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.

C-type natriuretic peptide inhibits ANP secretion and atrial dynamics in perfused atria: NPR-B-cGMP signaling

2000 ◽  
Vol 278 (1) ◽  
pp. H208-H221 ◽  
Author(s):  
Sook Jeong Lee ◽  
Sung Zoo Kim ◽  
Xun Cui ◽  
Suhn Hee Kim ◽  
Kyung Sun Lee ◽  
...  
Keyword(s):  
Stroke Volume ◽  
Natriuretic Peptide ◽  
Rank Order ◽  
Extracellular Fluid ◽  
Atrial Pacing ◽  
Atrial Myocytes ◽  
Cgmp Production ◽  
Cgmp Signaling ◽  
Intracellular Ca

The purpose of the present experiments was to define the role of C-type natriuretic peptide (CNP) in the regulation of atrial secretion of atrial natriuretic peptide (ANP) and atrial stroke volume. Experiments were performed in perfused beating and nonbeating quiescent atria, single atrial myocytes, and atrial membranes. CNP suppressed in a dose-related fashion the increase in atrial stroke volume and ANP secretion induced by atrial pacing. CNP caused a right shift in the positive relationships between changes in the secretion of ANP and atrial stroke volume or translocation of the extracellular fluid (ECF), which indicates the suppression of atrial myocytic release of ANP into the paracellular space. The effects of CNP on the secretion and contraction were mimicked by 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP). CNP increased cGMP production in the perfused atria, and the effects of CNP on the secretion of ANP and atrial dynamics were accentuated by pretreatment with an inhibitor of cGMP phosphodiesterase, zaprinast. An inhibitor of the biological natriuretic peptide receptor (NPR), HS-142-1, attenuated the effects of CNP. The suppression of ANP secretion by CNP and 8-BrcGMP was abolished by a depletion of extracellular Ca2+ in nonbeating atria. Natriuretic peptides increased cGMP production in atrial membranes with a rank order of potency of CNP > BNP > ANP, and the effect was inhibited by HS-142-1. CNP and 8-BrcGMP increased intracellular Ca2+ concentration transients in single atrial myocytes, and mRNAs for CNP and NPR-B were expressed in the rabbit atrium. From these results we conclude that atrial ANP release and stroke volume are controlled by CNP via NPR-B-cGMP mediated signaling, which may in turn act via regulation of intracellular Ca2+.

scholarly journals The calcium stored in the sarcoplasmic reticulum acts as a safety mechanism in rainbow trout heart

2014 ◽  
Vol 307 (12) ◽  
pp. R1493-R1501 ◽  
Author(s):  
Caroline Cros ◽  
Laurent Sallé ◽  
Daniel E. Warren ◽  
Holly A. Shiels ◽  
Fabien Brette
Keyword(s):  
Rainbow Trout ◽  
Sarcoplasmic Reticulum ◽  
Ventricular Myocytes ◽  
Adrenergic Stimulation ◽  
Relative Contribution ◽  
Safety Mechanism ◽  
Rapid Changes ◽  
Intracellular Ca ◽  
As Stress

Cardiomyocyte contraction depends on rapid changes in intracellular Ca2+. In mammals, Ca2+ influx as L-type Ca2+ current ( ICa) triggers the release of Ca2+ from sarcoplasmic reticulum (SR) and Ca2+-induced Ca2+ release (CICR) is critical for excitation-contraction coupling. In fish, the relative contribution of external and internal Ca2+ is unclear. Here, we characterized the role of ICa to trigger SR Ca2+ release in rainbow trout ventricular myocytes using ICa regulation by Ca2+ as an index of CICR. ICa was recorded with a slow (EGTA) or fast (BAPTA) Ca2+ chelator in control and isoproterenol conditions. In the absence of β-adrenergic stimulation, the rate of ICa inactivation was not significantly different in EGTA and BAPTA (27.1 ± 1.8 vs. 30.3 ± 2.4 ms), whereas with isoproterenol (1 μM), inactivation was significantly faster with EGTA (11.6 ± 1.7 vs. 27.3 ± 1.6 ms). When barium was the charge carrier, inactivation was significantly slower in both conditions (61.9 ± 6.1 vs. 68.0 ± 8.7 ms, control, isoproterenol). Quantification revealed that without isoproterenol, only 39% of ICa inactivation was due to Ca2+, while with isoproterenol, inactivation was Ca2+-dependent (∼65%) and highly reliant on SR Ca2+ (∼46%). Thus, SR Ca2+ is not released in basal conditions, and ICa is the main trigger of contraction, whereas during a stress response, SR Ca2+ is an important source of cytosolic Ca2+. This was not attributed to differences in SR Ca2+ load because caffeine-induced transients were not different in both conditions. Therefore, Ca2+ stored in SR of trout cardiomyocytes may act as a safety mechanism, allowing greater contraction when higher contractility is required, such as stress or exercise.

