Search

Five-sixths nephrectomy is a widely used experimental model of chronic kidney disease (CKD) that is associated with severe mitochondrial dysfunction of the remnant tissue. In this study, we assessed the effect of CKD on mitochondrial respiration separately in the rat kidney cortex and medulla 10 weeks after induction of CKD by subtotal 5/6 nephrectomy (SNX). Mitochondrial oxygen consumption was evaluated on mechanically permeabilized samples of kidney cortex and medulla using high-resolution respirometry and expressed per mg of tissue wet weight or IU citrate synthase (CS) activity. Mitochondrial respiration in the renal cortex of SNX rats was significantly reduced in all measured respiratory states if expressed per unit wet weight and remained lower if recalculated per IU citrate synthase activity, i.e. per mitochondrial mass. In contrast, the profound decrease in the activity of CS in SNX medulla resulted in significantly elevated respiratory states expressing the OXPHOS capacity when Complexes I and II or II only are provided with electrons, LEAK respiration after oligomycin injection, and Complex IV-linked oxygen consumption per unit CS activity suggesting compensatory hypermetabolic state in remaining functional mitochondria that is not sufficient to fully compensate for respiratory deficit expressed per tissue mass. The results document that CKD induced by 5/6 nephrectomy in the rat is likely to cause not only mitochondrial respiratory dysfunction (in the kidney cortex), but also adaptive changes in the medulla that tend to at least partially compensate for mitochondria loss.

Chronic volume overload induces multiple cardiac remodeling processes that finally result in eccentric cardiac hypertrophy and heart failure. We have hypothesized that chronic angiotensin-converting enzyme (ACE) inhibition by trandolapril might affect various remodeling processes differentially, thus allowing their dissociation. Cardiac remodeling due to chronic volume overload and the effects of trandolapril were investigated in rats with an aortocaval fistula (ACF rats). The aortocaval shunt was created using a needle technique and progression of cardiac remodeling to heart failure was followed for 24 weeks. In ACF rats, pronounced eccentric cardiac hypertrophy and contractile and proarrhythmic electrical remodeling were associated with increased mortality. Trandolapril substantially reduced the electrical proarrhythmic remodeling and mortality, whereas the effect on cardiac hypertrophy was less pronounced and significant eccentric hypertrophy was preserved. Effective suppression of electrical proarrhythmic remodeling and mortality but not hypertrophy indicates that the beneficial therapeutic effects of ACE inhibitor trandolapril in volume overload heart failure might be dissociated from pure antihypertrophic effects.

Metabolic syndrome is associated with hypercholesterolemia, cardiac remodeling, and increased susceptibility to ventricular arrhythmias. Effects of diet-induced hypercholesterolemia on susceptibility to torsades de pointes arrhythmias (TdP) together with potential indicators of arrhythmic risk were investigated in three experimental groups of Carlsson’s rabbit model: (1) young rabbits (YC, young control, age 12–16 weeks), older rabbits (AC, adult control, age 20–24 weeks), and older age-matched cholesterol-fed rabbits (CH, cholesterol, age 20–24 weeks). TdP was induced by α-adrenergic stimulation by methoxamine and IKr block in 83% of YC rabbits, 18% of AC rabbits, and 21% of CH rabbits. High incidence of TdP was associated with high incidence of single (SEB) and multiple ectopic beats (MEB), but the QTc prolongation and short-term variability (STV) were similar in all three groups. In TdP-susceptible rabbits, STV was significantly higher compared with arrhythmia-free rabbits but not with rabbits with other than TdP arrhythmias (SEB, MEB). Amplitude-aware permutation entropy analysis of baseline ECG could identify arrhythmia-resistant animals with high sensitivity and specificity. The data indicate that the TdP susceptibility in methoxamine-sensitized rabbits is affected by the age of rabbits but probably not by hypercholesterolemia. Entropy analysis could potentially stratify the arrhythmic risk and identify the low-risk individuals.

Metabolic syndrome is associated with hypercholesterolemia, cardiac remodeling, and increased susceptibility to ventricular arrhythmias. Effects of diet-induced hypercholesterolemia on susceptibility to torsades de pointes arrhythmias (TdP) together with potential indicators of arrhythmic risk were investigated in three experimental groups of Carlsson’s rabbit model: (1) young rabbits (YC, young control, age 12–16 weeks), older rabbits (AC, adult control, age 20–24 weeks), and older age-matched cholesterol-fed rabbits (CH, cholesterol, age 20–24 weeks). TdP was induced by α-adrenergic stimulation by methoxamine and IKr block in 83% of YC rabbits, 18% of AC rabbits, and 21% of CH rabbits. High incidence of TdP was associated with high incidence of single (SEB) and multiple ectopic beats (MEB), but the QTc prolongation and short-term variability (STV) were similar in all three groups. In TdP-susceptible rabbits, STV was significantly higher compared with arrhythmia-free rabbits but not with rabbits with other than TdP arrhythmias (SEB, MEB). Amplitude-aware permutation entropy analysis of baseline ECG could identify arrhythmia-resistant animals with high sensitivity and specificity. The data indicate that the TdP susceptibility in methoxamine-sensitized rabbits is affected by the age of rabbits but probably not by hypercholesterolemia. Entropy analysis could potentially stratify the arrhythmic risk and identify the low-risk individuals.

An idealized model of an arterial wall is proposed as a two-layer system. Distinct mechanical response of each layer is taken into account considering two types of strain energy functions in the hyperelasticity framework. The outer layer, considered as a fibre-reinforced composite, is modelled using the structural model of Holzapfel. The inner layer, on the other hand, is represented by a two-scale model mimicing smooth muscle tissue. For this model, material parameters such as shape, volume fraction and orientation of smooth muscle cells are determined using the microscopic measurements. The resulting model of an arterial ring is stretched axially and loaded with inner pressure to simulate the mechanical response of a porcine arterial segment during inflation and axial stretching. Good agreement of the model prediction with experimental data is promising for further progress.

Samples of porcine carotid artery are examined using Tissue bath MAYFLOWER, Perfusion of tubular organs Version, Type 813/6. Pressure-diameter diagrams are obtained for fixed axial extension and volumetric flow rate. Finite element analysis of the experiment, performed using COMSOL software, indicates a negligible effect of given flow rate on the mechanical response of the tested sample. Also the effect of clamped ends is shown to be local only. Hence, static analysis in MATLAB software is performed considering the arterial segment as an incompressible hyperelastic axisymmetric tube. Residual stress at the load-free configuration is taken into account resulting in the overall stiffening of the model. Comparison of theoretical and experimental pressure-diameter curves results in the identification of material parameters using the least square method. In addition to classical hyperelastic models, such as the neo-Hookean and the Fung’s exponential, two-scale model mimicking arrangement of soft tissue is considered.

Contractile functions and sympathetic innervation of the albino rat diabetic heart Thesis Summary: The aim of this thesis was to describe: 1. The impact of untreated long-termed diabetes induced by streptozotocin on cardiac contractile functions and their sympathetic regulation in rat. 2. The effect of insulin on cardiac contraction in control and diabetic myocardium. In the diabetic group, the contraction force was significantly decreased compared to control group. The norepinephrine-releasing mechanisms were altered in chronically diabetic rats and may contribute to the decreased norepinephrine concentration in the diabetic heart. Insulin exerted a significant negative inotropic effect in rat myocardium, both control and diabetic. This effect was probably related to processes of SR Ca2+ release triggering, whereas SR Ca2+ loading is not involved. MUDr. Jitka Švíglerová Plzeň, 2006