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J M Kootsey

Publications and source records attributed to J M Kootsey.

At least 19 recordsLinked to original sources
PubMed1996

A quasi-one-dimensional theory for anisotropic propagation of excitation in cardiac muscle.

It has been shown that propagation of excitation in cardiac muscle is anisotropic. Compared to propagation at right angles to the long axes of the fibers, propagation along the long axis is faster, the extracellular action potential (AP) is larger in amplitude, and the intracellular AP has a lower maximum rate of depolarization, a larger time constant of the foot, and a lower peak amplitude. These observations are contrary to the predictions of classical one-dimensional (1-D) cable theory and, thus far, no satisfactory theory for them has been reported. As an alternative description of propagation in cardiac muscle, this study provides a quasi-1-D theory that includes a simplified description of the effects of action currents in extracellular space as well as resistive coupling between surface and deeper fibers in cardiac muscle. In terms of classical 1-D theory, this quasi-1-D theory reveals that the anisotropies in the wave form of the AP arise from modifications in the effective membrane ionic current and capacitance. The theory also shows that it is propagation in the longitudinal, not in the transverse direction that deviates from classical 1-D cable theory.

Action Potentials↗
PubMed1992

Sodium-calcium exchange: derivation of a state diagram and rate constants from experimental data.

A mechanism is developed for Na(+)-Ca2+ exchange using a new approach made possible by the availability of computer software that allows the systematic search of a large parameter space for optimum sets of parameters to fit multiple sets of experimental data. The approach was to make the experimental data dictate the form of the mechanism: the qualitative features of the data dictating the number and nature of the states of the exchanger and their interrelationship, and the quantitative aspects of the data dictating the values of the rate constants that govern the amount of each state relative to the total amount of exchanger. A single set of experimental data served this initial purpose, namely, observations of equilibrium Ca(2+)-Ca2+ exchange in cardiac sarcolemmal vesicles (Slaughter et al., 1983, J. biol. Chem. 258, 3183-3190). From this data a minimum mechanism was induced having 56 states (SYM56), which gave satisfactory quantitative fits to the experimental data. With this set of parameters additional experimental data were fitted, from the same preparation, the single cardiac cell and the squid giant axon, with some changes in parameters, but none dramatic. In spite of the symmetric nature of the mechanism, i.e. binding constants for Na+ and Ca2+ do not depend on the orientation of the binding sites, the mechanism exhibits marked asymmetric behavior similar to that observed experimentally. Finally, in accounting for Ca(2+)-Ca2+ exchange in the absence of monovalent cations, Ca2+ influx becomes dependent on intracellular Ca(2+)--an unexpected outcome--exactly in keeping with the "essential activator" role of intracellular Ca2+ observed by DiPolo & Beaugé (1987, J. gen. Physiol. 90, 505-525). Observations of Na(+)-Ca2+ exchange in the retinal rod outer segment are well fitted with a simplified version of SYM56 comprising 25 states (namely, SYM25), supporting the notion that the exchanger in the retinal rod outer segment differs from that in cardiac sarcolemma and squid axon. Maximum turnover rate of 840 sec-1 for SYM56 and 20 sec-1 for SYM25 are comparable to those reported for the exchanger in cardiac muscle and retinal rod outer segment, respectively.

Animals↗
PubMed1991

Simulation of the voltage dependence of the Na, K pump applied to cardiac cells.

