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Effects of hyperhomocysteinemia on myocardial function, coronary circulation and redox status of the isolated rat heart: role of hydroxymethyl glutaryl coenzyme-A (HMG-COA) reductase inhibitors

dc.contributor.advisorŽivković, Vladimir
dc.contributor.otherJakovljević, Vladimir
dc.contributor.otherFolić, Marko
dc.contributor.otherĐurić, Dragan
dc.contributor.otherRadovanović, Milan
dc.creatorNikolić, Tamara
dc.date.accessioned2017-12-19T13:31:03Z
dc.date.available2017-12-19T13:31:03Z
dc.date.issued2017-10-02
dc.identifier.urihttp://eteze.kg.ac.rs/application/showtheses?thesesId=5492
dc.identifier.urihttps://fedorakg.kg.ac.rs/fedora/get/o:878/bdef:Content/download
dc.identifier.urihttp://nardus.mpn.gov.rs/123456789/9014
dc.descriptionCilj ove studije je bio da ispita efekte hronične primene hrane bogate metioninom i hronične administracije atorvastatina i simvastatina na funkciju miokarda izolovanog srca pacova, kao i ulogu biomarkera oksidacionog stresa u dobijenim promenama. U istraživanju je analizirano 90 pacova (Wistar albino soj, muški pol, starosti 4 nedelje, telesne mase 100±15 g) koje su u trajanju od 30 dana bile izložene ishrani bogatoj metioninom sa ili bez deficita vitamina V12 i V6 i/ili farmakološkom tretmanu (atorvastatinom u dozi 3 mg/kg ili simvastatinom u dozi od 5 mg/kg), nakon čega su sprovedena istraživanja na izolovanom srcu metodom retrogradne perfuzije po Langendorfu (Langendorff apparatus, Experimetria Ltd, 1062 Budapest, Hungary) pri promenljivom koronarnom perfuzionom pritisku od 40- 120 smH2O. Istraživanje je bilo podeljeno u devet (9) eksperimentalnih grupa. U levoj komori su kontinuirano praćeni parametri funkcije leve komore: a) dp/dt max - maksimalna stopa promene pritiska u levoj komori, b) dp/dt min - minimalna stopa promene pritiska u levoj komori, v) SLVP - sistolni pritisak leve komore, g) DLVP - dijastolni pritisak leve komore i d) HR - srčana frekvencija. U krvi smo određivali nivo homocisteina (Hcy), ukupni holesterol (tChol), HDL holesterol (HDL), trigliceridi (Tgy). U uzorcima krvi i u efluentu spektrofotometrijskim metodama određivani su biomarkeri oksidacionog stresa: indeks lipidne peroksidacije - meren kao TBARS, azot monoksid u formi nitrita (NO2-), superoksid anjon radikal (O2-), i vodonik peroksid (H2O2), kao i parametre antioksidacionog sistema zaštite: katalaza (CAT), superoksid dismutaza (SOD) i redukovani glutation (GSH). Rezultati istraživanja su prikazani kroz 21 tabelu i 49 grafikona. Sumarno posmatrano, hiperhomocisteinemija uzrokuje promene morfometrijskih karakteristika pacova nakon 4 nedelje trajanja, sa akcentom na smanjenje ukupne telesne mase pri ekstremno povišenim vrednostima homocisteina u krvi. Takođe, uočava se da su negativni efekti koje hiperhomocisteinemija ostvaruje na srčani mišić posredovani povećanjem reaktivnih kiseoničnih vrsta i lipidne peroksidacije kao i smanjenom sposobnošću antioksidativne zaštite. Sa druge strane inhibitori HMG-CoA reduktaze ostvaruju pozitivno dejstvo na kardiovaskularni sistem, snižavanjem oksidacionog stresa i povećanjem antioksidativne sposobnosti. Umerena hiperhomocisteinemija nije uzrokovala smanjenje kontraktilnosti miokarda, dok je teška hiperhomocisteinemija ispoljila negativno dejstvo na funkciju miokarda i uzrokovala dijastolnu disfunkciju miokarda. Ispitivani vitamini B kompleksa (vitamin B9, B6, B12) imaju esencijalnu ulogu i metabolizimu homocisteina i regulaciji nivoa homocisteina, odnosno njihova primena ima kardiprotektivnu ulogu koja se ostvaruje snižavanjem homocisteina u krvi. Simvastatin je pokazao snažnije antioksidantno dejstvo u kardiovaskularnom sistemu u odnosu na atorvastatin u terapijski ekvivalentnim dozama.sr