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.

Intracellular Ca transients in rat cardiac myocytes: role of Na-Ca exchange in excitation-contraction coupling

1990 ◽  
Vol 258 (5) ◽  
pp. C944-C954 ◽  
Author(s):  
D. M. Bers ◽  
W. J. Lederer ◽  
J. R. Berlin
Keyword(s):  
Voltage Clamp ◽  
Release Mechanism ◽  
Ca Current ◽  
Experimental Conditions ◽  
Release Process ◽  
Pipette Solution ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Intracellular Ca

Membrane current and intracellular Ca concentration ([Ca]i) transients were recorded from isolated rat ventricular myocytes under voltage-clamp control. The cells were dialyzed by the patch pipette solution, which contained the fluorescent Ca indicator indo-1 and 0.5 mM Na. Under these experimental conditions, Ca entry via Na-Ca exchange did not appear to be appreciable even in the absence of extracellular Na. Increasing the duration of voltage-clamp pulses from 5 to 80 ms produced [Ca]i transients of increasing amplitude, while the peak Ca current was not changed. This duration dependence of the [Ca]i transient was most demonstrable at more negative test potentials (e.g., -20 to -30 mV) and was not qualitatively modified by Na-free solutions. This latter result indicates that Ca extrusion by Na-Ca exchange is not responsible for the smaller [Ca]i transients observed when the membrane is repolarized after very brief depolarizations. Although the peak Ca current was not changed by increasing pulse duration, the integrated Ca current was increased. These observations are consistent with a Ca-release mechanism in cardiac excitation-contraction coupling in which 1) the Ca-release process can be modulated by membrane potential or 2) the Ca entering the cell via Ca channels has a preferential access [compared with Ca from the sarcoplasmic reticulum (SR)] to the site(s) that control SR Ca release. The role of Na-Ca exchange in the decline of [Ca]i during relaxation was also explored. Removal of extracellular Na (Nao) resulted in 20% slowing of the decline in [Ca]i during relaxation. From this, we conclude that the Na-Ca exchange competes with SR to remove Ca from the cytoplasm and that under our control conditions the exchanger may account for 20% of this decline. The Nao dependence of relaxation was reduced at more positive membrane potentials and increased by SR Ca loading.

Biochemistry and Morphology of Fragmented Sarcoplasmic Reticulum

1970 ◽  
Vol 28 ◽  
pp. 90-91 ◽  
Author(s):  
J. B. Peter ◽  
W. Fiehn ◽  
Robert F. Dunn
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Guinea Pig ◽  
Relaxation Cycle ◽  
Calcium Accumulation ◽  
Maximal Amount ◽  
Slow Twitch ◽  
Vesicle Protein ◽  
Fast Twitch ◽  
Kinetics Of

The function of the sarcoplasmic reticulum (SR) is well defined, but much confusion exists about the role of the SR in the contraction-relaxation cycle of slow-twitch muscles. Fragmented SR (FSR) was isolated from different guinea pig muscles. The muscles were classified as fast-twitch-red, fast-twitch-white or slow-twitch-intermediate according to their contractionrelaxation times and the histochemical characteristics of the component fibers.The kinetics of calcium accumulation showed no difference between FSR from fast-twitch-red or fast-twitch-white muscles, and the yield of FSR (expressed as mg vesicle protein per gram of muscle) was the same. By contrast the amount of FSR obtained per gram of slow-twitch-intermediate muscle was only half as high. Likewise, the maximal amount of calcium that could be stored in the presence of oxalate by FSR from slow-twitch-intermediate muscles was only half that of FSR from fast-twitch muscles.

