Biomedical subjects

W N Goolsby

Publications and source records attributed to W N Goolsby.

6 recordsLinked to original sources

PubMed1997

Modulation of propagation from an ectopic focus by electrical load and by extracellular potassium.

We previously developed a technique (R. Kumar, R. Wilders, R. W. Joyner, H. J. Jongsma, E. E. Verheijck, D. A. Golod, A. C. G. van Ginneken, and W. N. Goolsby. Circulation 94: 833-841, 1996) for study of a mathematical model cell with spontaneous activity, viz. a "real-time" simulation of a rabbit sinoatrial node cell (SAN model cell; R. Wilders, H. J. Jongsma, and A. C. van Ginneken. Biophys. J. 60: 1202-1216, 1991) simultaneously being electrically coupled via our "coupling clamp" [H. Sugiura and R. W. Joyner. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1591-H1604, 1992] circuit to a real, isolated ventricular myocyte. We now apply this technique to investigate effects of coupling conductance (Gc), cell size, and the modulation of membrane potential by elevated extracellular potassium concentration on the ability of an ectopic focus, represented by the SAN model cell, to successfully drive a ventricular cell. Values of Gc and the relative sizes of the two cells define three possible outcomes: 1) spontaneous pacing of the SAN model cell but not driving of the ventricular cell, 2) cessation of spontaneous pacing, or 3) pacing of the SAN model cell and driving of the ventricular cell. Below a critical size of the SAN model cell only the first two of these outcomes is possible. Above this critical size there is a range of Gc that allows successful operation of the system as an ectopic focus. Elevation of extracellular potassium concentration from 4 to 8 mM increases both the lower bound and upper bound of Gc for this range. Elevation of extracellular potassium concentration, as commonly observed in myocardial ischemia, may have effects on either inhibiting or releasing from inhibition an ectopic focus.

Animals↗

PubMed1996

Experimental model for an ectopic focus coupled to ventricular cells.

BACKGROUND: We used a mathematical model of a sinoatrial nodal cell (SAN model) electrically coupled to real ventricular cells (VCs) to investigate action potential conduction from an automatic focus. METHODS AND RESULTS: Since input resistance of a VC is less than that of an SAN cell, coupling of the SAN model, with a size factor of 1, to a VC produced either (1) spontaneous pacing at the slower rate of the SAN model but without driving (activation) of the VC for lower values of coupling conductance (Gj) or (2) inhibition of pacing of the SAN model by electrical coupling to the VC for higher values of Gj. When the SAN model was adjusted in size to be 3 to 5 times larger than a sinoatrial nodal cell, thus making effective SAN model capacitance 3 to 5 times larger and input resistance 3 to 5 times smaller, the SAN model propagated activity to the coupled VC for Gj above a critical value. When the VC was paced at 1 Hz, the coupled cell pair demonstrated a stable rhythm of alternating cycle lengths and alternating conduction directions. By increasing pacing frequency to 2 Hz, we converted this rhythm to a regular 2-Hz frequency in which each action potential originated in the VC. More complex periodic interactions were observed at intermediate cycle lengths and lower or higher values of Gj. CONCLUSIONS: The phenomena we observed demonstrate the critical role of the size of an automatic focus as well as the coupling in the propagation of activity from the focus into surrounding myocardium.

Action Potentials↗

PubMed1996

Modulating L-type calcium current affects discontinuous cardiac action potential conduction.

We have used pairs of cardiac cells (i.e., one real guinea pig ventricular cell and a real-time simulation of a numerical model of a guinea pig ventricular cell) to evaluate the effects on action potential conduction of a variable coupling conductance in combination with agents that either increase or decrease the magnitude of the L-type calcium current. For the cell pairs studied, we applied a direct repetitive stimulation to the real cell, making it the "leader" cell of the cell pair. We have demonstrated that significant delays in action potential conduction for a cell pair can occur either with a decreased value of coupling conductance or with an asymmetry in size such that the follower cell is larger than the leader cell. In both conditions we have shown that isoproterenol, applied to the real cell at very low concentrations, can reversibly decrease the critical coupling conductance (below which action potential conduction fails) for a cell pair with fixed cell sizes, or, for a fixed value of coupling conductance, increase the maximum allowable asymmetry in cell size for successful conduction. For either of these effects, we were able to show that treatment of the real cell with BayK 8644, which more specifically increases the magnitude of the L-type calcium current, was able to mimic the actions of isoproterenol. Treatment of the leader cell of the cell pair (the real cell) with nifedipine, which selectively lowers the magnitude of the L-type calcium current, had effects opposite those of isoproterenol or BayK 8644. The actions of nifedipine, isoproterenol, and BayK 8644 are all limited to conditions in which the conduction delay is on the order of 5 ms or more, whether this delay is caused by limited coupling conductance or by asymmetry in size of the cells. This limitation is consistent with the time course of the L-type calcium current and suggests that the effects of calcium channel blockers or beta-adrenergic blocking drugs, in addition to being selective for regions of the heart that depend on the L-type calcium current for the upstroke of the action potential, would also be somewhat selective for regions of the heart that have discontinuous conduction, either normally or because of some pathological condition.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1996

