scholarly journals Spontaneous calcium oscillations during diastole in the whole heart: the influence of ryanodine reception function and gap junction coupling

2011 ◽  
Vol 300 (5) ◽  
pp. H1822-H1828 ◽  
Author(s):  
Bradley N. Plummer ◽  
Michael J. Cutler ◽  
Xiaoping Wan ◽  
Kenneth R. Laurita
Keyword(s):  
Calcium Release ◽  
Calcium Oscillations ◽  
Cytoplasmic Calcium ◽  
Cell Coupling ◽  
Cellular Mechanisms ◽  
Open Probability ◽  
Temporal Synchronization ◽  
Time To Peak ◽  
Triggered Arrhythmias ◽  
Whole Heart

Triggered arrhythmias due to spontaneous cytoplasmic calcium oscillations occur in a variety of disease conditions; however, their cellular mechanisms in tissue are not clear. We hypothesize that spontaneous calcium oscillations in the whole heart are due to calcium release from the sarcoplasmic reticulum and are facilitated by calcium diffusion through gap junctions. Optical mapping of cytoplasmic calcium from Langendorff perfused guinea pig hearts ( n = 10) was performed using oxygenated Tyrode's solution (in mM): 140 NaCl, 0.7 MgCl, 4.5 KCl, 5.5 dextrose, 5 HEPES, and 5.5 CaCl2 (pH 7.45, 34°C). Rapid pacing was used to induce diastolic calcium oscillations. In all preparations, pacing-induced multicellular diastolic calcium oscillations (m-SCR) occurred across most of the mapping field, at all pacing rates tested. Ryanodine (1 μM) eliminated all m-SCR activity. Low-dose caffeine (1 mM) increased m-SCR amplitude (+10.4 ± 4.4%, P < 0.05) and decreased m-SCR time-to-peak (−17.4 ± 6.7%, P < 0.05) and its temporal synchronization (i.e., range) across the mapping field (−26.9 ± 17.1%, P < 0.05). Surprisingly, carbenoxolone increased the amplitude of m-SCR activity (+14.8 ± 4.1%, P < 0.05) and decreased m-SCR time-to-peak (−11.3 ± 9.6%, P < 0.01) and its synchronization (−37.0 ± 19.1%, P < 0.05), similar to caffeine. In isolated myocytes, carbenoxolone (50 μM) had no effect on the frequency of aftercontractions, suggesting the effect of cell-to-cell uncoupling on m-SCR activity is tissue specific. Therefore, in the whole heart, overt m-SCR activity caused by calcium release from the SR can be induced over a broad range of pacing rates. Enhanced ryanodine receptor open probability and, surprisingly, decreased cell-to-cell coupling increased the amplitude and temporal synchronization of spontaneous calcium release in tissue.

Cellular mechanisms of ventricular failure: myocyte kinetics and geometry with age

1992 ◽  
Vol 262 (6) ◽  
pp. H1770-H1781 ◽  
Author(s):  
J. M. Capasso ◽  
D. Fitzpatrick ◽  
P. Anversa
Keyword(s):  
Right Ventricular ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Cellular Mechanisms ◽  
Cell Width ◽  
Time To Peak ◽  
Fischer 344 ◽  
Contraction Duration ◽  
Cardiac Dynamics ◽  
Age Related

To determine whether heart failure is a consequence of alterations in cardiac cellular performance, myocytes were isolated from Fischer 344 rats at 4, 12, 20, and 29 mo of age and studied mechanically and morphometrically. Left ventricular myocyte length increased by 14.5, 14.4, and 24.0% at 12, 20, and 29 mo when compared with 4-mo-old animals. An 11.4 and 14.2% increase in length was seen for right ventricular myocytes from 4 to 12 mo and from 20 to 29 mo, respectively. Although no change in cell width was seen in either ventricle as a function of age, myocardial cells were more irregular in shape and consistently longer in the left ventricle at 20 and 29 mo. Left myocytes at 29 mo revealed diminished velocities of shortening (31.7%) and relengthening (59.5%). Contraction duration increased due to a 28.9% prolongation of time to peak shortening and a 26.5% increase in time to relengthening, resulting in a 25.8% decrease in myocyte shortening at 29 mo. Similar changes were observed in right ventricular myocytes, but they occurred later in life. Thus the alterations in myocyte geometry and depression in contractile performance seen here are major contributors to the eccentric dilated ventricular chamber and diminished pump function previously documented in the age-related transition from normal cardiac dynamics to left ventricular dysfunction and failure.