Altered β-adrenergic signal transduction in nonfailing hypertrophied myocytes from Dahl salt-sensitive rats

2000 ◽  
Vol 279 (5) ◽  
pp. H2502-H2508 ◽  
Author(s):  
Kohzo Nagata ◽  
Catherine Communal ◽  
Chee C. Lim ◽  
Mohit Jain ◽  
Thomas M. Suter ◽  
...  
Keyword(s):  
Ventricular Hypertrophy ◽  
Physiological Role ◽  
Cellular Level ◽  
Left Ventricular ◽  
Cell Shortening ◽  
Hypertrophied Myocardium ◽  
Intracellular Ca ◽  
Myocyte Contractility ◽  
Dose Dependent

Desensitization of the β-adrenergic receptor (β-AR) response is well documented in hypertrophied hearts. We investigated whether β-AR desensitization is also present at the cellular level in hypertrophied myocardium, as well as the physiological role of inhibitory G (Gi) proteins and the L-type Ca2+channel in mediating β-AR desensitization. Left ventricular (LV) myocytes were isolated from hypertrophied hearts of hypertensive Dahl salt-sensitive (DS) rats and nonhypertrophied hearts of normotensive salt-resistant (DR) rats. Cells were paced at a rate of 300 beats/min at 37°C, and myocyte contractility and intracellular Ca2+concentration ([Ca2+]i) were simultaneously measured. In response to increasing concentrations of isoproterenol, DR myocytes displayed a dose-dependent augmentation of cell shortening and the [Ca2+]i transient amplitude, whereas hypertrophied DS myocytes had a blunted response of both cell shortening and the [Ca2+]i transient amplitude. Interestingly, inhibition of Gi proteins did not restore β-AR desensitization in DS myocytes. The responses to increases in extracellular Ca2+ and an L-type Ca2+ channel agonist were also similar in both DS and DR myocytes. Isoproterenol-stimulated adenylyl cyclase activity, however, was blunted in hypertrophied myocytes. We concluded that compensated ventricular hypertrophy results in a blunted contractile response to β-AR stimulation, which is present at the cellular level and independent of alterations in inhibitory G proteins and the L-type Ca2+ channel.

scholarly journals Role of Reduced Sarco-Endoplasmic Reticulum Ca2+-ATPase Function on Sarcoplasmic Reticulum Ca2+ Alternans in the Intact Rabbit Heart

2021 ◽  
Vol 12 ◽  
Author(s):  
Lianguo Wang ◽  
Rachel C. Myles ◽  
I-Ju Lee ◽  
Donald M. Bers ◽  
Crystal M. Ripplinger
Keyword(s):  
Endoplasmic Reticulum ◽  
Sarcoplasmic Reticulum ◽  
Optical Mapping ◽  
Cyclopiazonic Acid ◽  
Rabbit Heart ◽  
Intracellular Ca ◽  
Cardiac Alternans ◽  
Intact Rabbit ◽  
Rapid Ventricular Pacing ◽  
Serca Inhibition

