Modeling of Arrhythmogenic Automaticity Induced by Stretch in Rat Atrial Myocytes

Youm, Jae-Boum,Leem, Chae-Hun,Zhang, Yin Hua,Kim, Na-Ri,Han, Jin,Earm, Yung-E. The Korean Society of Pharmacology 2008 The Korean Journal of Physiology & Pharmacology Vol.12 No.5

Since first discovered in chick skeletal muscles, stretch-activated channels (SACs) have been proposed as a probable mechano-transducer of the mechanical stimulus at the cellular level. Channel properties have been studied in both the single-channel and the whole-cell level. There is growing evidence to indicate that major stretch-induced changes in electrical activity are mediated by activation of these channels. We aimed to investigate the mechanism of stretch-induced automaticity by exploiting a recent mathematical model of rat atrial myocytes which had been established to reproduce cellular activities such as the action potential, $Ca^{2+}$ transients, and contractile force. The incorporation of SACs into the mathematical model, based on experimental results, successfully reproduced the repetitive firing of spontaneous action potentials by stretch. The induced automaticity was composed of two phases. The early phase was driven by increased background conductance of voltage-gated $Na^+$ channel, whereas the later phase was driven by the reverse-mode operation of $Na^+/Ca^{2+}$ exchange current secondary to the accumulation of $Na^+$ and $Ca^{2+}$ through SACs. These results of simulation successfully demonstrate how the SACs can induce automaticity in a single atrial myocyte which may act as a focus to initiate and maintain atrial fibrillation in concert with other arrhythmogenic changes in the heart.

A Computational Model of Cytosolic and Mitochondrial [Ca<SUP>2+</SUP>] in Paced Rat Ventricular Myocytes

Jae Boum Youm,Seong Woo Choi,Chang Han Jang,Hyoung Kyu Kim,Chae Hun Leem,Nari Kim,Jin Han 대한생리학회-대한약리학회 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.5

We carried out a series of experiment demonstrating the role of mitochondria in the cytosolic and mitochondrial Ca²⁺ transients and compared the results with those from computer simulation. In rat ventricular myocytes, increasing the rate of stimulation (1∼3 Hz) made both the diastolic and systolic [Ca²⁺] bigger in mitochondria as well as in cytosol. As L-type Ca²⁺ channel has key influence on the amplitude of Ca²⁺-induced Ca²⁺ release, the relation between stimulus frequency and the amplitude of Ca²⁺ transients was examined under the low density (1/10 of control) of L-type Ca²⁺ channel in model simulation, where the relation was reversed. In experiment, block of Ca²⁺ uniporter on mitochondrial inner membrane significantly reduced the amplitude of mitochondrial Ca²⁺ transients, while it failed to affect the cytosolic Ca²⁺ transients. In computer simulation, the amplitude of cytosolic Ca²⁺ transients was not affected by removal of Ca²⁺ uniporter. The application of carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) known as a protonophore on mitochondrial membrane to rat ventricular myocytes gradually increased the diastolic [Ca²⁺] in cytosol and eventually abolished the Ca²⁺ transients, which was similarly reproduced in computer simulation. The model study suggests that the relative contribution of L-type Ca²⁺ channel to total transsarcolemmal Ca²⁺ flux could determine whether the cytosolic Ca²⁺ transients become bigger or smaller with higher stimulus frequency. The present study also suggests that cytosolic Ca²⁺ affects mitochondrial Ca²⁺ in a beat-to-beat manner, however, removal of Ca²⁺ influx mechanism into mitochondria does not affect the amplitude of cytosolic Ca²⁺ transients.

A Computational Model of Cytosolic and Mitochondrial [$Ca^{2+}$] in Paced Rat Ventricular Myocytes

Youm, Jae-Boum,Choi, Seong-Woo,Jang, Chang-Han,Kim, Hyoung-Kyu,Leem, Chae-Hun,Kim, Na-Ri,Han, Jin The Korean Society of Pharmacology 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.4

We carried out a series of experiment demonstrating the role of mitochondria in the cytosolic and mitochondrial $Ca^{2+}$ transients and compared the results with those from computer simulation. In rat ventricular myocytes, increasing the rate of stimulation (1~3 Hz) made both the diastolic and systolic [$Ca^{2+}]$ bigger in mitochondria as well as in cytosol. As L-type $Ca^{2+}$ channel has key influence on the amplitude of $Ca^{2+}$ -induced $Ca^{2+}$ release, the relation between stimulus frequency and the amplitude of $Ca^{2+}$ transients was examined under the low density (1/10 of control) of L-type $Ca^{2+}$ channel in model simulation, where the relation was reversed. In experiment, block of $Ca^{2+}$ uniporter on mitochondrial inner membrane significantly reduced the amplitude of mitochondrial $Ca^{2+}$ transients, while it failed to affect the cytosolic $Ca^{2+}$ transients. In computer simulation, the amplitude of cytosolic $Ca^{2+}$ transients was not affected by removal of $Ca^{2+}$ uniporter. The application of carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) known as a protonophore on mitochondrial membrane to rat ventricular myocytes gradually increased the diastolic [$Ca^{2+}$] in cytosol and eventually abolished the $Ca^{2+}$ transients, which was similarly reproduced in computer simulation. The model study suggests that the relative contribution of L-type $Ca^{2+}$ channel to total transsarcolemmal $Ca^{2+}$ flux could determine whether the cytosolic $Ca^{2+}$ transients become bigger or smaller with higher stimulus frequency. The present study also suggests that cytosolic $Ca^{2+}$ affects mitochondrial $Ca^{2+}$ in a beat-to-beat manner, however, removal of $Ca^{2+}$ influx mechanism into mitochondria does not affect the amplitude of cytosolic $Ca^{2+}$ transients.

