scholarly journals Dantrolene suppresses spontaneous Ca2+ release without altering excitation-contraction coupling in cardiomyocytes of aged mice

2014 ◽  
Vol 307 (6) ◽  
pp. H818-H829 ◽  
Author(s):  
Timothy L. Domeier ◽  
Cale J. Roberts ◽  
Anne K. Gibson ◽  
Laurin M. Hanft ◽  
Kerry S. McDonald ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Dysfunction ◽  
Wave Amplitude ◽  
Left Ventricular ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Aged Mice ◽  
Cell Shortening ◽  
Antiarrhythmic Effects ◽  
Young Mice

Cardiac dysfunction in the aged heart reflects abnormalities in cardiomyocyte Ca2+ homeostasis including altered Ca2+ cycling through the sarcoplasmic reticulum (SR). The ryanodine receptor antagonist dantrolene exerts antiarrhythmic effects by preventing spontaneous diastolic Ca2+ release from the SR. We tested the hypothesis that dantrolene prevents spontaneous Ca2+ release without altering excitation-contraction coupling in aged myocardium. Left ventricular cardiomyocytes isolated from young (3 to 4 mo) and aged (24–26 mo) C57BL/6 mice were loaded with the Ca2+ indicator fluo-4. Amplitudes of action potential-induced Ca2+ transients at 1-Hz pacing were similar between young and aged mice, yet cell shortening was impaired in aged mice. Isoproterenol (1 μM) increased Ca2+ transient amplitude and cell shortening to identical levels in young and aged; dantrolene (1 μM) had no effect on Ca2+ transients or cell shortening during pacing. Under Ca2+ overload conditions induced with 10 mM extracellular Ca2+ concentration, spontaneous Ca2+ waves were of diminished amplitude and associated with lower SR Ca2+ content in aged versus young mice. Despite no effect in young mice, dantrolene increased SR Ca2+ content and Ca2+ wave amplitude in aged mice. In the presence of isoproterenol following rest from 1-Hz pacing, Ca2+ spark frequency was elevated in aged mice, yet the time to spontaneous Ca2+ wave was similar between young and aged mice; dantrolene decreased Ca2+ spark frequency and prolonged the time to Ca2+ wave onset in aged mice with no effect in young mice. Thus dantrolene attenuates diastolic Ca2+ release in the aged murine heart that may prove useful in preventing cardiac dysfunction.

scholarly journals Modification of sarcoplasmic reticulum (SR) Ca2+ release by FK506 induces defective excitation-contraction coupling only when SR Ca2+ recycling is disturbed

2005 ◽  
Vol 83 (4) ◽  
pp. 357-366 ◽  
Author(s):  
Shu Yoshihara ◽  
Hiroshi Satoh ◽  
Masao Saotome ◽  
Hideki Katoh ◽  
Hajime Terada ◽  
...  
Keyword(s):  
Steady State ◽  
Sarcoplasmic Reticulum ◽  
Normal Condition ◽  
Binding Protein ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Cell Shortening ◽  
Fk506 Binding Protein ◽  
Ec Coupling ◽  
Protein Dissociation

This study examined whether the effects of FK506-binding protein dissociation from sarcoplasmic reticulum (SR) Ca2+ release channels on excitation-contraction (EC) coupling changed when SR Ca2+ reuptake and (or) the trans-sarcolemmal Ca2+ extrusion were altered. The steady-state twitch Ca2+ transient (CaT), cell shortening, post-rest caffeine-induced CaT, and Ca2+ sparks were measured in rat ventricular myocytes using laser-scanning confocal microscopy. In the normal condition, 50 µmol FK506/L significantly increased steady-state CaT, cell shortening, and post-rest caffeine-induced CaT. When the cells were solely perfused with thapsigargin, FK506 did not reduce any of the states, but when low [Ca2+]0 (0.1 mmol/L) was perfused additionally, FK506 reduced CaT and cell shortening, and accelerated the reduction of post-rest caffeine-induced CaT. FK506 significantly increased Ca2+ spark frequency in the normal condition, whereas it mainly prolonged duration of individual Ca2+ sparks under the combination of thapsigargin and low [Ca2+]0 perfusion. Modification of SR Ca2+ release by FK506 impaired EC coupling only when released Ca2+ could not be taken back into the SR and was readily extruded to the extracellular space. Our findings could partly explain the controversy regarding the contribution of FK506-binding protein dissociation to defective EC coupling.Key words: FK506, ryanodine receptor, sarcoplasmic reticulum Ca2+-ATPase, Na+/Ca2+ exchange, excitation-contraction coupling

