scholarly journals Spontaneous Ca2+ release from the sarcoplasmic reticulum limits Ca2+-dependent twitch potentiation in individual cardiac myocytes. A mechanism for maximum inotropy in the myocardium.

1988 ◽  
Vol 91 (1) ◽  
pp. 133-155 ◽  
Author(s):  
M C Capogrossi ◽  
M D Stern ◽  
H A Spurgeon ◽  
E G Lakatta
Keyword(s):  
Mathematical Model ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Myocytes ◽  
Total Cell ◽  
Inotropic Response ◽  
Twitch Potentiation ◽  
Intact Muscle ◽  
Rat Myocytes ◽  
Plausible Mechanism ◽  
In Cells

We hypothesized that the occurrence of spontaneous Ca2+ release from the sarcoplasmic reticulum (SR), in diastole, might be a mechanism for the saturation of twitch potentiation common to a variety of inotropic perturbations that increase the total cell Ca. We used a videomicroscopic technique in single cardiac myocytes to quantify the amplitude of electrically stimulated twitches and to monitor the occurrence of the mechanical manifestation of spontaneous SR Ca2+ release, i.e., the spontaneous contractile wave. In rat myocytes exposed to increasing bathing [Ca2+] (Cao) from 0.25 to 10 mM, the Cao at which the peak twitch amplitude occurred in a given cell was not unique but varied with the rate of stimulation or the presence of drugs: in cells stimulated at 0.2 Hz in the absence of drugs, the maximum twitch amplitude occurred in 2 mM Cao; a brief exposure to 50 nM ryanodine before stimulation at 0.2 Hz shifted the Cao of the maximum twitch amplitude to 7 mM. In cells stimulated at 1 Hz in the absence of drugs, the maximum twitch amplitude occurred in 4 mM Cao; 1 microM isoproterenol shifted the Cao of the maximum twitch amplitude to 3 mM. Regardless of the drug or the stimulation frequency, the Cao at which the twitch amplitude saturated varied linearly with the Cao at which spontaneous Ca2+ release first occurred, and this relationship conformed to a line of identity (r = 0.90, p = less than 0.001, n = 25). The average peak twitch amplitude did not differ among these groups of cells. In other experiments, (a) the extent of rest potentiation of the twitch amplitude in rat myocytes was also limited by the occurrence of spontaneous Ca2+ release, and (b) in both rat and rabbit myocytes continuously stimulated in a given Cao, the twitch amplitude after the addition of ouabain saturated when spontaneous contractile waves first appeared between stimulated twitches. A mathematical model that incorporates this interaction between action potential-mediated SR Ca2+ release and the occurrence of spontaneous Ca2+ release in individual cells predicted the shape of the Cao-twitch relationship observed in other studies in intact muscle. Thus, the occurrence of spontaneous SR Ca2+ release is a plausible mechanism for the saturation of the inotropic response to Ca2+ in the intact myocardium.

scholarly journals Effects of rogue ryanodine receptors on Ca 2+ sparks in cardiac myocytes

2018 ◽  
Vol 5 (2) ◽  
pp. 171462 ◽  
Author(s):  
Xudong Chen ◽  
Yundi Feng ◽  
Yunlong Huo ◽  
Wenchang Tan
Keyword(s):  
Mathematical Model ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Myocytes ◽  
Ryanodine Receptors ◽  
Experimental Measurements ◽  
Release Mechanisms ◽  
Insight Into ◽  
Junctional Sarcoplasmic Reticulum

