Biomedical subjects

L Tung

Publications and source records attributed to L Tung.

At least 37 records · Page 2Linked to original sources

PubMed1998

An N-terminal inhibitory function, IF, suppresses transcription by the A-isoform but not the B-isoform of human progesterone receptors.

The B-isoform of human progesterone receptors (PR) contains three activation functions (AF3, AF1, and AF2), two of which (AF1 and AF2) are shared with the A-isoform. AF3 is in the B-upstream segment (BUS), the far N-terminal 164 amino acids of B-receptors; AF1 is in the 392-amino acid N-terminal region common to both receptors; and AF2 is in the C-terminal hormone binding domain. B-receptors are usually stronger transactivators than A-receptors due to transcriptional synergism between AF3 and one of the two downstream AFs. We now show that the N terminus of PR common to both isoforms contains an inhibitory function (IF) located in a 292-amino acid segment lying upstream of AF1. IF represses the activity of A-receptors but is not inhibitory in the context of B-receptors due to constraints imparted by BUS. As a result, IF inhibits AF1 or AF2 but not AF3, regardless of the position of IF relative to BUS. IF is functionally independent and strongly represses transcription when it is fused upstream of estrogen receptors. These data demonstrate the existence of a novel, transferable inhibitory function, mapping to the PR N terminus, which begins to assign specific roles to this large undefined region.

Gene Expression Regulation↗

PubMed1998

The reduction in electroporation voltages by the addition of a surfactant to planar lipid bilayers.

The effects of a nonionic surfactant, octaethyleneglycol mono n-dodecyl ether (C12E8), on the electroporation of planar bilayer lipid membranes made of the synthetic lipid 1-pamitoyl 2-oleoyl phosphatidylcholine (POPC), was studied. High-amplitude ( approximately 100-450 mV) rectangular voltage pulses were used to electroporate the bilayers, followed by a prolonged, low-amplitude ( approximately 65 mV) voltage clamp to monitor the ensuing changes in transmembrane conductance. The electroporation thresholds of the membranes were found for rectangular voltage pulses of given durations. The strength-duration relationship was determined over a range from 10 micros to 10 s. The addition of C12E8 at concentrations of 0.1, 1, and 10 microM to the bath surrounding the membranes decreased the electroporation threshold monotonically with concentration for all durations (p < 0.0001). The decrease from control values ranged from 10% to 40%, depending on surfactant concentration and pulse duration. For a 10-micros pulse, the transmembrane conductance 150 micros after electroporation (G150) increased monotonically with the surfactant concentration (p = 0.007 for 10 microM C12E8). These findings suggest that C12E8 incorporates into POPC bilayers, allowing electroporation at lower intensities and/or shorter durations, and demonstrate that surfactants can be used to manipulate the electroporation threshold of lipid bilayers.

Detergents↗

PubMed1998

Progesterone receptor variants found in breast cells repress transcription by wild-type receptors.

Progesterone, through its nuclear receptors (PR), regulates the development and growth of breast cancers. PR also serve as markers of hormone dependence and prognosis in patients with this disease, and functional PR are required to mediate the antiproliferative effects of progestin therapies. We find that normal and malignant breast cells and tissues can express anomalous forms of PR transcripts. We have isolated four variant PR mRNAs that contain precise deletions of exons encoding sections of the DNA- and hormone-binding domains. The transcripts lack exon 2 (PRdelta2), exon 4 (PRdelta4), exon 6 (PRdelta6), or exons 5 and 6 (PRdelta5,6). On immunoblots, PRdelta4, delta6. and delta5, 6 cloned into the background of the PR A-isoform comigrate with similar proteins present in breast tumor extracts; delta6 and delta5, 6 are dominant-negative transcriptional inhibitors of wild-type A- and B-receptors. We propose that expression of variant PR can compromise the accuracy of receptor measurements as markers of hormone-dependent cancers, and can modify the responses of tumors to progestin therapies.