Sustained high O2 use for Ca2+ handling in rat ventricular slices under decreased free shortening after ryanodine

2001 ◽  
Vol 281 (2) ◽  
pp. H566-H572 ◽  
Author(s):  
Hisaharu Kohzuki ◽  
Hiromi Misawa ◽  
Susumu Sakata ◽  
Yoshimi Ohga ◽  
Miyako Takaki
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cyclopiazonic Acid ◽  
Left Ventricular ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
High O2

We hypothesized that O2 wasting of Ca2+handling in the excitation-contraction coupling in ryanodine-treated failing hearts might derive from an increased external Ca2+extrusion via Na+/Ca2+ exchanger and futile Ca2+ cycling via sarcoplasmic reticulum (SR) Ca2+-ATPase. We tested this hypothesis by mechanoenergetic studies using rat left ventricular slices. After the slices were treated with ryanodine (0.1 μM), 1-Hz free shortening significantly decreased by 78–85%, whereas the observed O2consumption (V˙o 2) required for total Ca2+ handling, increased from 0.79 to 1.13 ml O2 · min−1 · 100 g LV−1 (155.6% of control). We reconfirmed that cyclopiazonic acid (10 μM), a blocker of SR Ca2+-ATPase, decreased V˙o 2 by 75–80% in normal slices. However, 100 μM of cyclopiazonic acid was needed to inhibit the V˙o 2 by 80% after ryanodine treatment. Blockade of a sarcolemmal Na+/Ca2+exchanger by KB-R7943 (10 μM) significantly decreasedV˙o 2 by 45% after ryanodine treatment without significant effects on normal slices. Our results indicated that the V˙o 2 increase following ryanodine treatment was derived from a net change of an increased external Ca2+ extrusion via Na+/Ca2+exchanger and futile Ca2+ cycling via SR Ca2+-ATPase.

Cardiac and muscle fatigue due to relative functional overload induced by excessive stimulation, hypersensitive excitation–contraction coupling, or diminished performance capacity correlates with sarcoplasmic reticulum failure

1991 ◽  
Vol 69 (2) ◽  
pp. 262-268 ◽  
Author(s):  
Peter James O'brien ◽  
Hua Shen ◽  
Janice Weiler ◽  
C. David Ianuzzo ◽  
Carin Wittnich ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Atpase Activity ◽  
Malignant Hyperthermia ◽  
Muscle Fatigue ◽  
Left Ventricular ◽  
Transport Activity ◽  
Excitation Contraction Coupling ◽  
Performance Capacity ◽  
Contraction Coupling ◽  
Ca Transport

The development of muscle fatigue due to exhaustive exercise is associated with impaired sarcoplasmic reticulum (SR) Ca-transport activity. This study tested the hypothesis that SR failure is a consistent feature of cardiac and skeletal muscle fatigue owing to relative functional overload regardless of the method of induction: excessive stimulation, diminished performance capacity, or excessive excitation–contraction coupling. The Ca-transport activity was determined using three unique models of muscle fatigue: chronic and rapid ventricular pacing in dogs; metabolic inhibition caused by global cardiac ischemia in swine; and the hypermetabolic syndrome of porcine malignant hyperthermia (MH). Both pacing- and ischemia-induced fatigue resulted in reduction of SR Ca-transport ATPase activity: from 275 ± 58 to 159 ± 57 nmol∙min−1∙mg−1 (mU/mg) and from 577 ± 82 to 177 ± 133 mU/mg, respectively. Both pacing-induced fatigue and halothane-induced MH resulted in reduction of Ca-sequestration activity of muscle homogenates from 5.95 ± 2.4 to 3.11 ± 0.67 nM/s at 300 nM Ca and 38.7 ± 10.5 to 16.3 ± 8.0 nM/s at 1500 nM Ca, respectively (all p < 0.01). The isolated SR Ca-ATPase activity correlated with Ca-sequestration activity of myocardial homogenates (r = 0.76; p < 0.005). Different models were used to study the relationship of Ca-transport activity with relaxation function, degree of acidosis, and ionized Ca concentration. In the pacing model Ca-ATPase activity and left ventricular diastolic area were correlated (r = −0.64), in the ischemia model Ca-ATPase activity was highly correlated with myocardial lactate concentration (r = −0.83) and acidity (r = −0.85) but not glycogen content, and in the malignant hyperthermia model Ca-sequestration activity was correlated with myocardial ionized Ca concentration (r = −0.63) (all p < 0.001). We conclude that failure of Ca sequestration by SR plays a major role in the pathogenesis of cardiac and muscle fatigue and failure owing to relative functional overload. A model is presented for the role of the SR in the pathogenesis of striated muscle fatigue.Key words: heart disease, fatigue, sarcoplasmic reticulum, Ca ATPase, Ca channel, malignant hyperthermia.