dc.descriptionThe aim of this study was to investigate the effects of chronic use of diet enriched in methionine and chronic administration of atorvastatin and simvastatin on myocardial function in isolated rat heart, and the role of biomarkers of oxidative stress in the obtained changes. In this study were analyzed 90 rats (Wistar albino strain, male, 4 weeks old, body weight 100 ± 15 g), which were for a period of 30 days subjected to the diet enriched in methionine, with or without vitamin deficiency B6, B9 and B12 and/or pharmacological treatment (Atorvastatin at a dose of 3 mg/kg or simvastatin at a dose of 5 mg/kg), followed by evaluation of experiments in the isolated heart by the Langendorf method of retrograde perfusion (Langendorff apparatus, Experimetria Ltd, 1062 Budapest, Hungary) at variable coronary perfusion pressure 40-120 cmH2O. This study was divided into nine (9) experimental groups. In the left ventricle the parameters of left ventricular function are continuously monitored: a) dp/dt max - maximum rate of change of left ventricle pressure, b) dp/dt min - minimum rate of change of left ventricle pressure, v) SLVP - systolic left ventricular pressure, G) DLVP - diastolic left ventricular pressure and d) HR - heart rate. In the blood, we determined the level of homocysteine (Hcy), total cholesterol (tChol), HDL cholesterol (HDL), triglycerides (Tgy). In the blood and effluent samples we measured biomarkers of oxidative stress: an index of lipid peroxidation - measured as TBARS, nitric oxide, in the form of nitrite (NO2-), superoxide anion radical (O2-), and hydrogen peroxide (H2O2), and the parameters of antioxidant protection system: catalase (CAT), superoxide dismutase (SOD) and reduced glutathione (GSH). The research results are presented in 21 tables and 49 graphs. Summarily, hyperhomocysteinemia causes changes in the morphometric characteristics of the rat after 4 weeks, with an emphasis on the reduction in total body weight at extremely elevated levels of homocysteine in the blood. It is also observed that the negative effects of hyperchomocysteinemia on the heart muscle mediated by the increase of reactive oxygen species and lipid peroxidation as well as the reduced ability of antioxidant protection. On the other hand, HMG-CoA reductase inhibitors have a positive effect on the cardiovascular system, by lowering oxidative stress and increasing antioxidant capacity. Moderate hyperhomocysteinaemia did not cause a decrease in myocardial contractility, whereas severe hyperhomocysteinemia exhibited a negative effect on myocardial function and caused diastolic myocardial dysfunction. The examined vitamins B complex (vitamin B9, B6, B12) have an essential role in metabolism of homocysteine and that is, their application has a cardioprotective role that is achieved by lowering homocysteine in the blood. Simvastatin showed a stronger antioxidant effect compared to atorvastatin in therapeutically equivalent doses in the cardiovascular system.en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Крагујевцу, Факултет медицинских наукаsr
dc.rightsAutorstvo-Nekomercijalno-Bez prerade 3.0 Srbija (CC BY-NC-ND 3.0)
dc.sourceУниверзитет у Крагујевцуsr
dc.subjecthiperhomocisteinemijasr
dc.subjectHyperhomocysteinaemiaen
dc.subjectkardiovaskularni sistemsr
dc.subjectoksidacioni stressr
dc.subjectkoronarni protoksr
dc.subjectinhibitori hidroksimetil-glutaril koenzim-A (HMG-CoA) reduktazesr
dc.subjectcardiovascular systemen
dc.subjectoxidative stressen
dc.subjectcoronary flowen
dc.subjecthydroxymethyl-glutaryl coenzyme-A (HMG-CoA) reductase inhibitorsen
dc.titleEfekti hiperhomocisteinemije na funkciju miokarda, koronarnu cirkulaciju i redoks status izolovanog srca pacova: uloga inhibitora hidroksimetil-glutaril koenzim-A (HMG-COA) reduktazesr
dc.title.alternativeEffects of hyperhomocysteinemia on myocardial function, coronary circulation and redox status of the isolated rat heart: role of hydroxymethyl glutaryl coenzyme-A (HMG-COA) reductase inhibitorsen
dc.typePhD thesis
dcterms.abstractЖивковић, Владимир; Јаковљевић, Владимир; Фолић, Марко; Ђурић, Драган; Радовановић, Милан; Николић, Тамара; Ефекти хиперхомоцистеинемије на функцију миокарда, коронарну циркулацију и редокс статус изолованог срца пацова: улога инхибитора хидроксиметил-глутарил коензим-A (ХМГ-ЦОA) редуктазе; Ефекти хиперхомоцистеинемије на функцију миокарда, коронарну циркулацију и редокс статус изолованог срца пацова: улога инхибитора хидроксиметил-глутарил коензим-A (ХМГ-ЦОA) редуктазе;


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