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Akinori Noma

Publications and source records attributed to Akinori Noma.

At least 19 recordsLinked to original sources
PubMed2006

A new multi-scale simulation model of the circulation: from cells to system.

We developed a comprehensive cell model that simulates the sequential cellular events from membrane excitation to contraction in the human ventricle. By combining this ventricular cell model with a lumped circulation model, we examined how blood pressure dynamics in the ventricle and aorta are related to the cellular processes. To convert cell contraction into ventricular pressure using Laplace's law, we introduced a simple geometric model of a ventricle: one shaped like a thin-walled hemisphere. The force of contraction of a single cell induces tension in the hemispheric ventricular wall, which generates the ventricular and aortic pressures in the lumped circulation model. The time courses of the hemodynamic properties, as well as the volume-pressure trajectory of the left ventricle, were well reproduced. Our multi-scale cardiovascular model, which covers from cardiac cells to the circulatory system, simulates the typical characteristics of heart mechanics, such as the pressure-volume relationship, stroke volume and the effect of the increased maximum free calcium concentration on cardiovascular hemodynamics. To test the cell-circulation coupling characteristics of the model, we simulated the effects of a decrease in L-type calcium channel conductance (cell level) on left ventricular pressure (system level). The variation due to different pacing frequencies for myocyte excitation was also investigated to assess the effects of heart rate on cardiac cells and the circulatory system.

Action Potentials↗
PubMed2006

A simulation study to rescue the Na+/Ca2+ exchanger knockout mice.

The Na(+)/Ca(2+) exchanger (NCX) is the major Ca(2+) efflux system in cardiac myocytes, and thereby its global knockout is embryonically lethal. However, Henderson et al. (2004) found that mice with the cardiospecific knockout of NCX1 lived to adulthood. No adaptation was detected in expression levels of other proteins except for a 50% reduction in the L-type Ca(2+) current (I(CaL)) as revealed in electrophysiological studies. To predict mechanisms of survival, we simulated cardiac myocyte activity in the absence of NCX using a mathematical model of guinea pig ventricular myocytes. The NCX knockout resulted in contracture of the model cell because of a rise in the cytoplasmic Ca(2+) ([Ca(2+)](i)). However, up-regulation of the sarcolemmal Ca(2+) pump (PMCA) and/or down-regulation of I(CaL) enables steady rhythmic contractions even if NCX is totally excluded. The simulation predicted that the steady activities are maintained by a functional up-regulation of PMCA by about 2.3 times in addition to the down-regulation of I(CaL) to a half, as observed in the experiment. However, the model analysis predicted that the myocyte depending on PMCA for Ca(2+) extrusion is unstable against any changes in ionic fluxes and energetically unfavorable in comparison with the control. The reason for the instability is that the activity of PMCA driven by the ATP hydrolysis is hardly affected by changes in [Ca(2+)](i), but NCX has a reversal potential in the middle level of the action potential and is immediately affected by the Ca(2+) flux via NCX itself. The source code of the model is available at http://www.sim-bio.org/.

Action Potentials↗
PubMed2006

A mathematical model of pacemaker activity recorded from mouse small intestine.

The pacemaker activity of interstitial cells of Cajal (ICCs) has been known to initiate the propagation of slow waves along the whole gastrointestinal tract through spontaneous and repetitive generation of action potentials. We studied the mechanism of the pacemaker activity of ICCs in the mouse small intestine and tested it using a mathematical model. The model includes ion channels, exchanger, pumps and intracellular machinery for Ca2+ regulation. The model also incorporates inositol 1,4,5-triphosphate (IP3) production and IP3-mediated Ca2+ release activities. Most of the parameters were obtained from the literature and were modified to fit the experimental results of ICCs from mouse small intestine. We were then able to compose a mathematical model that simulates the pacemaker activity of ICCs. The model generates pacemaker potentials regularly and repetitively as long as the simulation continues. The frequency was set at 20 min(-1) and the duration at 50% repolarization was 639 ms. The resting and overshoot potentials were -78 and +1.2 mV, respectively. The reconstructed pacemaker potentials closely matched those obtained from animal experiments. The model supports the idea that cyclic changes in [Ca2+]i and [IP3] play key roles in the generation of ICC pacemaker activity in the mouse small intestine.