scholarly journals Role of TFEB Mediated Autophagy, Oxidative Stress, Inflammation, and Cell Death in Endotoxin Induced Myocardial Toxicity of Young and Aged Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Fang Li ◽  
Fangfang Lang ◽  
Huilin Zhang ◽  
Liangdong Xu ◽  
Yidan Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cardiac Dysfunction ◽  
Myocardial Injury ◽  
Troponin I ◽  
Left Ventricular ◽  
Aged Mice ◽  
Lps Challenge ◽  
Age Dependent ◽  
Young Mice

Elderly patients are susceptible to sepsis. LPS induced myocardial injury is a widely used animal model to assess sepsis induced cardiac dysfunction. The age dependent mechanisms behind sepsis susceptibility were not studied. We analyzed age associated changes to cardiac function, cell death, inflammation, oxidative stress, and autophagy in LPS induced myocardial injury. Both young and aged C57BL/6 mice were used for LPS administration. The results demonstrated that LPS induced more cardiac injury (creatine kinase, lactate dehydrogenase, troponin I, and cardiac myosin-light chains 1), cardiac dysfunction (left ventricular inner dimension, LVID, and ejection fraction (EF)), cell death, inflammation, and oxidative stress in aged mice compared to young mice. However, a significant age dependent decline in autophagy was observed. Translocation of Transcription Factor EB (TFEB) to nucleus and formation of LC3-II were significantly reduced in LPS administered aged mice compared to young ones. In addition to that, downstream effector of TFEB, LAMP-1, was induced in response to LPS challenge in young mice. The present study newly demonstrates that TFEB mediated autophagy is crucial for protection against LPS induced myocardial injury particularly in aging senescent heart. Targeting this autophagy-oxidative stress-inflammation-cell death axis may provide a novel therapeutic strategy for cardioprotection in the elderly.

Cardiac dysfunction in terms of left ventricular mechanical work and energetics in hypothyroid rats

2002 ◽  
Vol 283 (2) ◽  
pp. H631-H641 ◽  
Author(s):  
Yoshimi Ohga ◽  
Susumu Sakata ◽  
Chikako Takenaka ◽  
Takehisa Abe ◽  
Tsuyoshi Tsuji ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Cardiac Dysfunction ◽  
Myocardial Oxygen Consumption ◽  
Left Ventricular ◽  
Mechanical Work ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Plasmic Reticulum ◽  
Heart Preparation ◽  
Whole Heart

We hypothesized that cardiac dysfunction in hypothyroidism is mainly caused by the impairment of Ca2+ handling in excitation-contraction coupling. To prove this hypothesis, we investigated left ventricular (LV) mechanical work and energetics without interference of preload and afterload in an excised, blood-perfused whole heart preparation from hypothyroid rats. We found that LV inotropism and lusitropism were significantly depressed, and these depressions were causally related to decreased myocardial oxygen consumption for Ca2+ handling and for basal metabolism. The oxygen costs of LV contractility for Ca2+ and for dobutamine in the hypothyroid rats did not differ from those in age-matched normal rats. The expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) significantly decreased and that of phospholamban significantly increased. The present results revealed that changes in LV energetics associated with decreased mechanical work in hypothyroid rats are mainly caused by the impairment of Ca2+ uptake via SERCA2. We conclude that the impairment of Ca2+ uptake plays an important role in the pathogenesis of cardiac dysfunction in hypothyroidism.

scholarly journals Remodeling of t-system and proteins underlying excitation-contraction coupling in aging versus failing human heart

