• Proceedings of the PSK Conference
• /
• 2003.04a
• /
• pp.126.2-127
• /
• 2003

The therapeutic potential of currently available antiarrhythmic drugs is limited by their tendency to induce proarrhythmic and extracardiac side effects. An ideal antiarrhythmic agent would selectively prolong the action potential duration more in extraordinarily depolarized cardiac myocytes than in normal cells. and show tissue selectivity. Voltage-gated K+ (Kv) channels represent a structurally and functionally diverse group of membrane proteins. (omitted)

• Proceedings of the Korean Biophysical Society Conference
• /
• 2002.06b
• /
• pp.9-11
• /
• 2002

Plasma membrane Na$^{＋}$-K$^{＋}$ ATPase (pump) is an essential component to maintain asymmetrical ion distribution across cell membrane. The Na$^{＋}$-K$^{＋}$ ATPase was discovered by Jens C. Skou in 1957 and since then physiological and biochemical properties of the enzyme have been extensively studied. Jens C. Skou was awarded the 1997 Nobel Prize in chemistry for his discovery of the Na $^{＋}$ - $K^{＋}$ ATPase.(omitted)

• The Korean Journal of Pharmacology
• /
• v.31 no.3
• /
• pp.279-284
• /
• 1995

The aim of the present study was to know whether exogenously administered nitric oxide (NO) may differently modulate muscle mechanics between heart and aorta. We used PIANO method to generate NO. In isolated rat atrial tissues, neither heart rate nor contractility was affected by PIANO $(STZ,\;30{\sim}100\;{\mu}M)$. Only high concentration $(100\;{\mu}M)$ of 8-bromo cyclic GMP slightly depressed cardiac contractility. However, the same concentrations of 8-Br cGMP and PIANO significantly relaxed the rat thoracic aorta contracted with phenylephrine $(0.1\;{\mu}M)$. In isolated rabbit cardiac atrial myocytes, the amplitude of calcium currents were decreased in the whole voltage range by the presence of streptozotocin, which was further potentiated by UV light. Calcium currents were also decreased in those preparations treated with bradykinin, nitroprusside and 8-Br cGMP. These findings suggest that exogenous NO may modulate calcium current in cardiac myocyte. However, it remains why this does not affect myocardial contractility and heart rate. We concluded that NO may differently regulate calcium signal between aorta and heart muscle.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1994.04a
• /
• pp.217-217
• /
• 1994

Calcium entry blockers, capable of inhibiting transmembrane influx of extracellular calcium through specific calcium channels, are useful drugs in the treatment of angina pectoris, hypertension, cardiac arrythmia, and various cardiovascular disorders. Compounds having isoquinoline structures have recently been reported to possess calcium antagonistic action. Therefore, in the present study, we have attempted to synthesize some isoquinoline and related compound.; in order to search for potentially effective chemicals acting on cardiovascular system, and evaluated their pharmacological properties focusing on calcium antagonistic actions. Almost all of the compounds so far synthesized, had inhibitory action against phenylephrine or high potassium-induced contraction in vascular smooth muscle with different degrees of potencies depending on their structures, However, some of tetrahydroisoquinoline analogs showed directly inhibit calcium current in isolated rabbit cardiac myocytes examined by patch clamp techniques. The pharmacological properties of these compounds need more intensive investigation as to whether these chemicals may have developed as a new cardiovascular active drugs. Therefore, we are now under investigation of the mechanism of action of these compounds.

• Proceedings of the Korean Biophysical Society Conference
• /
• 1997.07a
• /
• pp.31-31
• /
• 1997

Rapidly activating delayed K current (IKr) in cardiac muscles plays an important in repolarization. Expression of HERG cloned by the study on inherited LQT revealed that it encodes a potassium channel with biophysical properties similar to those of IKr in cardiac myocytes： outward currents activating on depolarization with large tail currents on repolarization, implying the inward rectifying property.(omitted)

• Proceedings of the PSK Conference
• /
• 2003.10b
• /
• pp.84.2-84.2
• /
• 2003

The number of patients suffering from atrial fibrillation is increasing and many cardiologists is trying to develop the ideal antiarrhythmic drugs for atrial fibrillation. An ideal antiarrhythmic agent would selectively prolong the action potential duration more in extraordinarily depolarized cardiac myocytes than in normal cells, and show tissue selectivity. Voltage-gated K$\^$+/ (Kv) channels represent a structurally and functionally diverse group of membrane proteins. These channels play an important role in determining the length of the cardiac action potential and are the targets for antiarrhythmic drugs. (omitted)

• Journal of Institute of Control, Robotics and Systems
• /
• v.10 no.12
• /
• pp.1164-1171
• /
• 2004