Action Potentials↗
PubMed2006

Calcium-mediated coupling between mitochondrial substrate dehydrogenation and cardiac workload in single guinea-pig ventricular myocytes.

We measured mitochondrial NADH autofluorescence or Ca(2+) using Rhod-2, simultaneously with cell shortening in isolated guinea-pig ventricular myocytes. When both frequency and amplitude of twitch shortening (work intensity) were increased by raising stimulus frequency in incremental steps from 0.1 to 3.3 Hz, the steady level of NADH signal increased in a frequency-dependent manner. Mitochondrial Ca(2+) also increased with increasing work intensity. Applying Ru360, an inhibitor of mitochondrial Ca(2+) uniporter, largely attenuated the response of both NADH fluorescence and mitochondrial Ca(2+). The increase in mitochondrial Ca(2+) was slow with t(1/2)=~12 s and no obvious cyclic changes were observed in the NADH signal. When a step change from 0.1 to 3.3 Hz stimulation was applied, the NADH signal first decreased to 83% and then increased to 155% of the control level. Upon returning to 0.1 Hz, the NADH signal showed an overshoot before declining to the control level. The biphasic onset time course was well explained by the delayed Ca(2+) activation of the substrate dehydrogenation superimposed on the feedback control of the ATP synthesis, while the offset time course with a delayed deactivation of dehydrogenation. A computer simulation using an oxidative phosphorylation linked to the cardiac excitation contraction model well reconstructed the response of NADH. This model simulation predicts that the activation of substrate dehydrogenation provides ~23% of driving force of the ATP synthesis to meet the increased workload induced by the jump of stimulus from 0.1 to 3.3 Hz, and remaining ~77% is supplied by the feedback control.

Animals↗
PubMed2006

Ionic mechanisms of cardiac cell swelling induced by blocking Na+/K+ pump as revealed by experiments and simulation.

Although the Na(+)/K(+) pump is one of the key mechanisms responsible for maintaining cell volume, we have observed experimentally that cell volume remained almost constant during 90 min exposure of guinea pig ventricular myocytes to ouabain. Simulation of this finding using a comprehensive cardiac cell model (Kyoto model incorporating Cl(-) and water fluxes) predicted roles for the plasma membrane Ca(2+)-ATPase (PMCA) and Na(+)/Ca(2+) exchanger, in addition to low membrane permeabilities for Na(+) and Cl(-), in maintaining cell volume. PMCA might help maintain the [Ca(2+)] gradient across the membrane though compromised, and thereby promote reverse Na(+)/Ca(2+) exchange stimulated by the increased [Na(+)](i) as well as the membrane depolarization. Na(+) extrusion via Na(+)/Ca(2+) exchange delayed cell swelling during Na(+)/K(+) pump block. Supporting these model predictions, we observed ventricular cell swelling after blocking Na(+)/Ca(2+) exchange with KB-R7943 or SEA0400 in the presence of ouabain. When Cl(-) conductance via the cystic fibrosis transmembrane conductance regulator (CFTR) was activated with isoproterenol during the ouabain treatment, cells showed an initial shrinkage to 94.2 +/- 0.5%, followed by a marked swelling 52.0 +/- 4.9 min after drug application. Concomitantly with the onset of swelling, a rapid jump of membrane potential was observed. These experimental observations could be reproduced well by the model simulations. Namely, the Cl(-) efflux via CFTR accompanied by a concomitant cation efflux caused the initial volume decrease. Then, the gradual membrane depolarization induced by the Na(+)/K(+) pump block activated the window current of the L-type Ca(2+) current, which increased [Ca(2+)](i). Finally, the activation of Ca(2+)-dependent cation conductance induced the jump of membrane potential, and the rapid accumulation of intracellular Na(+) accompanied by the Cl(-) influx via CFTR, resulting in the cell swelling. The pivotal role of L-type Ca(2+) channels predicted in the simulation was demonstrated in experiments, where blocking Ca(2+) channels resulted in a much delayed cell swelling.