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yankun Lyu ◽  
Vipin K. Verma ◽  
Younjee Lee ◽  
Iosif Taleb ◽  
Rachit Badolia ◽  
...  
Keyword(s):  
Heart Function ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Excitation Contraction Coupling ◽  
Transverse Tubular System ◽  
Contraction Coupling ◽  
Senescent Phenotype ◽  
Cellular Microstructure ◽  
T System

AbstractIt is well established that the aging heart progressively remodels towards a senescent phenotype, but alterations of cellular microstructure and their differences to chronic heart failure (HF) associated remodeling remain ill-defined. Here, we show that the transverse tubular system (t-system) and proteins underlying excitation-contraction coupling in cardiomyocytes are characteristically remodeled with age. We shed light on mechanisms of this remodeling and identified similarities and differences to chronic HF. Using left ventricular myocardium from donors and HF patients with ages between 19 and 75 years, we established a library of 3D reconstructions of the t-system as well as ryanodine receptor (RyR) and junctophilin 2 (JPH2) clusters. Aging was characterized by t-system alterations and sarcolemmal dissociation of RyR clusters. This remodeling was less pronounced than in HF and accompanied by major alterations of JPH2 arrangement. Our study indicates that targeting sarcolemmal association of JPH2 might ameliorate age-associated deficiencies of heart function.

scholarly journals Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2

2014 ◽  
Vol 306 (7) ◽  
pp. H1018-H1024 ◽  
Author(s):  
N. T. Boardman ◽  
J. M. Aronsen ◽  
W. E. Louch ◽  
I. Sjaastad ◽  
F. Willoch ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Left Ventricular ◽  
Lv Function ◽  
Mechanical Function ◽  
Transport Mechanisms ◽  
Working Capacity ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Plasmic Reticulum ◽  
The Relationship

Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 transports Ca2+ from the cytosol into the sarcoplasmic reticulum of cardiomyocytes and is essential for maintaining myocardial Ca2+ handling and thus the mechanical function of the heart. SERCA2 is a major ATP consumer in excitation-contraction coupling but is regarded to contribute to energetically efficient Ca2+ handling in the cardiomyocyte. Previous studies using cardiomyocyte-specific SERCA2 knockout (KO) mice have demonstrated that decreased SERCA2 activity reduces the Ca2+ transient amplitude and induces compensatory Ca2+ transport mechanisms that may lead to more inefficient Ca2+ transport. In this study, we examined the relationship between left ventricular (LV) function and myocardial O2 consumption (MV̇o2) in ex vivo hearts from SERCA2 KO mice to directly measure how SERCA2 elimination influences mechanical and energetic features of the heart. Ex vivo hearts from SERCA2 KO hearts developed mechanical dysfunction at 4 wk and demonstrated virtually no working capacity at 7 wk. In accordance with the reported reduction in Ca2+ transient amplitude in cardiomyocytes from SERCA2 KO mice, work-independent MV̇o2 was decreased due to a reduced energy cost of excitation-contraction coupling. As these hearts also showed a marked impairment in the efficiency of chemomechanical energy transduction (contractile efficiency, i.e, work-dependent MV̇o2), hearts from SERCA2 KO mice were found to be mechanically inefficient. This ex vivo evaluation of mechanical and energetic function in hearts from SERCA2 KO mice brings together findings from previous experimental and mathematical modeling-based studies and demonstrates that reduced SERCA2 activity not only leads to mechanical dysfunction but also to energetic dysfunction.

Calmodulin and Excitation-Contraction Coupling

Physiology ◽  
2000 ◽  
Vol 15 (6) ◽  
pp. 281-284 ◽  
Author(s):  
Susan L. Hamilton ◽  
Irina Serysheva ◽  
Gale M. Strasburg
Keyword(s):  
Skeletal Muscle ◽  
Ion Channels ◽  
Sarcoplasmic Reticulum ◽  
Release Channel ◽  
Excitation Contraction Coupling ◽  
Transverse Tubule ◽  
Contraction Coupling ◽  
Voltage Dependent ◽  
Important Regulator ◽  
Precise Role

Excitation-contraction coupling in cardiac and skeletal muscle involves the transverse-tubule voltage-dependent Ca2+ channel and the sarcoplasmic reticulum Ca2+ release channel. Both of these ion channels bind and are modulated by calmodulin in both its Ca2+-bound and Ca2+-free forms. Calmodulin is, therefore, potentially an important regulator of excitation-contraction coupling. Its precise role, however, has not yet been defined.

Sign in / Sign up

Export Citation Format

Share Document