Species Difference in the Contribution of T-Type Calcium Current to Cardiac Pacemaking as Revealed by R(−)-Efonidipine

Tanaka, Hikaru; Komikado, Chisa; Namekata, Iyuki; Nakamura, Hideki; Suzuki, Masuko; Tsuneoka, Yousuke; Shigenobu, Koki; Takahara, Akira

doi:10.1254/jphs.sc0070405

Cited by 21 publications

(13 citation statements)

References 15 publications

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“…* The arrhythmias and toxicity seen in the mouse cell assay indicate that the mouse cardiac cells are more sensitive to T-type Ca 2 + channel blockade than human cells, which is in agreement with the findings by Tanaka et al, who demonstrated that the contribution of T-type Ca 2 + current to cardiac pacing is much greater in the mouse than in larger species. 33 Future Directions…”

Section: The Stem Cell Assaymentioning

confidence: 99%

Impedance-Based Detection of Beating Rhythm and Proarrhythmic Effects of Compounds on Stem Cell-Derived Cardiomyocytes

Jonsson

Wang

Becker

2011

ASSAY and Drug Development Technologies

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The xCELLigence real time cell analyzer Cardio system offers a new system for real-time cell analysis that measures impedance-based signals in a label-free noninvasive manner. The aim of this study was to test whether impedance readings are a useful tool to detect compound effects on beating frequency (beats per minute, bpm) and arrhythmias of human induced pluripotent stem cell-and a mouse embryonic stem cell-derived cardiomyocyte line (hiPSC-CM and mESC-CM, respectively). Baseline values for control wells were 45 -3 and 179 -6 bpm, respectively (n = 6). Correspondingly, isoproterenol increased beating frequency by 77% and 71%, whereas carbachol decreased frequency by 11% and 100% (stopped in 5/6 mESC-CM wells). E-4031 decreased beating rate and caused arrhythmias in both cell types, however, more pronounced in the human iPSC-CMs. Amlodipine inhibited contractions in both models, and T-type calcium channel block strongly reduced beating rate and eventually stopped beating in mESC-CM but caused a smaller effect in hiPSC-CM. The results of this initial study show that, under the right conditions, the beating frequency of a monolayer of cells can be stably recorded over several days. Additionally, the system detects changes in beating frequency and amplitude caused by added reference compounds. This assay system has the potential to enable medium-throughput screening, but for implementation into routine daily work, extended validation, testing of additional batches of cardiomyocytes, and further assay optimization (e.g., frequency of media exchange, growth matrix, seeding density, age of cells after plating, and temperature control) will be needed.

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Section: The Stem Cell Assaymentioning

confidence: 99%

Impedance-Based Detection of Beating Rhythm and Proarrhythmic Effects of Compounds on Stem Cell-Derived Cardiomyocytes

Jonsson

Wang

Becker

2011

ASSAY and Drug Development Technologies

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“…N‐type Ca 2+ channels are localized at the nerve endings in the sympathetic and central nervous systems, which regulate the release of neurotransmitters [22–24]. T‐type Ca 2+ channels may be associated with the gradual depolarization phase of the sinus nodal action potential [25], which appears only in smaller animals [26,27].…”

Section: The Relationship Between Sympathetic Nerve Activity and Ca2+mentioning

confidence: 99%

Cilnidipine: A New Generation Ca²⁺ Channel Blocker with Inhibitory Action on Sympathetic Neurotransmitter Release

Takahara

2009

Cardiovascular Therapeutics

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Cilnidipine is a unique Ca2+ channel blocker with an inhibitory action on the sympathetic N‐type Ca2+ channels, which is used for patients with hypertension in Japan. Cilnidipine has been clarified to exert antisympathetic actions in various examinations from cell to human levels, in contrast to classical Ca2+ channel blockers. Furthermore, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in clinical practice or animal examinations. After the introduction of nifedipine as an antihypertensive drug, many Ca2+ channel blockers with long‐lasting action for blood pressure have been developed to minimize sympathetic reflex during antihypertensive therapy, which have been divided into three groups; namely, first, second, and third generation based on their pharmacokinetic profiles. Since cilnidipine directly inhibits the sympathetic neurotransmitter release by N‐type Ca2+ channel‐blocking property, the drug can be expected as fourth generation, providing an effective strategy for the treatment of cardiovascular diseases.

