scholarly journals In Silico Investigation into Cellular Mechanisms of Cardiac Alternans in Myocardial Ischemia

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Jiaqi Liu ◽  
Yinglan Gong ◽  
Ling Xia ◽  
Xiaopeng Zhao
Keyword(s):  
Myocardial Ischemia ◽  
Ionic Channels ◽  
Cellular Level ◽  
Calcium Handling ◽  
Cellular Mechanisms ◽  
Small Magnitude ◽  
Recovery From Inactivation ◽  
Intracellular Ca ◽  
Cardiac Alternans ◽  
Delayed Recovery

Myocardial ischemia is associated with pathophysiological conditions such as hyperkalemia, acidosis, and hypoxia. These physiological disorders may lead to changes on the functions of ionic channels, which in turn form the basis for cardiac alternans. In this paper, we investigated the roles of hyperkalemia and calcium handling components played in the genesis of alternans in ischemia at the cellular level by using computational simulations. The results show that hyperkalemic reduced cell excitability and delayed recovery from inactivation of depolarization currents. The inactivation time constantτfof L-type calcium current (ICaL) increased obviously in hyperkalemia. One cycle length was not enough forICaLto recover completely. Alternans developed as a result ofICaLresponding to stimulation every other beat. Sarcoplasmic reticulum calcium-ATPase (SERCA2a) function decreased in ischemia. This change resulted in intracellular Ca (Cai) alternans of small magnitude. A strong Na+-Ca2+exchange current (INCX) increased the magnitude ofCaialternans, leading to APD alternans through excitation-contraction coupling. Some alternated repolarization currents contributed to this repolarization alternans.

scholarly journals Refractoriness of sarcoplasmic reticulum Ca2+ release determines Ca2+ alternans in atrial myocytes

2012 ◽  
Vol 302 (11) ◽  
pp. H2310-H2320 ◽  
Author(s):  
Vyacheslav M. Shkryl ◽  
Joshua T. Maxwell ◽  
Timothy L. Domeier ◽  
Lothar A. Blatter
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cellular Level ◽  
Release Mechanism ◽  
Atrial Myocytes ◽  
Restitution Curve ◽  
Intracellular Ca ◽  
Cardiac Alternans ◽  
Kinetics Of ◽  
Beating Frequency

Cardiac alternans is a recognized risk factor for cardiac arrhythmia and sudden cardiac death. At the cellular level, Ca2+ alternans appears as cytosolic Ca2+ transients of alternating amplitude at regular beating frequency. Cardiac alternans is a multifactorial process but has been linked to disturbances in intracellular Ca2+ regulation. In atrial myocytes, we tested the role of voltage-gated Ca2+ current, sarcoplasmic reticulum (SR) Ca2+ load, and restitution properties of SR Ca2+ release for the occurrence of pacing-induced Ca2+ alternans. Voltage-clamp experiments revealed that peak Ca2+ current was not affected during alternans, and alternans of end-diastolic SR Ca2+ load, evaluated by application of caffeine or measured directly with an intra-SR fluorescent Ca2+ indicator (fluo-5N), were not a requirement for cytosolic Ca2+ alternans. Restitution properties and kinetics of refractoriness of Ca2+ release after activation during alternans were evaluated by four different approaches: measurements of 1) the delay (latency) of occurrence of spontaneous global Ca2+ releases and 2) Ca2+ spark frequency, both during rest after a large and small alternans Ca2+ transient; 3) the magnitude of premature action potential-induced Ca2+ transients after a large and small beat; and 4) the efficacy of a photolytically induced Ca2+ signal (Ca2+ uncaging from DM-nitrophen) to trigger additional Ca2+ release during alternans. The results showed that the latency of global spontaneous Ca2+ release was prolonged and Ca2+ spark frequency was decreased after the large Ca2+ transient during alternans. Furthermore, the restitution curve of the Ca2+ transient elicited by premature action potentials or by photolysis-induced Ca2+ release from the SR lagged behind after a large-amplitude transient during alternans compared with the small-amplitude transient. The data demonstrate that beat-to-beat alternation of the time-dependent restitution properties and refractory kinetics of the SR Ca2+ release mechanism represents a key mechanism underlying cardiac alternans.