We use simulation to study the dependence of the Na, K pump on membrane potential. Two consecutive mechanisms for the Na, K pump, based on a reduced Post-Albers scheme, are examined: one with six steps called GV3 and one with seven steps called MGV3. In GV3, a single voltage-dependent step combines both Na+ translocation and Na+ release into the extracellular medium. In MGV3, these two processes are allocated to two separate consecutive steps, but only the Na+ translocation step is voltage-dependent. Using the optimization software SCoPfit, numerical values of rate coefficients, symmetry factor (beta), and pump site density were found by fitting the models to published experimental data so that both GV3 and MGV3 could quantitatively reproduce steady-state current-voltage relationships for both forward and backward running of the pump, as well as [Na+]in and [K+]out activation curves. Using the rate coefficient values found by SCoPfit, we simulated a voltage-clamp experiment with both models running under their Na(+)-Na+ exchange mode, and we computed the transient currents generated following voltage steps in both depolarizing and hyperpolarizing directions from a basic potential of -40 mV. The voltage dependence of the rate constant (1/tau) of decay of the transient currents could qualitatively be reproduced when beta = 0.884 for GV3, and 0.932 for MGV3. The quantitative discrepancy between published experimental data and the theoretical curve generated by GV3 at potentials more negative than -20 mV was considerably reduced by using model MGV3. This finding alone suggests that a more detailed mechanism containing a single voltage-dependent step may reproduce all major steady-state and transient characteristics of the Na, K pump without the need of a second voltage sensitive step. However, the quantitative discrepancy between published experimental data and the theoretical curve generated by MGV3 at potentials more negative than -60 mV may be fully removed if either beta itself is voltage-dependent, or if a second voltage-dependent step is included in the model.

Animals↗
PubMed1991

Kinetic analysis of chloride conductance in frog skeletal muscle at pH 5.

At pH 5 the steady-state chloride chord conductance in frog skeletal muscle rises to an asymptotic maximum at very negative voltages and approaches an asymptotic minimum at positive voltages. When a two-pulse test paradigm is used, the conductance computed from steady-state currents during the first (conditioning) voltage step are not duplicated by the conductance at the onset of a second (test) step. If the test step is to a more negative voltage than the conditioning step the steady-state conductance is overestimated; if it is to a less negative voltage the conductance is underestimated. In some fibres the initial currents accompanying steps from the resting potential are inwardly rectified. From this it was inferred that chloride channel conductance is voltage dependent: in those fibres in which no such initial inward rectification was observed it was inferred that at rest the voltage-dependent chloride channels are all closed. Time-dependent ("gated") changes of conductance could be reasonably described by a first-order process, but the relaxations were not simple exponentials. Simulation of the experimental set-up predicted the type of deviation from exponentiality seen experimentally, although the observed deviations were often more pronounced than those predicted.

Animals↗
PubMed1987

Propagating depolarization in anisotropic human and canine cardiac muscle: apparent directional differences in membrane capacitance. A simplified model for selective directional effects of modifying the sodium conductance on Vmax, tau foot, and the propagation safety factor.

As yet there is no model or simulation that accounts for the anisotropic difference in the shape of the upstroke and safety factor of propagating cardiac action potentials: fast upstrokes occur with slow transverse propagation and slow upstrokes occur with fast longitudinal propagation. The purpose of this paper is to demonstrate, however, that a simplified cable model based on directional differences in the effective membrane capacitance predicts in detail the experimentally measured directionally dependent behavior of the upstroke in response to modification of the sodium conductance. Quinidine and lidocaine produced greater relative decreases in Vmax and conduction velocity with longitudinal propagation than with transverse propagation, as predicted on the basis that the shape differences should produce an anisotropic distribution in the membrane uptake of sodium channel binding drugs. The simulation predictions of the effects of positive shifts of the take-off potential due to premature action potentials were also confirmed experimentally: there was a greater relative decrease in conduction velocity, Vmax, and Vamp with a greater increase in tau foot during longitudinal propagation than with transverse propagation. The major anisotropic differences in shape occurred when the take-off potential approached the least negative value that produced a propagated response. The extensive experimental verification of the results of a simplified model based on directional differences of effective membrane capacitance, combined with directional differences in effective axial resistivity, provides an initial quantitative basis for the anisotropic behavior of propagating depolarization in response to modification of the sodium conductance in cardiac muscle.

Action Potentials↗
PubMed1987

Complexity and significance in computer simulations of physiological systems.