Mechanisms Underlying Type I mGluR-Induced Activation of Lobster Gastric Mill Neurons

2006 ◽  
Vol 96 (6) ◽  
pp. 3378-3388 ◽  
Author(s):  
Rafael Levi ◽  
Allen I. Selverston
Keyword(s):  
G Protein ◽  
Calcium Release ◽  
Metabotropic Glutamate Receptor ◽  
Cyclopiazonic Acid ◽  
Stomatogastric Ganglion ◽  
Type I ◽  
Gastric Mill ◽  
Concentration Increase ◽  
Cellular Mechanisms ◽  
Excitatory Effect

In addition to ionotropic effects, glutamate and acetylcholine have metabotropic modulatory effects on many neurons. Here we show that in the stomatogastric ganglion of the lobster, glutamate, one of the main ionotropic neurotransmitters, modulates the excitability of gastric mill neurons. The neurons in this well-studied system produce rhythmic output to a subset of lobster foregut muscles. Recently, metabotropic glutamate receptor (mGluR) agonists were suggested as modulators of the rhythmic output, in addition to the previously described muscarinic modulation by acetylcholine. However, the cellular mechanisms responsible for these effects on the pattern are not known. Using intracellular recording methods and calcium imaging, we show that glutamate has an excitatory effect on specific neurons in the stomatogastric ganglion, which is mediated by mGluRs. Responses to the application of mGluR type I agonists are transient oscillations in the system, probably arising from network interactions. We show that the excitatory effect is sensitive to phospholipase-C and IP3 and is G-protein dependent. The G-protein dependency was demonstrated by GDPβS and GTPγS injection into identified neurons. The depolarizations and oscillations were accompanied by an increase of intracellular Ca2+ levels and correlated Ca2+ oscillations. By using cyclopiazonic acid, an endoreticular Ca2+ uptake inhibitor, we show that some internal calcium release may augment the response, but is not crucial for its production. Interestingly, although Ca2+ concentration increase is typically associated with the phosphoinositide pathway, in the lobster, the Ca2+ concentration increase—either voltage dependent or independent—cannot account for the observed depolarization.

P1622Cancer drugs induce functional and structural impairment in adult cardiomyocytes

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C Altomare ◽  
V Biemmi ◽  
E Torre ◽  
M Rocchetti ◽  
M Ferrandi ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Structural Changes ◽  
Decay Amplitude ◽  
Sampling Rate ◽  
Growth Factor Receptor ◽  
Cellular Mechanisms ◽  
Systolic Volume ◽  
Functional Changes ◽  
Time To Peak

Abstract Introduction The addition of anti-human epidermal growth factor receptor 2 (HER2; ErbB2) monoclonal antibody Trastuzumab (TRZ) to Doxorubicin (DOXO) chemotherapy is associated with a synergistic increase in cardiac toxicity. While previous studies have addressed the toxicity of both agents on isolated cardiomyocytes (CMs), little is known regarding this process in vivo, especially with respect to electrophysiological changes. Purpose To investigate electrical and structural changes in LV and RV CMs using an in vivo rat model of DOXO/TRZ cardiotoxicity. Methods Rats received 6 IP injections of either DOXO or TRZ over a 2-week period, or 6 doses of DOXO followed by 6 doses of TRZ (COMBO), or saline as a control. In-vivo echocardiography was performed. Electrical activity and Ca2+ handling were assessed in LV and RV CMs from rat hearts. Single cell patch-clamp and field stimulation experiments were performed. Spontaneous sarcoplasmic reticulum Ca2+ release events (Ca2+ sparks) were recorded at x100 magnification in line-scan mode (sampling rate 0.7 kHz) from 2 μM Fluo4-AM loaded CMs. To assess T-tubular disarray, CMs were incubated with di-3-ANEPPDHQ and periodic component was quantified by Fast Fourier Transform (FFT) analysis of confocal microscopy images. Results DOXO, and to a greater extent COMBO treatment was associated with significant increases in both LV end-systolic and end-diastolic volumes, and decreases in LVEF and fractional shortening. By contrast, TRZ alone merely increased LV end-systolic volume. Electrophysiological studies showed increases in action potential duration (APD), beat-to-beat variability of repolarization (BVR), delayed after depolarizations (DADs), and Ca2+-sparks in both DOXO and COMBO groups. Stimulated intracellular Ca2+ transients (1,2 and 4 Hz) showed significant changes with respect to time to peak, tau decay, amplitude, and fractional release in the DOXO group. These changes were associated with a significant downregulation of sarco/endoplasmic reticulum Ca2+ ATPase pump (SERCA) expression. From a structural viewpoint, these changes were associated with T-tubular disarray in the DOXO and COMBO groups. Conclusions DOXO, and to a greater extent COMBO treatment (but not TRZ alone) cause LV dysfunction in vivo. Moreover, both DOXO and COMBO treatments, but not TRZ alone, induce electrophysiological abnormalities and both structural and functional changes in the sarcoplasmic reticulum. These findings provide novel insights into the cellular mechanisms of CM dysfunction and arrhythmias associated with combined DOXO/TRZ therapy. Acknowledgement/Funding Swiss League against Cancer

