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New antiarrhythmic targets to control intracellular calcium handling.

Driessen HE, Bourgonje VJ, van Veen TA, Vos MA - Neth Heart J (2014)

Bottom Line: Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies.New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling.These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM, Utrecht, the Netherlands, h.e.driessen@gmail.com.

ABSTRACT
Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

No MeSH data available.


Related in: MedlinePlus

Action potential and ion currents. Phases of the action potential and the responsible ion currents are discussed in the text
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Fig1: Action potential and ion currents. Phases of the action potential and the responsible ion currents are discussed in the text

Mentions: The action potential (AP) is generated via a complex interaction of ion channels, and membrane voltage [7], and is generally divided into five phases. They are established through a fine-tuned interaction of sodium (Na+), potassium (K+), and Ca2+ currents. The inward Na+ current (INa) is responsible for the upstroke during phase 0 (Fig. 1, phase 0). The total Na+ current is formed by the peak and late INa: the latter contributes to depolarisation currents during the plateau phase. During phase 1, the Na+ channel inactivates considerably and at the same time Ito1 and Ito2 (transient outward currents) create outward currents of K+ and chloride, respectively, to form the notch (Fig. 1, phase 1). Subsequently, Ca2+ enters the cell through voltage-gated Ca2+channels (L-type calcium channels, LTCC) (ICa,L) and is involved in creating the plateau phase of the AP since inward movement of Ca2+ is counterbalanced by outward K+ flow driven by the delayed rectifier potassium currents IKs and IKr (Fig. 1, phase 2). The plateau phase delays repolarisation of the AP creating time for contraction and relaxation of the cardiomyocytes in between action potentials. Full repolarisation occurs when the LTCC closes and IKs and IKr take over dominantly (Fig. 1, phase 3). Finally, K+ restores the negative membrane potential via the IK1 current (Fig. 1, phase 4) [7].Fig. 1


New antiarrhythmic targets to control intracellular calcium handling.

Driessen HE, Bourgonje VJ, van Veen TA, Vos MA - Neth Heart J (2014)

Action potential and ion currents. Phases of the action potential and the responsible ion currents are discussed in the text
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4016334&req=5

Fig1: Action potential and ion currents. Phases of the action potential and the responsible ion currents are discussed in the text
Mentions: The action potential (AP) is generated via a complex interaction of ion channels, and membrane voltage [7], and is generally divided into five phases. They are established through a fine-tuned interaction of sodium (Na+), potassium (K+), and Ca2+ currents. The inward Na+ current (INa) is responsible for the upstroke during phase 0 (Fig. 1, phase 0). The total Na+ current is formed by the peak and late INa: the latter contributes to depolarisation currents during the plateau phase. During phase 1, the Na+ channel inactivates considerably and at the same time Ito1 and Ito2 (transient outward currents) create outward currents of K+ and chloride, respectively, to form the notch (Fig. 1, phase 1). Subsequently, Ca2+ enters the cell through voltage-gated Ca2+channels (L-type calcium channels, LTCC) (ICa,L) and is involved in creating the plateau phase of the AP since inward movement of Ca2+ is counterbalanced by outward K+ flow driven by the delayed rectifier potassium currents IKs and IKr (Fig. 1, phase 2). The plateau phase delays repolarisation of the AP creating time for contraction and relaxation of the cardiomyocytes in between action potentials. Full repolarisation occurs when the LTCC closes and IKs and IKr take over dominantly (Fig. 1, phase 3). Finally, K+ restores the negative membrane potential via the IK1 current (Fig. 1, phase 4) [7].Fig. 1

Bottom Line: Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies.New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling.These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM, Utrecht, the Netherlands, h.e.driessen@gmail.com.

ABSTRACT
Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

No MeSH data available.


Related in: MedlinePlus