1 mg/kg b.w.) for last 14 days. It has been shown that URB597 given to hypertensive rats caused an increase in the level of AEA and expression of CB1, CB2 receptor as well as decrease in the level of 2-AG and the activity of FAAH and MAGL what was accompanied by an increase in free arachidonic acid. URB597 caused also the significant changes in liver redox status. The ROS, GSH, GSSG, vitamin A levels and activity Cu,Zn-SOD, CAT, GSH-T were increased, while the activity of GSH-Px, GSSG-R as well as the level of vitamin C, E were diminished in comparison to hypertensive rats. The antioxidant defense was changes also on transcriptional level. Results showed that URB597 administration enhanced level of Nrf2 and its activator - cJun and caused decrease in other Nrf2 activators [KAP1, p21, p62, ERK1/2, pERK1/2] and its inhibitors [Keap1, Bach1]. Moreover expression of HO-1 was decreased. The consequence of above disturbances in redox status was increase in oxidative damages of lipid (4-HNE, MDA, 8-isoprostanes), protein (dityrosine, tryptophane, carbonyl group) and DNA (8-OH dG). This work was supported by Ministry of Science and Higher Education grant No. 40/KNOW/2013.