Sarcoplasmic reticulum (SR) Ca2+ cycling is tightly regulated by ryanodine receptor (RyR) Ca2+ release and sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ uptake during each excitation–contraction coupling cycle. We previously showed that RyR refractoriness plays a key role in the onset of SR Ca2+ alternans in the intact rabbit heart, which contributes to arrhythmogenic action potential duration (APD) alternans. Recent studies have also implicated impaired SERCA function, a key feature of heart failure, in cardiac alternans and arrhythmias. However, the relationship between reduced SERCA function and SR Ca2+ alternans is not well understood. Simultaneous optical mapping of transmembrane potential (Vm) and SR Ca2+ was performed in isolated rabbit hearts (n = 10) using the voltage-sensitive dye RH237 and the low-affinity Ca2+ indicator Fluo-5N-AM. Alternans was induced by rapid ventricular pacing. SERCA was inhibited with cyclopiazonic acid (CPA; 1–10 μM). SERCA inhibition (1, 5, and 10 μM of CPA) resulted in dose-dependent slowing of SR Ca2+ reuptake, with the time constant (tau) increasing from 70.8 ± 3.5 ms at baseline to 85.5 ± 6.6, 129.9 ± 20.7, and 271.3 ± 37.6 ms, respectively (p < 0.05 vs. baseline for all doses). At fast pacing frequencies, CPA significantly increased the magnitude of SR Ca2+ and APD alternans, most strongly at 10 μM (pacing cycle length = 220 ms: SR Ca2+ alternans magnitude: 57.1 ± 4.7 vs. 13.4 ± 8.9 AU; APD alternans magnitude 3.8 ± 1.9 vs. 0.2 ± 0.19 AU; p < 0.05 10 μM of CPA vs. baseline for both). SERCA inhibition also promoted the emergence of spatially discordant alternans. Notably, at all CPA doses, alternation of SR Ca2+ release occurred prior to alternation of diastolic SR Ca2+ load as pacing frequency increased. Simultaneous optical mapping of SR Ca2+ and Vm in the intact rabbit heart revealed that SERCA inhibition exacerbates pacing-induced SR Ca2+ and APD alternans magnitude, particularly at fast pacing frequencies. Importantly, SR Ca2+ release alternans always occurred before the onset of SR Ca2+ load alternans. These findings suggest that even in settings of diminished SERCA function, relative refractoriness of RyR Ca2+ release governs the onset of intracellular Ca2+ alternans.

Store-operated Ca2+ entry modulates sarcoplasmic reticulum Ca2+ loading in neonatal rabbit cardiac ventricular myocytes

2006 ◽  
Vol 290 (6) ◽  
pp. C1572-C1582 ◽  
Author(s):  
Jingbo Huang ◽  
Casey van Breemen ◽  
Kuo-Hsing Kuo ◽  
Leif Hove-Madsen ◽  
Glen F. Tibbits
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Heart Surgery ◽  
Ventricular Myocytes ◽  
Open Heart Surgery ◽  
Cell Types ◽  
Reverse Mode ◽  
Nonselective Cation Channels ◽  
Intracellular Ca ◽  
Neonatal Cardiomyocyte

Store-operated Ca2+ entry (SOCE), which is Ca2+ entry triggered by the depletion of intracellular Ca2+ stores, has been observed in many cell types, but only recently has it been suggested to occur in cardiomyocytes. In the present study, we have demonstrated SOCE-dependent sarcoplasmic reticulum (SR) Ca2+ loading (loadSR) that was not altered by inhibition of L-type Ca2+ channels, reverse mode Na+/Ca2+ exchange (NCX), or nonselective cation channels. In contrast, lowering the extracellular [Ca2+] to 0 mM or adding either 0.5 mM Zn2+ or the putative store-operated channel (SOC) inhibitor SKF-96365 (100 μM) inhibited loadSR at rest. Interestingly, inhibition of forward mode NCX with 30 μM KB-R7943 stimulated SOCE significantly and resulted in enhanced loadSR. In addition, manipulation of the extracellular and intracellular Na+ concentrations further demonstrated the modulatory role of NCX in SOCE-mediated SR Ca2+ loading. Although there is little knowledge of SOCE in cardiomyocytes, the present results suggest that this mechanism, together with NCX, may play an important role in SR Ca2+ homeostasis. The data reported herein also imply the presence of microdomains unique to the neonatal cardiomyocyte. These findings may be of particular importance during open heart surgery in neonates, in which uncontrolled SOCE could lead to SR Ca2+ overload and arrhythmogenesis.

scholarly journals Role of sarcoplasmic reticulum in regulation of tonic contraction of rabbit basilar artery

