Propagated repolarization in heart muscle

The effect of current flow on the transmembrane action potential of single fibers of ventricular muscle has been examined. Pulses of repolarizing current applied during the plateau of the action potential displace membrane potential much more than do pulses of depolarizing current. The application of sufficiently strong pulses of repolarizing current initiates sustained repolarization which persists after the end of the pulse. This sustained repolarization appears to propagate throughout the length of the fiber. Demonstration of propagated repolarization is made difficult by appearance of break excitation at the end of the repolarizing pulse. The thresholds for sustained repolarization and break excitation are separated by reducing the concentration of Ca⁺⁺ in the environment of the fiber. In fibers in such an environment it is easier to demonstrate apparently propagated repolarization and also, by further increase of the strength of the repolarizing current, to demonstrate graded break excitation.     

Transverse propagation of action potentials between parallel chains of cardiac muscle and smooth muscle cells in PSpice simulations

Background  

The goal of our study is to examine the effect of stimulating a two-dimensional sheet of myocardial cells. We assume that the stimulating electrode is located in a bath perfusing the tissue.     

Transverse propagation of action potentials between parallel chains of cardiac muscle and smooth muscle cells in PSpice simulations

Background  

We previously examined transverse propagation of action potentials between 2 and 3 parallel chain of cardiac muscle cells (CMC) simulated using the PSpice program. The present study was done to examine transverse propagation between 5 parallel chains in an expanded model of CMC and smooth muscle cells (SMC).     

A model for propagation of action potentials in smooth muscle

A modified Hodgkin & Huxley (1952) model for axons was used to simulate smooth muscle action potentials. The modifications were such as to match our own experimental results and published data on the passive and active behavior of smooth muscle.A brief account of the modifications introduced to the HH model is as follows. The resting ionic conductances were obtained from the data of Casteels (1969). Chloride conductance was replaced by an ad hoc leakage conductance ($\text{g}\text{?}{}_{\mathrm{L}}$) in order to obtain a resting membrane resistance of about 11 kΩcm². The ionic equilibrium potentials were according to Kao & Nishiyama (1969). The rate constants m, n and h have similar form to those in axons, but their different numerical values produce action potentials that match the duration of the smooth muscle action potential (about 16 ms) at half its maximum amplitude. The effective membrane capacitance was taken as 2.5 μF/cm².The results obtained by implementing those smooth muscle parameters in the HH formulation include: (a) a membrane potential that matches the main characteristics of experimentally recorded action potentials in uterine smooth muscle and guinea-pig taenia-coli, and (b) a propagated action potential which, on a cable diameter of 5 μm (similar to the diameter of a single smooth muscle cell), has a speed of propagation within the range of the values experimentally recorded in smooth muscle. This observed velocity of propagation is not compatible with a large cable and it is concluded that “functional units” are not required to sustain propagation of action potentials in smooth muscle.     

Boundary effects influence velocity of transverse propagation of simulated cardiac action potentials

Background  

We previously demonstrated that transverse propagation of excitation (cardiac action potentials simulated with PSpice) could occur in the absence of low-resistance connections (gap – junction channels) between parallel chains of myocardial cells. The transverse transmission of excitation between the chains was strongly dependent on the longitudinal resistance of the interstitial fluid space between the chains: the higher this resistance, the closer the packing of the parallel chains within the bundle. The earlier experiments were carried out with 2-dimensional sheets of cells: 2 × 3, 3 × 4, and 5 × 5 models (where the first number is the number of parallel chains and the second is the number of cells in each chain). The purpose of the present study was to enlarge the model size to 7 × 7, thus enabling the transverse velocities to be compared in models of different sizes (where all circuit parameters are identical in all models). This procedure should enable the significance of the role of edge (boundary) effects in transverse propagation to be determined.     