Ca(2+)- and pH-dependent halothane stimulation of Ca2+ release in sarcoplasmic reticulum from frog muscle

1996 ◽  
Vol 271 (2) ◽  
pp. C540-C546 ◽  
Author(s):  
M. Beltran ◽  
R. Bull ◽  
P. Donoso ◽  
C. Hidalgo
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Release Kinetics ◽  
Frog Muscle ◽  
Time Range ◽  
Frog Skeletal Muscle ◽  
Open Probability ◽  
Filtration System ◽  
Stimulation Of

The effect of halothane on calcium release kinetics was studied in triad-enriched sarcoplasmic reticulum vesicles from frog skeletal muscle. Release from vesicles passively equilibrated with 3 mM 45CaCl2 was measured in the millisecond time range by use of a fast-filtration system. Halothane (400 microM) increased release rate constants at pH 7.1 and 7.4 as a function of extravesicular pCa. In contrast, halothane at pH 6.8 produced the same stimulation of release from pCa 7.0 to 3.0; no release took place in these conditions in the absence of halothane. Halothane shifted the calcium activation curve at pH 7.1, but not at pH 7.4, to the left and increased channel open probability at pH 7.1 in the cis pCa range of 7.0 to 5.0. These results indicate that cytosolic pCa and pH modulate the stimulatory effects of halothane on calcium release. Furthermore, halothane stimulated release in frog skeletal muscle at low pH and resting calcium concentration, indicating that in frog muscle halothane can override the closing of the release channels produced by these conditions, as it does in malignant hyperthermia-susceptible porcine muscle.

scholarly journals Bursting and calcium oscillations in pancreatic β-cells: specific pacemakers for specific mechanisms

2010 ◽  
Vol 299 (4) ◽  
pp. E517-E532 ◽  
Author(s):  
L. E. Fridlyand ◽  
N. Tamarina ◽  
L. H. Philipson
Keyword(s):  
Mathematical Models ◽  
Calcium Concentration ◽  
Calcium Oscillations ◽  
Cell Physiology ◽  
Cytoplasmic Calcium ◽  
Β Cells ◽  
Β Cell ◽  
Endoplasmic Reticulum Calcium ◽  
Key Aspects ◽  
Potential Interactions

Oscillatory phenomenon in electrical activity and cytoplasmic calcium concentration in response to glucose are intimately connected to multiple key aspects of pancreatic β-cell physiology. However, there is no single model for oscillatory mechanisms in these cells. We set out to identify possible pacemaker candidates for burst activity and cytoplasmic Ca2+ oscillations in these cells by analyzing published hypotheses, their corresponding mathematical models, and relevant experimental data. We found that although no single pacemaker can account for the variety of oscillatory phenomena in β-cells, at least several separate mechanisms can underlie specific kinds of oscillations. According to our analysis, slowly activating Ca2+-sensitive K+ channels can be responsible for very fast Ca2+ oscillations; changes in the ATP/ADP ratio and in the endoplasmic reticulum calcium concentration can be pacemakers for both fast bursts and cytoplasmic calcium oscillations, and cyclical cytoplasmic Na+ changes may underlie patterning of slow calcium oscillations. However, these mechanisms still lack direct confirmation, and their potential interactions raises new issues. Further studies supported by improved mathematical models are necessary to understand oscillatory phenomena in β-cell physiology.