scholarly journals IP3R1 regulates Ca2+ transport and pyroptosis through the NLRP3/Caspase-1 pathway in myocardial ischemia/reperfusion injury

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Guixi Mo ◽  
Xin Liu ◽  
Yiyue Zhong ◽  
Jian Mo ◽  
Zhiyi Li ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Cell Model ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Rat Cardiomyocytes ◽  
Adult Rat ◽  
Caspase 1 ◽  
Intracellular Ca ◽  
Myocardial Ischemia Reperfusion

AbstractIntracellular ion channel inositol 1,4,5-triphosphate receptor (IP3R1) releases Ca2+ from endoplasmic reticulum. The disturbance of IP3R1 is related to several neurodegenerative diseases. This study investigated the mechanism of IP3R1 in myocardial ischemia/reperfusion (MI/R). After MI/R modeling, IP3R1 expression was silenced in myocardium of MI/R rats to explore its role in the concentration of myocardial enzymes, infarct area, Ca2+ level, NLRP3/Caspase-1, and pyroptosis markers and inflammatory factors. The adult rat cardiomyocytes were isolated and cultured to establish hypoxia/reperfusion (H/R) cell model. The expression of IP3R1 was downregulated or ERP44 was overexpressed in H/R-induced cells. Nifedipine D6 was added to H/R-induced cells to block Ca2+ channel or Nigericin was added to activate NLRP3. IP3R1 was highly expressed in myocardium of MI/R rats, and silencing IP3R1 alleviated MI/R injury, reduced Ca2+ overload, inflammation and pyroptosis in MI/R rats, and H/R-induced cells. The binding of ERP44 to IP3R1 inhibited Ca2+ overload, alleviated cardiomyocyte inflammation, and pyroptosis. The increase of intracellular Ca2+ level caused H/R-induced cardiomyocyte pyroptosis through the NLRP3/Caspase-1 pathway. Activation of NLRP3 pathway reversed the protection of IP3R1 inhibition/ERP44 overexpression/Nifedipine D6 on H/R-induced cells. Overall, ERP44 binding to IP3R1 inhibits Ca2+ overload, thus alleviating pyroptosis and MI/R injury.

Myocardial ischemia and delayed recovery after anesthesia in a patient with Cockayne syndrome: A case report

2001 ◽  
Vol 59 (12) ◽  
pp. 1488-1491 ◽  
Author(s):  
Man K. Yuen ◽  
M.R. Chandra Rodrigo ◽  
J.Claude Law Min ◽  
C.K. Antonio Tong
Keyword(s):  
Case Report ◽  
Myocardial Ischemia ◽  
Cockayne Syndrome ◽  
Delayed Recovery

scholarly journals Novel neuronal and astrocytic mechanisms in thalamocortical loop dynamics

2002 ◽  
Vol 357 (1428) ◽  
pp. 1675-1693 ◽  
Author(s):  
Vincenzo Crunelli ◽  
Kate L. Blethyn ◽  
David W. Cope ◽  
Stuart W. Hughes ◽  
H. Rheinallt Parri ◽  
...  
Keyword(s):  
Low Voltage ◽  
Electrical Coupling ◽  
Low Frequency ◽  
Network Activity ◽  
Thalamic Neuron ◽  
Cellular Mechanisms ◽  
Brain Areas ◽  
Sensory Stimuli ◽  
Loop Dynamics ◽  
Intracellular Ca

