Developmental Changes in Transient Outward Current in Mouse Ventricle

Wang, Li; Duff, Henry J.

doi:10.1161/01.res.81.1.120

Cited by 114 publications

(111 citation statements)

References 14 publications

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“…Age-dependent differences in the action potential shape have been shown in isolated cells from several species (12)(13)(14)(15)(16), including human atria (4,5). In mouse ventricle (15,16) and rat ventricle (13,14), the neonatal action potential has a slower early repolarization phase and more pronounced early plateau.…”

Section: Discussionmentioning

confidence: 99%

“…In mouse ventricle (15,16) and rat ventricle (13,14), the neonatal action potential has a slower early repolarization phase and more pronounced early plateau. Similar age-dependent differences have been demonstrated in the human atria from intact atrial strips (5) The effects of changes in the action potential waveform on the amplitude of I Ca and the Ca 2ϩ transient have been most clearly shown by using the technique of applying recorded action potentials as voltage waveforms to which the cell is "voltage clamped."…”

Section: Discussionmentioning

confidence: 99%

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Calcium Transients in Infant Human Atrial Myocytes

et al. 2005

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Isolated infant human atrial cells have a slower early repolarization than adult human atrial cells. In addition, from room temperature voltage-clamp studies, infant cells have lower basal L-type calcium currents than adult cells. We hypothesized that the slower repolarization increases the calcium transient of infant human atrial cells. Atrial myocytes were enzymatically dissociated from biopsies of human right atrial appendages of infant (3-8 mo) patients who were undergoing open-heart surgery. Intracellular calcium transients were measured with fluorescence microscopy with application of either square waves or action potential waveforms at physiologic temperature. After repetitive application (1 Hz) of 100-ms duration conditioning depolarizations to 10 mV (from Ϫ80 mV), a test pulse of varying duration (⌬T; 2-100 ms) produced smaller transients (expressed as percentage of the last conditioning pulse) at shorter durations (33 Ϯ 7% for ⌬T ϭ 2 ms, 80 Ϯ 4% for ⌬T ϭ 25 ms). The time course and amplitude of the calcium current, which leads via sarcoplasmic reticulum (SR) calcium release to the calcium transient of cardiac cells, depend not only on the properties of the calcium channel but also on the action potential waveform. Changes in the action potential repolarization rate have been shown to have effects to either increase or decrease the net calcium current and the release of calcium from the SR (1-3). In our recent work comparing action potential waveforms and the amplitude and time course of transient outward current in isolated infant versus adult human atrial cells (4), we showed 1) that infant atrial cells had transient outward current that inactivated much more rapidly than adult atrial cells and 2) that infant cells had a much slower early repolarization phase [consistent with previous work on atrial strips (5)]. The time for 30% repolarization from the peak of the action potential (APD 30 ) was 24.4 Ϯ 11.4 ms for infant atrial cells compared with only 3.6 Ϯ 0.4 ms for adult atrial cells. We have also shown that infant cells have a lower basal amplitude of calcium current than do either young adult or older adult atrial cells (6), with peak L-type calcium current (I Ca ) from voltage steps to 10 mV at room temperature being 1.2 Ϯ 0.1 pA/pF for infant cells and 2.6 Ϯ 0.3 pA/pF for adult cells.The lower I Ca (from square wave voltage-clamp studies) and the prolonged early repolarization phase of the infant atrial cells (from current clamp single-cell studies) may be related in a functional sense if the prolongation of the early repolarization served to increase the calcium entry and thus the intracellular calcium transient in infant atrial cells compared with the faster

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Calcium Transients in Infant Human Atrial Myocytes

et al. 2005

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“…In a variety of species, including the mouse, neonatal cells are significantly smaller than adult myocytes (21,42,49). We assumed that the neonatal cell was a cylinder 50 m in length and 9 m in diameter.…”

Section: Methodsmentioning

confidence: 99%

“…Wang and Duff (49) showed that transient outward current (I to) density increases greatly during development in the mouse, suggesting that these currents play a smaller role in repolarization in neonatal hearts than in adult hearts. I to was also shown to inactivate faster, and with simpler kinetics, in day 1 neonatal compared with adult cells.…”

