This paper is about a way of correction of endothelial dysfunction with the inhibitor of arginase: L-norvaline. There is an imbalance between vasoconstriction and vasodilatation factors of endothelium on the basis of endothelial dysfunction. Among vasodilatation agents, nitrogen oxide plays the basic role. Amino acid L-arginine serves as a source of molecules of nitrogen oxide in an organism. Because of the high activity of arginase enzyme which catalyzes the hydrolysis of L-arginine into ornithine and urea, the bioavailability of nitrogen oxide decreases. The inhibitors of arginase suppress the activity of the given enzyme, raising and production of nitrogen oxide, preventing the development of endothelial dysfunction.
Introduction. The drugs affecting a mitochondrial dysfunction, oxidative stresses, apoptosis and inflammation of the vascular wall, have a high potential for the prevention and treatment of atherosclerotic lesions. In this regard, the use of EPOR/CD131 heteroreceptor agonists which have a similar spectrum of pharmacological effects, is one of the promising strategies in the treatment of cardiovascular diseases.Materials and Methods. The study was carried out on 68 C57Bl/6J male mice. Atherosclerosis was simulated in transgenic animals with an endotheliospecific knockdown of the Polg gene by simulating a balloon injury and keeping on a Western diet. Then, the studied drugs were injected once every 3 days at the dose of 20 μg/kg for 27 days. On the 28-th day, the animals were euthanized and the area of atherosclerotic plaques was assessed. The gene expression associated with the processes of inflammation, antioxidant protection, apoptosis, and angiogenesis was also determined in the aortic tissues. In addition, the endothelium protective effect of peptides on primary cultures of endothelial cells of wild and transgenic Polg-D257A mice was studied.Results. No statistically significant effect of drugs on the area of lipid infiltration have been found. However, the studied peptides have significantly reduced the expression of proinflammatory genes (iNos, Icam1, Vcam1, Sele, Il6, Tnfa), the genes associated with angiogenesis (Vegfa, Kdr, and Hif1a), the expression of proapoptic factors; they decreased the Bax/Bcl-2 ratio by more than 1.5 times. In addition, when supplemented with H2 O2 in vitro, peptides dose-dependently increased endothelial cell survival.Conclusion. The erythropoietin-based peptides can be used to improve the functional state of the vascular wall against the background of atherosclerotic lesions and have a depressing effect on pathobiological processes associated with a mitochondrial dysfunction. In addition, the studied peptides have a significant endothelial protective effect in the induction of oxidative stress in vitro.
Experimental NO deficiency induced by L-NAME injection led to the development of arterial hypertension, endothelial dysfunction, and cardiomyocyte hypertrophy and reduced blood content of nitrates and nitrites. Impaza, NO donors, activators of NO-synthase, antioxidants, and antihypertensive preparations produced endothelium-protective effect of different degree.
An important task of pharmacology is to find effective agents to improve retinal microcirculation and resistance to ischemia. The purpose of the study is to pharmacologically evaluate the retinoprotective effect of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate in a rat model of retinal ischemia–reperfusion. A retinal ischemia–reperfusion model was used, in which an increase in intraocular pressure (IOP) to 110 mmHg was carried out within 30 min. The retinoprotective effect of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate at a dose of 3.8 mg/kg, in comparison with nicotinic acid at a dose of 2 mg/kg and emoxipine at a dose of 2 mg/kg, was estimated by the changes in the eye fundus during ophthalmoscopy, the retinal microcirculation level with laser Doppler flowmetry (LDF), and electroretinography (ERG) after 72 h of reperfusion. The use of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate prevented the development of ischemic injuries in the fundus and led to an increase in the retinal microcirculation level to 747 (median) (lower and upper quartiles: 693;760) perfusion units (p = 0.0002) in comparison with the group that underwent no treatment. In the group with the studied substance, the b-wave amplitude increased significantly (p = 0.0022), and the b/a coefficient increased reliably (p = 0.0002) in comparison with the group with no treatment. Thus, 2-ethyl-3-hydroxy-6-methylpyridine nicotinate has established itself as a potential retinoprotector.
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