pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2023-11-4-312-323pmedpharm-1384Research ArticleОРИГИНАЛЬНАЯ СТАТЬЯRESEARCH ARTICLEИзучение возможностей фармакологической коррекции легочной гипертензии, индуцированной гипоксией, с использованием соединения фенольной природы с лабораторным шифром КУД975Studying the possibilities of pharmacological correction of hypoxia-induced pulmonary hypertension using a phenolic compound with a laboratory cypher KUD975https://orcid.org/0000-0002-4115-1564КорокинаЛ. В.KorokinaL. V.

кандидат медицинских наук, доцент кафедры фармакологии и клинической фармакологии ФГАОУ ВО «Белгородский государственный национальный исследовательский университет» (НИУ «БелГУ»). 

308015, Россия, г. Белгород, ул. Победы, д. 85

Candidate of Sciences (Medicine), Associate Professor of the Department of Pharmacology and Clinical Pharmacology of Belgorod State National Research University.

85, Pobeda Str., Belgorod, Russia, 308015

Korokina@mail.ruФедеральное государственное автономное образовательное учреждение высшего образования «Белгородский государственный национальный исследовательский университет»РоссияBelgorod State National Research UniversityRussian Federation202309012024114312323Copyright © Корокина Л.В., 20242024Корокина Л.В.Korokina L.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/1384Цель

Цель. Изучение фармакологической активности селективного ингибитора аргиназы-2 и тромбина из группы соединений фенольной природы с лабораторным шифром КУД975 на модели артериальной легочной гипертензии, индуцированной гипоксией.

Материалы и методы

Материалы и методы. Для моделирования легочной гипертензии (ЛГ) животных помещали в нормобарическую гипоксическую камеру и подвергали 5 неделям гипоксии с содержанием кислорода в воздухе 10%. После 3-х недель гипоксии животным вводили исследуемое соединение КУД975 (внутрижелудочно в дозе 2 мг/кг 1 раз в сут в течение 2 недель). В качестве препарата сравнения использовали L-норвалин (внутрижелудочно 20 мг/кг). Для оценки развития ЛГ и ее коррекции проводили измерение показателей кардиогемодинамики, анализ газового состава крови, изучение количества циркулирующих предшественников эндотелиальных клеток (ПЭК), количественную ПЦР с оценкой экспрессии мРНК VEGF-R2, SDF-1 (стромальный фактор роста-1) и MCP-1 (моноцитарный хемоаттрактантный белок-1). Далее проводили гистологическое исследование легких и сердца, оценивали степень отека легких и концентрацию кардиотрофина-1 и предсердного натрийуретического пептида.

Результаты

Результаты. Введение исследуемого соединения фенольной природы с лабораторным шифром КУД975, как и препарата сравнения L-норвалина, привело к уменьшению систолического давления в полости правого желудочка сердца на фоне моделирования ЛГ. В настоящем исследовании показано снижение количества циркулирующих ПЭК более чем в 2 раза в группе животных с моделированием циркуляторной легочной гипертензии, индуцированной ЛГ (171,3±12,1), в сравнении с группой интактных животных (296,1±31,7; p=0,0018). Восстановление ПЭК было отмечено в группе животных, получавших КУД975 и L-норвалин, до 247,5±34,2 (p=0,0009 в сравнении с легочной артериальной гипертензией (ЛАГ) и 235,6±36,4 (p=0,008 в сравнении с ЛАГ) соответственно. Исследуемые соединения оказывали протективное действие, статистически значимо повышая экспрессию мРНК VEGF-R2 и снижая экспрессию мРНК SDF-1, а также снижая коэффициент влажности легких и концентрации кардиотрофина-1 и предсердного натурийуретического пептида и предотвращая сосудистое ремоделирование, вызванное гипоксией.

Заключение

Заключение. При изучении фармакологической активности показано, что соединение фенольной природы с лабораторным шифром КУД975 нормализует показатели гемодинамики, уменьшает признаки ремоделирования сердца и легочных сосудов и обладает выраженным эндотелиопротективным действием на модели ЛГ, индуцированной гипоксией, и превосходит активность препарата сравнения L-норвалин.

The aim of our work was to study a pharmacological activity of a selective arginase-2 and thrombin inhibitor from a phenolic compounds group with a laboratory cypher KUD975 on a model of arterial pulmonary hypertension induced by hypoxia.

Materials and methods

Materials and methods. To simulate pulmonary hypertension (РН), animals were placed in a normobaric hypoxic chamber and subjected to 5 weeks of hypoxia with an oxygen content of 10% in the air. After 3 weeks of hypoxia, the animals were administered with the test compound KUD975 (intragastrically, at a dose of 2 mg/kg once a day for 2 weeks). L-norvaline (intragastrically, 20 mg/kg) was used as a reference drug. To assess the development and correction of РН, measurements of cardiohemodynamics, analysis of blood gas composition, study of the number of circulating endothelial precursor cells (EPCs), quantitative PCR assessing the expression of mRNA VEGF-R2, SGF-1 (stromal growth factor-1) and MCP-1 (monocyte chemoattractant protein-1). Next, a histological examination of the lungs and heart was performed, the degree of pulmonary edema and the concentration of cardiotrophin-1 and atrial natriuretic peptide were assessed.

Results

Results. The administration of the studied phenolic compound with laboratory cypher KUD975, as well as the reference drug L-norvaline, led to a decrease in the right ventricular systolic pressure against the background of modeling РН. The present study shows a more than twice-fold decrease in the number of circulating (EPCs) in the animals group with modeling a hypoxia-induced circulatory РН (171.3±12.1) in comparison with the group of intact animals (296.1±31.7; p=0.0018). The recovery of EPCs was noted in the animals group administered with KUD-975 and L-norvaline, up to 247.5±34.2 (p=0.0009 compared with a pulmonary arterial hypertension (PAH) and 235.6±36.4 (p=0.008 compared to PAH), respectively. The studied compounds had a protective effect by statistically significantly increasing the expression of VEGF-R2 mRNA and decreasing the expression of SGF-1 mRNA, reducing the lung moisture coefficient and the concentrations of cardiotrophin-1 and atrial natriuretic peptide and preventing vascular remodeling caused by hypoxia.

Conclusion

Conclusion. When studying the pharmacological activity, it was shown that the phenolic compound with the laboratory cypher KUD975 normalizes hemodynamic parameters, reduces the signs of remodeling of the heart and pulmonary vessels and has a pronounced endothelial protective effect on the model of hypoxia-induced РН, and is superior to the activity of the reference drug L-norvaline.

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The authors declare that there are no conflicts of interest present.