Action potential conduction between a ventricular cell model and an isolated ventricular cell.

We used the Luo and Rudy (LR) mathematical model of the guinea pig ventricular cell coupled to experimentally recorded guinea pig ventricular cells to investigate the effects of geometrical asymmetry on action potential propagation. The overall correspondence of the LR cell model with the recorded real cell action potentials was quite good, and the strength-duration curves for the real cells and for the LR model cell were in general correspondence. The experimental protocol allowed us to modify the effective size of either the simulation model or the real cell. 1) When we normalized real cell size to LR model cell size, required conductance for propagation between model cell and real cell was greater than that found for conduction between two LR model cells (5.4 nS), with a greater disparity when we stimulated the LR model cell (8.3 +/- 0.6 nS) than when we stimulated the real cell (7.0 +/- 0.2 nS). 2) Electrical loading of the action potential waveform was greater for real cell than for LR model cell even when real cell size was normalized to be equal to that of LR model cell. 3) When the size of the follower cell was doubled, required conductance for propagation was dramatically increased; but this increase was greatest for conduction from real cell to LR model cell, less for conduction from LR model cell to real cell, and least for conduction from LR model cell to LR model cell. The introduction of this "model clamp" technique allows testing of proposed membrane models of cardiac cells in terms of their source-sink behavior under conditions of extreme coupling by examining the symmetry of conduction of a cell pair composed of a model cell and a real cardiac cell. We have focused our experimental work with this technique on situations of extreme uncoupling that can lead to conduction block. In addition, the analysis of the geometrical factors that determine success or failure of conduction is important in the understanding of the process of discontinuous conduction, which occurs in myocardial infarction.

Action Potentials↗

PubMed1996

Model clamp and its application to synchronization of rabbit sinoatrial node cells.

A method for coupling an isolated cardiac cell to a simulated cardiac cell, i.e., the real-time solution of a mathematical model of such cell, has been developed. With this "model clamp" technique, the real cell and the model cell are coupled by any desired value of intercellular coupling conductance, producing the effect of mutual interaction by electrical coupling through gap junctional channels. We implemented the model clamp technique with our previously published model of an isolated rabbit sinoatrial node cell. We used this model clamp system to study synchronization of sinoatrial node cells with regard to the critical value of intercellular coupling conductance required for frequency entrainment and the common interbeat interval during frequency entrainment. This common interbeat interval lay between the intrinsic intervals of the real cell and the model cell, but was closer to that of the intrinsically faster beating cell. Critical coupling conductance increased with increasing difference in intrinsic interbeat interval of the real cell and the model cell and ranged between 50 and 300 pS in 11 hybrid cell pairs.

Action Potentials↗

PubMed1990

Potassium channels and the repolarization of cardiac cells.

What is the contribution of a particular potassium current to the repolarization of cardiac myocytes? The traditional answer to this question requires clamping the cells with step voltages, finding models that describe how individual currents depend on voltage and time, driving these models with action potentials to calculate the action currents, and evaluating the contribution of each pathway to repolarization from the action currents. Another method is to measure the action currents directly from beating cells. We isolated potassium channels in cell-attached patches and averaged the current over many beats. The average channel current, mean value of i(t), is a miniature version of the action current through corresponding channels in the membrane outside the patch. The time integral of this current, scaled by channel density, N, and membrane capacity, C, is the contribution of that particular pathway to the action potential: Vi(t) = -Ni integral of to mean value of i(u) du/C Using this procedure, we have found that the delayed rectifier, IK, turns on virtually without delay following the upstroke of the action potential and gradually declines during the plateau and repolarization phases, having nearly the shape of the action potential itself. The inward rectifier, IKl, may conduct little current during the plateau and is under the control of internal Ca. The traditional method of measuring action currents from step voltage-clamp records gives qualitatively similar results. Differences may arise because factors other than voltage modulate potassium currents in beating cells.

Animals↗