Stretch-activated K^(+) Channels in Rat Atrial Myocytes

Youm, Jae Boum The Korean Physiological Society and The Korean So 2003 The Korean Journal of Physiology & Pharmacology Vol.7 No.6

Role of Stretch-Activated Channels in Stretch-Induced Changes of Electrical Activity

Jae Boum Youm,Su-Hyun Jo,Chae Hun Leem,Won-Kyung Ho,Yung E. 대한생리학회-대한약리학회 2004 The Korean Journal of Physiology & Pharmacology Vol.8 No.1

We developed a cardiac cell model to explain the phenomenon of mechano-electric feedback (MEF), based on the experimental data with rat atrial myocytes. It incorporated the activity of ion channels, pumps, exchangers, and changes of intracellular ion concentration. Changes in membrane excitability and Ca<SUP>2⁢</SUP> transients could then be calculated. In the model, the major ion channels responsible for the stretch-induced changes in electrical activity were the stretch-activated channels (SACs). The re</SUP>lationship between the extent of stretch and activation of SACs was formulated based on the experimental findings. Then, the effects of mechanical stretch on the electrical activity were reproduced. The shape of the action potential (AP) was significantly changed by stretch in the model simulation. The duration was decreased at initial fast phase of repolarization (AP duration at 20% repolarization level from 3.7 to 2.5 ms) and increased at late slow phase of repolarization (AP duration at 90% repolarization level from 62 to 178 ms). The resting potential was depolarized from ⁣75 to ⁣61 mV. This mathematical model of SACs may quantitatively predict changes in cardiomyocytes by mechanical stretch.

Stretch-activated K<SUP>⁢</SUP> Channels in Rat Atrial Myocytes

Jae Boum Youm 대한생리학회-대한약리학회 2003 The Korean Journal of Physiology & Pharmacology Vol.13 No.4

Mechanical stimuli to the cardiac myocytes initiate many biochemical and physiological events. Stretch-activated cation channels have been suggested to mediate these events. In this study, cell-attached and inside-out excised-patch clamp methods were used to identify stretch-activated cation channels in adult rat atrial myocytes. Channel openings were increased in cell-attached configuration when negative pressure was applied to the pipette, and also in inside-out excised patches by negative pressure. The channel was not permeable to Cl<SUP>⁣</SUP>, Na<SUP>⁢</SUP> and Cs<SUP>⁢</SUP>, but selectively permeable to K<SUP>⁢</SUP>, and the degree of activation was dependent on the magnitude of negative pressure (full activation at <FONT FACE= 바탕 >∼ ⁣50 mmHg). In symmetrical 140 mM KCl, the slope conductance was 51.2⁑3 pS between the potentials of ⁣80 and 0 mV and 55⁑6 pS between 0 and ⁢80 mV (n=5). Glibenclamide (100<FONT FACE= 바탕 >μM) or ATP (2 mM) failed to block the channel openings, indicating that it is not ATP-sensitive K<SUP>⁢</SUP> channel. Arachidonic acid (30<FONT FACE= 바탕 >μM), which has been shown to activate a K<SUP>⁢</SUP> channel cooperatively with membrane stretch, did not affect the channel activity. GdCl<SUB>3</SUB> (100<FONT FACE= 바탕 >μM) also did not alter the activity. These results demonstrate that the mechanical stretch in rat atrial myocytes activates a novel K<SUP>⁢</SUP>-selective cation channel, which is not associated with other K<SUP>⁢</SUP> channels such as ATP-sensitive and arachidonic acid-activated K<SUP>⁢</SUP> channel.

Protein Kinase C Activates ATP-sensitive Potassium Channels in Rabbit Ventricular Myocytes

Nari Kim,Jae Boum Youm,Hyun Joo,Hyungkyu Kim,Euiyong Kim,Jin Han 대한생리학회-대한약리학회 2005 The Korean Journal of Physiology & Pharmacology Vol.9 No.4