scholarly journals Modulatory Effect of 2-(4-Hydroxyphenyl)amino-1,4-naphthoquinone on Endothelial Vasodilation in Rat Aorta

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Javier Palacios ◽  
Fredi Cifuentes ◽  
Jaime A. Valderrama ◽  
Julio Benites ◽  
David Ríos ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Calcium Release ◽  
Vascular Dysfunction ◽  
Rat Aorta ◽  
Cellular Mechanisms ◽  
No Donor ◽  
Pharmacological Agents ◽  
Naphthoquinone Derivative ◽  
Low Cytotoxicity ◽  
Endothelium Damage

The vascular endothelium plays an essential role in the control of the blood flow. Pharmacological agents like quinone (menadione) at various doses modulate this process in a variety of ways. In this study,Q7, a 2-phenylamino-1,4-naphthoquinone derivative, significantly increased oxidative stress and induced vascular dysfunction at concentrations that were not cytotoxic to endothelial or vascular smooth muscle cells.Q7reduced nitric oxide (NO) levels and endothelial vasodilation to acetylcholine in rat aorta. It also blunted the calcium release from intracellular stores by increasing the phenylephrine-induced vasoconstriction when CaCl2was added to a calcium-free medium but did not affect the influx of calcium from extracellular space.Q7increased the vasoconstriction to BaCl2(10−3 M), an inward rectifying K+channels blocker, and blocked the vasodilation to KCl (10−2 M) in aortic rings precontracted with BaCl2. This was recovered with sodium nitroprusside (10−8 M), a NO donor. In conclusion,Q7induced vasoconstriction was through a modulation of cellular mechanisms involving calcium fluxes through K+channels, and oxidative stress induced endothelium damage. These findings contribute to the characterization of new quinone derivatives with low cytotoxicity able to pharmacologically modulate vasodilation.

TEMPERATURE EFFECTS ON THE STOCHASTIC GATING OF THE IP3R CALCIUM RELEASE CHANNEL: A NUMERICAL SIMULATION STUDY

2009 ◽  
Vol 17 (04) ◽  
pp. 817-852 ◽  
Author(s):  
H. H. HAERI ◽  
S. M. HASHEMIANZADEH ◽  
M. MONAJJEMI
Keyword(s):  
Calcium Ion ◽  
Temperature Effects ◽  
Calcium Release ◽  
Effect Of Temperature ◽  
Gillespie Algorithm ◽  
Reaction Paths ◽  
Calcium Release Channel ◽  
Open Probability ◽  
Release Channel ◽  
Time Domains

The importance of the kinetic study of endoplasmatic calcium ion channels in different intracellular processes is known today. Although there are few experimental reports on the temperature dependency of IP3R channel functions, we did not find any detailed theoretical study on this subject. For this purpose, we used a modified Gillespie algorithm to investigate the effect of temperature on the conditions affecting the open state of a single subunit of the De Young-Keizer (DYK) model. Population of the states was considered as the subject of fluctuation. Key features of the channel, such as bell-shaped dependency of open probability to the Calcium concentrations were modeled at different temperatures, too. The range of temperature variation was selected by regarding the experimental data on IP3R channel. By increasing the temperature, we had the very slow time domains (t: 10-1 s ) and the much slower time domains (t: 100 s ) in addition to other time domains, which could be seen as new time categories in InsP3R studies, and so the results were reported in these time domains, as well. We found out that increase in temperature declined the open probability in some concentrations of Ca 2+ and/or IP3. Also, by introducing the intensity graphs, broadening of the range of fluctuations and lowering of the order of frequency of fluctuations for the population of each state were observed due to the temperature increments. The temperature effects on the activation and inactivation states of the channel were studied in the framework of the reaction paths. We did not find similar paths at different time domains; several paths observed which were totally different all together. These time-dependent reaction paths are also depending on the Ca 2+ and/or the IP3 concentrations. So, one can predict the most probable reaction paths at different concentrations and temperatures and also determine which kind of the path it is; a path for closing the channel or a path to open it. Finally, the temperature effects on the calcium inhibited states were studied. We found out that calcium ion inhibitions were shifted to lower calcium concentration by increasing the temperature. The results suggests that inhibiting role of calcium is not only [ Ca 2+] and/or [IP3] dependent, but also temperature dependent.

scholarly journals Divalent cation activation and inhibition of single calcium release channels from sheep cardiac sarcoplasmic reticulum.