Ca 2+ sparks and Ca 2+ quarks, arising from clustered and rogue ryanodine receptors (RyRs), are significant Ca 2+ release events from the junctional sarcoplasmic reticulum (JSR). Based on the anomalous subdiffusion of Ca 2+ in the cytoplasm, a mathematical model was developed to investigate the effects of rogue RyRs on Ca 2+ sparks in cardiac myocytes. Ca 2+ quarks and sparks from the stochastic opening of rogue and clustered RyRs are numerically reproduced and agree with experimental measurements. It is found that the stochastic opening Ca 2+ release units (CRUs) of clustered RyRs are regulated by free Ca 2+ concentration in the JSR lumen (i.e. [Ca 2+ ] lumen ). The frequency of spontaneous Ca 2+ sparks is remarkably increased by the rogue RyRs opening at high [Ca 2+ ] lumen , but not at low [Ca 2+ ] lumen . Hence, the opening of rogue RyRs contributes to the formation of Ca 2+ sparks at high [Ca 2+ ] lumen . The interplay of Ca 2+ sparks and Ca 2+ quarks has been discussed in detail. This work is of significance to provide insight into understanding Ca 2+ release mechanisms in cardiac myocytes.

scholarly journals The interaction of electrically stimulated twitches and spontaneous contractile waves in single cardiac myocytes.

1986 ◽  
Vol 88 (5) ◽  
pp. 615-633 ◽  
Author(s):  
M C Capogrossi ◽  
B A Suarez-Isla ◽  
E G Lakatta
Keyword(s):  
Electrical Stimulation ◽  
Time Delay ◽  
Sarcoplasmic Reticulum ◽  
Action Potential ◽  
Cardiac Myocytes ◽  
Delay Interval ◽  
Interstimulus Interval ◽  
Marked Effect ◽  
Rat Myocytes ◽  
The Waves

Spontaneous myofilament motion that propagates within cells as a contractile wave is a manifestation of localized Ca2+ release from sarcoplasmic reticulum (SR). At 37 degrees C, when bathing [Ca2+] (Cao) is 1.0 mM, rat myocytes exhibit contractile waves at rest and the interwave interval averages 9.1 +/- 1.5 s (n = 6). We determined whether there was an interaction between this type of SR Ca2+ release and that induced by electrical stimulation to cause a twitch, and whether such an interaction had functional significance. Progressive decreases in SR Ca2+ loading effected by graded concentrations of caffeine produced proportional decreases in the mechanical amplitude of the twitch and of the spontaneous contractile wave. Regular electrical stimulation in physiologic Cao abolished the waves and, after stimulation, waves did not reappear for a period of time (delay interval). Over a range of stimulation frequencies (6-72 min-1), the delay interval ranged from 11.4 +/- 3.6 to 12.4 +/- 1.7 s and was usually greater than the interwave interval at rest. The delay interval for a wave to occur after a twitch was reduced in the presence of increased Cao, glycosides, or catecholamines. When the interstimulus interval exceeded the delay interval, waves could appear between twitches and had a marked effect of shortening the duration of the action potential and decreasing the amplitude of the subsequent twitch. The magnitude of this effect varied inversely with time (up to 2 s) between the onset of the spontaneous diastolic wave and the subsequent stimulated twitch. A reduction of the interstimulus interval to less than the delay interval prevented the occurrence of diastolic waves. These results demonstrate the presence of an interaction between spontaneous and action potential-mediated Ca2+ release, which can be interpreted on the basis of a common Ca2+ pool and perhaps common release mechanisms. This interaction can explain many of the known effects of electrical stimulation on phenomena that are thought to result from spontaneous Ca2+ oscillations in intact tissue.

scholarly journals Effects of β-adrenoceptor stimulation on contractility, [Ca2+]i, and Ca2+ current in diabetic rat cardiomyocytes

1998 ◽  
Vol 274 (6) ◽  
pp. H1849-H1857 ◽  
Author(s):  
Atsushi Tamada ◽  
Yuichi Hattori ◽  
Hideki Houzen ◽  
Yoichi Yamada ◽  
Ichiro Sakuma ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Myocytes ◽  
Ventricular Myocytes ◽  
Diabetic Rat ◽  
Inotropic Response ◽  
Dibutyryl Camp ◽  
Rat Cardiomyocytes ◽  
Adrenergic Response ◽  
Significant Difference ◽  
Intracellular Ca

