Ion fluxes in cardiac excitation and contraction and their relation to myocardial contractility.

Langer, G. A.

doi:10.1152/physrev.1968.48.4.708

Cited by 304 publications

(104 citation statements)

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“…I NaK then continued to increase, and with supplementation by I stim influx eventually exceeded efflux and [K ϩ ] i changes reversed. Thus slow I NaK adaptation accounted for the [K ϩ ] i transient reversal, as previously postulated (11)(12)(13)(14)(15)27). At the time of each integration, APD 90 and APD 50 were measured to within 0.5 ms. After the onset of …”

Section: Stimulus Current Assignmentmentioning

confidence: 61%

“…1 ] i also increased to over 500% of initial values midway through the simulation, but returned to near baseline after 10 h. Figure 2 shows that the [K ϩ ] i transient reversal only occurs when the stimulus is attributed to K ϩ . Because this phenomenon is well documented experimentally (7,(11)(12)(13)(14)(15) and in human tissues (27), additional simulations were conducted to determine the ionic mechanisms underlying the reversal. The quantity of charge carried by each K ϩ current was calculated by numerical integration over one cycle after each minute of sustained stimulation.…”

Section: Stimulus Current Assignmentmentioning

confidence: 99%

“…13 is V j n ϩ 1 ϭ V j n Ϫ ⌬t ͑I ion ϩ I stim ϩ I couple ͒ C m (14) where V j n is the voltage at time step n and location j. ⌬t and ⌬x are the time and space discretization steps fixed at 5 s and 0.025 cm, respectively.…”

Section: Potential Limitationsmentioning

confidence: 99%

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Time-dependent transients in an ionically based mathematical model of the canine atrial action potential

Kneller

Ramírez

Chartier

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. Time-dependent transients in an ionically based mathematical model of the canine atrial action potential. Am J Physiol Heart Circ Physiol 282: H1437-H1451, 2002. First published November 29, 2001 10.1152/ajpheart.00489.2001.-Ionically based cardiac action potential (AP) models are based on equations with singular Jacobians and display time-dependent AP and ionic changes (transients), which may be due to this mathematical limitation. The present study evaluated transients during long-term simulated activity in a mathematical model of the canine atrial AP. Stimulus current assignment to a specific ionic species contributed to stability. Ionic concentrations were least disturbed with the K ϩ stimulus current. All parameters stabilized within 6-7 h. Inward rectifier, Na , respectively. Time-dependent AP shortening was largely due to the outward shift of Na ϩ /Ca 2ϩ exchange related to intracellular Na ϩ (Na i ϩ ) accumulation. AP duration (APD) reached a steady state after ϳ40 min. AP transients also occurred in canine atrial preparations, with the APD decreasing by ϳ10 ms over 35 min, compared with ϳ27 ms in the model. We conclude that model APD and ionic transients stabilize with the appropriate stimulus current assignment and that the mathematical limitation of equation singularity does not preclude meaningful long-term simulations. The model agrees qualitatively with experimental observations, but quantitative discrepancies highlight limitations of long-term model simulations. ionic drift; action potential transients; atrial fibrillation; electrophysiology; ion channels and transporters THE ESTABLISHMENT of the original DiFrancesco-Noble (DN) model of cardiac myocyte electrophysiology spawned the development of numerous other dynamic models patterned after the DN formulation (5). These models explicitly include transmembrane ion channels and pumps, the intracellular calcium sequestering and release activity of the sarcoplasmic reticulum (SR), and changing intracellular ionic concentrations. The incorporation of concentration changes into the cardiac electrical model was an important development because such changes occur rapidly in the small volume of the cardiac cell and can have profound effects on action potential (AP) properties.Dynamic models are finely tuned to reproduce electrophysiological behavior observed experimentally during observation periods of short duration. However, the original DN model was noted to produce a continual cycle-by-cycle (transient) accumulation (K ϩ ) or depletion (Na ϩ , Ca 2ϩ ) of intracellular ionic species (5). AP morphology and the pre-and postcycle values of the ionic concentrations were not constant as would be expected of steady-state behavior. Transient changes were negligible over a few cardiac cycles, but departures from the prestimulus initial concentrations were cumulative and became substantial over many cycles. Guan et al. (9) noted that the original DN equations are mathematically dependent (Jacobian is singular), and therefore that model fixed points are unsta...