Monophasic action potentials generated by bidomain modeling as a tool for detecting cardiac repolarization times

Unipolar electrograms (EGs) and hybrid (or unorthodox or unipolar) monophasic action potentials (HMAPs) are currently the only proposed extracellular electrical recording techniques for obtaining cardiac recovery maps with high spatial resolution in exposed and isolated hearts. Estimates of the repolarization times from the HMAP downstroke phase have been the subject of recent controversies. The goal of this paper is to computationally address the controversies concerning the HMAP information content, in particular the reliability of estimating the repolarization time from the HMAP downstroke phase. Three-dimensional numerical simulations were performed by using the anisotropic bidomain model with a region of short action potential durations. EGs, transmembrane action potentials (TAPs), and HMAPs elicited by an epicardial stimulation close or away from a permanently depolarized site were computed. The repolarization time was computed as the moment of EG fastest upstroke (RT(eg)) during the T wave, of HMAP fastest downstroke (RT(HMAP)), and of TAP fastest downstroke (RT(tap)). The latter was taken as the gold standard for repolarization time. We also compared the times (RT90(HMAP), RT90(tap)) when the HMAP and TAP first reach 90% of their resting value during the downstroke. For all explored sites, the HMAP downstroke closely followed the TAP downstroke, which is the expression of local repolarization activity. Results show that HMAP and TAP markers are highly correlated, and both markers RT(HMAP) and RT(eg) (RT90(HMAP)) are reliable estimates of the TAP reference marker RT(tap) (RT90(tap)). Therefore, the downstroke phase of the HMAP contains valuable information for assessing repolarization times.     

How different two almost identical action potentials can be: A model study on cardiac repolarization

Spatial heterogeneity in the properties of ion channels generates spatial dispersion of ventricular repolarization, which is modulated by gap junctional coupling. However, it is possible to simulate conditions in which local differences in excitation properties are electrophysiologically silent and only play a role in pathological states. We use a numerical procedure on the Luo-Rudy phase 1 model of the ventricular action potential (AP1) in order to find a modified set of model parameters which generates an action potential profile (AP2) almost identical to AP1. We show that, although the two waveforms elicited from resting conditions as a single AP are very similar and belong to membranes sharing similar passive electrical properties, the modified membrane generating AP2 is a weaker current source than the one generating AP1, has different sensitivity to up/down-regulation of ion channels and to extracellular potassium, and a different electrical restitution profile. We study electrotonic interaction of AP1- and AP2 - type membranes in cell pairs and in cable conduction, and find differences in source-sink properties which are masked in physiological conditions and become manifest during intercellular uncoupling or partial block of ion channels, leading to unidirectional block and spatial repolarization gradients. We provide contour plot representations that summarize differences and similarities. The present report characterizes an inverse problem in cardiac cells, and strengthen the recently emergent notion that a comprehensive characterization and validation of cell models and their components are necessary in order to correctly understand simulation results at higher levels of complexity.     

Synaptic potentials in smooth muscle cells]

Investigations were carried out on smooth muscle cells (SMC) of rat and rabbit anococcygeus by the method of a double "sugar bridge" in the presence of tetraethylammonium (1 mM/1) in the Krebs solution. Stimulation of the muscle strip by the electric current rectangular pulse of the maximal value and of short duration caused the development of excitatory postsynaptic potentials (EP SP) in the rat and rabbit SMC, and of inhibitory postsynaptic potentials in the rabbit SMC. The value of postsynaptic potentials displayed a linear dependence on the level of the membrane potential. Elimination of chlorine ions from the external solution decreased the EP SP of the SMC of rabbit anococcygeus and shifted the reversion potential in the direction of sodium balance potential. Apparently generation of the EP SP of the SMC of rabbit anococcygeus was associated with the increased permeability of the membrane both for sodium and for chlorine ions.     

Action potentials in gastrointestinal smooth muscle.

Recent investigation of the ultrastructure and electrophysiology of gastrointestinal smooth muscle layers has revealed a fascinating heterogeneity in cell type, cell structure, intercellular communication, and generated electrical activities. Networks of interstitial cells of Cajal (ICC) have been identified in many muscle layers and evidence is accumulating for a role of these networks in gut pacemaking activity. Synchronized motility in the organs of the gut result from interaction between ICC, neural-tissue, and smooth muscle cells. Regulation of cell to cell communication between the different cell types will be an important area for further research. Progress has been made in the elucidation of the ionic basis of the slow wave type action potentials and the spike-like action potentials. The mechanism underlying smooth muscle autorhythmicity seems different from that encountered in cardiac tissue, and evidence exists for metabolic regulation of the frequency of slow wave type action potentials.     

