The effects of modulation of translocator protein and NO synthase on functional and biochemical changes of the heart in the experimental model of myocardial infarction induced by isoprenaline

[A. Ilić]

130 str.

Medicina - Fiziološke nauke / Medicine - Physiological sciences

Cilj: Istraživanje efekata primene modulatora TSPO proteina, PK-11195 i 4’-ClDzp kao i inhibitora NO sintaze, L-NAME, na kardiometaboličke parametre, parametre oksidativnog stresa i inflamacije, biohemijske biomarkere u serumu i plazmi, kao i patohistološke promene na srcu kod pacova sa infarktom miokarda (MI) indukovanim izoprenalinom (ISO). Materijal i metode: Istraživanje je sprovedeno tokom 3 uzastopna dana. Mužjaci pacova soja Wistar albino su raspodeljeni nasumično u osam grupa (osam do deset životinja u svakoj grupi): kontrolna grupa (K, fiziološki rastvor 0,9% NaCl (f.r.) 0,2 mL subkutano (s.c.) dva puta u intervalu od 24 h), eksperimentalna grupa I (ISO, 85 mg/kg telesne mase (t.m.) u 1 mL fiziološkog rastvora, s.c. dva puta u intervalu od 24 h), eksperimentalna grupa IFR (ISO, 85 mg/kg t.m. u 1 mL fiziološkog rastvora, s.c. dva puta u intervalu od 24 h i f.r. 0,5 mL intraperitonealno (i.p.)), eksperimentalna grupa ILN (ISO, 85 mg/kg t.m. u 1 mL fiziološkog rastvora, s.c. dva puta u intervalu od 24 h i L-NAME, 50 mg/kg t.m. u f.r. intraperitonealno (i.p.)), eksperimentalna grupa IP (ISO, 85 mg/kg t.m. u 1 mL fiziološkog rastvora, s.c. dva puta u intervalu od 24 h, i PK-11195, 5 mg/kg t.m. u f.r., i.p.), eksperimentalna grupa IPLN (ISO, 85 mg/kg t.m. u 1 mL fiziološkog rastvora, s.c. dva puta u intervalu od 24 h, PK-11195, 5 mg/kg t.m. u f.r., i.p., i L-NAME, 50 mg/kg t.m. u f.r. i.p.), eksperimentalna grupa IC (ISO, 85 mg/kg t.m. u 1 mL fiziološkog rastvora, s.c. dva puta u intervalu od 24 h, i 4’-ClDzp, 0,5 mg/kg t.m. u f.r., i.p.), eksperimentalna grupa ICLN (ISO, 85 mg/kg t.m. u 1 mL fiziološkog rastvora, s.c. dva puta u intervalu od 24 h, 4’-ClDzp, 0,5 mg/kg t.m. u f.r., i.p. i LNAME, 50 mg/kg t.m. u f.r. i.p.). Određivani su kardiometabolički biomarkeri u serumu: koncentracija visoko senzitivnog troponina T (hsTnT), aktivnost laktat dehidrogenaze (LDH), kreatin kinaze (CK), aspartat aminotransferaze (AST), koncentracija homocisteina (Hcy), ukupnog holesterola (TH), lipoproteina velike gustine (HDL), trigilicerida (TG); hemostatski biomarkeri u plazmi: koncentracija fibrinogena (FIB) i von Wilebrandovog faktora (vWF); kao i hepato-renalnopankreatični biomarkeri u serumu: koncentracija uree, kreatinina, mokraćne kiseline (MK), ukupnih proteina, albumina, aktivnost alanin aminotransferaze (ALT), alkalne fosfataze (ALP) i alfa amilaze (α-AMY) i markeri inflamacije: interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 10 (IL-10) i faktor nekroze tumora alfa (TNF-α). U homogenatu tkiva srca određivani su parametri oksidativnog stresa: aktivnost enzima glutation peroksidaze (GPx) i superoksid dismutaze (SOD), koncentracija glutationa, i ukupna S – glutationilacija proteina. Pored toga, za patohistološku analizu korišćeno je tkivo srca. Rezultati: Aplikovanje izoprenalina je dovelo do pojave difuznog transmuralnog infarkta sa povećanim koncentracijama hsTnT i Hcy, značajnim smanjenjem telesne mase i povećanjem kardiosomatskog indeksa (KSI), i smanjilo je koncentraciju LDH i AST. Primena ISO je dovela do povećanja koncentracije FIB i smanjenja koncentracije TH, HDL i TG. Primena ISO nije uticala na CK i vWF, kao i na parametre bubrežne funkcije, mokraćne kiseline (MK), uree i kreatinina. Koncentracija albumina u serumu je bila povećana, dok je koncentracija TP bila smanjena nakon aplikacije ISO. Primena ISO je bila praćena promenama u markerima inflamacije, povećanjem koncentracije TNF-α i smanjenjem koncentracije IL-10, dok su koncentracije IL-1β i IL-6 ostale nepromenjene nakon primene ISO. Aktivnost GPx i SOD kao i koncentracija glutationa nije imala značajne promene nakon primene ISO. Ukupna S-glutationilacija je bila povećana usled primene ISO. Zajednička primena PK-11195 i L-NAME povećala je koncentraciju hsTnT, AST, Hcy, TH, FIB, kreatinina, MK, UP, IL-10 i SOD, a smanjila je koncentraciju LDH, HDL, uree, ALB, TNF-α, IL-6 i GPx. Efekti PK-11195 su se odrazili na smanjenje koncentracije hsTnT i povećanje koncentracije Hcy, promene u lipidnom statusu i na parametre hepato-renalno-pankreatične funkcije kao i na markere inflamacije, određene parametre oksidativnog stresa i hemostatske parametre. Takođe, primena PK-11195 nije pokazala značajnu patohistološku promenu u tkivu srca...