Aniline Compounds↗
PubMed2006

Modeling the calcium gate of cardiac gap junction channel.

We addressed the question how Ca2+ transients affect gap junction conductance (Gj) during action potential (AP) propagation by constructing a dynamic gap junction model coupled with a cardiac cell model. The kinetics of the Ca2+ gate was determined based on published experimental findings that the Hill coefficient for the [Ca2+]i-Gj relationship ranges from 3 to 4, indicating multiple ion bindings. It is also suggested that the closure of the Ca2+ gate follows a single exponential time course. After adjusting the model parameters, a two-state (open-closed) model, assuming simultaneous ion bindings, well described both the single exponential decay and the [Ca2+]i-Gj relationship. Using this gap junction model, 30 cardiac cell models were electrically connected in a one-dimensional cable. However, Gj decreased in a cumulative manner by the repetitive Ca2+ transients, and a conduction block was observed. We found that a reopening of the Ca2+ gate is possible only by assuming a sequential ion binding with one rate limiting step in a multistate model. In this model, the gating time constant (T) has a bell-shaped dependence on [Ca2+]i, with a peak around the half-maximal concentration of [Ca2+]i. Here we propose a five-state model including four open states and one closed state, which allows normal AP propagation; namely, the Gj is decreased -15% by a single Ca2+ transient, but well recovers to the control level during diastole. Under the Ca(2+)-overload condition, however, the conduction velocity is indeed decreased as demonstrated experimentally. This new gap junction model may also be useful in simulations of the ventricular arrhythmia.

Action Potentials↗
PubMed2005

simBio: a Java package for the development of detailed cell models.

Quantitative dynamic computer models, which integrate a variety of molecular functions into a cell model, provide a powerful tool to create and test working hypotheses. We have developed a new modeling tool, the simBio package (freely available from ), which can be used for constructing cell models, such as cardiac cells (the Kyoto model from Matsuoka et al., 2003, 2004 a, b, the LRd model from Faber and Rudy, 2000, and the Noble 98 model from Noble et al., 1998), epithelial cells (Strieter et al., 1990) and pancreatic beta cells (Magnus and Keizer, 1998). The simBio package is written in Java, uses XML and can solve ordinary differential equations. In an attempt to mimic biological functional structures, a cell model is, in simBio, composed of independent functional modules called Reactors, such as ion channels and the sarcoplasmic reticulum, and dynamic variables called Nodes, such as ion concentrations. The interactions between Reactors and Nodes are described by the graph theory and the resulting graph represents a blueprint of an intricate cellular system. Reactors are prepared in a hierarchical order, in analogy to the biological classification. Each Reactor can be composed or improved independently, and can easily be reused for different models. This way of building models, through the combination of various modules, is enabled through the use of object-oriented programming concepts. Thus, simBio is a straightforward system for the creation of a variety of cell models on a common database of functional modules.

Algorithms↗
PubMed2005

Regulation of oxidative phosphorylation in intact mammalian heart in vivo.

A dynamic computer model of oxidative phosphorylation in intact heart was developed by modifying the model of oxidative phosphorylation in intact skeletal muscle published previously. Next, this model was used for theoretical studies on the regulation of oxidative phosphorylation in intact heart in vivo during transition between different work intensities. It is shown that neither a direct activation of ATP usage alone nor a direct activation of both ATP usage and substrate dehydrogenation, including the calcium-activated tricarboxylate acid cycle dehydrogenases, can account for the constancy of [ADP], [PCr], [P(i)] and [NADH] during a significant increase in oxygen consumption and ATP turnover encountered in intact heart in vivo. Only a direct activation of all oxidative phosphorylation complexes in parallel with a stimulation of ATP usage and substrate dehydrogenation enabled to reproduce the experimental data concerning the constancy of metabolite concentrations. The molecular background of the differences between heart and skeletal muscle in the kinetic behaviour of the oxidative phosphorylation system is also discussed.

