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The role of renal dysfunction in pathophysiology of congestive heart failure progression: preclinical animal studies
Kala, Petr ; Veselka, Josef (advisor) ; Štengl, Milan (referee) ; Štěrba, Martin (referee)
The role of renal dysfunction in pathophysiology of congestive heart failure progression: preclinical animal studies. Abstract The thesis describes effects and pharmacological targets of eicosanoids, especially epoxyeicosatrienoic acids (EETs) that are epoxygenase metabolites of arachidonic acid (AA), in animal model of congestive heart failure (CHF) induced by volume overload via aorto- caval fistula (ACF) in hypertensive transgenic rats (TGR). Our data show that ACF TGR exhibits tissue deficiency of EETs in the left ventricle and kidney, probably mainly caused by increased EETs degradation by soluble epoxide hydrolase (sEH). Treatment by orally active EETs analogue (EET-A) improved the survival rate in ACF TGR compared to placebo. However, after adding EET-A to angiotensin-convertase enzyme inhibitor (ACEi) treatment, the survival of ACF TGR only tended to improve compared with the effects of EET-A or ACEi given alone. The protective effects of EET-A treatment were mediated by improving cardiac parameters and reducing lung congestion, not dominantly by renal mechanisms. We also found that among male (not in female) the combination of sEH inhibitor (sEHi) and ACEi treatment worsened the mortality of ACF TGR compared to ACEi monotherapy. Our data support the notion that targeting the CYP-dependent...
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Pharmacological possibilities for amending renal dysfunction in experimental model of heart failure
Krátký, Vojtěch ; Charvátová, Zuzana (advisor) ; Bednářová, Vladimíra (referee) ; Melenovský, Vojtěch (referee)
Mechanisms underlying the development of renal dysfunction and pharmacological possibilities for its amending in patients with chronic heart failure are still incompletely understood. The aim of the study was thus to compare the effect of treatment with an ACE inhibitor (ACEi), AT1 receptor blocker (ARB) or combined angiotensin receptor-neprilysin inhibitor (ARNi) on renal hemodynamic and excretory functions in experimental models of heart failure induced by placing an aorto-caval fistula (ACF) in combination with hypertension or preexisting renal disease. In normotensive and especially in hypertensive rats with high- output heart failure 20 weeks after ACF placement, ARB administration, dissimilarly to an ACEi treatment, was shown to prevent renal hypoperfusion and hypoxia. In addition, heart failure rats treated with ARB exhibited lower ROS generation, improved renal NO bioavailability, and normal renal SNS activity. The failure of ACEi to ameliorate renal hypoperfusion in rats with heart failure may be a consequence of insufficiently suppressed intrarenal RAS along with enhanced renal SNS activity in the face of depleted compensatory mechanisms, namely NO. Combined ARNi treatment in rats with induced heart failure superimposed on progressive renal dysfunction significantly improved survival...
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