Objective: Investigation of the effects of TSPO protein modulators, PK-11195, and 4'-ClDzp, as well as NO synthase inhibitor, L-NAME, on cardiometabolic parameters, parameters of oxidative stress and inflammation, biochemical biomarkers in serum and plasma, as well as pathohistological changes in the heart in rats with isoprenaline (ISO)-induced myocardial infarction (MI). Material and methods: The research was conducted over 3 consecutive days. Male Wistar albino rats were randomly divided into eight groups (eight to ten animals in each group): control group (K, saline solution 0.9% NaCl (saline) 0.2 mL subcutaneously (sc.) twice at an interval of 24h), experimental group I (ISO, 85 mg/kg body weight (b.w.) in 1 mL saline solution, sc. twice at an interval of 24h), experimental group IFR (ISO, 85 mg/kg b.w. in 1 mL saline solution, sc. twice at an interval of 24h plus saline 0.5 mL intraperitoneally (ip.), experimental group ILN (ISO, 85 mg/kg body weight in 1 mL saline solution, sc. twice at an interval of 24h plus L-NAME, 50 mg/ kg b.w. in saline ip.), experimental group IP (ISO, 85 mg/kg b.w. in 1 mL saline solution, sc. twice at an interval of 24h plus PK-11195, 5 mg/kg b.w. in saline ip.), experimental group IPLN (ISO, 85 mg/kg b.w. in 1 mL saline solution, sc. twice at an interval of 24h plus PK-11195, 5 mg/kg b.w. in saline ip. plus LNAME, 50 mg/ kg b.w. in saline ip.), experimental group IC (ISO, 85 mg/kg b.w. in 1 mL saline solution, sc. twice in an interval of 24h plus 4'ClDzp, 0.5 mg/kg body weight. in saline i.p.), experimental group ICLN (ISO, 85 mg/kg b.w. in 1 mL saline, sc. twice at an interval of 24h plus 4'ClDzp, 0.5 mg/kg b.w. in saline ip. plus L-NAME, 50 mg/kg b.w. ip.). Cardiometabolic biomarkers were determined in the serum: concentration of high-sensitivity troponin T (hsTnT), the activity of lactate dehydrogenase (LDH), creatine kinase (CK), aspartate aminotransferase (AST), the concentration of homocysteine (Hcy), total cholesterol (TH), high-density lipoprotein (HDL), triglyceride (TG), hemostatic biomarkers in plasma: concentration of fibrinogen (FIB) and von Willebrand factor (vWF); as well as hepato-renal-pancreatic serum biomarkers: concentration of urea, creatinine, uric acid (MC), total protein, albumin, the activity of alanine aminotransferase (ALT), alkaline phosphatase (ALP) and alpha-amylase (α-AMY), and markers inflammation: interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 10 (IL-10) and tumor necrosis factor-alpha (TNF-α). Oxidative stress parameters were determined in the heart tissue homogenate: activity of glutathione peroxidase (GPx) and superoxide dismutase (SOD), glutathione concentration, and total Sglutathionylation protein. In addition, heart tissue was used for pathohistological analysis. Results: Application of isoprenaline led to the occurrence of diffuse transmural infarction, increased concentrations of hsTnT and Hcy, a significant decrease in body weight, and an increase in the cardiosomatic index (KSI), and decreased the concentration of LDH and AST. The application of ISO led to an increase in the concentration of FIB, and a decrease in the concentration of TH, HDL, and TG. CK and vWF were not affected by ISO administration, as well as parameters of renal function, uric acid (MC), urea, and creatinine. Serum albumin concentration was increased, while TP concentration was decreased after ISO application. Application of ISO was accompanied by changes in inflammation markers, an increase in the concentration of TNF-α, and a decrease in the concentration of IL-10, while the concentrations of IL-1β and IL-6 remained unchanged after the application of ISO. GPx and SOD activity as well as glutathione concentration had no significant changes after ISO administration. Total S-glutathionylation was increased by ISO administration. The joint administration of PK-11195 and L-NAME increased the concentration of hsTnT, AST, Hcy, TH, FIB, creatinine, MK, UP, IL-10, and SOD, and decreased the concentration of LDH, HDL, urea, ALB, TNF-α, IL- 6 and GPx. The effects of PK-11195 were reflected in a decrease in hsTnT concentration and an increase in Hcy concentration, changes in lipid status and parameters of hepatorenal- pancreatic function as well as markers of inflammation, certain parameters of oxidative stress and hemostatic parameters. Also, the administration of PK-11195 did not show significant pathohistological changes in heart tissue...

infarkt miokarda, izoprenalin, 4’-ClDzp, PK-11195, L-NAME, metabolizam srca, biohemijski markeri, oksidativni stres, markeri inflamacije, veličina infarktnog polja, pacov

myocardial infarction, isoprenaline, 4'ClDzp, PK-11195, L-NAME, cardiac metabolism, biochemical markers, oxidative stress, inflammatory markers, infarct field size, rat.

612.176:616.127-005.8(043.3)

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