Mechanisms Underlying Spontaneous Action Potential Generation Induced by Catecholamine in Pulmonary Vein Cardiomyocytes: A Simulation Study

Figures

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  Figure 1. Bifurcation diagrams of the Ca2+ dynamics model: (A) A bifurcation diagram with the total Ca2+ content within the cell on the abscissa and total amount of Ca2+ within the junction space (jnc; [Ca2+tot]jnc) on the ordinate (upper) and the corresponding frequency is shown with the same parameter as in the upper panel on the abscissa (bottom); (B) a bifurcation diagram with the open probability of type II inositol 1,4,5-trisphosphate receptors (pO_InsP3R) on the abscissa and total amount of Ca2+ within the jnc ([Ca2+tot]jnc) on the ordinate (upper) and the corresponding frequency is shown with the same parameter as in the upper panel on the abscissa (bottom). Stable equilibrium points, unstable equilibrium points and stable limit cycles were plotted in red, black and green respectively in the upper panels of A and B; (C) results of time integration calculated using the same Ca2+ dynamics model as in (A). Catot was changed as indicated in the lower panel in (C), and the spontaneous frequency was 0.04, 0.16, and 0.29 Hz at 4.18, 4.20, and 4.22 femtomole Catot, respectively. Note, the Ca2+ transient ([Ca2+]blk) is plotted in (C) instead of [Ca2+tot]jnc in the bifurcation diagram. The…

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  Figure 2. Membrane excitation in the absence of adrenergic (AR) stimulation: (A) Two records of action potential evoked by applying −5 (3 ms in duration) or –0.5 pA/pF (180 ms) current pulses were superimposed. The star mark indicates an action potential (AP) evoked with a smaller pulse; (B) the Ca2+-transient (black, μM) and the developed force of contraction (red, mN/mm2); (C,D) membrane currents shown at a low gain and at a high gain, respectively. Outward and inward currents are shown in the upper and the lower panels, respectively. Resting potential = −66.0 mV, [Na+]cyt = 5.7 mM, [K+]cyt = 117 mM, and [Ca2+]SRrl = 0.71 mM.

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  Figure 3. (A) Time-dependent changes in JRyR, JIP3R (blue and red in the middle panel), [Ca2+]SRup and [Ca2+]SRrl (black and red in the bottom panel), when the repetitive action potential (AP; top panel) was evoked. (B) The transient depolarization (TD) when triggering APs was interfered with by increasing the inward rectifier potassium current (IK1) conductance six-fold. Almost the same time course of JRyR, [Ca2+]SRup, and [Ca2+]SRrl were observed but are not demonstrated. (C,D) Records were obtained as in A and B in the presence of noradrenaline (NA) stimulation. The triggering AP by the preceding TD in (C) was much delayed if compared with records in (A). This is because the amplitude of TD was partially depressed through the enlargement of INaK through an accumulation of [Na+]i during the repetitive APTDs.

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  Figure 4. The influence of activating the individual components of NA-target molecules; (A) L-type Ca2+ channel (LCC), sarcoplasmic/endoplasmic reticulum calcium pump (SERCA), and Na+/K+ of the β1-AR; (B) InsP3R of the α1-AR. Catot (femtomole) was plotted against the simulation time (min). The horizontal bars above the record indicate the duration of modification of each factor. The desensitization of the α1-AR was removed to determine the maximum influence of their influence on Catot, except in the last application of 0.15 mM [IP3]. The desensitization of the β1-AR was intact, but small in magnitude. The control level of Catot was reduced in (A) by decreasing scfICab to 0.87 to avoid a relatively large increase in JCa_SR evoked by increasing Catot near the activation threshold in the absence of β1-AR stimulation. The horizontal thin brown line indicates the threshold level of Catot in the presence of NA stimulation.

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  Figure 5. Initiation of a train of APTD by the α1-adrenergic receptor (AR) stimulation. The application of 0.12 μM ISO and 0.15 μM IP3 is indicated by the horizontal bars at the top of each column and the pair of vertical lines. (A) APTD was not induced. (B,C) The random triggering signals applied are shown in the lower part of B1 and C1 (random (RND) stim) to induce APTD. The responses of Vm (1), Catot (2), [Ca2+]SRup and [Ca2+]SRrl (3), and [Na+]i (5 in A and 4 in B,C) are shown in each column. The time courses of afICaL (×0.5, red), afSERCA (black), afNa/K (blue), and pOInsP3R (×100, green) shown in Figure 5(A4) are applicable to responses in (B,C). The rate of APTD discharge (/min/100) appears only in Figure 5(B4). The horizontal green and brown lines are the threshold Catot measured in the absence and presence of AR stimulation, respectively.

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  Figure 6. Latency histogram of the initiation of repetitive APTD generation at different amplitudes of ICaL. The latency was measured from the onset of NA application to the time of the initial fifth APTD discharge within a train. Vertical and horizontal axes for (B–D) are the same as in (A). The bin width was 30 s. The amplitude of ICaL in each series of simulation is indicated at up-right corner of (A–D) together with the number of successful triggerings of the repetitive generation of APTDs in 1000 trials.

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  Figure 7. Signal transduction pathways for the α1- and β1-ARs, intracellular Ca2+ compartments, and distribution of Ca2+-transporting channels and transporters. Components in gray are not included in the model. Open arrows between compartments indicate the usual diffusion paths of Ca2+. The activation of type II ryanodine receptors (RyRs) and inactivation of LCC are determined by [Ca2+]nd. The Ca2+ flux through InsP3R directs to jnc. If both LCC and RyRs are closed, [Ca2+]nd equals [Ca2+]jnc.