The Effect of Long-Term Administration of Fatty Acid Amide Hydrolase Inhibitor URB597 on Oxidative Metabolism in the Heart of Rats with Primary and Secondary Hypertension

Abstract

Fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597) may influence redox balance and blood pressure through the modulation of endocannabinoids levels. Therefore, this study aimed to compare changes in oxidative metabolism and apoptosis in the hearts of rats with spontaneous hypertension (SHR) and secondary hypertension (11-deoxycorticosterone acetate; DOCA-salt rats) treated by URB597 via intraperitoneal injection for 14 days. The results showed that URB597 decreased the activity of NADPH and xanthine oxidases in both groups of rats. Moreover, in the heart of SHR rats, URB597 led to an increase of enzymatic and nonenzymatic antioxidant activity and levels (catalase, vitamin C, glutathione/glutathione disulfide [GSH/GSSG]) and upregulation of the thioredoxin system; however, NRf2 expression was downregulated. The opposite effect in relation to Nrf2 activity and the thioredoxin system was observed in DOCA-salt rats after URB597 administration. Despite improvement in antioxidant parameters, URB597 enhanced oxidative modifications of phospholipids (4-hydroxynonenal and isoprostanes) and proteins (carbonyl groups) in SHR heart, whereas 4-hydroxynonenal and carbonyl groups levels decreased in the heart of DOCA-salt rats. Obtained results suggest that examined lipid mediators are involved in peroxisome proliferator-activated receptors (PPAR)-independent and PPAR-dependent modulation of cardiac inflammatory reactions. Furthermore, decreased expression of pro-apoptotic proteins (Bax and caspase 3 and 9) was observed after URB597 administration in the heart of both groups of hypertensive rats, whereas expression of the antiapoptotic protein (Bcl-2) increased in SHR rats. Long-term administration of URB597 altered cardiac redox status depending on the type of hypertension. URB597 enhanced oxidative metabolism and reduced pro-apoptotic factors in the heart of SHR rats, increasing the probability of heart metabolic disorders occurrence or progression.

Chronic Cannabidiol Administration Fails to Diminish Blood Pressure in Rats with Primary and Secondary Hypertension Despite Its Effects on Cardiac and Plasma Endocannabinoid System, Oxidative Stress and Lipid Metabolism

“…The elevated BP was connected with a redox imbalance, similarly to our previous papers [48,49]. Thus, GSSG increased and GSH decreased in heart and plasma of both hypertensive models.…”

“…They may have positive effects and be used as a target in pharmacotherapy [46] but in some cases, can also exert untoward actions [47]. In this context, one should keep in mind that the FAAH inhibitor URB597 and hypertension may affect cardiac and plasma oxidative stress, endocannabinoid levels and lipid metabolism in a model-dependent manner [48,49].…”

The Effects of Cannabidiol, a Non-Intoxicating Compound of Cannabis, on the Cardiovascular System in Health and Disease

“…Inhibition of FAAH can exert a hypotensive effect, which depends on the age of the animals and experimental model of hypertension. Endocannabinoids has also shown a modulating effect of on oxidative stress and inflammation in hypertension, which are the important part of the pathogenesis of this disease [19,20,27,113,114]. Taking into account both the vasorelaxant effect, modulation of inflammatory and oxidative processes and endocannabinoid metabolism [23,27,30,31,71], certain benefits may be expected from their use in hypertension.…”

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

“…These cell-type specific differences can be associated not only with different expression of receptors, but also with differences in the levels of endocannabinoid metabolic pathways in different cells. The main AEA and 2-AG metabolizing enzymes are FAAH and monoacylglycerol lipase (MAGL), respectively, which degrade endocannabinoids to arachidonic acid [121,122]. Other enzymes significantly involved in endocannabinoid metabolism are COX and LOX, which metabolize endocannabinoids to eicosanoids [123].…”