Fatty acid amide hydrolase inhibitor (URB597) as a regulator of myocardial lipid metabolism in spontaneously hypertensive rats.

Highlights • Fatty acid amide hydrolase inhibition by URB597 treatment decreases blood pressure in spontaneously hypertensive rats. • URB597 upregulates intramyocardial fatty acids metabolism in normotensive as well as hypertensive conditions. • URB597 enhances myocardial fatty acids uptake but not oxidation in spontaneously hypertensive rats. Abstract Pressure overload, which is typical of hypertension, is known to evoke alterations not only in the morphology of the heart but also in the preference of myocardial energetic substrates usage. Nowadays, the endocannabinoid system (ECS) serves as a potential therapeutic target for cardiovascular disorders and, simultaneously, affects whole body metabolism homeostasis. Therefore, an open question is whether ECS, apart from decreasing blood pressure, also affects cardiac muscle metabolism in hypertensive conditions. All experiments were conducted on a genetic model of primary hypertension i.e. spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKY) served as a normotensive control. ECS was chronically activated by 2-weeks intraperitoneal injections of fatty acid amide hydrolase (FAAH) inhibitor – URB597. Lipid analyses in the left ventricle and serum were based on ex vivo heart perfusion in Langendorff perfusion system, thin layer chromatography, and gas liquid chromatography. The total expression of selected proteins was determined using Western blot as well as immunohistochemical techniques. As expected, URB597 markedly reduced systolic as well as mean blood pressures in SHRs. Moreover, prolonged FAAH inhibition resulted in stimulation of 3H-palmitate uptake and incorporation into different lipid fractions in cardiomyocytes in the hypertensive as well as normotensive conditions. An increase in fatty acid oxidation caused by URB597 treatment was observed only in WKY rats, but not SHRs, and was accompanied by an elevation in peroxisome proliferator-activated receptor alpha (PPARα) and β-hydroxyacyl-CoA dehydrogenase (β-HAD) expressions. Chronic activation of ECS significantly upregulates palmitate uptake and its esterification but not oxidation in the SHR's myocardium. [ABSTRACT FROM AUTHOR]