Breast↗

PubMed1998

Postshock potential gradients and dispersion of repolarization in cells stimulated with monophasic and biphasic waveforms.

INTRODUCTION: Even though the clinical advantage of biphasic defibrillation waveforms is well documented, the mechanisms that underlie this greater efficacy remain incompletely understood. It is established, though, that the response of relatively refractory cells to the shock is important in determining defibrillation success or failure. We used two computer models of an isolated ventricular cell to test the hypothesis that biphasic stimuli cause a more uniform response than the equivalent monophasic shocks, decreasing the likelihood that fibrillation will be reinduced. METHODS AND RESULTS: Models of reciprocally polarized and uniformly polarized cells were used. Rapid pacing and elevated [K]o were simulated, and either 10-msec rectangular monophasic or 5-msec/5-msec symmetric biphasic stimuli were delivered in the relative refractory period. The effects of stimulus intensity and coupling interval on response duration and postshock transmembrane potential (Vm) were quantified for each waveform. With reciprocal polarization, biphasic stimuli caused a more uniform response than monophasic stimuli, resulting in fewer large gradients of Vm (only for shock strengths < or = 1.25x threshold vs < or = 2.125x threshold) and a smaller dispersion of repolarization (1611 msec2 vs 1835 msec2). The reverse was observed with uniform polarization: monophasic pulses caused a more uniform response than did biphasic stimuli. CONCLUSION: These results show that the response of relatively refractory cardiac cells to biphasic stimuli is less dependent on the coupling interval and stimulus strength than the response to monophasic stimuli under conditions of reciprocal polarization. Because this may lead to fewer and smaller spatial gradients in Vm, these data support the hypothesis that biphasic defibrillation waveforms will be less likely to reinduce fibrillation. Further, published experimental results correlate to a greater degree with conditions of reciprocal polarization than of uniform polarization, providing indirect evidence that interactions between depolarized and hyperpolarized regions play a role in determining the effects of defibrillation shocks on cardiac tissue.

Computer Simulation↗

PubMed1998

Stretch-induced changes in arrhythmogenesis and excitability in experimentally based heart cell models.

Mechanoelectric coupling in the heart is well documented and has been suggested as a cause of arrhythmia. One hypothesized mechanism for the stretch sensitivity of cardiac muscle is the presence of stretch-activated channels (SACs). This study uses modeling to explore the influence of SACs on cardiac resting potential, excitation threshold, and action potential in the context of arrhythmia. We added a putative SAC, modeled as a linear, time-independent conductance with reversal potential of -20 or -50 mV, to guinea pig and frog ventricular membrane models. Increased stretch conductance led to resting potential depolarization, a decreased excitation threshold, altered action potential duration, and, under certain conditions, early afterdepolarizations. We conclude that stretch increases cellular excitability, making the heart prone to ectopic activity. Regional effects of stretch on action potential duration can vary and are influenced by factors such as the SAC reversal potential, ionic conditions, and baseline currents, all of which may lead to an increased dispersion of refractoriness throughout the heart and therefore an increased risk of arrhythmia.

Action Potentials↗

PubMed1997

A generalized activating function for predicting virtual electrodes in cardiac tissue.

To fully understand the mechanisms of defibrillation, it is critical to know how a given electrical stimulus causes membrane polarizations in cardiac tissue. We have extended the concept of the activating function, originally used to describe neuronal stimulation, to derive a new expression that identifies the sources that drive changes in transmembrane potential. Source terms, or virtual electrodes, consist of either second derivatives of extracellular potential weighted by intracellular conductivity or extracellular potential gradients weighted by derivatives of intracellular conductivity. The full response of passive tissue can be considered, in simple cases, to be a convolution of this "generalized activating function" with the impulse response of the tissue. Computer simulations of a two-dimensional sheet of passive myocardium under steady-state conditions demonstrate that this source term is useful for estimating the effects of applied electrical stimuli. The generalized activating function predicts oppositely polarized regions of tissue when unequally anisotropic tissue is point stimulated and a monopolar response when a point stimulus is applied to isotropic tissue. In the bulk of the myocardium, this new expression is helpful for understanding mechanisms by which virtual electrodes can be produced, such as the hypothetical "sawtooth" pattern of polarization, as well as polarization owing to regions of depressed conductivity, missing cells or clefts, changes in fiber diameter, or fiber curvature. In comparing solutions obtained with an assumed extracellular potential distribution to those with fully coupled intra- and extracellular domains, we find that the former provides a reliable estimate of the total solution. Thus the generalized activating function that we have derived provides a useful way of understanding virtual electrode effects in cardiac tissue.