2001 ◽  
Vol 281 (4) ◽  
pp. H1481-H1489 ◽  
Author(s):  
Tania Szado ◽  
Megan McLarnon ◽  
Xiaodong Wang ◽  
Casey van Breemen
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Basilar Artery ◽  
Cerebral Arteries ◽  
Force Measurements ◽  
Force Development ◽  
Plasmic Reticulum ◽  
Intracellular Ca ◽  
Subsequent Addition ◽  
Measuring Force

Superficial sarcoplasmic reticulum (SR) regulates smooth muscle force development directly by Ca2+ release and removal to and from the cytoplasm (Somlyo and Somlyo. J Cardiovasc Pharmacol 8, Suppl8: S42–S47, 1986) by buffering Ca2+ influx and contributing to Ca2+ extrusion (Mueller and van Breemen. Nature 281: 682–683, 1979) and indirectly by releasing Ca2+ near Ca2+-activated K+channels (KCa) to hyperpolarize the plasma membrane (Bolton and Imaizumi. Cell Calcium 20: 141–152, 1996 and Nelson et al. Science 270: 633–637, 1995). In the rabbit basilar artery, relative contributions of direct effects and those mediated through activation of KCa were evaluated by measuring force and intracellular Ca2+ concentration ([Ca2+]i) in response to the SR-depleting agents thapsigargin and ryanodine and the large conductance KCa (BKCa) blockers iberiotoxin (IbTX) and tetraethylammonium ion (TEA). A large contraction was observed in response to KCa blockade with either 3 mM TEA or 100 nM IbTX and also after addition of 10 μM ryanodine or 2 μM thapsigargin. When KCa was blocked first with TEA or IbTX, subsequent addition of thapsigargin or ryanodine also increased force. Measurements of fura 2 fluorescence showed parallel increases in [Ca2+]i in response to sequential blockade of sarco(endo)plasmic reticulum Ca2+-ATPase and KCa regardless of the order of application. It appears that a significant fraction of KCa remains activated in the absence of SR function and that SR contributes to relaxation after blockade of KCa. We found that depletion of SR before stimulating Ca2+ influx through voltage-gated Ca2+ channels markedly reduced force development rate and that thapsigargin abolished this effect. We conclude that the SR of rabbit cerebral arteries modulates constriction by direct and indirect mechanisms.

scholarly journals The development of L-type Ca2+ current mediated alternans does not depend on the restitution slope in canine ventricular myocardium

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Noémi Tóth ◽  
Jozefina Szlovák ◽  
Zsófia Kohajda ◽  
Gergő Bitay ◽  
Roland Veress ◽  
...  
Keyword(s):  
Ionic Currents ◽  
Ventricular Myocardium ◽  
Underlying Mechanism ◽  
Patch Clamp Technique ◽  
Fast Phase ◽  
Restitution Curve ◽  
Cardiac Alternans ◽  
Rapid Pacing ◽  
Relationship Of

AbstractCardiac alternans have crucial importance in the onset of ventricular fibrillation. The early explanation for alternans development was the voltage-driven mechanism, where the action potential (AP) restitution steepness was considered as crucial determining factor. Recent results suggest that restitution slope is an inadequate predictor for alternans development, but several studies still claim the role of membrane potential as underlying mechanism of alternans. These controversial data indicate that the relationship of restitution and alternans development is not completely understood. APs were measured by conventional microelectrode technique from canine right ventricular papillary muscles. Ionic currents combined with fluorescent measurements were recorded by patch-clamp technique. APs combined with fluorescent measurements were monitored by sharp microelectrodes. Rapid pacing evoked restitution-independent AP duration (APD) alternans. When non-alternating AP voltage command was used, Ca2+i-transient (CaT) alternans were not observed. When alternating rectangular voltage pulses were applied, CaT alternans were proportional to ICaL amplitude alternans. Selective ICaL inhibition did not influence the fast phase of APD restitution. In this study we found that ICaL has minor contribution in shaping the fast phase of restitution curve suggesting that ICaL—if it plays important role in the alternans mechanism—could be an additional factor that attenuates the reliability of APD restitution slope to predict alternans.

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