Propagation of action potentials between parallel chains of cardiac muscle cells in PSpice simulation

Propagation of action potentials between parallel chains of cardiac muscle cells was simulated using the PSpice program. Excitation was transmitted from cell to cell along a strand of three or four cells not connected by low-resistance tunnels (gap-junction connexons) in parallel with one or two similar strands. Thus, two models were used: a 2 x 3 model (two parallel chains of three cells each) and a 3 x 4 model (three parallel chains of four cells each). The entire surface membrane of each cell fired nearly simultaneously, and nearly all the propagation time was spent at the cell junctions, thus giving a staircase-shaped propagation profile. The junctional delay time between contiguous cells in a chain was about 0.2-0.5 ms. A significant negative cleft potential develops in the narrow junctional clefts, whose magnitude depends on several factors, including the radial cleft resistance (Rjc). The cleft potential (Vjc) depolarizes the postjunctional membrane to threshold by a patch-clamp action. Therefore, one mechanism for the transfer of excitation from one cell to the next is by the electric field (EF) that is generated in the junctional cleft when the prejunctional membrane fires. Propagation velocity increased with elevation of Rjc. With electrical stimulation of the first cell of the first strand (cell A1), propagation rapidly spread down that chain and then jumped to the second strand (B chain), followed by jumping to the third strand (C chain) when present. The rapidity by which the parallel chains became activated depended on the longitudinal resistance of the narrow extracellular cleft between the parallel strands (Rol2). The higher the Rol2 resistance, the faster the propagation (lower propagation time) over the cardiac muscle sheet (2-dimensional). The transverse resistance of the cleft had no effect. When the first cell of the second strand (cell B1) was stimulated, propagation spread down the B chain and jumped to the other two strands (A and C) nearly simultaneously. When cell C1 was stimulated, propagation traveled down the C chain and jumped to the B chain, followed by excitation of the A chain. Thus, there was transverse propagation of excitation as longitudinal propagation was occurring. Therefore, transmission of excitation by the EF mechanism can occur between myocardial cells lying closely parallel to one another without the requirement of a specialized junction.     

Characteristics of cardiac action potentials in marsupials

Summary Standard microelectrode techniques were used to record action potentials from single atrial, ventricular and Purkinje fibers of hearts taken from three species of marsupial (Macropus rufus, Macropus robustus andMacropus eugenii) and from dogs, sheep and guinea-pigs. The major electrophysiological parameters of marsupial potentials were qualitatively similar to the values for placental mammals. The grouped data for ventricular action potentials from studies on 6 adult male red kangaroos (Macropus rufus) were (mean ±SD): Resting potential –69.5±5.0 mV; action potential amplitude 92.7±5.7 mV; action potential duration (to 90% repolarization): 182.5±17.5 ms; maximum rate of depolarization: 196.5±80.1 V/s. The major point of difference was the short duration of the red kangaroo ventricular action potential compared to those of the placental mammals, and compared to atrial cells from the kangaroos. It is suggested that this explains the short QT interval reported by others for kangaroo electrocardiograms, and that it may also be implicated in the high frequency of sudden death previously noted in these animals.     

3D current-voltage-time surfaces unveil critical repolarization differences underlying similar cardiac action potentials: A model study

The number of mathematical models of cardiac cellular excitability is rapidly growing, and compact graphical representations of their properties can make new acquisitions available for a broader range of scientists in cardiac field. Particularly, the intrinsic over-determination of the model equations systems when fitted only to action potential (AP) waveform and the fact that they are frequently tuned on data covering only a relatively narrow range of dynamic conditions, often lead modellers to compare very similar AP profiles, which underlie though quite different excitable properties. In this study I discuss a novel compact 3D representation of the cardiac cellular AP, where the third dimension represents the instantaneous current–voltage profile of the membrane, measured as repolarization proceeds. Measurements of this type have been used previously for in vivo experiments, and are adopted here iteratively at a very high time, voltage, current-resolution on (i) the same human ventricular model, endowed with two different parameters sets which generate the same AP waveform, and on (ii) three different models of the same human ventricular cell type. In these 3D representations, the AP waveforms lie at the intersection between instantaneous time–voltage–current surfaces and the zero-current plane. Different surfaces can share the same intersection and therefore the same AP; in these cases, the morphology of the current surface provides a compact view of important differences within corresponding repolarization dynamics.Refractory period, supernormal excitability window, and extent of repolarization reserve can be visualized at once. Two pivotal dynamical properties can be precisely assessed, i.e. all-or-nothing repolarization window and membrane resistance during recovery. I discuss differences in these properties among the membranes under study, and show relevant implications for cardiac cellular repolarization.     