Computer Simulation↗

PubMed1997

Dose-dependent reduction of cardiac transmembrane potential by high-intensity electrical shocks.

Cardiac tissue dysfunction can result from high-intensity electrical shocks and is manifested as changes in transmembrane potential (Vm). Ten-millisecond shock pulses (SPs) of varying intensity and polarity were applied to frog ventricle in diastole, and Vm was quantified directly under the stimulating electrode by an optical method using voltage-sensitive dye. As SP intensities were increased, the shock-induced action potential (AP) plateau and AP amplitude (APAs) decreased sigmoidally toward 75-85% of the control AP amplitude (APAc) and zero, respectively. APAs was shifted toward lower current densities for anodal compared with cathodal SPs (half-maximal values 185 and 238 mA/cm2, respectively; P = 0.02). Recovery of APAs was marginally significant 1 s after SP delivery (P = 0.063). The peak change in Vm during SP (across all intensity levels) was -200% APAc for anodal and +125% APAc for cathodal pulses. In conclusion, we show that SP reduces APA in a sigmoidal fashion at strengths > 10-20 x diastolic threshold and is more deleterious for anodal polarities.

Action Potentials↗

PubMed1997

The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT.

Steroid receptor antagonists, such as the antiestrogen tamoxifen or the antiprogestin RU486, can have inappropriate agonist-like effects in tissues and tumors. To explain this paradox we postulated that coactivators are inadvertently brought to the promoters of DNA-bound, antagonist-occupied receptors. The human (h) progesterone receptor (PR) hinge-hormone binding domain (H-HBD) was used as bait in a two-hybrid screen of a HeLa cDNA library, in which the yeast cells were treated with RU486. We have isolated and characterized two interesting steroid receptor-interacting proteins that regulate transcription in opposite directions. The first is L7/SPA, a previously described 27-kDa protein containing a basic region leucine zipper domain, having no known nuclear function. When coexpressed with tamoxifen-occupied estrogen receptors (hER) or RU486-occupied hPR or glucocorticoid receptors (hGR), L7/SPA increases the partial agonist activity of the antagonists by 3- to 10-fold, but it has no effect on agonist-mediated transcription. The interaction of L7/SPA with hPR maps to the hinge region, and indeed, the hPR hinge region squelches L7/SPA-dependent induction of antagonist-mediated transcription. Interestingly, pure antagonists that lack partial agonist effects, such as the antiestrogen ICI164,384 or the antiprogestin ZK98299, cannot be up-regulated by L7/SPA. We also isolated, cloned, and sequenced the human homolog (hN-CoR) of the 270-kDa mouse (m) thyroid/retinoic acid receptor corepressor. Binding of hN-CoR maps to the hPR-HBD. mN-CoR, and a related human corepressor, SMRT, suppress RU486 or tamoxifen-mediated partial agonist activity by more than 90%. This suppression is completely squelched by overexpression of the hPR H-HBD. Additionally, both corepressors reverse the antagonist-dependent transcriptional up-regulation produced by L7/SPA. Our data suggest that the direction of transcription by antagonist-occupied steroid receptors can be controlled by the ratio of coactivators to corepressors recruited to the transcription complex by promoter-bound receptors. In normal tissues and in hormone-resistant breast cancers in which the agonist activity of mixed antagonists predominates, steroid receptors may be preferentially bound by coactivators. This suggests a strategy by which such partial agonist activity can be eliminated and by which candidate receptor ligands can be screened for this activity.

