Functional consequences of changes in the distribution of Ca extrusion pathways between t-tubular and surface membranes in a model of human ventricular cardiomyocyte.

The sarcolemmal Ca efflux pathways, Na-Ca-exchanger (NCX) and Ca-ATPase (PMCA), play a crucial role in the regulation of intracellular Ca load and Ca transient in cardiomyocytes. The distribution of these pathways between the t-tubular and surface membrane of ventricular cardiomyocytes varies between species and is not clear in human. Moreover, several studies suggest that this distribution changes during the development and heart diseases.

[Evaluation of the Clinical Outcomes of Autologous Chondrocyte Implantation in the Management of Chondral Lesions of the Knee after 10+ Years].

Purpose Of The Study: The authors present the outcomes of more than ten-year clinical follow-up of patients who underwent surgical treatment of deep chondral defect of the knee (medial or lateral condyle). The method of treatment was the implantation of autologous cultured chondrocytes in the form of a solid chondral graft. The aim was also to compare the mid-term and long-term outcomes and to evaluate how the knee condition affects the everyday life and sports activities more than 10 years after surgery.

A new approach to the determination of tubular membrane capacitance: passive membrane electrical properties under reduced electrical conductivity of the extracellular solution.

The transverse-axial tubular system (tubular system) of cardiomyocytes plays a key role in excitation-contraction coupling. To determine the area of the tubular membrane in relation to the area of the surface membrane, indirect measurements through the determination of membrane capacitances are currently used in addition to microscopic methods. Unlike existing electrophysiological methods based on an irreversible procedure (osmotic shock), the proposed new approach uses a reversible short-term intermittent increase in the electrical resistance of the extracellular medium.

Fraction of the T-Tubular Membrane as an Important Parameter in Cardiac Cellular Electrophysiology: A New Way of Estimation.

The transverse-axial tubular system (t-tubules) plays an essential role in excitation-contraction coupling in cardiomyocytes. Its remodelling is associated with various cardiac diseases. Numerous attempts were made to analyse characteristics essential for proper understanding of the t-tubules and their impact on cardiac cell function in health and disease.

Aminophylline at clinically relevant concentrations affects inward rectifier potassium current in a dual way.

Bronchodilator aminophylline may induce atrial or less often ventricular arrhythmias. The mechanism of this proarrhythmic side effect has not been fully explained. Modifications of inward rectifier potassium (Kir) currents including I are known to play an important role in arrhythmogenesis; however, no data on the aminophylline effect on these currents have been published.

Divergent estimates of the ratio between Na+-Ca2+ current densities in t-tubular and surface membranes of rat ventricular cardiomyocytes.

The ratio between Na+-Ca2+ exchange current densities in t-tubular and surface membranes of rat ventricular cardiomyocytes (JNaCa-ratio) estimated from electrophysiological data published to date yields strikingly different values between 1.7 and nearly 40. Possible reasons for such divergence were analysed by Monte Carlo simulations assuming both normal and log-normal distribution of the measured data.

Distribution of data in cellular electrophysiology: Is it always normal?

The distribution of data presented in many electrophysiological studies is presumed to be normal without any convincing evidence. To test this presumption, the cell membrane capacitance and magnitude of inward rectifier potassium currents were recorded by the whole-cell patch clamp technique in rat atrial myocytes. Statistical analysis of the data showed that these variables were not distributed normally.

A new simple approach to estimation of membrane capacitance from current responses to voltage clamp steps.

A variety of techniques of cell capacitance measurement have been proposed and applied in cellular electrophysiology. They are mostly based on the evaluation of membrane current responses to small changes in the membrane voltage. One of the currently used approaches applies the least-squares fit of an exponential current decay in response to voltage clamped rectangular pulses.

Current density as routine parameter for description of ionic membrane current: is it always the best option?

The current density (J) is a parameter routinely used to characterize individual ionic membrane currents. Its evaluation is based on the presumption that the magnitude of whole-cell ionic membrane current (I) is directly proportional to the cell membrane capacitance (C), i.e.

The intriguing effect of ethanol and nicotine on acetylcholine-sensitive potassium current IKAch: Insight from a quantitative model.