Complexity in a theoretical model may or may not be associated with a high level of arbitrariness, depending on how the model is constructed. In this paper I use examples from cardiac electrophysiology to illustrate two techniques for maintaining significance in complex simulations. First, the approaches of analysis and synthesis are compared as methods of constructing models of complex systems. When a model is constructed by synthesis of known principles, facts, and subunits, it may have any degree of complexity without losing significance; the same is not true for analysis models. Significance can also be maintained by assembling a limited model to test a specific hypothesis of mechanism.

Adenosine Triphosphate↗
PubMed1986

Reconstruction of transport currents during repolarization: biochemical basis.

A philosophy and approach is described for including enzyme-mediated transport currents in reconstructions of ion regulation and electrical activity in cardiac muscle. Data from physiological and biochemical experiments on isolated transport systems are combined with the principles of physical chemistry to construct mechanistic descriptions of the systems. These descriptions are then combined (unmodified) together with the results of morphological measurements on cells to reconstruct the behavior of the ion regulation system. Some results from a preliminary model of this type are described: calcium regulation by the plasmalemma, including sodium-calcium exchange, the calcium pump (ATPase), and a calcium leak. This subsystem is stable at physiological values of ion concentrations and transmembrane potential and the net flux through the leak is within the range determined experimentally. Under these conditions, most of the calcium entering the cell through the leak is shown to be restored by the calcium pump. From calculations with an action potential of arbitrary waveform, it is shown that sodium-calcium exchange can make a small, but measurable contribution to repolarization in the cardiac cell.

Computer Simulation↗
PubMed1985

A minimum mechanism for Na+-Ca++ exchange: net and unidirectional Ca++ fluxes as functions of ion composition and membrane potential.

Both simultaneous and consecutive mechanisms for Na+-Ca++ exchange are formulated and the associated systems of steady-state equations are solved numerically, and the net and unidirectional Ca++ fluxes computed for a variety of ionic and electrical boundary conditions. A simultaneous mechanism is shown to be consistent with a broad range of experimental data from the squid giant axon, cardiac muscle and isolated sarcolemmal vesicles. In this mechanism, random binding of three Na+ ions and one Ca++ on apposing sides of a membrane are required before a conformational change can occur, translocating the binding sites to the opposite sides of the membranes. A similar (return) translocation step is also permitted if all the sites are empty. None of the other states of binding can undergo such translocating conformational changes. The resulting reaction scheme has 22 reaction steps involving 16 ion-binding intermediates. The voltage dependence of the equilibrium constant for the overall reaction, required by the 3:1 Na+: Ca++ stoichiometry was obtained by multiplying and dividing, respectively, the forward and reverse rate constants of one of the translocational steps by exp(-FV/2RT). With reasonable values for the membrane density of the enzyme (approximately 120 sites micron 2) and an upper limit for the rate constants of both translocational steps of 10(5) . sec-1, satisfactory behavior was obtainable with identical binding constants for Ca++ on the two sides of the membrane (10(6) M-1), similar symmetry also being assumed for the Na+ binding constant (12 to 60 M-1). Introduction of order into the ion-binding process eliminates behavior that is consistent with experimental findings.

Animals↗
PubMed1983

Electrical and biochemical properties of an enzyme model of the sodium pump.

