Acute desensitization of acetylcholine and endothelin-1 activated inward rectifier K+ current in myocytes from the cardiac atrioventricular node

Choisy, Stéphanie C.M.; James, Andrew F.; Hancox, Jules C.

doi:10.1016/j.bbrc.2012.05.148

Cited by 6 publications

(2 citation statements)

References 44 publications

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“…The ultrarapid delayed rectifier K + current (I Kur ) and the acetylcholine‐activated K + current (I K,ACh ) were measured as the current sensitive to 50 μM 4‐aminopyridine (4‐AP) or 10 μM carbachol (CCh), respectively, in the presence of 10 μM nifedipine to block the L‐type Ca 2+ current. Voltage clamp protocols are shown in the corresponding figures and have been described previously (Choisy et al , ; Wang et al , ). Current density was calculated by dividing current amplitude by C m .…”

Section: Methodsmentioning

confidence: 99%

Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology

et al. 2015

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Drugs targeting atrial-specific ion channels, Kv1.5 or Kir3.1/3.4, are being developed as new therapeutic strategies for atrial fibrillation. However, current preclinical studies carried out in non-cardiac cell lines or animal models may not accurately represent the physiology of a human cardiomyocyte (CM). In the current study, we tested whether human embryonic stem cell (hESC)-derived atrial CMs could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during hESC differentiation, we generated atrial-like (hESC-atrial) and ventricular-like (hESC-ventricular) CMs. We found the expression of atrial-specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding Kir 3.1), in hESC-atrial CMs and further demonstrated that these ion channel genes are regulated by COUP-TF transcription factors. Moreover, in response to multiple ion channel blocker, vernakalant, and Kv1.5 blocker, XEN-D0101, hESC-atrial but not hESC-ventricular CMs showed action potential (AP) prolongation due to a reduction in early repolarization. In hESC-atrial CMs, XEN-R0703, a novel Kir3.1/3.4 blocker restored the AP shortening caused by CCh. Neither CCh nor XEN-R0703 had an effect on hESC-ventricular CMs. In summary, we demonstrate that hESC-atrial CMs are a robust model for pre-clinical testing to assess atrial selectivity of novel antiarrhythmic drugs.

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Section: Methodsmentioning

confidence: 99%

Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology

et al. 2015

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“…Parasympathetic action on the AP’s waveform has been mostly evaluated in atrial and nodal myocytes (sinus and atrio-ventricular). In both cell types, acetylcholine induces an increase in the AP repolarization rate mediated by a K + current activated by acetylcholine ( I KACh ; Engelstein et al, 1994; Corey et al, 1998; Wickman et al, 1999; Choisy et al, 2012). There was a general belief that this mechanism is absent in the ventricle (Coote, 2013).…”

Section: Discussionmentioning

confidence: 99%

Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level

et al. 2019

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The relationship between cardiac excitability and contractility depends on when Ca 2+ influx occurs during the ventricular action potential (AP). In mammals, it is accepted that Ca 2+ influx through the L-type Ca 2+ channels occurs during AP phase 2. However, in murine models, experimental evidence shows Ca 2+ influx takes place during phase 1. Interestingly, Ca 2+ influx that activates contraction is highly regulated by the autonomic nervous system. Indeed, autonomic regulation exerts multiple effects on Ca 2+ handling and cardiac electrophysiology. In this paper, we explore autonomic regulation in endocardial and epicardial layers of intact beating mice hearts to evaluate their role on cardiac excitability and contractility. We hypothesize that in mouse cardiac ventricles the influx of Ca 2+ that triggers excitation–contraction coupling (ECC) does not occur during phase 2. Using pulsed local field fluorescence microscopy and loose patch photolysis, we show sympathetic stimulation by isoproterenol increased the amplitude of Ca 2+ transients in both layers. This increase in contractility was driven by an increase in amplitude and duration of the L-type Ca 2+ current during phase 1. Interestingly, the β-adrenergic increase of Ca 2+ influx slowed the repolarization of phase 1, suggesting a competition between Ca 2+ and K + currents during this phase. In addition, cAMP activated L-type Ca 2+ currents before SR Ca 2+ release activated the Na + -Ca 2+ exchanger currents, indicating Ca v 1.2 channels are the initial target of PKA phosphorylation. In contrast, parasympathetic stimulation by carbachol did not have a substantial effect on amplitude and kinetics of endocardial and epicardial Ca 2+ transients. However, carbachol transiently decreased the duration of the AP late phase 2 repolarization. The carbachol-induced shortening of phase 2 did not have a considerable effect on ventricular pressure and systolic Ca 2+ dynamics. Interestingly, blockade of muscarinic receptors by atropine prolonged the duration of phase 2 indicating that, in isolated hearts, there is an intrinsic release of acetylcholine. In addition, the acceleration of repolarization induced by carbachol was blocked by the acetylcholine-mediated K + current inhibition. Our results reveal the transmural ramifications of autonomic regulation in intact mice hearts and support our hypothesis that Ca 2+ influx that triggers ECC occurs in AP phase 1 and not in phase 2.

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Cholinergic and Constitutive Regulation of Atrial Potassium Channel

Dobrev¹,

Voigt²,

Nattel³

2014

Cardiac Electrophysiology: From Cell to Bedside

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Acute desensitization of acetylcholine and endothelin-1 activated inward rectifier K+ current in myocytes from the cardiac atrioventricular node

Cited by 6 publications

References 44 publications

Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology

Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology

Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level

Cholinergic and Constitutive Regulation of Atrial Potassium Channel

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