In this review, we summarize three sets of findings that have recently been observed in thalamic astrocytes and neurons, and discuss their significance for thalamocortical loop dynamics. (i) A physiologically relevant ‘window’ component of the low–voltage–activated, T–type Ca 2+ current ( I Twindow ) plays an essential part in the slow (less than 1 Hz) sleep oscillation in adult thalamocortical (TC) neurons, indicating that the expression of this fundamental sleep rhythm in these neurons is not a simple reflection of cortical network activity. It is also likely that I Twindow underlies one of the cellular mechanisms enabling TC neurons to produce burst firing in response to novel sensory stimuli. (ii) Both electrophysiological and dye–injection experiments support the existence of gap junction–mediated coupling among young and adult TC neurons. This finding indicates that electrical coupling–mediated synchronization might be implicated in the high and low frequency oscillatory activities expressed by this type of thalamic neuron. (iii) Spontaneous intracellular Ca 2+ ([Ca 2+ ] i ) waves propagating among thalamic astrocytes are able to elicit large and long–lasting N –methyl–D–aspartate–mediated currents in TC neurons. The peculiar developmental profile within the first two postnatal weeks of these astrocytic [Ca 2+ ] i transients and the selective activation of these glutamate receptors point to a role for this astrocyte–to–neuron signalling mechanism in the topographic wiring of the thalamocortical loop. As some of these novel cellular and intracellular properties are not restricted to thalamic astrocytes and neurons, their significance may well apply to (patho)physiological functions of glial and neuronal elements in other brain areas.

Effects of oxygen tension on energetics of cultured vascular smooth muscle

2002 ◽  
Vol 283 (1) ◽  
pp. H110-H117 ◽  
Author(s):  
Anders Lindqvist ◽  
Karl Dreja ◽  
Karl Swärd ◽  
Per Hellstrand
Keyword(s):  
Chronic Hypoxia ◽  
Lactate Production ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Adrenergic Stimulation ◽  
Cellular Mechanisms ◽  
Mitochondrial Uncoupling ◽  
Vascular Abnormalities ◽  
Intracellular Ca ◽  
Glycogen Stores

Chronic hypoxia is a clinically important condition known to cause vascular abnormalities. To investigate the cellular mechanisms involved, we kept rings of a rat tail artery for 4 days in hypoxic culture (HC) or normoxic culture (NC) (Po 2 = 14 vs. 110 mmHg) and then measured contractility, oxygen consumption ( J o2 ), and lactate production ( J lac) in oxygenated medium. Compared with fresh rings, basal ATP turnover ( J ATP) was decreased in HC, but not in NC, with a shift from oxidative toward glycolytic metabolism. J o2 during mitochondrial uncoupling was reduced by HC but not by NC. Glycogen stores were increased 40-fold by HC and fourfold by NC. Maximum tension in response to norepinephrine and the Jo2 versus tension relationship ( J o2 vs. high K+ elicited force) were unaffected by either HC or NC. Force transients in response to caffeine were increased in HC, whereas intracellular Ca2+ wave activity during adrenergic stimulation was decreased. Protein synthesis rate was reduced by HC. The results show that long-term hypoxia depresses basal energy turnover, impairs mitochondrial capacity, and alters Ca2+homeostasis, but does not affect contractile energetics. These alterations may form a basis for vascular damage by chronic hypoxia.

5-HT Prolongs Ventral Root Bursting Via Presynaptic Inhibition of Synaptic Activity During Fictive Locomotion in Lamprey

2005 ◽  
Vol 93 (2) ◽  
pp. 980-988 ◽  
Author(s):  
Eric J. Schwartz ◽  
Tatyana Gerachshenko ◽  
Simon Alford
Keyword(s):  
Synaptic Transmission ◽  
Presynaptic Inhibition ◽  
Cellular Level ◽  
Ventral Horn ◽  
Pattern Generation ◽  
Ventral Root ◽  
Synaptic Activity ◽  
Fictive Locomotion ◽  
Cellular Mechanisms ◽  
Bath Application