Several signal transduction pathways have been implicated in ischemic preconditioning induced by the activation of ATP-sensitive K<SUP>⁢</SUP> (K<SUB>ATP</SUB>) channels. We examined whether protein kinase C (PKC) modulated the activity of K<SUB>ATP</SUB> channels by recording K<SUB>ATP</SUB> channel currents in rabbit ventricular myocytes using patch-clamp technique and found that phorbol 12,13-didecanoate (PDD) enhanced pinacidil-induced K<SUB>ATP</SUB> channel activity in the cell-attached configuration; and this effect was prevented by bisindolylmaleimide (BIM). K<SUB>ATP</SUB> channel activity was not increased by 4α-PDD. In excised inside- out patches, PKC stimulated K<SUB>ATP</SUB> channels in the presence of 1 mM ATP, and this effect was abolished in the presence of BIM. Heat-inactivated PKC had no effect on channel activity. PKC-induced activation of K<SUB>ATP</SUB> channels was reversed by PP2A, and this effect was not detected in the presence of okadaic acid. These results suggest that PKC activates K<SUB>ATP</SUB> channels in rabbit ventricular myocytes.

e-MITOCHONDRIA RESEARCH FOR SYSTEMS BIOLOGY AND PROTEOMICS

Hyun Joo(주현),Jae boum Youm(염재범),Taeho Kim(김태호),Nari Kim(김나리),Won sun Park(박원선),Sunghyun Kang(강성현),Dang Van Cuong,Hyoung kyu Kim(김형규),Tran Min Khoa,Vu Thi hu,Hyunju Kim(김현주),Hyejin Moon(문혜진),Hyunsuk Le 한국생물공학회 2005 한국생물공학회 학술대회 Vol.2005 No.10

Protein Kinase C Activates ATP-sensitive Potassium Channels in Rabbit Ventricular Myocytes

Kim, Na-Ri,Youm, Jae-Boum,Joo, Hyun,Kim, Hyung-Kyu,Kim, Eui-Yong,Han, Jin The Korean Society of Pharmacology 2005 The Korean Journal of Physiology & Pharmacology Vol.9 No.4

Several signal transduction pathways have been implicated in ischemic preconditioning induced by the activation of ATP-sensitive $K^+$ $(K_{ATP})$ channels. We examined whether protein kinase C (PKC) modulated the activity of $K_{ATP}$ channels by recording $K_{ATP}$ channel currents in rabbit ventricular myocytes using patch-clamp technique and found that phorbol 12,13-didecanoate (PDD) enhanced pinacidil-induced $K_{ATP}$ channel activity in the cell-attached configuration; and this effect was prevented by bisindolylmaleimide (BIM). $K_{ATP}$ channel activity was not increased by $4{\alpha}-PDD$. In excised insideout patches, PKC stimulated $K_{ATP}$ channels in the presence of 1 mM ATP, and this effect was abolished in the presence of BIM. Heat-inactivated PKC had no effect on channel activity. PKC-induced activation of $K_{ATP}$ channels was reversed by PP2A, and this effect was not detected in the presence of okadaic acid. These results suggest that PKC activates $K_{ATP}$ channels in rabbit ventricular myocytes.

The angiotensin receptor blocker and PPAR-γ agonist, telmisartan, delays inactivation of voltage-gated sodium channel in rat heart: novel mechanism of drug action.

Kim, Hyoung Kyu,Youm, Jae Boum,Lee, Sung Ryul,Lim, Se Eun,Lee, Sun-Young,Ko, Tae Hee,Long, Le Thanh,Nilius, Bernd,Won, Du Nam,Noh, Jung-Hyun,Ko, Kyung Soo,Rhee, Byoung Doo,Kim, Nari,Han, Jin Springer-Verlag 2012 Pfl ugers Arch Vol.464 No.6

<P>Telmisartan is an angiotensin II receptor blocker and partial peroxisome proliferator-activated receptor gamma agonist that modulates the renin-angiotensin-aldosterone system. It is used primarily to manage hypertension, diabetic nephropathy, and congestive heart failure. Recent studies have reported that myocardial infarction (MI) has occurred in telmisartan-treated patients. The purpose of the study was to investigate the specific conditions and underlying mechanisms that may result in telmisartan-induced MI. We evaluated the effect of telmisartan on whole hearts, cardiomyocytes, and cardiac sarcolemmal ion channels. Hearts of 8-week-old male Sprague-Dawley rats were perfused with 3, 10, 30, or 100?μM telmisartan or losartan or with normal Tyrode's solution (control) for 3?h. We found that telmisartan induced myocardial infarction, with an infarct size of 21?% of the total at 30?μM (P?<?0.0001) and 63?% of the total area at 100?μM (P?<?0.001). Telmisartan also induced cardiac dysfunction (e.g., decreased heart rate, diminished coronary flow, hypercontracture, and arrhythmia). Confocal microscopy demonstrated that 30?μM telmisartan significantly elevated the intracellular Ca(2+) level, leading to hypercontracture and cell death. Patch clamp analysis of isolated cardiomyocytes revealed that telmisartan induced Na(+) overload by slowing the inactivation of voltage-gated Na(+) current (I (Na)), activating the reverse mode of Na(+)-Ca(2+) exchanger activity, and causing Ca(2+) overload. Telmisartan significantly delayed the inactivation of the voltage-gated Na(+) channel, causing cytosolic Na(+) overload, prolonged action potential duration, and subsequent Ca(2+) overload. Above 30?μM, telmisartan may potentially cause cardiac cell death and MI.</P>