The mechanism of the diminished inotropic response to β-adrenoceptor stimulation in diabetic hearts was studied in enzymatically isolated diabetic rat ventricular myocytes in comparison with age-matched controls. The increases in contractions and intracellular Ca2+ concentration ([Ca2+]i) transients produced by isoproterenol were markedly diminished in diabetic myocytes. The inotropic and [Ca2+]iresponses to forskolin and dibutyryl cAMP (DBcAMP) were also reduced. No significant difference was found in the stimulating effects of isoproterenol, forskolin, and DBcAMP on the L-type Ca2+ current ( I Ca) between control and diabetic myocytes. The rise of [Ca2+]iin response to rapid caffeine application, an index of sarcoplasmic reticulum (SR) Ca2+ content, was significantly decreased in diabetic myocytes. Isoproterenol, forskolin, and DBcAMP enhanced this [Ca2+]iresponse to caffeine in control myocytes more markedly than in diabetic myocytes. The changes in the isoproterenol responses observed in diabetic myocytes were prevented by insulin therapy. We conclude that 1) diabetes causes an impairment of the contractile and [Ca2+]iresponses of cardiac myocytes when stimulated at both β-adrenoceptors and the postreceptor level without affecting the I Ca response and 2) altered SR functions of uptake and/or release of Ca2+ may primarily contribute to the diminished β-adrenergic response.

Spread of Ca2+ in the sarcomere during fast and slow activation of mammalian cardiac myocytes

2001 ◽  
Vol 79 (1) ◽  
pp. 82-86
Author(s):  
Masato Konishi ◽  
Yoichiro Kusakari ◽  
Kenichi Hongo ◽  
Satoshi Kurihara
Keyword(s):  
Mathematical Model ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Compartment Model ◽  
Mechanical Activity ◽  
Binding Reaction ◽  
The Mathematical Model ◽  
And Diffusion ◽  
Apparent Equilibrium

A multi-compartment model was used to estimate Ca2+ gradients in a sarcomere of a cardiac myocyte. The mathematical model assumed Ca2+ release from the sarcoplasmic reticulum as a driving function, and calculated Ca2+ binding to myoplasmic buffers, Ca2+ uptake by the sarcoplasmic reticulum, and diffusion of Ca2+ (and the buffers). During the fast Ca2+ transient similar to those observed during a twitch, the model predicted a large Ca2+ gradient in the sarcomere. A trajectory of the instantaneous relation between spatially averaged concentrations of Ca2+ and the Ca2+-troponin complex showed a counterclockwise loop, indicating non-equilibrium Ca2+ binding to troponin. During slow changes in [Ca2+] with time to peaks of ~500 ms or longer, the gradient of [Ca2+] was largely dissipated and the apparent equilibrium of the Ca2+-troponin binding reaction was suggested with little hysteresis of the trajectory. We conclude that a steady-state relation between [Ca2+] and mechanical activity can be achieved uniformly in the sarcomere by slowing the rate of Ca2+ release from the sarcoplasmic reticulum.Key words: calcium, troponin, cardiac myocytes, mathematical model.

scholarly journals A mathematical model of spontaneous calcium release in cardiac myocytes

2011 ◽  
Vol 300 (5) ◽  
pp. H1794-H1805 ◽  
Author(s):  
Wei Chen ◽  
Gary Aistrup ◽  
J. Andrew Wasserstrom ◽  
Yohannes Shiferaw
Keyword(s):  
Mathematical Model ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Myocytes ◽  
Calcium Release ◽  
Cardiac Tissue ◽  
Ectopic Beat ◽  
Ionic Model ◽  
Triggered Activity ◽  
Voltage Dependent ◽  
Key Features

In cardiac myocytes, calcium (Ca) can be released from the sarcoplasmic reticulum independently of Ca influx from voltage-dependent membrane channels. This efflux of Ca, referred to as spontaneous Ca release (SCR), is due to Ryanodine receptor fluctuations, which can induce spontaneous Ca sparks, which propagate to form Ca waves. This release of Ca can then induce delayed after-depolarizations (DADs), which can lead to arrhythmogenic-triggered activity in the heart. However, despite its importance, to date there is no mathematical model of SCR that accounts for experimentally observed features of subcellular Ca. In this article, we present an experimentally based model of SCR that reproduces the timing distribution of spontaneous Ca sparks and key features of the propagation of Ca waves emanating from these spontaneous sparks. We have coupled this model to an ionic model for the rabbit ventricular action potential to simulate SCR within several thousand cells in cardiac tissue. We implement this model to study the formation of an ectopic beat on a cable of cells that exhibit SCR-induced DADs.