Section: Methodsmentioning

confidence: 99%

Mathematical model of the neonatal mouse ventricular action potential

Wang¹,

Sobie²

2008

American Journal of Physiology-Heart and Circulatory Physiology

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Wang LJ, Sobie EA. Mathematical model of the neonatal mouse ventricular action potential. Am J Physiol Heart Circ Physiol 294: H2565-H2575, 2008. First published April 11, 2008 doi:10.1152/ajpheart.01376.2007.-Therapies for heart disease are based largely on our understanding of the adult myocardium. The dramatic differences in action potential (AP) shape between neonatal and adult cardiac myocytes, however, indicate that a different set of molecular interactions in neonatal myocytes necessitates different treatment for newborns. Computational modeling is useful for synthesizing data to determine how interactions between components lead to systems-level behavior, but this technique has not been used extensively to study neonatal heart cell function. We created a mathematical model of the neonatal (day 1) mouse myocyte by modifying, on the basis of experimental data, the densities and/or formulations of ion transport mechanisms in an adult cell model. The new model reproduces the characteristic AP shape of neonatal cells, with a brief plateau phase and longer duration than the adult (action potential duration at 80% repolarization ϭ 60.1 vs. 12.6 ms). The simulation results are consistent with experimental data, including 1) decreased density and altered inactivation of transient outward K ϩ currents, 2) increased delayed rectifier K ϩ currents, 3) Ca 2ϩ entry through T-type as well as L-type Ca 2ϩ channels, 4) increased Ca 2ϩ influx through Na ϩ /Ca 2ϩ exchange, and 5) Ca 2ϩ transients resulting from transmembrane Ca 2ϩ entry rather than release from the sarcoplasmic reticulum (SR). Simulations performed with the model generated novel predictions, including increased SR Ca 2ϩ leak and elevated intracellular Na ϩ concentration in neonatal compared with adult myocytes. This new model can therefore be used for testing hypotheses and obtaining a better quantitative understanding of differences between neonatal and adult physiology. ionic currents; excitation-contraction coupling; cardiac development; cardiac myocyte DEVELOPMENTAL CHANGES in heart morphology and function occur in all species. A number of studies performed in recent years have shed light on the changes in electrophysiology and ion transport that take place in myocytes as hearts develop. These studies have generally found that cells from immature ventricles, compared with adult myocytes, display 1) a reduction in the density of outward K ϩ currents (28, 51), 2) greater activity and expression of Na ϩ /Ca 2ϩ exchange (NCX) (2), and 3) intracellular Ca 2ϩ transients that depend less on sarcoplasmic reticulum (SR) Ca 2ϩ release and more on transmembrane Ca 2ϩ influx (21, 32). In addition, action potentials (APs) recorded in myocytes from neonatal mouse and rat hearts have a brief plateau phase and are longer in duration than the extremely short spikelike APs seen in adult cells from these species (30,42,50).It is important to understand these developmental changes in heart cell function for a number of reasons. First, therapies developed to treat electro...

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“…Other investigators also found that the DM-related suppression of I to explains the prolongation of APD in diabetic laboratory rat ventricular muscle [21] and ventricular myocytes from diabetic laboratory rats [32]. Recently, Wang and Duff [33] examined developmental changes in the I to in mouse ventricular myocytes by whole-cell patch-clamp techniques, and concluded that the developmental increase in the density of I to contributes to the age-related shortening of APD in mouse ventricle. Based on this finding, we can speculate that the diabetic state may lead to a lack of development of ionic channels responsible for I to and/or a decrease in the density of the channels, compared to the non-diabetic state.…”

Section: Discussionmentioning

confidence: 97%

Electrophysiological Properties of Ventricular Muscle Obtained from Spontaneously Diabetic Mice.

Aomine

Yamato

2000

Exp. Anim.

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Abstract:The electrophysiological properties of cardiac muscle in KK/Ta mouse (hereafter referred to as KK mouse), an animal model of human non-insulin-dependent diabetes mellitus, were investigated, and the findings compared with those obtained from a nondiabetic control mouse (C57BL/6J mouse; referred to as B6 mouse). The ages of the B6 mice were 23.9 ± 5.4 weeks (n=24) and those of the KK mice used were 25.7 ± 10.8 weeks (n=34). The KK mice had mild obesity, hyperglycemia and hyperinsulinemia. Ventricular muscles from both mice were examined by light microscopy. Partial myocardial fibrosis and filament disorder in the ventricular muscles were found only in the KK mice. The resting membrane potential of the ventricular muscle was less negative in the KK mice than in the control mice. The maximum rate of rise in the upstroke of the action potential was significantly decreased in the KK mice compared with that of the control mice. These suggest a decrease in a time-independent K + current (I K1 ) in the KK mice. The duration of the action potential (APD) at all levels of repolarization was significantly longer in the KK mice than in the B6 mice. A blocker of transient outward current (I to ), 4-aminopyridine, significantly prolonged the APD of the B6 mice, but failed to prolong it in the KK mice, suggesting that I to in the diabetic mice is very small. A Ca 2+ channel blocker, CoCl 2 , dramatically lengthened all levels of APD in both groups, suggesting that there is no difference between B6 mice and KK mice in L-type Ca 2+ current via Ca 2+ channels. These suggest the malfunction or deficiency of ionic channels which carry, at least, I to and I K1 in diabetic mice.

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Developmental Changes in Transient Outward Current in Mouse Ventricle

Cited by 114 publications

References 14 publications

Calcium Transients in Infant Human Atrial Myocytes

Calcium Transients in Infant Human Atrial Myocytes

Mathematical model of the neonatal mouse ventricular action potential

Electrophysiological Properties of Ventricular Muscle Obtained from Spontaneously Diabetic Mice.

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