Properties of calcium channels in cardiac muscle and vascular smooth muscle

The voltage-dependent slow channels in the myocardial cell membrane are the major pathway by which Ca²⁺ ions enter the cell during excitation for initiation and regulation of the force of contraction of cardiac muscle. The slow channels have some special properties, including functional dependence on metabolic energy, selective blockade by acidosis, and regulation by the intracellular cyclic nucleotide levels. Because of these special properties of the slow channels, Ca²⁺ influx into the myocardial cell can be controlled by extrinsic factors (such as autonomic nerve stimulation or circulating hormones) and by intrinsic factors (such as cellular pH or ATP level). The slow Ca²⁺ channels of the heart are regulated by cAMP in a stimulatory fashion. Elevation of cAMP produces a very rapid increase in number of slow channels available for voltage activation during excitation. The probability of a slow channel opening and the mean open time of the channel are increased. Therefore, any agent that increases the cAMP level of the myocardial cell will tend to potentiate I_si, Ca²⁺ influx, and contraction. The myocardial slow Ca²⁺ channels are also regulated by cGMP, in a manner that is opposite to that of CAMP. The effect of cGMP is presumably mediated by means of phosphorylation of a protein, as for example, a regulatory protein (inhibitory-type) associated with the slow channel. Preliminary data suggest that calmodulin also may play a role in regulation of the myocardial slow Ca²⁺ channels, possibly mediated by the Ca²⁺-calmodulin-protein kinase and phosphorylation of some regulatory-type of protein. Thus, it appears that the slow Ca²⁺ channel is a complex structure, including perhaps several associated regulatory proteins, which can be regulated by a number of extrinsic and intrinsic factors.VSM cells contain two types of Ca²⁺ channels: slow (L-type) Ca²⁺ channels and fast (T-type) Ca²⁺ channels. Although regulation of voltage-dependent Ca²⁺ slow channels of VSM cells have not been fully clarified yet, we have made some progress towards answering this question. Slow (L-type, high-threshold) Ca²⁺ channels may be modified by phosphorylation of the channel protein or an associated regulatory protein. In contrast to cardiac muscle where cAMP and cGMP have antagonistic effects on Ca²⁺ slow channel activity, in VSM, cAMP and cGMP have similar effects, namely inhibition of the Ca²⁺ slow channels. Thus, any agent that elevates cAMP or cGMP will inhibit Ca²⁺ influx, and thereby act to produce vasodilation. The Ca²⁺ slow channels require ATP for activity, with a K_0.5 of about 0.3 mM. C-kinase may stimulate the Ca²⁺ slow channels by phosphorylation. G-protein may have a direct action on the Ca²⁺ channels, and may mediate the effects of activation of some receptors. These mechanisms of Ca²⁺ channel regulation may be invoked during exposure to agonists or drugs, which change second messenger levels, thereby controlling vascular tone.     

Simulated propagation of cardiac action potentials.

We have used numerical methods for solving cable equations, combined with previously published mathematical models for the membrane properties of ventricular and Purkinje cells, to simulate the propagation of cardiac action potentials along a unidimensional strand. Two types of inhomogeneities have been simulated and the results compared with experimentally observed disturbances in cardiac action potential propagation. Changes in the membrane model for regions of the strand were introduced to simulate regions of decreased excitability. Regional changes in the intercellular coupling were also studied. The results illustrate and help to explain the disturbances in propagation which have been reported to occur at regions of decreased excitability, regions with changing action potential duration, or regions with changing intercellular coupling. The propagational disturbances seen at all of these regions are discussed in terms of the changing electrical load imposed upon the propagating impulse.