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.
The aim of the study was to test whether P-αB can be positioned as a preventing and treating agent for cardiovascular diseases.Materials and methods. The study was performed on sexually mature male Wistar rats. Endothelial dysfunction was modulated by a 7-days intraperitoneal administration of L-NAME at the dose of 2.5 mg/100 g. P-αB, or erythropoietin (EPO), was used for therapy at the dose of 2.5 µg/100 g × 3 times for 7 days, the total dose was 7.5 µg/100 g. The function of endothelium was estimated by an endothelium-dependent and endothelium-independent vasodilation. In addition, a histological assessment of the abdominal aortic wall state and the analysis of eNos, Tnf and Il-1β genes expression were performed. To estimate prothrombotic properties, P-αB and EPO were administered, at the doses of 2.5 and 5 µg/100 g (3 times a day for 7 days, the total doses were 7.5 µg/100 g and 15 µg/100 g, respectively) and on the 8th day, the time of ferric (III) chloride-induced carotid artery thrombosis was estimated.Results. Theresults of the functional tests for endothelium-dependent and endothelium-independent vasodilatation, as well as the histological picture of the aorta have evidenced that P-αB and EPO do not affect L-NAME-induced hypertension but improve the endothelium function. At the same time, P-αB shows a significantly higher endothelial-protective activity, reducing the coefficient of endothelial dysfunction from 5.1±0.15 to 2.72±0.12. In addition, P-αB has significantly increased the expression of eNos and reduced the expression level of Tnf and Il-1β mRNA genes. Carrying out Ferric (III) chloride-induced carotid artery thrombosis has revealed that P-αB (5 µg/100 g × 3 times a day for 7 days, total dose was 15 µg/100 g) has a lower but statistically significant prothrombotic activity than EPO.Conclusion. P-αB can be positioned as an atheroprotector because of its ability to prevent the death of endothelial cells, as well as to reduce remodeling and proinflammatory activation of the vascular wall. However, the prothrombotic properties of P-αB limit its use as a preventing and treating agent for atherosclerosis-associated diseases.
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.
For the first time in vitro experiments there were studied the inhibitory activity and safety of potential molecules arginase II selective inhibitors from the group of norleucine derivatives. Also first the substance under the code ZB49-0010C from the group of norleucine derivatives showed the greatest selectivity and inhibitory activity against arginase II in experiments in vitro. However, this substance in vivo exerts dose-dependent hypotensive action and cardioprotective and endothelial protective effects on the L-NAME induced and homocysteine-induced endothelial dysfunction (ED), which are most pronounced at a dose of 10 mg/kg in intragastric administration. Endothelial protective effect consists of in preventing the increase of coefficient of endothelial dysfunction (CED) and the decrease in the concentration of stable metabolites of nitric oxide in the blood plasma. Cardioprotective effect consists of in preventing the increase of the level of left ventricular pressure during the test for adrenoreactivity and reducing of the cardiac reserve during the overload resistance test, and also in preventing the development of the left ventricular hypertrophy. As part of the study there was investigated the dose-dependent anti-ischemic effect of the arginase II selective inhibitor, substance ZB49-0010C on the chronic limb ischemia in rats, which most pronounced at a dose of 10 mg/kg and consists of in preventing the fall in microcirculatory level on the 29th day of the experiment in the ischemic limb and a protective effect based on the morphological examination of the muscle tissue.
Исследовано протективное действие карбамилированного дарбэпоэтина в дозе 300 мкг/кг на модели ишемической нейропатии зрительного нерва у крыс линии Wistar. Выявлено, что карбамилированный дарбэпоэтин предотвращает развитие повреждений диска зрительного нерва и сосудов сетчатки, вызванных внутрижелудочным введением неселективного ингибитора NO-синтаз N-нитро-L-аргинин-метилового эфира (L-NAME) в дозе 12,5 мг/кг в течение 28 сут и однократным повышением внутриглазного давления до 110 мм рт. ст. Обнаруженный протективный эффект подтвержден результатами офтальмоскопии, электроретинографии и иммуногистохимии на 29 сут эксперимента. У крыс в группе с коррекцией карбамилированным дарбэпоэтином коэффициент b/a (степень развития функциональных повреждений сетчатки) достоверно возрастает на 31,6 % (p < 0,05). Карбамилированный дарбэпоэтин ингибирует экспрессию белка р53 в нейронах сетчатки и индуцирует экспрессию эндотелиальной NO-синтазы в сосудах сетчатки, вследствие чего наблюдается протективный эффект.
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