The electrochemical properties of a widely accepted six-step reaction scheme for the Na+, K+-ATPase have been studied by computer simulation. Rate coefficients were chosen to fit the nonvectorial biochemical data for the isolated enzyme and a current-voltage (I-V) relation consistent with physiological observations was obtained with voltage dependence restricted to one (but not both) of the two translocational steps. The vectorial properties resulting from these choices were consistent with physiological activation of the electrogenic sodium pump by intracellular and extracellular sodium (Na+) and potassium (K+) ions. The model exhibited K+/K+ exchange but little Na+/Na+ exchange unless the energy available from the splitting of adenosine triphosphate (ATP) was reduced, mimicking the behavior seen in squid giant axon. The vectorial ionic activation curves were voltage dependent, resulting in large shifts in apparent Km's with depolarization. At potentials more negative than the equilibrium or reversal potential transport was greatly diminished unless the free energy of ATP splitting was reduced. While the pump reversal potential is at least 100 mV hyperpolarized relative to the resting potential of most cells, the voltage-dependent distribution of intermediate forms of the enzyme allows the possibility of considerable slope conductance of the pump I-V relation in the physiological range of membrane potentials. Some of the vectorial properties of an electrogenic sodium pump appear to be inescapable consequences of the nonvectorial properties of the isolated enzyme. Future application of this approach should allow rigorous quantitative testing of interpretative ideas concerning the mechanism and stoichiometry of the sodium pump.

Animals↗
PubMed1983

The nature of electrical propagation in cardiac muscle.

It has long been appreciated that cardiac muscle is composed of individual cells connected by low-resistance connections, but most concepts of cardiac impulse conduction have been based on a simplified model of propagation assuming continuously uniform intracellular resistivity in the direction of propagation. In this article we describe the development of the application of the theory of continuous media to propagation in cardiac muscle and review some of the successes achieved with this theory. New evidence is cited that propagation in cardiac muscle often displays a discontinuous nature. We consider the hypothesis that this previously unrecognized aspect of propagation can be explained by discontinuities in axial resistance related to known structural complexities of cardiac muscle. A major implication is that the combination of discontinuities of effective axial resistivity at several size levels can produce a wide variety of complex abnormalities of propagation, including most currently known cardiac conduction disturbances that have been considered to require spatial nonuniformity of membrane properties.

Action Potentials↗
PubMed1982

Active modulation of electrical coupling between cardiac cells of the dog. A mechanism for transient and steady state variations in conduction velocity.

Propagation velocities of action potentials were measured simultaneously along the longitudinal and transverse axes of cardiac fibers in ventricular muscle. The anisotropic distribution of propagation velocities was found to be altered transiently and in the steady state by the rate and pattern of stimulation and by ouabain. The relative amount of velocity change varied with the direction of propagation and was greatest in the direction perpendicular to the long fiber axis. None of the variables usually associated with the membrane ionic mechanism of depolarization--resting potential, Vmax, and taufoot--showed enough variation to account for the observed changes in velocity. A simplified anisotropic propagation model representing the internal current pathway as an alternating sequence of cytoplasmic and junctional resistance is presented, taking into account the larger contribution to the internal resistance made by the cell couplings in the transverse direction than in the longitudinal direction. On the basis of this model, it was concluded that the observed changes in velocity were due to changes in cell coupling. Both transient and steady state velocity changes were found to correspond to changes in the action potential duration, suggesting that there is a common factor, such as the internal calcium and/or sodium concentrations, linking the control of the action potential duration and the coupling resistance between cardiac cells.

Action Potentials↗
PubMed1980

The origin of the T-wave.

Of all the features of the electrocardiogram, the T wave shows the earliest and most dramatic correlation with abnormalities of electrical behavior in the heart. Yet, it has remained difficult to make quantitative connections between the T wave and electrical activity in the heart at the cellular level. It is the purpose of this paper to review attempts at deriving T waves from a knowledge of the membrane electrical activity in the heart and the geometry and conductive properties of the heart and its surrounding medium. We first summarize the problem of calculating T-wave potentials on the body surface, based on physical laws. Next, we review the empirical conclusions that have been reached through observations of the T wave, including its connection with repolarization of the cell membrane, the distributed nature of the current source during the T wave, and the gradient in action potential duration responsible for the positive polarity of the normal T wave. Six quantitative models have been proposed for the T wave; we compare these models and comment on their accuracy and underlying assumptions. Finally, we discuss ideas that have been suggested for the membrane mechanism of repolarization and the T wave.

Action Potentials↗