Abstract
Hypertension coincides with myocardial alternations in lipid (including sphingolipids) and glucose metabolism. The latest data indicate that accumulation of metabolically active lipids, especially ceramide (CER) and diacylglycerol (DAG) significantly influences intracellular signaling pathways along with inducing insulin resistance. Since, it was demonstrated that the endocannabinoid system (ECS) affects myocardial metabolism it seems to be a relevant tool in alleviating metabolic disturbances within the cardiac muscle due to hypertension. All designed experiments were conducted on the animal model of primary hypertension, i.e., spontaneously hypertensive rat (SHR) with chronic ECS activation by injections of fatty acid amide hydrolase (FAAH) inhibitor—URB597. Lipid analyses were performed using chromatography techniques (gas liquid, thin layer, and high performance liquid chromatography). Colorimetric and immunoenzymatic testes were applied in order to determine plasma concentrations of insulin and glucose. Total myocardial expression of selected proteins was measured by Western blotting and/or immunohistochemistry methods. SHRs exhibited significantly intensified myocardial de novo pathway of CER synthesis as well as DAG accumulation compared to the control Wistar Kyoto rats. Besides, intramyocardial level of potentially cardioprotective sphingolipid, i.e., sphingosine-1-phosphate was considerably decreased in SHRs, whereas URB597 treatment restored the level of this derivative. Unexpectedly, ECS upregulation protected overloaded cardiac muscle against CER and DAG accumulation. Moreover, chronic URB597 treatment improved intramyocardial insulin signaling pathways in both normotensive and hypertensive conditions. It seems that the enhanced ECS triggers protective mechanisms in the heart due to decreasing the level of lipid mediators of insulin resistance.
Highlights
Nowadays, hypertension is one of the most common civilization diseases according to the WorldHealth Organization
It is important to note that present study, which was based on a genetic model of primary hypertension (SHRs), has revealed the link between chronic activation of endocannabinoid system (ECS) by URB597 treatment (2-week) and insulin signaling pathway in cardiomyocytes subjected to the increased afterload
In the same research we revealed that chronic URB597 treatment enhances fatty acid oxidation only in normotensive conditions, which was linked with an elevation in peroxisome proliferator-activated receptor alpha (PPARα) expression, with parallel no effects in spontaneously hypertensive rat (SHR) [20]
Summary
Hypertension is one of the most common civilization diseases according to the WorldHealth Organization. The incidence of hypertension has risen dramatically since in 2017 the recommended threshold for its diagnosis was established at 130/80 mmHg Chronically elevated blood pressure (BP) triggers ventricular hypertrophy and contractile impairments in cardiac muscle together with its clinical manifestations (cardiovascular diseases, CVDs). At present relieving health consequences of hypertension and related myocardial metabolic alternations is critical. For this purpose a suitable and commonly used genetic model of primary hypertension, i.e., spontaneously hypertensive rats (SHRs), has been selected. These animals with age spontaneously develop hypertension, in which systolic blood pressure can reach the level of 180-200 mmHg [5]
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