Na+ entry via store-operated channels modulates Ca2+signaling in arterial myocytes

2000 ◽  
Vol 278 (1) ◽  
pp. C163-C173 ◽  
Author(s):  
Assaf Arnon ◽  
John M. Hamlyn ◽  
Mordecai P. Blaustein
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cyclopiazonic Acid ◽  
General Mechanism ◽  
Tetraacetic Acid ◽  
Pump Activity ◽  
In Cells

In many nonexcitable cells, hormones and neurotransmitters activate Na+ influx and mobilize Ca2+ from intracellular stores. The stores are replenished by Ca2+influx via “store-operated” Ca2+ channels (SOC). The main routes of Na+ entry in these cells are unresolved, and no role for Na+ in signaling has been recognized. We demonstrate that the SOC are a major Na+ entry route in arterial myocytes. Unloading of the Ca2+stores with cyclopiazonic acid (a sarcoplasmic reticulum Ca2+ pump inhibitor) and caffeine induces a large external Na+-dependent rise in the cytosolic Na+ concentration. One component of this rise in cytosolic Na+ concentration is likely due to Na+/Ca2+exchange; it depends on elevation of cytosolic Ca2+ and is insensitive to 10 mM Mg2+ and 10 μM La3+. Another component is inhibited by Mg2+ and La3+, blockers of SOC; this component persists in cells preloaded with 1,2-bis(2-aminophenoxy)ethane- N, N, N′, N′-tetraacetic acid to buffer Ca2+ transients and prevent Na+/Ca2+exchange-mediated Na+ entry. This Na+ entry apparently is mediated by SOC. The Na+ entry influences Na+ pump activity and Na+/Ca2+exchange and has unexpectedly large effects on cell-wide Ca2+ signaling. The SOC pathway may be a general mechanism by which Na+ participates in signaling in many types of cells.

Differential effects of phospholamban and Ca2+/calmodulin-dependent kinase II on [Ca2+]i transients in cardiac myocytes at physiological stimulation frequencies

2008 ◽  
Vol 294 (5) ◽  
pp. H2352-H2362 ◽  
Author(s):  
Andreas A. Werdich ◽  
Eduardo A. Lima ◽  
Igor Dzhura ◽  
Madhu V. Singh ◽  
Jingdong Li ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Myocytes ◽  
Wild Type ◽  
Dependent Protein Kinase ◽  
Frequency Dependent ◽  
Physiological Range ◽  
Dependent Protein ◽  
Isolated Cardiac Myocytes

In cardiac myocytes, the activity of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) is hypothesized to regulate Ca2+ release from and Ca2+ uptake into the sarcoplasmic reticulum via the phosphorylation of the ryanodine receptor 2 and phospholamban (PLN), respectively. We tested the role of CaMKII and PLN on the frequency adaptation of cytosolic Ca2+ concentration ([Ca2+]i) transients in nearly 500 isolated cardiac myocytes from transgenic mice chronically expressing a specific CaMKII inhibitor, interbred into wild-type or PLN null backgrounds under physiologically relevant pacing conditions (frequencies from 0.2 to 10 Hz and at 37°C). When compared with that of mice lacking PLN only, the combined chronic CaMKII inhibition and PLN ablation decreased the maximum Ca2+ release rate by more than 50% at 10 Hz. Although PLN ablation increased the rate of Ca2+ uptake at all frequencies, its combination with CaMKII inhibition did not prevent a frequency-dependent reduction of the amplitude and the duration of the [Ca2+]i transient. High stimulation frequencies in the physiological range diminished the effects of PLN ablation on the decay time constant and on the maximum decay rate of the [Ca2+]i transient, indicating that the PLN-mediated feedback on [Ca2+]i removal is limited by high stimulation frequencies. Taken together, our results suggest that in isolated mouse ventricular cardiac myocytes, the combined chronic CaMKII inhibition and PLN ablation slowed Ca2+ release at physiological frequencies: the frequency-dependent decay of the amplitude and shortening of the [Ca2+]i transient occurs independent of chronic CaMKII inhibition and PLN ablation, and the PLN-mediated regulation of Ca2+ uptake is diminished at higher stimulation frequencies within the physiological range.