Animals↗

PubMed1996

Role of phosphorylation on DNA binding and transcriptional functions of human progesterone receptors.

To study the function of human progesterone receptor (hPR) phosphorylation, we have tested four sets of serine to alanine substitution mutants: 10 serine clusters, located in regions common to both hPR isoforms (the M-series mutants) were mutated in A-receptors and B-receptors; 6 serine clusters located in the B-upstream segment (BUS; the B-series mutants) were mutated individually and collectively and cloned into B-receptors and into BUS-DBD-NLS, a constitutive transactivator, in which the AF3 function of BUS is fused to the DNA binding domain (DBD) and nuclear localization signal (NLS) of hPR. Transcription by most of the M-series mutants resembles that of wild-type A- or B-receptors. Mutation of 3 sites, Ser190 at the N terminus of A-receptors, a cluster of serines just upstream of the DBD, or Ser676 in the hinge region, inhibits transcription by 20-50% depending on cell or promoter context. These sites lie outside the AF1 activation function. M-series mutants are substrates for a hormone-dependent phosphorylation step, and they all bind well to DNA. Progressive mutation of the B-series clusters leads to the gradual dephosphorylation of BUS, but only the 6-site mutant, involving 10 serine residues, is completely dephosphorylated. These data suggest that in BUS alternate serines are phosphorylated or dephosphorylated at any time. However, even when BUS is completely dephosphorylated, both BUS-DBD-NLS and full-length B-receptors remain strong transactivators. Mutant B-receptors also do not acquire the dominant negative properties of A-receptors, and they retain the ability to activate transcription in synergy with 8-Br-cAMP and antiprogestins. We conclude that phosphorylation has subtle effects on the complex transcriptional repertoire that distinguishes the two hPR isoforms and does not influence transactivation mediated by AF1 or AF3, but subserves other functions.

Animals↗

PubMed1996

Poloxamer 188 decreases susceptibility of artificial lipid membranes to electroporation.

The effect of a nontoxic, nonionic block co-polymeric surface active agent, poloxamer 188, on electroporation of artificial lipid membranes made of azolectin, was investigated. Two different experimental protocols were used in our study: charge pulse and voltage clamp. For the charge pulse protocol, membranes were pulsed with a 10-micronsecond rectangular voltage waveform, after which membrane voltage decay was observed through an external 1-M omega resistance. For the voltage clamp protocol the membranes were pulsed with a waveform that consisted of an initial 10-microsecond rectangular phase, followed by a negative sloped ramp that decayed to zero in the subsequent 500 microseconds. Several parameters characterizing the electroporation process were measured and compared for the control membranes and membranes treated with 1.0 mM poloxamer 188. For both the charge pulse and voltage clamp experiments, the threshold voltage (amplitude of initial rectangular phase) and latency time (time elapsed between the end of rectangular phase and the onset of membrane electroporation) were measured. Membrane conductance (measured 200 microseconds after the initial rectangular phase) and rise time (tr; the time required for the porated membrane to reach a certain conductance value) were also determined for the voltage clamp experiments, and postelectroporation time constant (PE tau; the time constant for transmembrane voltage decay after onset of electroporation) for the charge pulse experiments. The charge pulse experiments were performed on 23 membranes with 10 control and 13 poloxamer-treated membranes, and voltage pulse experiments on 49 membranes with 26 control and 23 poloxamer-treated membranes. For both charge pulse and voltage clamp experiments, poloxamer 188-treated membranes exhibited a statistically higher threshold voltage (p = 0.1 and p = 0.06, respectively), and longer latency time (p = 0.04 and p = 0.05, respectively). Also, poloxamer 188-treated membranes were found to have a relatively lower conductance (p = 0.001), longer time required for the porated membrane to reach a certain conductance value (p = 0.05), and longer postelectroporation time constant (p = 0.005). Furthermore, addition of poloxamer 188 was found to reduce the membrane capacitance by approximately 4-8% in 5 min. These findings suggest that poloxamer 188 adsorbs into the lipid bilayers, thereby decreasing their susceptibility to electroporation.