Recent experimental work has revealed unusual features of the effect of certain drugs on cardiac inwardly rectifying potassium currents, including the constitutively active and acetylcholine-induced components of acetylcholine-sensitive current (IKAch). These unusual features have included alternating susceptibility of the current components to activation and inhibition induced by ethanol or nicotine applied at various concentrations, and significant correlation between the drug effect and the current magnitude measured under drug-free conditions. To explain these complex drug effects, we have developed a new type of quantitative model to offer a possible interpretation of the effect of ethanol and nicotine on the IKAch channels.

Inward rectifying potassium currents resolved into components: modeling of complex drug actions.

Inward rectifier potassium currents (I ) belong to prominent ionic currents affecting both resting membrane voltage and action potential repolarization in cardiomyocytes. In existing integrative models of electrical activity of cardiac cells, they have been described as single current components. The proposed quantitative model complies with findings indicating that these channels are formed by various homomeric or heteromeric assemblies of channel subunits with specific functional properties.

Different Densities of Na-Ca Exchange Current in T-Tubular and Surface Membranes and Their Impact on Cellular Activity in a Model of Rat Ventricular Cardiomyocyte.

The ratio of densities of Na-Ca exchanger current () in the t-tubular and surface membranes (-ratio) computed from the values of and membrane capacitances () measured in adult rat ventricular cardiomyocytes before and after detubulation ranges between 1.7 and 25 (potentially even 40). Variations of action potential waveform and of calcium turnover within this span of the -ratio were simulated employing previously developed model of rat ventricular cell incorporating separate description of ion transport systems in the t-tubular and surface membranes.

Nicotine at clinically relevant concentrations affects atrial inward rectifier potassium current sensitive to acetylcholine.

Nicotine abuse is associated with variety of diseases including arrhythmias, most often atrial fibrillation (AF). Altered inward rectifier potassium currents including acetylcholine-sensitive current I are known to be related to AF pathogenesis. Since relevant data are missing, we aimed to investigate I changes at clinically relevant concentrations of nicotine.

Effect of ethanol and acetaldehyde at clinically relevant concentrations on atrial inward rectifier potassium current IK1: separate and combined effect.

Atrial fibrillation is the most common arrhythmia at alcohol consumption. Its pathogenesis is complex, at least partly related to changes of cardiac inward rectifier potassium currents including IK1. Both ethanol and acetaldehyde have been demonstrated to considerably modify IK1 in rat ventricular myocytes.

Effect of ethanol at clinically relevant concentrations on atrial inward rectifier potassium current sensitive to acetylcholine.

Alcohol intoxication tends to induce arrhythmias, most often the atrial fibrillation. To elucidate arrhythmogenic mechanisms related to alcohol consumption, the effect of ethanol on main components of the ionic membrane current is investigated step by step. Considering limited knowledge, we aimed to examine the effect of clinically relevant concentrations of ethanol (0.

Acute effects of ethanol on action potential and intracellular Ca(2+) transient in cardiac ventricular cells: a simulation study.

Alcohol consumption may result in electrocardiographic changes and arrhythmias, at least partly due to effects of ethanol on cardiac ionic currents. Contractility and intracellular Ca(2+) dynamics seem to be altered as well. In this study, we integrated the available (mostly animal) experimental data into previously published models of the rat and human ventricular myocytes to assess the share of ionic current components in ethanol-induced changes in AP configuration and cytosolic Ca(2+) transient in ventricular cardiomyocytes.

Acetaldehyde at clinically relevant concentrations inhibits inward rectifier potassium current I(K1) in rat ventricular myocytes.

Considering the effects of alcohol on cardiac electrical behavior as well as the important role of the inward rectifier potassium current I(K1) in arrhythmogenesis, this study was aimed at the effect of acetaldehyde, the primary metabolite of ethanol, on I(K1) in rat ventricular myocytes. Acetaldehyde induced a reversible inhibition of I(K1) with IC(50) = 53.7+/-7.

Dual effect of ethanol on inward rectifier potassium current IK1 in rat ventricular myocytes.

