Uticaj selektivne blokade elemenata tkivnog renin angiotenzin aldeosteron sistema na izolovano srce pacova u hemijski izazvanom diabetes mellitus-u

Abstract

Izvod: Dijabetes karakteriše pojačana aktivnost RAAS. Hiperglikemija je najznačajniji metabolički uzročnik tkivnih promena i aktivacije RAAS. Posledice aktivacije RAAS u srčanom tkivu su oksidacioni stres, fibroza i apoptoza. U poslednje vreme se uviđa da modulacija RAAS, inhibitorima ASE i blokatorima AT1 receptora, nije dovoljno efikasna, dok direktni inhibitor renina pokazuje efekat i na intracelularni i ekstracelularni tkivni RAAS. Kombinovana primena modulatora RAAS dovodi do povećanog kardiovaskularnog mortaliteta što je ukazalo na postojanje neželjenih efekata na miokard. Mehanizam kardijalnog oštećenja nakon primene modulatora RAAS je važno istraživačko pitanje. Ovim istraživanjem su sagledavani akutni efekti perfuzije modulatorima RAAS na zdrav i miokard u dijabetesu. Utvrditi razlike u kardiodinamskim parametrima, koronarnom protoku, stvaranju NO i parametrima oksidacionog stresa između srca zdravih i pacova nakon 4 nedelje hiperglikemije. Utvrditi akutne efekte perfuzije modulatorima RAAS (zofenopril, valsartan, spironolakton i aliskiren) na srca zdravih i pacova nakon četiri nedelje hiperglikemije. Korišteni su pacovi soja Wistar albino podeljeni u 8 grupa po 12 životinja. Životinje su žrtvovane a srce je izolovano i postavljeno na Lagendorf-ov aparat. Četiri grupe su činile zdrave životinje kojima su kroz izolovano srce perfuzijom puštani pojedinačno zofenopril 1.5 μM, valsartan 1μM, spironolakton 0.1 μM i aliskiren 1 μM. Na isti način su tretirani i pacovi kojima je 4 nedelje pred eksperiment hemisjki indukovan dijabetes upotrebom streptozotocina. Određivani su kardiodinamski parametri: brzine promene pristiska u levoj komori (dp/dt max i dp/dt min), pritisak u levoj komori (SLVP i DLVP), srčana frekvenca (NR) i koronarni protok (CF). Iz koronarnog efluenta određivana koncentracija NO i parametara oksidacionog stresa: O2.-, H2O2 i TBARS. Svi parametri su određivani pri različitim perfuzionim pritiscima od 40-120 cm H20. Hronična hiperglikemija je dovela do dijastolne disfunkcije izolovanog srca pacova. Poremećaj je funkcionalne prirode. Nije uočen poremećaj sistolne funkcije ni srčane frekvence. Koronarni protok je blago cmanjen pri višim perfuzionim pritiscima. Parametri oksidacionog stresa O2.- i N2O2 su sniženi u grupi sa dijabetesom dok je TBARS povišen. Nije bilo izmene koncentracije NO. Modulatori RAAS ostvaruju različite efekte na miokardu zdravih u odnosu na miokard pacova sa dijabetesom. Ova razlika je i kvantitativna a pri primeni nekih lekova i kvalitativna. Akutni efekti modulatora RAAS su izraženiji u kontrolnoj grupi. Aliskiren dovodi do negativnog inotropnog i lusitropnog efekta, što je manje izraženo u dijabetesu a potencirano je porastom pritiska.

Abstract: Diabetes is characterized by an increase in the activity of RAAS. Hyperglycemia is the most important metabolic cause of tissue changes and RAAS activation. The consequences of RAAS activation in the cardiac tissue are oxidative stress, fibrosis and apoptosis. Recently, it has been noted that RAAS modulation with ACE inhibitors and blockers of AT1 receptors is not effective enough, while a direct renin inhibitor proved to have effect on both, intracellular and extracellular tissue RAAS. A combined use of RAAS modulators leads to an increased cardiovascular mortality, which indicates the presence of adverse effects on myocardium. The 166 mechanism of cardiac damage after the administration of RAAS modulators is an important research issue. This research examined the acute effects of perfusion with RAAS modulators on healthy and diabetic myocardium. To identify the differences in cardiodynamic parameters, coronary flow, NO production and oxidative stress parameters between the hearts of healthy rats and the hearts of rats that had been hyperglycemic for 4 weeks. To determine the acute effects of perfusion with RAAS modulators (zofenopril, valsartan, spironolactone and aliskiren) on the hearts of healthy rats and the hearts of rats after four weeks of hyperglycemia. We used rats of albino Wistar strain, divided into 8 groups of 12 animals each. The animals were sacrificed and the hearts were isolated and mounted on Langendorff' apparatus. Four groups consisted of healthy animals into whose isolated hearts were by perfusion separately released zofenopril 1.5 uM, 1μM valsartan, spironolactone 0.1 uM and 1 uM aliskiren. In the same way were treated the rats to which diabetes had been induced chemically, using streptozotocin, 4 weeks before the experiment. The cardiodynamic parameters were measured: rate of the change of the left ventricular pressure (dp / dt max and dp / dt min), left ventricular pressure (SLVP and DLVP), heart rate (HR) and coronary flow (CF). The coronary effluent was used to determine the NO concentration and oxidative stress parameters: O2.-, H2O2 and TBARS. All parameters were determined at different perfusion pressures: 40-120 cm H2O. Chronic hyperglycemia led to diastolic dysfunction in isolated rat heart. The disorder is functional in nature. No systolic dysfunction or heart rate irregularities were observed. The coronary flow was slightly decreased at higher perfusion pressures. Parameters of oxidative stress O2.- and H2O2 were lower in the diabetic group, while TBARS were increased. There were no changes to the NO concentration. RAAS modulators affected myocardium of healthy and diabetic rats differently. The difference is quantitative and, in case of administration of certain drugs, it is also qualitative. Acute effects of RAAS modulators were more pronounced in the control group.