Mechanisms underlying variations in excitation–contraction coupling across the mouse left ventricular free wall

Dilly, Keith W.; Rossow, Charles F.; Votaw, V. Scott; Meabon, James S.; Cabarrus, Jennifer L.; Santana, Luis Fernando

doi:10.1113/jphysiol.2005.102020

Cited by 49 publications

(85 citation statements)

References 46 publications

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“…In studies of isolated ventricular myocytes, endocardial cells display an action potential duration (APD) that is consistently longer than that of epicardial cells (9,26,28,51). Furthermore, ventricular M cells with distinct electrophysiological characteristics have been identified in the midmyocardium of some mammals, including rabbit (26), dog (40), and human (10,19).…”

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confidence: 99%

Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium

Myles

Bernus

Burton

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Myles RC, Bernus O, Burton FL, Cobbe SM, Smith GL. Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium. Am J Physiol Heart Circ Physiol 299: H1812-H1822, 2010. First published October 1, 2010; doi:10.1152/ajpheart.00518.2010.-Although transmural heterogeneity of action potential duration (APD) is established in single cells isolated from different tissue layers, the extent to which it produces transmural gradients of repolarization in electrotonically coupled ventricular myocardium remains controversial. The purpose of this study was to examine the relative contribution of intrinsic cellular gradients of APD and electrotonic influences to transmural repolarization in rabbit ventricular myocardium. Transmural optical mapping was performed in left ventricular wedge preparations from eight rabbits. Transmural patterns of activation, repolarization, and APD were recorded during endocardial and epicardial stimulation. Experimental results were compared with modeled data during variations in electrotonic coupling. A transmural gradient of APD was evident during endocardial stimulation, which reflected differences previously seen in isolated cells, with the longest APD at the endocardium and the shortest at the epicardium (endo: 165 Ϯ 5 vs. epi: 147 Ϯ 4 ms; P Ͻ 0.05). During epicardial stimulation, this gradient reversed (epi: 162 Ϯ 4 vs. endo: 148 Ϯ 6 ms; P Ͻ 0.05). In both activation sequences, transmural repolarization followed activation and APD shortened along the activation path such that significant transmural gradients of repolarization did not occur. This correlation between transmural activation time and APD was recapitulated in simulations and varied with changes in intercellular coupling, confirming that it is mediated by electrotonic current flow between cells. These data suggest that electrotonic influences are important in determining the transmural repolarization sequence in rabbit ventricular myocardium and that they are sufficient to overcome intrinsic differences in the electrophysiological properties of the cells across the ventricular wall. action potential remodeling; electrophysiology TRANSMURAL DIFFERENCES in cellular electrophysiology are known to exist in mammalian ventricular myocardium (13,47). In studies of isolated ventricular myocytes, endocardial cells display an action potential duration (APD) that is consistently longer than that of epicardial cells (9,26,28,51). Furthermore, ventricular M cells with distinct electrophysiological characteristics have been identified in the midmyocardium of some mammals, including rabbit (26), dog (40), and human (10,19). At slow stimulation rates, M cells display an APD that is much longer than cells isolated from either epi-or endocardial regions. The dominant influence of these cellular electrophysiological heterogeneities in intact myocardium has been suggested by studies using microelectrode recordings from three regions on the transmural surface of isolated canine ve...

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confidence: 99%

Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium

Myles

Bernus

Burton

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Myocyte CS by changes in sarcomere length and Ca 2ϩ transients were recorded simultaneously from single isolated myocytes with an epifluorescence inverted microscope with Ionoptix software and camera (Ionoptix, Milton, MA) as previously described (5,6,10,12). Cells were superfused with Tyrode's solution at 25°C and field stimulated as previously described (21).…”

Section: Isolation Of Adult Mouse Cardiac Ventricular Myocytes From P2x4mentioning

confidence: 99%

“…2-meSATP and ATP were obtained from Sigma Chemical (St. Louis, MO). Fura 2-AM was obtained from Molecular Probes (Eugene, OR) and used according to manufacturer's instructions as previously described (5,6,10,12). cAMP EIA kit was from GE Healthcare (Piscataway, NJ).…”

Section: Isolation Of Adult Mouse Cardiac Ventricular Myocytes From P2x4mentioning

confidence: 99%

Section: Isolation Of Adult Mouse Cardiac Ventricular Myocytes From P2x4mentioning

confidence: 99%

“…Steady-state recordings were measured under baseline control conditions and after exposure to 2-meSATP. Various CS and Ca 2ϩ transient parameters such as amplitude, maximal rates of rise and fall, time to 50% peak, and time to 50% decline were measured with Ionoptix curve-fitting algorithm software as previously described (5,6,12,13).Cyclic AMP was determined with an enzymatic immunoassay kit according to manufacturer's instructions, similar to the method used to estimate cAMP level in dispersed mammalian cardiac ventricular myocytes (28,14). In brief, myocytes were isolated and plated in a 96-well plate at a density of 10 3 cells/well.…”

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Characterization and mechanism of P2X receptor-mediated increase in cardiac myocyte contractility