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Section: Stimulus Current Assignmentmentioning

confidence: 61%

Section: Stimulus Current Assignmentmentioning

confidence: 99%

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Time-dependent transients in an ionically based mathematical model of the canine atrial action potential

Kneller

Ramírez

Chartier

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…If the binding rates are compared to the influx of sodium per unit of time, the rate of binding at rest should also be included in the comparison. According to Shanes (1958) and Langer (1968) about 0.5 mmol Na/kg enter the cell per min under resting conditions. Each depolarization adds another 0.04 mmol/kg and increases the actual Na concentration by about 0.1%.…”

Section: Discussionmentioning

confidence: 98%

Interdependence of Ion Transport and the Action of Ouabain in Heart Muscle

Bentfeld

Lüllmann

Peters

et al. 1977

British J Pharmacology

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I The influence of ouabain (0.4 jM) on contractile force and cellular Na and K concentrations was investigated in isolated left atria of the guinea-pig at rest and at different beat frequencies. Simultaneously the binding of ouabain to the tissue was determined. 2 Strict dependence of rates of onset of positive iontropic action and of binding of ouabain on beat frequency are limited to conditions where no alterations of cellular Na and K concentrations occur. A correlation was observed between sodium flux per unit time and the development of positive inotropism and binding to the receptors of ouabain. 3 Ouabain exerts its positive inotropic effect without affecting the intracellular Na and K concentrations in spite of the fact that under these conditions even the majority of binding sites, i.e. Na-Kadenosine triphosphatases (Na-K-ATPases), are occupied by the drug. The positive inotropic effect. may be explained by a ouabain-induced conformational alteration of the Na-K-ATPase which leads to structural alterations of the plasmalemma connected with an increased availability of coupling calcium. 4 Increasing the frequency of stimulation over a critical value, which appears to be determined by an overloading of the Na pump, induces a decrease in contractile force, cellular accumulation of Na and loss of K, and eventually contracture.

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“…The present results are in agreement with these observations. It has been proposed that the positive inotropic effect of cardiac glycosides is related to the inhibition of the sodium pump (Langer, 1968;Akera et al. 1970;Besch, Allen, Glick & Schwartz, 1970).…”

Section: Discussionmentioning

confidence: 99%

Stimulation and Inhibition of the Sodium Pump by Cardioactive Steroids in Relation to Their Binding Sites and Their Inotropic Effect on Guinea‐pig Isolated Atria

Ghysel-Burton

Godfraind

1979

British J Pharmacology

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I The actions of ouabain, ouabagenin and dihydroouabain on the contractility and on the ionic content have been investigated in left guinea-pig atria stimulated at 3.3 Hz. The specific binding of ouabain and its displacement by the other cardenolides have been determined. 2 The action of either ouabain or ouabagenin on Na and K content was qualitatively different according to the concentration employed. Low doses evoked a reduction of Nai whereas high doses produced an increase. Dihydroouabain evoked only a Nai gain.3 The increase of KCI concentration from 2.7 to 12 mm decreased Na, in untreated atria and displaced ouabain dose-effect curves to the right.4 ED50 values for the positive inotropic effect were lower than ED50 values for the inhibition of the pump and were not similarly affected by an increase in KCI concentration. 5 The specific binding of ouabain occurred at high and low affinity sites, related to Na pump stimulation and inhibition respectively. 6 The increase in KCI reduced the affinity of the two groups of sites for ouabain and increased the capacity of the high-affinity sites whereas the capacity of the other sites remained unchanged. 7 The results confirm the existence of two specific binding sites for ouabain in guinea-pig heart and suggest that the inhibition of the Na pump is not the only mechanism responsible for the positive inotropic effect of cardiac glycosides.

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Ion fluxes in cardiac excitation and contraction and their relation to myocardial contractility.

Cited by 304 publications

References 0 publications

Time-dependent transients in an ionically based mathematical model of the canine atrial action potential

Time-dependent transients in an ionically based mathematical model of the canine atrial action potential

Interdependence of Ion Transport and the Action of Ouabain in Heart Muscle

Stimulation and Inhibition of the Sodium Pump by Cardioactive Steroids in Relation to Their Binding Sites and Their Inotropic Effect on Guinea‐pig Isolated Atria

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