Locomotor pattern generation is maintained by integration of the intrinsic properties of spinal central pattern generator (CPG) neurons in conjunction with synaptic activity of the neural network. In the lamprey, the spinal locomotor CPG is modulated by 5-HT. On a cellular level, 5-HT presynaptically inhibits synaptic transmission and postsynaptically inhibits a Ca2+-activated K+ current responsible for the slow afterhyperpolarization (sAHP) that follows action potentials in ventral horn neurons. To understand the contribution of these cellular mechanisms to the modulation of the spinal CPG, we have tested the effect of selective 5-HT analogues against fictive locomotion initiated by bath application of N-methyl-d-aspartate (NMDA). We found that the 5-HT1D agonist, L694-247, dramatically prolongs the frequency of ventral root bursting. Furthermore, we show that L694-247 presynaptically inhibits synaptic transmission without altering postsynaptic Ca2+ -activated K+ currents. We also confirm that 5-HT inhibits synaptic transmission at concentrations that modulate locomotion. To examine the mechanism by which selective presynaptic inhibition modulates the frequency of fictive locomotion, we performed voltage- and current-clamp recordings of CPG neurons during locomotion. Our results show that 5-HT decreases glutamatergic synaptic drive within the locomotor CPG during fictive locomotion. Thus we conclude that presynaptic inhibition of neurotransmitter release contributes to 5-HT–mediated modulation of locomotor activity.

scholarly journals Developmental plasticity of cardiac anoxia-tolerance in juvenile common snapping turtles ( Chelydra serpentina )

2019 ◽  
Vol 286 (1905) ◽  
pp. 20191072 ◽  
Author(s):  
Ilan M. Ruhr ◽  
Heather McCourty ◽  
Afaf Bajjig ◽  
Dane A. Crossley ◽  
Holly A. Shiels ◽  
...  
Keyword(s):  
Developmental Plasticity ◽  
Hypoxia Tolerance ◽  
Anoxia Tolerance ◽  
Ros Production ◽  
Oxygen Species ◽  
Early Exposure ◽  
Cellular Mechanisms ◽  
Isolated Cardiomyocytes ◽  
Intracellular Ca ◽  
The Common

For some species of ectothermic vertebrates, early exposure to hypoxia during embryonic development improves hypoxia-tolerance later in life. However, the cellular mechanisms underlying this phenomenon are largely unknown. Given that hypoxic survival is critically dependent on the maintenance of cardiac function, we tested the hypothesis that developmental hypoxia alters cardiomyocyte physiology in a manner that protects the heart from hypoxic stress. To test this hypothesis, we studied the common snapping turtle, which routinely experiences chronic developmental hypoxia and exploits hypoxic environments in adulthood. We isolated cardiomyocytes from juvenile turtles that embryonically developed in either normoxia (21% O 2 ) or hypoxia (10% O 2 ), and subjected them to simulated anoxia and reoxygenation, while simultaneously measuring intracellular Ca 2+ , pH and reactive oxygen species (ROS) production. Our results suggest developmental hypoxia improves cardiomyocyte anoxia-tolerance of juvenile turtles, which is supported by enhanced myofilament Ca 2+ -sensitivity and a superior ability to suppress ROS production. Maintenance of low ROS levels during anoxia might limit oxidative damage and a greater sensitivity to Ca 2+ could provide a mechanism to maintain contractile force. Our study suggests developmental hypoxia has long-lasting effects on turtle cardiomyocyte function, which might prime their physiology for exploiting hypoxic environments.

scholarly journals Growth dynamics of the Arabidopsis fruit is mediated by cell expansion

2019 ◽  
Vol 116 (50) ◽  
pp. 25333-25342 ◽  
Author(s):  
Juan-José Ripoll ◽  
Mingyuan Zhu ◽  
Stephanie Brocke ◽  
Cindy T. Hon ◽  
Martin F. Yanofsky ◽  
...  
Keyword(s):  
Computational Modeling ◽  
Cell Expansion ◽  
Growth Dynamics ◽  
Spatial Separation ◽  
Cellular Level ◽  
Fruit Growth ◽  
Signaling Cascades ◽  
Comprehensive Understanding ◽  
Cellular Mechanisms ◽  
Plant Reproductive Success