Adenosine Triphosphate↗
PubMed2004

Two types of spontaneous depolarizations in the interstitial cells freshly prepared from the murine small intestine.

To explore the electrophysiological properties of the interstitial cells of Cajal (ICCs) and fibroblast-like cells (FLCs), we developed a new preparation by treating the murine small intestine with collagenase. This thin muscle layer preparation contained at least two types of interstitial cells around the enteric nerve bundles, and the cluster of smooth muscle cells displayed a rhythmic contraction. We morphologically identified ICCs and FLCs and conducted patch clamp experiments on each type of cell. The c-kit-positive CD34-negative ICCs showed spontaneous and rhythmic potential fluctuations, and a large transient inward current was evoked by depolarization under voltage clamp conditions. Once the inward current was triggered, it took a regenerative time course and lasted approximately 500 ms. The current was inactivated by continuous depolarization, and by removal of external Ca2+. The application of acetylcholine (ACh) prolonged the duration of spontaneous depolarization as well as the depolarization-induced inward current. This inward current showed a reversal potential of around +3 mV and was considered to be due to non-selective cation channels. The c-kit-negative CD34-positive FLCs showed irregular or regular potential fluctuations, and spontaneous outward current was observed under voltage clamp conditions. This outward current showed a reversal potential of around -80 mV and might be classified as a potassium current. We failed to observe major time- and voltage-dependent currents except the above two currents in the interstitial cells.

Acetylcholine↗
PubMed2004

Mutations in two matrix metalloproteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice.

The matrix metalloproteinase (MMP) family (approximately 25 members in mammals) has been implicated in extracellular matrix remodeling associated with embryonic development, cancer formation and progression, and various other physiological and pathological events. Inactivating mutations in individual matrix metalloproteinase genes in mice described so far, however, are nonlethal at least up to the first few weeks after birth, suggesting functional redundancy among MMP family members. Here, we report that mice lacking two MMPs, MMP-2 (nonmembrane type) and MT1-MMP (membrane type), die immediately after birth with respiratory failure, abnormal blood vessels, and immature muscle fibers reminiscent of central core disease. In the absence of MMP-2 and MT1-MMP, myoblast fusion in vitro is also significantly retarded. These findings suggest functional overlap in mice between the two MMPs with distinct molecular natures.

Animals↗
PubMed2004

Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome.

INTRODUCTION: Beta-blockers are widely used to prevent the lethal cardiac events associated with the long QT syndrome (LQTS), especially in KCNQ1-related LQTS (LQT1) patients. Some LQT1 patients, however, are refractory to this therapy. METHODS AND RESULTS: Eighteen symptomatic LQTS patients (12 families) were genetically diagnosed as having heterozygous KCNQ1 variants and received beta-blocker therapy. Cardiac events recurred in 4 members (3 families) despite continued therapy during mean follow-up of 70 months. Three of these patients (2 families) had the same mutation [A341V (KCNQ1)]; and the other had R243H (KCNQ1). The latter patient took aprindine, which seemed to be responsible for the event. By functional assay using a heterologous mammalian expression system, we found that A341V (KCNQ1) is a loss-of-function type mutation (not dominant negative). Further genetic screening revealed that one A341V (KCNQ1) family cosegregated with S706C (KCNH2) and another with G144S (KCNJ2). Functional assay of the S706C (KCNH2) mutation was found to reduce the current density of expressed heterozygous KCNH2 channels with a positive shift (+8 mV) of the activation curve. Action potential simulation study was conducted based on the KYOTO model to estimate the influence of additional gene modifiers. In both models mimicking LQT1 plus 2 and LQT1 plus 7, the incidence of early afterdepolarization was increased compared with the LQT1 model under the setting of beta-adrenergic stimulation. CONCLUSION: Multiple mutations in different LQTS-related genes may modify clinical characteristics. Expanded gene survey may be required in LQT1 patients who are resistant to beta-blocker therapy.

Action Potentials↗
PubMed2004

An in silico study of energy metabolism in cardiac excitation-contraction coupling.