Electric Conductivity↗

PubMed1996

Mechanisms of cardiac cell excitation with premature monophasic and biphasic field stimuli: a model study.

The mechanisms by which extracellular electric field stimuli induce the (re)excitation of cardiac cells in various stages of refractoriness are still not well understood. We modeled the interactions between an isolated cardiac cell and imposed extracellular electric fields to determine the mechanisms by which relatively low-strength uniform monophasic and biphasic field stimuli induce premature reexcitations. An idealized ventricular cell was simulated with 11 subcellular membrane patches, each of which obeyed Luo-Rudy (phase 1) kinetics. Implementing a standard S1-S2 pulse protocol, strength-interval maps of the cellular excitatory responses were generated for rectangular monophasic and symmetric biphasic field stimuli of 2, 5, 10, and 20 ms total duration. In contrast to previously documented current injection studies, our results demonstrate that a cardiac cell exhibits a significantly nonmonotonic excitatory response to premature monophasic and, to a much lesser degree, biphasic field stimuli. Furthermore, for monophasic stimuli at low field strengths, the cell is exquisitely sensitive to the timing of the shock, demonstrating a classic all-or-none depolarizing response. However, at higher field strengths this all-or-none sensitivity reverts to a more gradual transition of excitatory responses with respect to stimulus prematurity. In contrast, biphasic stimuli produce such graded responses at all suprathreshold stimulus strengths. Similar behaviors are demonstrated at all S2 stimulus durations tested. The generation of depolarizing (sodium) currents is triggered by one or more of the sharp field gradient changes produced at the stimulus edges-i.e., make, break, and transphasic (for biphasic stimuli)-with the magnitude of these edge-induced current contributions dependent on both the prematurity and the strength of the applied field. In all cases, however, depolarizing current arises from the partial removal of sodium inactivation from at least part of the cell, because of either the natural process of repolarization or a localized acceleration of this process by the impressed field.

Animals↗

PubMed1996

Modeling the interaction between propagating cardiac waves and monophasic and biphasic field stimuli: the importance of the induced spatial excitatory response.

INTRODUCTION: Biphasic (BP) defibrillation waveforms have been shown to be significantly more efficacious than equivalent monophasic (MP) waveforms. However, when defibrillation fails, it tends to do so first in distal regions of the heart where induced field gradient magnitudes are lowest. We tested the hypothesis that the improved efficacy of BP waveforms results from their enhanced ability to prevent the initiation of new postshock activation fronts behind preexisting wavetails, rather than from any significantly improved ability to terminate preexisting wavefronts. METHODS AND RESULTS: An idealized computer model of a one-dimensional cardiac strand was used to investigate the spatial and temporal interactions between an underlying propagation front (or tail) and uniform MP or BP field stimuli of various intensities. Axial discontinuities from intercellular junctions induced sawtooth patterns of polarization during such field stimuli, enabling the shocks to interact directly with all cells. MP and BP diastolic thresholds were essentially equal. All suprathreshold MP and BP field stimuli successfully terminated preexisting wavefronts by directly depolarizing tissue ahead of those fronts, thus blocking their continued progression. However, the postshock response at the wavetail was significantly dependent on the shape and strength of the administered field. Low-strength MP stimuli induced an all-or-none excitation response across the wavetail, producing a sharp spatial transmembrane voltage gradient from which a new sustained anterogradely propagating wavefront was initiated. In contrast, low-strength BP field stimuli induced a spatially graded excitatory response whose voltage gradient was insufficient to initiate such a wavefront. Higher-strength MP and BP stimuli both produced graded excitatory responses with no subsequent propagation. CONCLUSIONS: Shock-induced spatial "all-or-none" excitatory responses facilitate, and graded excitatory responses prevent, the postshock initiation of new propagating wavefronts. Moreover, BP field stimuli can induce such graded excitatory responses at significantly lower stimulus strengths than otherwise equivalent MP stimuli. Therefore, these results support an alternative "graded excitatory response" mechanism for the improved efficacy of BP over MP field stimuli in low gradient regions.

