RESUMO
The diversity of pathogenetic mechanisms underlying arterial hypertension leads to the necessity to devise a personalized approach to the diagnosis and treatment of the disease. Metabolomics is one of the promising methods for personalized medicine, as it provides a comprehensive understanding of the physiological processes occurring in the body. The metabolome is a set of low-molecular substances available for detection in a sample and representing intermediate and final products of cell metabolism. Changes in the content and ratio of metabolites in the sample mark the corresponding pathogenetic mechanisms by highlighting them, which is especially important for such a multifactorial disease as arterial hypertension. To identify metabolomic markers for hypertensive conditions of different origins, three forms of arterial hypertension (AH) were studied: rats with hereditary AH (ISIAH rat strain); rats with AH induced by L-NAME administration (a model of endothelial dysfunction with impaired NO production); rats with AH caused by the administration of deoxycorticosterone in combination with salt loading (hormone-dependent form - DOCA-salt AH). WAG rats were used as normotensive controls. 24-hour urine samples were collected from all animals and analyzed by quantitative NMR spectroscopy for metabolic profiling. Then, potential metabolomic markers for the studied forms of hypertensive conditions were identified using multivariate statistics. Analysis of the data obtained showed that hereditary stress-induced arterial hypertension in ISIAH rats was characterized by a decrease in the following urine metabolites: nicotinamide and 1-methylnicotinamide (markers of inflammatory processes), N- acetylglutamate (nitric oxide cycle), isobutyrate and methyl acetoacetate (gut microbiota). Pharmacologically induced forms of hypertension (the L-NAME and DOCA+NaCl groups) do not share metabolomic markers with hereditary AH. They are differentiated by N,N-dimethylglycine (both groups), choline (the L-NAME group) and 1-methylnicotinamide (the group of rats with DOCA-salt hypertension).
RESUMO
The etiology of essential hypertension is intricate, since it employs simultaneously various body systems related to the regulation of blood pressure in one way or another: the sympathetic nervous system, renin-angiotensin-aldosterone and hypothalamic-pituitary-adrenal systems, renal and endothelial mechanisms. The pathogenesis of hypertension is influenced by a variety of both genetic and environmental factors, which determines the heterogeneity of the disease in human population. Hence, there is a need to perform research on experimental models - inbred animal strains, one of them being ISIAH rat strain, which is designed to simulate inherited stress-induced arterial hypertension as close as possible to primary (or essential) hypertension in humans. To determine specific markers of diseases, various omics technologies are applied, including metabolomics, which makes it possible to evaluate the content of low-molecular compounds - amino acids, lipids, carbohydrates, nucleic acids fragments - in biological samples available for clinical analysis (blood and urine). We analyzed the metabolic profile of the blood serum of male ISIAH rats with a genetic stress-dependent form of arterial hypertension in comparison with the normotensive WAG rats. Using the method of nuclear magnetic resonance spectroscopy (NMR spectroscopy), 56 metabolites in blood serum samples were identified, 18 of which were shown to have significant interstrain differences in serum concentrations. Statistical analysis of the data obtained showed that the hypertensive status of ISIAH rats is characterized by increased concentrations of leucine, isoleucine, valine, myo-inositol, isobutyrate, glutamate, glutamine, ornithine and creatine phosphate, and reduced concentrations of 2-hydroxyisobutyrate, betaine, tyrosine and tryptophan. Such a ratio of the metabolite concentrations is associated with changes in the regulation of glucose metabolism (metabolic markers - leucine, isoleucine, valine, myo-inositol), of nitric oxide synthesis (ornithine) and catecholamine pathway (tyrosine), and with inflammatory processes (metabolic markers - betaine, tryptophan), all of these changes being typical for hypertensive status. Thus, metabolic profiling of the stress-dependent form of arterial hypertension seems to be an important result for a personalized approach to the prevention and treatment of hypertensive disease.
RESUMO
The main effect of arginase inhibition after administration of L-norvaline is a decrease in BP. At the same time, norvaline causes various side effects in normotensive and hypertensive animals. In our experiments, L-norvaline was administered intraperitoneally (30 mg/kg) for 7 days to normotensive WAG rats (Wistar Albino Glaxo) and hypertensive ISIAH rats (Inherited, Stress-Induced Arterial Hypertension). In ISIAH rats, BP decrease was accompanied by an increase in diuresis, while in WAG rats, diuresis remained unchanged or little changed. At the same time, hypertensive rats demonstrated an increase of catecholamine content in the adrenal glands, while in normotensive animals, it was decreased. The differences in the effects of norvaline can be associated with different mechanisms of BP maintenance in normotensive and hypertensive animals. Normally, BP is maintained by the regulatory influences of the nitric oxide system. In hypertension, this system is weakened, and the hypotensive effects are probably achieved via increased diuresis.