A new multi-scale simulation model is proposed to analyze heart mechanics. Electrophysiology of a cardiac cell is numerically approximated using the previous model of human ventricular myocyte. The ion transports across cell membrane initiated by action potential induce an excitation-contraction mechanism in the cell via cross bridge dynamics. Negroni and Lascano model (NL model) is employed to calculate the tension of cross bridge which is closely related to the ion dynamics in cytoplasm. To convert the tension on cell level into contraction force of cardiac muscle, we introduce a simple geometric model of ventricle with a thin-walled hemispheric shape. It is assumed that cardiac tissue is composed of a set of cardiac myocytes and its orientation on the hemispheric surface of ventricle remains constant everywhere in the domain. Application of Laplace law to the ventricle model enables us to determine the ventricular pressure that induces blood circulation in a body. A lumped parameter model with 7 compartments is utilized to describe the systemic circulation interacting with the cardiac cell mechanism via NL model and Laplace law. Numerical simulation shows that the ion transports in cell level eventually generate blood hemodynamics on system level via cross bridge dynamics and Laplace law. Computational results using the present multi-scale model are well compared with the existing ones. Especially it is shown that the typical characteristics of heart mechanics, such as pressure volume relation, stroke volume and ejection fraction, can be generated by the present multi-scale cardiovascular model, covering from cardiac cells to circulation system.

• The Korean Journal of Physiology and Pharmacology
• /
• v.23 no.5
• /
• pp.393-402
• /
• 2019

Aurora kinases inhibitors, including ZM447439 (ZM), which suppress cell division, have attracted a great deal of attention as potential novel anti-cancer drugs. Several recent studies have confirmed the anti-cancer effects of ZM in various cancer cell lines. However, there have been no studies regarding the cardiac safety of this agent. We performed several cytotoxicity, invasion and migration assays to examine the anti-cancer effects of ZM. To evaluate the potential effects of ZM on cardiac repolarisation, whole-cell patch-clamp experiments were performed with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cells with heterogeneous cardiac ion channel expression. We also conducted a contractility assay with rat ventricular myocytes to determine the effects of ZM on myocardial contraction and/or relaxation. In tests to determine in vitro efficacy, ZM inhibited the proliferation of A549, H1299 (lung cancer), MCF-7 (breast cancer) and HepG2 (hepatoma) cell lines with $IC_{50}$ in the submicromolar range, and attenuated the invasive and metastatic capacity of A549 cells. In cardiac toxicity testing, ZM did not significantly affect $I_{Na}$, $I_{Ks}$ or $I_{K1}$, but decreased $I_{hERG}$ in a dose-dependent manner ($IC_{50}$: $6.53{\mu}M$). In action potential (AP) assay using hiPSC-CMs, ZM did not induce any changes in AP parameters up to $3{\mu}M$, but it at $10{\mu}M$ induced prolongation of AP duration. In summary, ZM showed potent broad-spectrum anti-tumor activity, but relatively low levels of cardiac side effects compared to the effective doses to tumor. Therefore, ZM has a potential to be a candidate as an anti-cancer with low cardiac toxicity.

• BMB Reports
• /
• v.34 no.6
• /
• pp.517-525
• /
• 2001

Six renaturable protein kinases that utilize the myelin basic protein (MBP) as a substrate were activated during prolonged exposure of cardiac myocytes to okadaic acid (OA). We characterized the substrate preference and activation of these kinases, with particular emphasis on 3 novel kinases-MBPK-55, MBPK-62 and MBPK-87. The transcription factors c-Jun, Elk, ATF2, and c-Fos that are used to assess mitogen-activated protein kinase activation were all poor substrates for these three kinases. MAPKAPK2 was also not phosphorylated. In contrast, Histone IIIS was phosphorylated by MBPK-55 and MBPK-62. These protein kinases were activated in cultured cardiac fibroblasts, H9c2 cardiac myoblasts, and Cos cells. High concentrations (0.5 to $1\;{\mu}M$) of OA were essential for the activation of the protein kinases in all of the cell types examined, whereas calyculin A [an inhibitor of protein phosphatase 1 (PP1) and PP2A], cyclosporin A (a PP2B inhibitor), and an inactive OA analog all failed to activate these kinases. The high dose of okadaic acid that is required for kinase activation was also required for phosphatase inhibition, as assessed by immunoblotting whole cell lysates with anti-phosphothreonine antibodies. A variety of chemical inhibitors, including PD98059 (MEK-specific), genistein (tyrosine kinase-specific) and Bisindolylmaleimide I (protein kinase C-specific), failed to inhibit the OA activation of these kinases. Thus, MBPK-55 and MBPK-62 are also Histone IIIS kinases that are widely expressed and specifically activated upon exposure to high OA concentrations.

• The Korean Journal of Physiology and Pharmacology
• /
• v.8 no.1
• /
• pp.33-41
• /
• 2004

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 $Ca^{2+}$ 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 relationship 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.