Introduction: The aim of this study was to examine the effectiveness of innovative peptides obtained by addition of polypeptide motifs with antiaggregation activity (Arg-Gly-Asp, Lys-Gly-Asp and Pro-Gly-Pro) to a peptide mimicking the space structure of the α-helix B of erythropoietin pHBSP (Pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser). Materials and methods: The cytoprotective activity of innovative peptides mimicking the space structure of the α-helix B of erythropoietin at the doses of 5 μg/ml, 30 μg/ml and 50 μg/ml was studied on human endothelial cell culture in a simulated oxidative stress. An ADMA-like model of preeclampsia was simulated in the experiment. The study was conducted in 260 female Wistar rats, weighing 250–300 g. Results and discussion: Innovative peptides mimicking the space structure of the α-helix B of erythropoietin retain their cytoprotective activity in a simulated oxidative stress in HUVEC cell culture at the doses of 5 μg/ml, 30 μg/ml, and 50 μg/ml. The compounds with laboratory codes P-αB1 and P-αB3 had the most pronounced cytoprotective activity. Administration of N-nitro-L-arginine-methyl ether to pregnant females for 7 days causes the morphofunctional changes similar to clinical changes in preeclampsia. The innovative peptide under laboratory code P-αB4 at the dose of 50 μg/kg mimicking the space structure of the α-helix B of erythropoietin shows the most pronounced protective properties. Conclusion: Innovative peptides mimicking the space structure of the α-helix B of erythropoietin have a pronounced positive influence on the morphofunctional disorders in animals with ADMA-like preeclampsia.

Citation: Lokteva TI, Rozhkov IS, Gureev VV, Gureeva AV , Zatolokina MA, Avdeyeva EV, Zhilinkova LA, Prohoda EE, Yarceva EO (2020) Correction of morphofunctional disorders of the cardiovascular system with asialized erythropoietin and arginase II selective inhibitors KUD 974 and KUD 259 in experimental preeclampsia. Research Results in Pharmacology 6(1): 29-40. https:// Abstract Introduction: Preeclampsia remains one of the most common causes of maternal and perinatal mortality worldwide. A significant role in the pathogenesis of this pathology is assigned to placental ischemia and endothelial dysfunction. Therefore, the aim of the present study was to study the effectiveness of asialized erythropoietin and arginase II selective inhibitors: KUD-259 and KUD-974 in the correction of morphofunctional disorders of the cardiovascular system in experimental preeclampsia. Materials and methods:The study was performed in 260 female Wistar rats, each weighing 250-300 g. An AD-MA-like preeclampsia was reproduced in the experiment. To assess the emerging morphofunctional disorders, the following parameters were used: blood pressure, coefficient of endothelial dysfunction, microcirculation in the placenta, proteinuria, fluid content in the omentum, concentration of terminal metabolites in the blood plasma, and morphometric parameters of fetuses. Results and discussion:The administration of arginase II selective inhibitor KUD-974 in combination with asialized erythropoietin leads to a pronounced correction of emerging changes: a decrease in systolic and diastolic blood pressure in 1.5 and 1.7 times, a decrease in proteinuria in 3.6 times and a decrease in fluid content in the omentum. When arginase II selective inhibitor KUD 974 and asialized erythropoietin are used with methyldopa, the positive effects of the former are enhanced. Conclusion:Arginase II selective inhibitors KUD-259 and KUD-974 and asialized erythropoietin have a pronounced positive effect on the correction of morphofunctional disorders in animals with ADMA-like preeclampsia.

Introduction: Over the past decade, preeclampsia has been the subject of an increased attention, as this complication is the most common cause of maternal mortality, triggering every third case of obstetric morbidity and taking lives of up to 50.000 young women worldwide each year. Despite a large number of ongoing studies, no clear algorithm for monitoring pregnant women with this pathology has been developed yet. Materials and methods: The study was conducted on 220 female Wistar rats weighing 250–300 g. In the experiment, ADMA-like preeclampsia model was used. Results and discussion: The introduction of L-NAME to the animals from the 14th till the 20th day of pregnancy causes the following disturbances: a rise in systolic and diastolic blood pressure in 1.4 and 1.5 times, an increase in proteinuria in 3.3 times and an increase in the content of fluid in the greater omentum from 44.39 ± 1.62% to 55.02 ± 1.74%, all of which correspond to the disorders in pregnant women in case of preeclampsia. The use of the selective inhibitor of arginase II KUD 975 (3mg/kg/day) in combination with acetylsalicylic acid (10mg/kg/day) leads to a pronounced correction in the emerging changes: a decrease in systolic and diastolic blood pressure in 1.2 and 1.3 times, a decrease in proteinuria in 1.9 times and a decrease in the fluid content in the greater omentum. Conclusion: Selective inhibitor of arginase II KUD 975 and small doses of acetylsalicylic acid have a pronounced positive effect in the correction of morphofunctional disorders in animals with ADMA-like preeclampsia.

Introduction. Preeclampsia is a formidable disease of the second half of pregnancy, leading to severe complications, including disability and even death. Many authors have recognized the correlation between the severity of preeclampsia and the degree of disturbances in the hemostasis system. In this regard, the objective of this study was to assess inhibition of platelet aggregation and the possibility of its correction with resverаtrol and nicorandil. Materials and methods. The study was performed on 250 mature white Wistar female rats weighing 250–300 g. The platelet aggregation induced by ADP, collagen, ristomycin, adrenaline was determined, as well as PTT, TT, aPTT, fibrinogen, and the clotting time. Results and discussion. Introduction of resverаtrol and nicorandil resulted in a decrease in thrombocyte aggregation capacity from 53.8 ± 2.60% to 22.1 ± 1.25% and 37.1 ± 1.79%, respectively, when using ADP as an inducer. The clotting time was from 841 ± 42 s up to 1135 ± 33 s and 1034 ± 26 s, respectively. In addition, there was an increase in temporal parameters of plasma-coagulation hemostasis and a decrease in plasma fibrinogen content. The use of glibenclamide resulted in partial cancellation of the positive effects of resverаtrol and nicorandil, with an increase in platelet aggregation to 28.9 ± 1.8% and 43.9 ± 1.2% when using ADP as an inducer and a decrease in the thrombosis time to 988 ± 26 s and 950 ± 22 s, respectively. Conclusion. In animals with experimental preeclampsia, there were disturbances in the hemostasis system, comparable to those in the clinical situation. The use of resverаtrol and nicorandil leads to a pronounced correction of hemostasis parameters. The positive effects of the studied pharmacological agents are mediated by several mechanisms, including K+ATP channels.

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