Alcohol consumption may result in electrocardiographic changes and arrhythmias. Important role of modifications of the inward rectifier potassium current I(K1) in arrhythmogenesis is well established. Considering lack of relevant data, we aimed at studying the effect of 0.

Effect of Ca2+ efflux pathway distribution and exogenous Ca2+ buffers on intracellular Ca2+ dynamics in the rat ventricular myocyte: a simulation study.

We have used a previously published computer model of the rat cardiac ventricular myocyte to investigate the effect of changing the distribution of Ca(2+) efflux pathways (SERCA, Na(+)/Ca(2+) exchange, and sarcolemmal Ca(2+) ATPase) between the dyad and bulk cytoplasm and the effect of adding exogenous Ca(2+) buffers (BAPTA or EGTA), which are used experimentally to differentially buffer Ca(2+) in the dyad and bulk cytoplasm, on cellular Ca(2+) cycling. Increasing the dyadic fraction of a particular Ca(2+) efflux pathway increases the amount of Ca(2+) removed by that pathway, with corresponding changes in Ca(2+) efflux from the bulk cytoplasm. The magnitude of these effects varies with the proportion of the total Ca(2+) removed from the cytoplasm by that pathway.

Effect of ion concentration changes in the limited extracellular spaces on sarcolemmal ion transport and Ca2+ turnover in a model of human ventricular cardiomyocyte.

We have developed a computer model of human cardiac ventricular myocyte (CVM), including t-tubular and cleft spaces with the aim of evaluating the impact of accumulation-depletion of ions in restricted extracellular spaces on transmembrane ion transport and ionic homeostasis in human CVM. The model was based on available data from human CVMs. Under steady state, the effect of ion concentration changes in extracellular spaces on [Ca2+]i-transient was explored as a function of critical fractions of ion transporters in t-tubular membrane (not documented for human CVM).

Role of t-tubules in the control of trans-sarcolemmal ion flux and intracellular Ca2+ in a model of the rat cardiac ventricular myocyte.

The t-tubules of mammalian ventricular myocytes are invaginations of the surface membrane that form a complex network within the cell, with restricted diffusion to the bulk extracellular space. The trans-sarcolemmal flux of many ions, including Ca(2+), occurs predominantly across the t-tubule membrane and thus into and out of this restricted diffusion space. It seems possible, therefore, that ion concentration changes may occur in the t-tubule lumen, which would alter ion flux across the t-tubule membrane.

Estimation of rate constants of drug binding to open channels of cardiac transient outward current.

An improved approach to the evaluation of the rate constants of drugs binding to the open channel underlying the transient outward potassium current I(t0) is described. It is based on an analysis of a quantitative model formulated by a set of twelve differential equations. The rate constants are calculated from the time constants resulting from an approximation of the time course of apparent inactivation of the recorded I(t0) by two exponentials in the absence and by three exponentials in the presence of a blocking agent.

Effect of ethanol on action potential and ionic membrane currents in rat ventricular myocytes.

Aim: Even though alcohol intoxication is often linked to arrhythmias, data describing ethanol effect on cardiac ionic channels are rare. In addition, ethanol is used as a solvent of hydrophobic compounds in experimental studies. We investigated changes of the action potential (AP) configuration and main ionic membrane currents in rat cardiomyocytes under 20-1500 m(M) ethanol.

Effect of antipsychotic drug perphenazine on fast sodium current and transient outward potassium current in rat ventricular myocytes.

Antipsychotic drug perphenazine belongs to the phenothiazine group commonly reported to induce ECG changes and tachyarrhythmias. Data about its effect on ionic membrane currents in cardiomyocytes are missing. We analyzed the effect of perphenazine (0.

A model of the guinea-pig ventricular cardiac myocyte incorporating a transverse-axial tubular system.

A model of the guinea-pig cardiac ventricular myocyte has been developed that includes a representation of the transverse-axial tubular system (TATS), including heterogeneous distribution of ion flux pathways between the surface and tubular membranes. The model reproduces frequency-dependent changes of action potential shape and intracellular ion concentrations and can replicate experimental data showing ion diffusion between the tubular lumen and external solution in guinea-pig myocytes. The model is stable at rest and during activity and returns to rested state after perturbation.