The heart produces and uses ATP at a high rate. Each step involved in ATP metabolism has been extensively studied. However, functional coupling between ATP production and membrane excitation-contraction coupling, which is the main ATP consumption process, is not yet fully understood because of complicated interactions and the lack of quantitative data obtained in vivo. Computer simulation is a powerful tool for integrating experimental data and for solving their complicated interactions. To investigate the mechanisms underlying cardiac excitation-contraction-energy metabolism coupling, we have developed a computer model of cardiac excitation-contraction coupling (Kyoto model) that includes the major processes of ATP production, such as oxidative phosphorylation that was originally developed for skeletal muscle by Korzeniewski and Zoladz [Biophys Chem 92: 17-34, 2001], creatine kinase, and adenylate kinase. In this review, we briefly summarize cardiac energy metabolism and discuss the regulation of mitochondrial ATP synthesis, using the Kyoto model.

Adenosine Triphosphate↗
PubMed2003

NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function.

Reactivation of the fetal cardiac gene program is a characteristic feature of hypertrophied and failing hearts that correlates with impaired cardiac function and poor prognosis. However, the mechanism governing the reversible expression of fetal cardiac genes remains unresolved. Here we show that neuron-restrictive silencer factor (NRSF), a transcriptional repressor, selectively regulates expression of multiple fetal cardiac genes, including those for atrial natriuretic peptide, brain natriuretic peptide and alpha-skeletal actin, and plays a role in molecular pathways leading to the re-expression of those genes in ventricular myocytes. Moreover, transgenic mice expressing a dominant-negative mutant of NRSF in their hearts exhibit dilated cardiomyopathy, high susceptibility to arrhythmias and sudden death. We demonstrate that genes encoding two ion channels that carry the fetal cardiac currents I(f) and I(Ca,T), which are induced in these mice and are potentially responsible for both the cardiac dysfunction and the arrhythmogenesis, are regulated by NRSF. Our results indicate NRSF to be a key transcriptional regulator of the fetal cardiac gene program and suggest an important role for NRSF in maintaining normal cardiac structure and function.

Actins↗
PubMed2003

Reinduction of T-type calcium channels by endothelin-1 in failing hearts in vivo and in adult rat ventricular myocytes in vitro.

BACKGROUND: In ventricular myocardium, the T-type Ca2+ current (ICa,T), which is temporarily observed during fetal and neonatal periods, has been shown to reappear in failing/remodeling hearts. However, its pathophysiological regulation has not been elucidated. METHODS AND RESULTS: We utilized Dahl salt-sensitive (DS) rats with hypertension at the stage of concentric left ventricular (LV) hypertrophy (11 weeks old, LVH) and at the heart failure stage (16 to 18 weeks old, CHF). Some were treated with bosentan (100 mg/kg per day) during the period from LVH to CHF. In LVH, neither the presence of ICa,T (measured in the freshly isolated LV myocytes) nor an increase in alpha-1G mRNA expression were detected. This condition was associated with increases in tissue angiotensin II (AII) but not with endothelin (ET)-1 peptides. In contrast, in CHF, when the tissue AII remained elevated and ET-1 de novo increased, ICa,T was recorded in most of the cells (-0.87+/-0.18 pA/pF at -30 mV, P<0.01 versus LVH). This was associated with a significant increase in the alpha-1G mRNA level. The chronic bosentan treatment eliminated both the elevation of alpha-1G mRNA level and ICa,T from the cells, whereas it did not affect the cell size and membrane capacitance. In addition, 48-hour exposure to ET-1 but not AII induced ICa,T in normal adult myocytes in culture from Sprague-Dawley rats. CONCLUSIONS: ICa,T channels reappear in failing but not in hypertrophied LV cardiomyocytes in a manner depending on the tissue ET-1 activation.

Angiotensin II↗
PubMed2003

The electrophysiological properties of spontaneously beating pacemaker cells isolated from mouse sinoatrial node.