Cell Membrane↗

PubMed1996

Nuclear receptor coactivators and corepressors.

The nuclear receptors belong to a superfamily of proteins, many of which are ligand-regulated, that bind to specific DNA sequences and control specific gene transcription. Recent data show that, in addition to contacting the basal transcription machinery directly, nuclear receptors inhibit or enhance transcription by recruiting an array of coactivator or corepressor proteins to the transcription complex. In this review we define the properties of these putative coregulatory factors; we describe the basal and coregulatory factors that are currently known to interact with nuclear receptors; we suggest various mechanisms by which coactivators and corepressors act; we discuss issues that are raised by the presence of multiple, perhaps competing, coregulatory factors; and we speculate how these additional regulatory layers may explain the heterogeneity of hormone responses that are observed in normal and malignant tissues.

Animals↗

PubMed1996

Novel mechanisms of antiprogestin action.

Endocrine therapy used either prophylactically or therapeutically for the treatment of locally advanced or metastatic breast cancers offers many advantages to patients whose tumors contain functional estrogen (ER) and progesterone (PR) receptors. The range of treatments defined as endocrine include surgical ablation of endocrine glands, administration of pharmacologic doses of steroid hormones, chemical blockade of steroid hormone biosynthesis, and inhibition of endogenous steroid hormone action at the tumor with synthetic antagonists. The last of these approaches is the most widely used, making the antiestrogen tamoxifen the preferred first-line therapeutic agent for treatment of hormone-dependent metastatic breast cancer. The wide-spread use of tamoxifen reflects its efficacy and low toxicity, and the fact that it makes good physiological sense to block the local proliferative effects of estrogens directly at the breast. But are estrogens the only hormones with a proliferative impact on the breast and on breast cancers? This chapter focuses on evidence that progesterone also has proliferative actions in the breast; on preliminary data showing that progesterone antagonists may be new tools for the management of metastatic breast cancer; and on recent data suggesting that antiprogestin-occupied PR have novel mechanisms of action that bear on tissue specificity and development of hormone resistance.

Animals↗

PubMed1995

Surprises with antiprogestins: novel mechanisms of progesterone receptor action.

When hormone antagonists have inappropriate agonist-like effects, the clinical consequences are grave. We describe novel molecular mechanisms by which antiprogestin-occupied progesterone receptors behave like agonists. These mechanisms include agonist-like transcriptional effects that do not require receptor binding to DNA at progesterone response elements, or that result from cross-talk between progesterone receptors and other signalling pathways. We discuss the complex structural organization of progesterone receptors, and demonstrate that the B receptor isoform has a unique third activation domain that may confer agonist-like properties in the presence of antiprogestins, whereas the A receptor isoform is a dominant-negative inhibitor. We argue that these novel mechanisms play a role in the apparent hormone resistance of breast cancers and the variable tissue-specific responses to antagonists.

Breast Neoplasms↗

PubMed1995

Novel mechanisms of antiprogestin action.

When hormone antagonists have unexpected agonist-like effects, the clinical consequences are grave. We describe novel molecular mechanisms by which antiprogestin-occupied progesterone receptors behave like agonists. These mechanisms include agonist-like transcriptional effects that do not require receptor binding to DNA at progesterone response elements, or that result from cross-talk between progesterone receptor and other signalling pathways. We discuss the complex structural organization of progesterone receptors and demonstrate that the B-receptor isoform has a unique third activation domain that may confer agonist-like properties in the presence of antiprogestins. By contrast, the A-receptor isoform is a dominant-negative inhibitor. We argue that these novel mechanisms play a role in the apparent hormone resistance of breast cancers and the variable tissue-specific responses to progestins.

