Structural and functional remodeling of the atrioventricular node with aging in rats: The role of hyperpolarization-activated cyclic nucleotide–gated and ryanodine 2 channels

Saeed, Yawer; Temple, Ian P.; Borbas, Zoltan; Atkinson, Andrew; Yanni, Joseph; Mączewski, Michał; Mackiewicz, Urszula; Aly, M. I.; Logantha, Sunil Jit R. J.; Garratt, Clifford J.; Dobrzynski, Halina

doi:10.1016/j.hrthm.2017.12.027

Cited by 33 publications

(23 citation statements)

References 33 publications

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“…SERCA2 refills the sarcoplasmic reticulum with Ca 2+ and is regulated by phospholamban 18,20,46 . Inhibiting the voltage-clock by blocking I f with Cs + and disrupting the Ca 2+ -clock with ryanodine slowed pacemaking in AVR, similar to observations in SN and AVN 18,48 . Expression levels of mRNA transcripts for voltage- and Ca 2+ -clock components in AVR are generally comparable to SN 1,3 .…”

Section: Discussionsupporting

confidence: 70%

Sinus node-like pacemaker mechanisms regulate ectopic pacemaker activity in the adult rat atrioventricular ring

Logantha

Kharche

Zhang

et al. 2019

Sci Rep

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In adult mammalian hearts, atrioventricular rings (AVRs) surround the atrial orifices of atrioventricular valves and are hotbed of ectopic activity in patients with focal atrial tachycardia. Experimental data offering mechanistic insights into initiation and maintenance of ectopic foci is lacking. We aimed to characterise AVRs in structurally normal rat hearts, identify arrhythmia predisposition and investigate mechanisms underlying arrhythmogenicity. Extracellular potential mapping and intracellular action potential recording techniques were used for electrophysiology, qPCR for gene and, Western blot and immunohistochemistry for protein expression. Conditions favouring ectopic foci were assessed by simulations. In right atrial preparations, sinus node (SN) was dominant and AVRs displayed 1:1 impulse conduction. Detaching SN unmasked ectopic pacemaking in AVRs and pacemaker action potentials were SN-like. Blocking pacemaker current I f , and disrupting intracellular Ca 2+ release, prolonged spontaneous cycle length in AVRs, indicating a role for SN-like pacemaker mechanisms. AVRs labelled positive for HCN4, and SERCA2a was comparable to SN. Pacemaking was potentiated by isoproterenol and abolished with carbachol and AVRs had abundant sympathetic nerve endings. β 2 -adrenergic and M 2 -muscarinic receptor mRNA and β 2 -receptor protein were comparable to SN. In computer simulations of a sick SN, ectopic foci in AVR were unmasked, causing transient suppression of SN pacemaking.

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Section: Discussionsupporting

confidence: 70%

Sinus node-like pacemaker mechanisms regulate ectopic pacemaker activity in the adult rat atrioventricular ring

Logantha

Kharche

Zhang

et al. 2019

Sci Rep

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“…The slowing of the conduction velocity was primarily the result of the reduction in I Ca,L : decreasing I f alone resulted in a reduction in the conduction velocity of 0.85% and decreasing I Ca,L alone resulted in a reduction in the conduction velocity of 24%. The lack of effect of I f is consistent with our earlier simulations [8], but it is inconsistent with experimental data showing that I f does influence AV node conduction [6][7].…”

Section: Simulation Of Av Node Conduction Using Original Av Node (N Tsupporting

confidence: 62%

Heart Block in the Athlete – Role of Ion Channel Remodelling as Studied Using a One-Dimensional Computational Model of the Atrioventricular Node

D’Souza

Wang

et al. 2018

2018 Computing in Cardiology Conference (CinC)

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In swim-trained mice, we previously observed atrioventricular (AV) node dysfunction characterised by first-degree heart block and a prolonged Wenckebach cycle length. Notably, patch clamp recordings from isolated AV node myocytes demonstrated a significant reduction of I f (by ~60%) and I Ca,L (by ~40%) in swimtrained mice as compared to sedentary control mice. The effect of the observed changes in ionic currents was investigated using a one-dimensional computational model of the AV node. This was used in conjunction with a biophysically-detailed model of the rabbit AV node action potential. On decreasing I f by ~60% and I Ca,L by ~40% to mimic the effect of athletic training, the conduction velocity of the AV node model was reduced by 25% from 9.5 to 7.1 cm/s. The reduction was solely the result of the decrease in I Ca,L. The decrease in I f (modelled in the conventional way as a time-dependent hyperpolarization-activated inward current) had no effect on the conduction velocity, despite experimental evidence that I f can affect AV node conduction. However, if the model of I f was modified to incorporate an instantaneous current, the decrease in I f also contributed to the reduction in the conduction velocity. We conclude that ionic remodelling of the AV node is a key mechanism underlying heart block in the athlete.

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“…RyRs change their physiological function during the aging process. Although there are no studies on the effects of age on Ca 2+ sparks in arterial smooth muscle, age-dependent alterations in RyR function influence the node cycle length and atrio-His interval in hearts of rats [73]. RyRs may modulate gap junction formation during stress and aging.…”

Section: Ryanodine Receptorsmentioning

confidence: 99%

“…These effects have been attributed to long-lasting activated ryanodine receptors by caffeine. With aging, expression of Cx40, SERCA type 2a, and the L-type Ca 2+ channel Ca v 1.3 increases while the expression of Cx43 and RyR2 decreases in certain parts of the heart, such as the inferior nodal extension and proximal penetrating bundle [73]. Gap junction impairment could also disturb cell-cell communications between VSMCs necessary for vascular adaptation to pressure and local blood flow control [75].…”

Section: Ryanodine Receptorsmentioning

confidence: 99%

Elementary calcium signaling in arterial smooth muscle

et al. 2019

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Vascular smooth muscle cells (VSMCs) of small peripheral arteries contribute to blood pressure control by adapting their contractile state. These adaptations depend on the VSMC cytosolic Ca 2+ concentration, regulated by complex local elementary Ca 2+ signaling pathways. Ca 2+ sparks represent local, transient, rapid calcium release events from a cluster of ryanodine receptors (RyRs) in the sarcoplasmic reticulum. In arterial SMCs, Ca 2+ sparks activate nearby calciumdependent potassium channels, cause membrane hyperpolarization and thus decrease the global intracellular [Ca 2+ ] to oppose vasoconstriction. Arterial SMC Ca v 1.2 L-type channels regulate intracellular calcium stores content, which in turn modulates calcium efflux through RyRs. Ca v 3.2 T-type channels contribute to a minor extend to Ca 2+ spark generation in certain types of arteries. Their localization within cell membrane caveolae is essential. We summarize present data on local elementary calcium signaling (Ca 2+ sparks) in arterial SMCs with focus on RyR isoforms, large-conductance calcium-dependent potassium (BK Ca) channels, and cell membrane-bound calcium channels (Ca v 1.2 and Ca v 3.2), particularly in caveolar microdomains.

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Structural and functional remodeling of the atrioventricular node with aging in rats: The role of hyperpolarization-activated cyclic nucleotide–gated and ryanodine 2 channels

Cited by 33 publications

References 33 publications

Sinus node-like pacemaker mechanisms regulate ectopic pacemaker activity in the adult rat atrioventricular ring

Sinus node-like pacemaker mechanisms regulate ectopic pacemaker activity in the adult rat atrioventricular ring

Heart Block in the Athlete – Role of Ion Channel Remodelling as Studied Using a One-Dimensional Computational Model of the Atrioventricular Node

Elementary calcium signaling in arterial smooth muscle

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