In order to examine the phenotypic consequences of genetic manipulation in the function of the sinoatrial (SA) node, it is a prerequisite to record the electrical activities of a single pacemaker cell of the SA node of mouse heart. In the present study, we isolated spontaneously beating pacemaker cells from the SA node by enzymatic digestion. The rate of spontaneous action potential firing was 294 + 59 min-1 at 33-34 degrees C. The maximal diastolic potential (MDP) was -56.7 +/- 7.4 mV and the overshoot was 22.7 +/- 6.2 mV. With hyperpolarizing voltage clamp pulses, the hyperpolarization-activated, cyclic nucleotide-sensitive cation current (I(h) or I(f)) was recorded. lb started to activate at-70 to approximately -80 mV, more negative than MDP. The half-maximal activation of Ih was obtained at -107.9 +/- 10.4 mV. The inward-rectifier K+ current (IK1) was also recorded in spontaneously beating myocytes. However, the amplitude of outward IK1 was negligibly small (9.1 +/- 3.4 pA at -60 mV). With depolarization, voltage-gated Na+ current, L-type Ca2+ current and T-type Ca2+ current were consistently observed. The sustained inward current (I(st)) was also recorded in spontaneously beating pacemaker cells. E4031-sensitive, rapidly activating delayed rectifier K+ current (I(Kr)) was activated by depolarization, although the amplitude was no more than 38.3 +/- 22.2 pA at 0 mV. The chromanol 293B-sensitive, slowly activating delayed rectifier K+ current (I(Ks)) was not present. The major repolarizing current was the slowly inactivating, 4-aminopyridine-insensitive outward current. We concluded that mouse pacemaker cells possess similar membrane currents, including I(st), to those of other species.

Action Potentials↗
PubMed2003

Role of individual ionic current systems in ventricular cells hypothesized by a model study.

Individual ion channels or exchangers are described with a common set of equations for both the sinoatrial node pacemaker and ventricular cells. New experimental data are included, such as the new kinetics of the inward rectifier K+ channel, delayed rectifier K+ channel, and sustained inward current. The gating model of Shirokov et al. (J Gen Physiol 102: 1005-1030, 1993) is used for both the fast Na+ and L-type Ca2+ channels. When combined with a contraction model (Negroni and Lascano: J Mol Cell Cardiol 28: 915-929, 1996), the experimental staircase phenomenon of contraction is reconstructed. The modulation of the action potential by varying the external Ca2+ and K+ concentrations is well simulated. The conductance of I(CaL) dominates membrane conductance during the action potential so that an artificial increase of I(to), I(Kr), I(Ks), or I(KATP) magnifies I(CaL) amplitude. Repolarizing current is provided sequentially by I(Ks), I(Kr), and I(K1). Depression of ATP production results in the shortening of action potential through the activation of I(KATP). The ratio of Ca2+ released from SR over Ca2+ entering via I(CaL) (Ca2+ gain = approximately 15) in excitation-contraction coupling well agrees with the experimental data. The model serves as a predictive tool in generating testable hypotheses.

Action Potentials↗
PubMed2003

Role of individual ionic current systems in the SA node hypothesized by a model study.

This paper discusses the development of a cardiac sinoatrial (SA) node pacemaker model. The model successfully reconstructs the experimental action potentials at various concentrations of external Ca2+ and K+. Increasing the amplitude of L-type Ca2+ current (I(CaL)) prolongs the duration of the action potential and thereby slightly decreases the spontaneous rate. On the other hand, a negative voltage shift of I(CaL) gating by a few mV markedly increases the spontaneous rate. When the amplitude of sustained inward current (I(st)) is increased, the spontaneous rate is increased irrespective of the I(CaL) amplitude. Increasing [Ca2+](o) shortens the action potential and increases the spontaneous rate. When the spontaneous activity is stopped by decreasing I(CaL) amplitude, the resting potential is nearly constant (-35 mV) over 1-15 mM [K+](o) as observed in the experiment. This is because the conductance of the inward background non-selective cation current balances with the outward [K+](o)-dependent K+ conductance. The unique role of individual voltage- and time-dependent ion channels is clearly demonstrated and distinguished from that of the background current by calculating an instantaneous zero current potential ("lead potential") during the course of the spontaneous activity.

Action Potentials↗