1990 ◽  
Vol 95 (5) ◽  
pp. 981-1005 ◽  
Author(s):  
R H Ashley ◽  
A J Williams
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Lipid Bilayers ◽  
Calcium Release ◽  
Single Channel ◽  
Fluctuation Analysis ◽  
Open Probability ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Channel Opening ◽  
Lifetime Analysis ◽  
Single Channel Currents

Single Ca2+ release channels from vesicles of sheep cardiac junctional sarcoplasmic reticulum have been incorporated into uncharged planar lipid bilayers. Single-channel currents were recorded from Ca2(+)-activated channels that had a Ca2+ conductance of approximately 90 pS. Channel open probability increased sublinearly as the concentration of free Ca2+ was raised at the myoplasmic face, and without additional agonists the channels could not be fully activated even by 100 microM free Ca2+. Lifetime analysis revealed a minimum of two open and three closed states, and indicates that Ca2+ activated the channels by interacting with at least one of the closed states to increase the rate of channel opening. Correlations between adjacent lifetimes suggested there were at least two pathways between the open- and closed-state aggregates. An analysis of bursting behavior also revealed correlations between successive burst lengths and the number of openings per burst. The latter had two geometric components, providing additional evidence for at least two open states. One component appeared to comprise unit bursts, and the lifetime of most of these fell within the dominant shorter open-time distribution associated with over 90% of all openings. A cyclic gating scheme is proposed, with channel activation regulated by the binding of Ca2+ to a closed conformation of the channel protein. Mg2+ may inhibit activation by competing for this binding site, but lifetime and fluctuation analysis suggested that once activated the channels continue to gate normally.

scholarly journals Agonist-dependent Phosphorylation of the Inositol 1,4,5-Trisphosphate Receptor

1999 ◽  
Vol 113 (6) ◽  
pp. 851-872 ◽  
Author(s):  
Andrew P. LeBeau ◽  
David I. Yule ◽  
Guy E. Groblewski ◽  
James Sneyd
Keyword(s):  
Acinar Cells ◽  
Calcium Oscillations ◽  
Pancreatic Acinar Cells ◽  
Ip3 Receptors ◽  
Ip3 Receptor ◽  
Open Probability ◽  
Probability Curve ◽  
Long Period ◽  
Inositol 1,4,5 Trisphosphate ◽  
S Period

The properties of inositol 1,4,5-trisphosphate (IP3)-dependent intracellular calcium oscillations in pancreatic acinar cells depend crucially on the agonist used to stimulate them. Acetylcholine or carbachol (CCh) cause high-frequency (10–12-s period) calcium oscillations that are superimposed on a raised baseline, while cholecystokinin (CCK) causes long-period (&gt;100-s period) baseline spiking. We show that physiological concentrations of CCK induce rapid phosphorylation of the IP3 receptor, which is not true of physiological concentrations of CCh. Based on this and other experimental data, we construct a mathematical model of agonist-specific intracellular calcium oscillations in pancreatic acinar cells. Model simulations agree with previous experimental work on the rates of activation and inactivation of the IP3 receptor by calcium (DuFour, J.-F., I.M. Arias, and T.J. Turner. 1997. J. Biol. Chem. 272:2675–2681), and reproduce both short-period, raised baseline oscillations, and long-period baseline spiking. The steady state open probability curve of the model IP3 receptor is an increasing function of calcium concentration, as found for type-III IP3 receptors by Hagar et al. (Hagar, R.E., A.D. Burgstahler, M.H. Nathanson, and B.E. Ehrlich. 1998. Nature. 396:81–84). We use the model to predict the effect of the removal of external calcium, and this prediction is confirmed experimentally. We also predict that, for type-III IP3 receptors, the steady state open probability curve will shift to lower calcium concentrations as the background IP3 concentration increases. We conclude that the differences between CCh- and CCK-induced calcium oscillations in pancreatic acinar cells can be explained by two principal mechanisms: (a) CCK causes more phosphorylation of the IP3 receptor than does CCh, and the phosphorylated receptor cannot pass calcium current; and (b) the rate of calcium ATPase pumping and the rate of calcium influx from the outside the cell are greater in the presence of CCh than in the presence of CCK.

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