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“…The RMP of USMCs of around −55 mV is close to the voltage level for the window current from I CaT (Blanks et al, 2007 ). However, experimental studies in cardiac SAN cells illustrate that maneuvres designed to reduce I CaT result in alterations of SAN APs (Hagiwara et al, 1988 ; Masumiya et al, 1998 ; Tanaka et al, 2008 ). In our study, modest reduction of I CaT hyperpolarizes the USMC model RMP and diminishes the bursting spikes with a mild effect on the SAN model cell AP.…”

Section: Discussionmentioning

confidence: 99%

Computational modeling of inhibition of voltage-gated Ca channels: identification of different effects on uterine and cardiac action potentials

2014

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The uterus and heart share the important physiological feature whereby contractile activation of the muscle tissue is regulated by the generation of periodic, spontaneous electrical action potentials (APs). Preterm birth arising from premature uterine contractions is a major complication of pregnancy and there remains a need to pursue avenues of research that facilitate the use of drugs, tocolytics, to limit these inappropriate contractions without deleterious actions on cardiac electrical excitation. A novel approach is to make use of mathematical models of uterine and cardiac APs, which incorporate many ionic currents contributing to the AP forms, and test the cell-specific responses to interventions. We have used three such models—of uterine smooth muscle cells (USMC), cardiac sinoatrial node cells (SAN), and ventricular cells—to investigate the relative effects of reducing two important voltage-gated Ca currents—the L-type (ICaL) and T-type (ICaT) Ca currents. Reduction of ICaL (10%) alone, or ICaT (40%) alone, blunted USMC APs with little effect on ventricular APs and only mild effects on SAN activity. Larger reductions in either current further attenuated the USMC APs but with also greater effects on SAN APs. Encouragingly, a combination of ICaL and ICaT reduction did blunt USMC APs as intended with little detriment to APs of either cardiac cell type. Subsequent overlapping maps of ICaL and ICaT inhibition profiles from each model revealed a range of combined reductions of ICaL and ICaT over which an appreciable diminution of USMC APs could be achieved with no deleterious action on cardiac SAN or ventricular APs. This novel approach illustrates the potential for computational biology to inform us of possible uterine and cardiac cell-specific mechanisms. Incorporating such computational approaches in future studies directed at designing new, or repurposing existing, tocolytics will be beneficial for establishing a desired uterine specificity of action.

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Species Difference in the Contribution of T-Type Calcium Current to Cardiac Pacemaking as Revealed by R(−)-Efonidipine

Cited by 21 publications

References 15 publications

Impedance-Based Detection of Beating Rhythm and Proarrhythmic Effects of Compounds on Stem Cell-Derived Cardiomyocytes

Impedance-Based Detection of Beating Rhythm and Proarrhythmic Effects of Compounds on Stem Cell-Derived Cardiomyocytes

Cilnidipine: A New Generation Ca²⁺ Channel Blocker with Inhibitory Action on Sympathetic Neurotransmitter Release

Computational modeling of inhibition of voltage-gated Ca channels: identification of different effects on uterine and cardiac action potentials

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Species Difference in the Contribution of T-Type Calcium Current to Cardiac Pacemaking as Revealed by R(−)-Efonidipine

Cited by 21 publications

References 15 publications

Impedance-Based Detection of Beating Rhythm and Proarrhythmic Effects of Compounds on Stem Cell-Derived Cardiomyocytes

Impedance-Based Detection of Beating Rhythm and Proarrhythmic Effects of Compounds on Stem Cell-Derived Cardiomyocytes

Cilnidipine: A New Generation Ca2+ Channel Blocker with Inhibitory Action on Sympathetic Neurotransmitter Release

Computational modeling of inhibition of voltage-gated Ca channels: identification of different effects on uterine and cardiac action potentials

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Product

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Cilnidipine: A New Generation Ca²⁺ Channel Blocker with Inhibitory Action on Sympathetic Neurotransmitter Release