Molecular identification of a TTX-sensitive Ca2+current

2001 ◽  
Vol 280 (5) ◽  
pp. C1327-C1339 ◽  
Author(s):  
Silvia Guatimosim ◽  
Eric A. Sobie ◽  
Jader dos Santos Cruz ◽  
Laura A. Martin ◽  
W. J. Lederer
Keyword(s):  
Cardiac Myocytes ◽  
Ion Selectivity ◽  
Inactivation Kinetics ◽  
Experimental Conditions ◽  
Guinea Pig Heart ◽  
Hek 293 ◽  
Hek 293 Cells ◽  
293 Cells ◽  
Intracellular Ca ◽  
Rat Myocytes

The TTX-sensitive Ca2+ current [ I Ca(TTX)] observed in cardiac myocytes under Na+-free conditions was investigated using patch-clamp and Ca2+-imaging methods. Cs+ and Ca2+were found to contribute to I Ca(TTX), but TEA+ and N-methyl-d-glucamine (NMDG+) did not. HEK-293 cells transfected with cardiac Na+ channels exhibited a current that resembled I Ca(TTX) in cardiac myocytes with regard to voltage dependence, inactivation kinetics, and ion selectivity, suggesting that the cardiac Na+ channel itself gives rise to I Ca(TTX). Furthermore, repeated activation of I Ca(TTX) led to a 60% increase in intracellular Ca2+ concentration, confirming Ca2+ entry through this current. Ba2+ permeation of I Ca(TTX), reported by others, did not occur in rat myocytes or in HEK-293 cells expressing cardiac Na+channels under our experimental conditions. The report of block of I Ca(TTX) in guinea pig heart by mibefradil (10 μM) was supported in transfected HEK-293 cells, but Na+current was also blocked (half-block at 0.45 μM). We conclude that I Ca(TTX) reflects current through cardiac Na+ channels in Na+-free (or “null”) conditions. We suggest that the current be renamed I Na(null) to more accurately reflect the molecular identity of the channel and the conditions needed for its activation. The relationship between I Na(null)and Ca2+ flux through slip-mode conductance of cardiac Na+ channels is discussed in the context of ion channel biophysics and “permeation plasticity.”

Abstract 274: Spatiotemporal Regulation of β Adrenergic Signaling In Heart failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Yang K Xiang ◽  
Federica Barbagallo ◽  
Bing Xu ◽  
Qin Fu
Keyword(s):  
Heart Failure ◽  
Plasma Membrane ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Myocytes ◽  
Cardiac Disease ◽  
Spatiotemporal Regulation ◽  
Disease Therapy ◽  
Functional Implications ◽  
Underlying Mechanisms

Our long-term goal is to understand mechanisms that govern spatiotemporal regulation of cAMP/PKA signaling in cardiac myocytes under physiological and pathophysiological conditions, and their implication in cardiac disease therapy. Here we use a series of biosensors to measure cAMP/PKA activity under βAR subtype regulation. In failing cardiac myocytes, the cAMP and PKA activity are shifted from the plasma membrane to the intracellular sarcoplasmic reticulum and the myofilaments. Meanwhile, β2AR displays an increased role in signaling to the myofilaments in failing myocytes when compared to the control myocytes. Moreover, we show that an increased βAR association with phosphodiesterases promotes the alteration in spatiotemporal propagation of cAMP/PKA signaling in failing myocytes. These observations and the underlying mechanisms and functional implications will be discussed.

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