Shen¹,

Shutt²,

Pappano³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Shen J-B, Shutt R, Pappano A, Liang BT. Characterization and mechanism of P2X receptor-mediated increase in cardiac myocyte contractility. Am J Physiol Heart Circ Physiol 293: H3056-H3062, 2007. First published September 14, 2007; doi:10.1152/ajpheart.00515.2007.-Cardiac P2X purinergic receptors can mediate an increase in myocyte contractility and a potentially important role in the heart. The P2X4 receptor (P2X4R) is an important subunit of native cardiac P2X receptors. With transgenic mice with cardiac-specific overexpression of P2X4R (Tg) used as a model, the objectives here were to characterize the P2X receptor-mediated cellular contractile and Ca 2ϩ transient effects and to determine the mechanism underlying the receptorinduced increase in myocyte contractility. In response to the agonist 2-methylthioATP (2-meSATP), Tg myocytes showed an increased intracellular Ca 2ϩ transient, as defined by fura 2 fluorescence ratio, and an enhanced contraction shortening that were unaccompanied by cAMP accumulation or L-type Ca 2ϩ channel activation. The increased Ca 2ϩ transient was not associated with any alteration in action potential duration, resting membrane potential, or diastolic fluorescence ratio or rates of rise and decline of the Ca 2ϩ transient. Simultaneous Ca 2ϩ transient and contraction measurements did not show any agonist-mediated change in myofilament Ca 2ϩ sensitivity. However, activation of the overexpressed P2X4 receptor caused an enhanced SR Ca 2ϩ loading, as evidenced by a 2-meSATP-evoked increase in the caffeine-induced inward current and Ca 2ϩ transient. Similar data were obtained in wild-type mouse ventricular myocytes. Thus an increased SR Ca 2ϩ content, occurring in the absence of cAMP accumulation or L-type Ca 2ϩ channel activation, is the principal mechanism by which cardiac P2X receptor mediates a stimulatory effect on cardiac myocyte contractility. purines; calcium; sarcoplasmic reticulum RECEPTORS FOR PURINE NUCLEOTIDES, known as P2 purinergic receptors, are activated by extracellular adenine nucleotides such as ATP and ADP (16,18). The P2 receptor subfamily includes the ligand-gated receptor channel P2X receptor and the G protein-coupled P2Y receptor (1,18,26). Previous studies have shown that extracellular ATP can cause a nonselective cationic current in murine (21), rat (20), and guinea pig (17) cardiac ventricular myocytes. Evidence is accumulating to indicate that the cardiac myocyte P2X receptor mediates this ATP-evoked current. Of the P2X receptor family members, the P2X 4 receptor is an important subunit of the native cardiac myocyte P2X receptor (21). Activation of the P2X receptor leads to the opening of its channel permeable to Na ϩ , K ϩ , and Ca 2ϩ with reversal potential near 0 mV. ATP or the P2X receptor agonist 2-methylthioATP (2-meSATP) can also stimulate an increase in myocyte contractility and in intact heart contractile function (8,15). Transgenic mice with cardiacspecific overexpression of the P2X 4 receptor (Tg) showed an increased myocyte contractility caused by ATP...

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Contractile heterogeneity in ventricular myocardium

Pan

Yang

Cheng

et al. 2018

Journal Cellular Physiology

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The transmural heterogeneity of the contractility in ventricular muscle has not been well-studied. Here, we investigated the calcium transient and sarcomere contraction/relaxation in the endocardial (Endo) and epicardial (Epi) myocytes. Endo and Epi myocytes were isolated from C57/BL6 mice by Langendorff perfusion. Ca transient and sarcomere contraction/relaxation were recorded simultaneously at different stimulation frequencies using a dual excitation fluorescence photomultiplier system. We found that the Endo myocytes have higher baseline diastolic calcium, significantly larger calcium transient and stronger sarcomere shortening than Epi myocytes. However, both the rising and decline phases for calcium transient and sarcomere shortening were slower in Endo than in Epi myocytes. When simulation frequency was increased from 1 to 3 Hz, a greater percent increase in the diastole calcium level, Ca transient and sarcomere shortening amplitude has been observed in the Endo myocytes. Accordingly, the frequency-dependent acceleration in the decay rate of calcium transient and sarcomere relaxation was more profound in the Endo than in Epi myocytes. Western blot analysis showed that CaMKII activity was significantly higher in Epi than in Endo myocardium before stimulation. However, this transmural heterogeneity was reversed by rapid pacing. CaMKII inhibition by KN93 diminished the frequency-dependent alterations of Ca transient and sarcomere contraction. Our results suggest that the contractility of ventricular myocytes is heterogeneous. The Endo-myocardium is the major force generating layer in the heart, both at slow and fast heart rate, and the transmural heterogeneity of CaMKII activation plays an important role in the frequency-dependent alterations.

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Mechanisms underlying variations in excitation–contraction coupling across the mouse left ventricular free wall

Abstract: Ca

Cited by 49 publications

References 46 publications

Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium

Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium

Characterization and mechanism of P2X receptor-mediated increase in cardiac myocyte contractility

Contractile heterogeneity in ventricular myocardium

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