Cell Line↗

PubMed1995

Spatial distribution of cardiac transmembrane potentials around an extracellular electrode: dependence on fiber orientation.

Recent theoretical models of cardiac electrical stimulation or defibrillation predict a complex spatial pattern of transmembrane potential (Vm) around a stimulating electrode, resulting from the formation of virtual electrodes of reversed polarity. The pattern of membrane polarization has been attributed to the anisotropic structure of the tissue. To verify such model predictions experimentally, an optical technique using a fluorescent voltage-sensitive dye was used to map the spatial distribution of Vm around a 150-microns-radius extracellular unipolar electrode. An S1-S2 stimulation protocol was used, and vm was measured during an S2 pulse having an intensity equal to 10x the cathodal diastolic threshold of excitation. The recordings were obtained on the endocardial surface of bullfrog atrium in directions parallel and perpendicular to the cardiac fibers. In the longitudinal fiber direction, the membrane depolarized for cathodal pulses (and hyperpolarized for anodal pulses) but only in a region within 445 +/- 112 microns (and 616 +/- 78 microns for anodal pulses) from the center of the electrode (n = 9). Outside this region, vm reversed polarity and reached a local maximum at 922 +/- 136 microns (and 988 +/- 117 microns for anodal pulses) (n = 9). Beyond this point vm decayed to zero over a distance of 1.5-2 mm. In the transverse fiber direction, the membrane depolarized for cathodal pulses (and hyperpolarized for anodal pulses) at all distances from the electrode. The amplitude of the response decreased with distance from the electrode with an exponential decay constant of 343 +/- 110 microns for cathodal pulses and 253 +/- 91 microns for anodal pulses (n = 7). The results were qualitatively similar in both fiber directions when the atrium was bathed in a solution containing ionic channel blockers. A two-dimensional computer model was formulated for the case of highly anisotropic cardiac tissue and qualitatively accounts for nearly all the observed spatial and temporal behavior of vm in the two fiber directions. The relationships between vm and both the "activating function" and extracellular potential gradient are discussed.

Animals↗

PubMed1995

Cardiac responses to premature monophasic and biphasic field stimuli. Results from cell and tissue modeling studies.

Experimental and clinical observations confirm that certain biphasic (BP) defibrillation shocks are significantly more efficacious than equivalent monophasic (MP) shocks, yet the mechanisms underlying these improvements are still not well understood. The authors used two separate, but related, computer models to investigate in detail the excitation responses of active cardiac cells and tissue to idealized premature extracellular MP and BP field stimuli. The results revealed a large disparity in MP and BP excitation responses to low-strength, but not high-strength, fields. In particular, at these low-strength levels, the polarity reversal within BP shocks effectively extends excitability to earlier cellular refractory states than can be achieved with simple MP shocks. Moreover, whereas low-strength MP shocks induce a distinct all-or-none excitatory response to varying shock prematurities, the excitatory response to equivalent BP shocks remains highly graded. In tissue simulations where such field stimuli intersected propagating wave fronts, the all-or-none excitatory response elicited by low-strength MP shocks created a postshock discontinuity in the spatial transmembrane voltage profile, which initiated a new propagation wave front. In contrast, the graded excitatory response elicited by BP waveforms effectively prevented the formation of postshock wave fronts. High-strength MP and BP stimuli prevented renewed propagation equally well. In conclusion, these results suggest a new mechanisms for BP defibrillation superiority over MP waveforms: that the graded excitatory response to BP stimuli at low-field strengths effectively prevents the formation of large spatial transmembrane voltage gradients, which can lead to renewal of propagated wave fronts.

Action Potentials↗