Analysis of Mechanisms Underlying the Development of Endothelial Dysfunction and Functional Disorders in Experimental Diabetes Mellitus and Their Pathogenetic Correction.

On the model of alloxan-induced diabetes mellitus in rats, the development of oxidative stress and violation of the NO-producing function of the endothelium and internal organs was established. Structural changes in the vascular endothelium due to increased level of atherogenic LDL preventing access of L-arginine to endothelial NO synthase (eNOS) contribute to the development of endothelial dysfunction, which is paralleled by oxidative modification of L-arginine and the formation of inhibitors of eNOS expression (asymmetric dimethylarginine, L-NAME). These findings are indicative of reduced eNOS expression in experimental diabetes mellitus. Administration of L-arginine and its combination with L-carnitine caused an increase in the production NO metabolites and eNOS expression levels by 2.13 and 3.8 times, respectively. In parallel, improvement in the electrolyte excretory function of the kidneys, an increase in the Na,K-ATPase activity in organ homogenates, and a decrease in organ-specific enzymes in blood plasma were observed, which indicates the effectiveness of the correction of the identified violations. A way to eliminate metabolic and functional disorders with combinations of L-arginine and L-carnitine is pathogenetically substantiated. This methodological approach can be recommended for the prevention of microvascular complications in patients with type 1 diabetes mellitus.

Analysis of the Mechanisms of Impairment of Functional Parameters of Internal Organs in Saturnism in an Experiment in Rats.

In rats with lead intoxication (intramuscular administration of lead acetate in a dose 5 mg/kg for 30 days), the development of oxidative stress, reduced expression of endothelial NO synthase and total metabolites of NO production, as well as an increased content of norepinephrine were observed. Lead-induced nephropathy developed; diuresis and sodium excretion increased due to a decrease in tubular transport of water and sodium ions. Activation of free-radical reactions in cells of the renal cortex and medulla contributed to inhibition of Na,K-ATPase. LPO caused damage to cardiomyocytes, hepatocytes, which was seen from elevation of AST, ALT, γ-glutamyl transpeptidase, and alkaline phosphatase in the blood serum and a decrease in activity of Na,K-ATPase in the organs tissues. Metabolic disorders revealed in saturnism in experimental rats (LPO activation, reduced expression of endothelial NO synthase and total metabolites of NO, and increased blood norepinephrine) contributed to the development of vascular endothelial dysfunction and hemodynamics disturbances, and damage to cells of internal organs: kidney, myocardium, liver.

Oxidative Stress and Biochemical Markers of Endothelial Dysfunction and Organ Damage under Conditions of Experimental Nonferrous Metal Intoxication.

Chronic nickel intoxication caused by parenteral nickel chloride administration (0.5 mg/kg of body weight) to Wistar rats led to ROS generation inducing LPO in erythrocyte membranes and homogenates of renal, liver, and myocardial tissue. Superoxide dismutase (SOD) activity was inhibited, while catalase activity and ceruloplasmin concentration increased. LPO and its products disrupted nitric oxide production and reduced its bioavailability, which led to the development of endothelial dysfunction and impaired microcirculatory hemodynamics. At the same time, damage of cytoplasmic membranes of internal organs (kidney, liver, and myocardium) was revealed, which was seen from reduced Na+, K+-ATPase activity in homogenates of these organs and increased serum activity of organ-specific (ALT, AST, and γ-glutamyl transpeptidase) and excretory (alkaline phosphatase) enzymes.

[Lipid peroxidation, activity of Na+,k(+) -ATPase and exzymes of antioxidant defence in rats with nephropathy induced by cobalt chloride].

Chronic parenteral administration of cobalt chloride (6 mg/kg) to male rats for 2 weeks or 1 month was accompanied by activation of lipid peroxidation (LPO), a decrease of superoxide dismutase activity and an increase of catalase activity. The membrane toxic action also resulted in a decrease of cortical and medullar Na+,K(+)-ATPase activity of kidneys, and the decrease in renal functions (glomerular filtration, renal water reabsorption, spontaneous diuresis, electrolyte excretion).