INTEGRATIVE AND BIOCHEMICAL PARAMETERS IN RATS IN THE SIMULATION OF DOXORUBICIN CHRONIC HEART FAILURE AND DURING THE USE OF Β-ADRENERGIC BLOCKERS

Year 2023, , 228 - 238, 20.01.2023

Igor Belenichev , Pavlo Bak , Olena Popazova , Victor Ryzhenko , Nina Bukhtiyarova , Andrii Puzyrenko

https://doi.org/10.33483/jfpau.1131302

Cited By: 1

Abstract

Objective: In the treatment of chronic heart failure, β-blockers are actively used - Carvedilol, Nebivolol, Metoprolol, Bisoprolol, etc. However, they have a number of serious adverse reactions, and their therapeutic efficacy does not always meet the needs of the clinic. All this prompted the creation of a new potential drug Hypertril (bromide 1-(β-phenylethyl)-4-amino-1,2,4-triazolium. We aimed to conduct a comparative assessment of β-blockers of different generations and "Hypertril" in the conditions of modeling the doxorubicin model of chronic heart failure (CHF) in terms of the effect on biochemical markers of myocardial damage and integrative parameters.

Material and Method: CHF was modeled on 85 white outbred rats weighing 190–220 g by administering doxorubicin at a total dose of 15 mg/kg, nebivolol (10 mg/kg), carvedilol (50 mg/kg), bisoprolol (10 mg/kg), metoprolol (15 mg/kg) and hypertril (3.5 mg/kg) were administered intragastrically once a day as a suspension 1% starchy mucus for 30 days after 14 days of doxorubicin administration. The cardioprotective effect of drugs was assessed by improving integrative parameters (survival, heart mass index, severity in points) and by normalizing cardiospecific markers (NT-proBNP, D-dimer, eNOS, MB-CPK, and ST2).

Result and Discussion: The introduction of Hypertril not only prolonged the life of animals with CHF in comparison with the reference drugs, but also prevented early death and contributed to a decrease in the severity of symptoms (hydrothorax, ascites, scrotal edema). The administration of hypertril to rats with CHF led to a decrease in mortality, a decrease in the heart mass index, in the blood of the main cardiospecific markers to the values of intact animals, and also led to an increase in expression of eNOS, which testified to its significant cardioprotective effect with NO-mimetic effect. The obtained results demonstrated the undoubted advantage of Hypertril over the basic β-adrenergic blockers and experimentally substantiated further in-depth studies to create a drug based on it for the treatment of CHF.

Keywords

Bromide 1-(β-phenylethyl)-4-amino-1,2,4-triazolium, cardioprotection, chronic heart failure, hypertril, endothelial dysfunction, metoprolol, β-blockers

DOKSORUBİSİN İLE OLUŞTURULAN KRONİK KALP YETMEZLİĞİ MODELİNDE VE Β-ADRENERJİK BLOKERLERİN KULLANIMI SIRASINDA SIÇANLARDA BÜTÜNLEYİCİ VE BİYOKİMYASAL PARAMETRELER

Abstract

Amaç: Kronik kalp yetmezliğinin tedavisinde karvedilol, nebivolol, metoprolol, bisoprolol vb. β-blokerler aktif olarak kullanılmaktadır. Bununla birlikte, bir dizi ciddi yan etkileri bulunmakta olup tedavi edici etkinlikleri her zaman kliniğin ihtiyaçlarını karşılamamaktadır. Bütün bunlar yeni bir potansiyel ilacın (Hypertril, bromür 1-(β-feniletil)-4-amino-1,2,4-triazolyum)) geliştirilmesine yol açmaktadır. Farklı nesil β-blokerlerin ve Hipetrilin farkli koşullar altında (miyokard hasarının biyokimyasal belirteçleri ve integratif parametreler üzerindeki etkisi açısından kronik kalp yetmezliğinin (KKY) doksorubisin modellenmesiyle) karşılaştırmalı bir değerlendirmesinin yapılması amaçlanmıştır.

Gereç ve Yöntem: KKY, doksorubisin toplam 15 mg/kg dozunda uygulanarak 190-220 gram ağırlığındaki 85 beyaz fare üzerinde modellenmiştir. Nebivolol (10 mg/kg), karvedilol (50 mg/kg), bisoprolol (10 mg/kg), metoprolol (15 mg/kg) ve Hipertril (3.5 mg/kg) 14 günlük doksorubisin uygulamasından sonra 30 gün boyunca % 1 nişastalı mukus süspansiyonu olarak günde bir kez intragastrik olarak uygulanmıştır. İlaçların kardiyoprotektif etkisi, integratif parametrelerin iyileştirilmesi (sağkalım, kalp kütle indeksi, noktalardaki şiddet) ve kardiyospesifik belirteçlerin normalleştirilmesiyle (NT-proBNP, D-dimer, eNOS, MB-CPK ve ST2) değerlendirilmiştir.

Sonuç ve Tartışma: Hipertril'in tanıtılması, referans ilaçlara kıyasla KKY'li hayvanların ömrünü uzatmakla kalmamış, aynı zamanda erken ölümü önlemiş ve belirtilerin şiddetinin (hidrotoraks, asit, skrotal ödem) azalmasına katkıda bulunmuştur.
KKY’li farelere hipertril uygulanması, ölüm oranında azalışa, kalp kitle indeksinde düşüşe ve ayrıca NO-mimetik etki ile önemli kardiyoprotektif etkisine tanıklık eden eNOS ifadesinde bir artışa yol açmıştır. Elde edilen sonuçlar, Hypertril'in temel β-adrenerjik blokerlerin üzerindeki tartışmasız avantajını göstermiştir ve KYY tedavisi için buna dayalı bir ilaç oluşturmak amacıyla deneysel olarak derinlemesine çalışmalar yapılmıştır.

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