Fruit have evolved a sophisticated tissue and cellular architecture to secure plant reproductive success. Postfertilization growth is perhaps the most dramatic event during fruit morphogenesis. Several studies have proposed that fertilized ovules and developing seeds initiate signaling cascades to coordinate and promote the growth of the accompanying fruit tissues. This dynamic process allows the fruit to conspicuously increase its size and acquire its final shape and means for seed dispersal. All these features are key for plant survival and crop yield. Despite its importance, we lack a high-resolution spatiotemporal map of how postfertilization fruit growth proceeds at the cellular level. In this study, we have combined live imaging, mutant backgrounds in which fertilization can be controlled, and computational modeling to monitor and predict postfertilization fruit growth in Arabidopsis. We have uncovered that, unlike leaves, sepals, or roots, fruit do not exhibit a spatial separation of cell division and expansion domains; instead, there is a separation into temporal stages with fertilization as the trigger for transitioning to cell expansion, which drives postfertilization fruit growth. We quantified the coordination between fertilization and fruit growth by imaging no transmitting tract (ntt) mutants, in which fertilization fails in the bottom half of the fruit. By combining our experimental data with computational modeling, we delineated the mobility properties of the seed-derived signaling cascades promoting growth in the fruit. Our study provides the basis for generating a comprehensive understanding of the molecular and cellular mechanisms governing fruit growth and shape.

scholarly journals Intracellular ANG II induces cytosolic Ca2+ mobilization by stimulating intracellular AT1 receptors in proximal tubule cells

2006 ◽  
Vol 290 (6) ◽  
pp. F1382-F1390 ◽  
Author(s):  
Jia L. Zhuo ◽  
Xiao C. Li ◽  
Jeffrey L. Garvin ◽  
L. Gabriel Navar ◽  
Oscar A. Carretero
Keyword(s):  
Proximal Tubule ◽  
Biological Effects ◽  
Physiological Role ◽  
Ang Ii ◽  
Cellular Mechanisms ◽  
Proximal Tubule Cells ◽  
Intracellular Ca ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells ◽  
First Time

Intracellular ANG II induces biological effects in nonrenal cells, but it is not known whether it plays a physiological role in renal proximal tubule cells (PTCs). PTCs express angiotensinogen, renin, and angiotensin-converting enzyme mRNAs, suggesting the presence of high levels of intracellular ANG II. We determined if microinjection of ANG II directly in single PTCs increases intracellular calcium concentration ([Ca2+]i) and, if so, elucidated the cellular mechanisms involved. Changes in [Ca2+]i responses were studied by fluorescence imaging using the Ca2+ indicator fluo 3. ANG II (1 nM) was microinjected directly in the cells, whereas cell-surface angiotensin type 1 (AT1) receptors were blocked by losartan (10 μM). When ANG II (1 nM) was added to the perfusate, there was a marked increase in [Ca2+]i that was blocked by extracellular losartan. With losartan in the perfusate, intracellular microinjection of ANG II elicited a robust increase in cytoplasmic [Ca2+]i that peaked at 30 s (basal: 2.2 ± 0.3 vs. ANG II: 14.9 ± 0.4 relative fluorescence units; P < 0.01). Chelation of extracellular Ca2+ with EGTA (2 mM) did not alter microinjected ANG II-induced [Ca2+]i responses (Ca2+ free + ANG II: 12.3 ± 2.6 relative fluorescence units, not significant vs. ANG II); however, pretreatment with thapsigargin to deplete intracellular Ca2+ stores or with U-73122 to inhibit phospholipase C (1 μM each) markedly attenuated microinjected ANG II-induced [Ca2+]i responses. Combined microinjection of ANG II and losartan abolished [Ca2+]i responses, whereas a combination of ANG II and PD-123319 had no effect. These data demonstrate for the first time that direct microinjection of ANG II in single PTCs increases [Ca2+]i by stimulating intracellular AT1 receptors and releases Ca2+ from intracellular stores, suggesting that intracellular ANG II may play a physiological role in PTC function.

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