Influence of experimental diabetes on sarcoplasmic reticulum function in rat ventricular muscle

1991 ◽  
Vol 260 (2) ◽  
pp. H341-H354 ◽  
Author(s):  
R. A. Bouchard ◽  
D. Bose
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Experimental Diabetes ◽  
Cardiac Contractility ◽  
Cellular Mechanisms ◽  
Time To Peak ◽  
Relative Contribution ◽  
Force Relation ◽  
Complete Relaxation ◽  
Streptozotocin Induced Diabetes ◽  
Fractional Release

We examined whether the decrease in cardiac contractility in streptozotocin-induced diabetes in the rat is accompanied by reduced or excessive loading of the sarcoplasmic reticulum (SR) with Ca2+. Pooled SR Ca2+ content and fractional release on stimulation were estimated with rapid cooling contracture (RCC) and twitch height measurements, respectively. Interval-force relation was studied to assess the ability of diabetic tissue to alter the relative contribution of SR Ca2+ for contraction. Two months after injection with streptozotocin, peak isometric contraction and steady-state RCC decreased in parallel to approximately 50% of control values. The time to peak force development and complete relaxation was prolonged to 156 and 161% in diabetes in the presence of 1.25 and 2.5 mM extracellular Ca2+ concentration [Ca2+]o, respectively. A stepwise increase in the rate of stimulation from 0.2 to 0.5 and 1.0 Hz resulted in a negative force staircase, the slope of which was identical in control and diabetic animals in each [Ca2+]o tested. Postrest contractions and RCC, after variable test intervals, were significantly depressed after 0.2 and 0.5 Hz stimulation in diabetic muscles at 1.25 mM [Ca2+]o. This defect of SR Ca2+ availability was reversed by increasing the stimulation frequency to 1.0 Hz or by elevating [Ca2+]o to 2.5 mM. The results suggest that the marked reduction of developed tension in diabetic tissues was a consequence of depleted SR Ca2+ stores, rather than a result of chronic SR Ca2+ overloading. The maintained integrity of the interval-force relation in the presence of diabetes implies that the cellular mechanisms responsible for frequency- and time-dependent alterations in SR Ca2+ availability are not disturbed at this stage of disease.

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

scholarly journals Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime

2021 ◽  
Author(s):  
María Florencia Racioppi ◽  
Juan Ignacio Burgos ◽  
Malena Morell ◽  
Luis Alberto Gonano ◽  
Martín Vila Petroff
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Contractility ◽  
Cellular Mechanisms ◽  
Rat Cardiomyocytes ◽  
Calcium Calmodulin Dependent ◽  
Differential Behavior ◽  
Proven Efficacy ◽  
Dependent Inhibition ◽  
Atpase Inhibition ◽  
Unique Mechanism

Background Istaroxime is an inhibitor of Na + /K + ATPase with proven efficacy to increase cardiac contractility and to accelerate relaxation attributable to a relief in phospholamban‐dependent inhibition of the sarcoplasmic reticulum Ca 2+ ATPase. We have previously shown that pharmacologic Na + /K + ATPase inhibition promotes calcium/calmodulin‐dependent kinase II activation, which mediates both cardiomyocyte death and arrhythmias. Here, we aim to compare the cardiotoxic effects promoted by classic pharmacologic Na + /K + ATPase inhibition versus istaroxime. Methods and Results Ventricular cardiomyocytes were treated with ouabain or istaroxime at previously tested equi‐inotropic concentrations to compare their impact on cell viability, apoptosis, and calcium/calmodulin‐dependent kinase II activation. In contrast to ouabain, istaroxime neither promoted calcium/calmodulin‐dependent kinase II activation nor cardiomyocyte death. In addition, we explored the differential behavior promoted by ouabain and istaroxime on spontaneous diastolic Ca 2+ release. In rat cardiomyocytes, istaroxime did not significantly increase Ca 2+ spark and wave frequency but increased the proportion of aborted Ca 2+ waves. Further insight was provided by studying cardiomyocytes from mice that do not express phospholamban. In this model, the lower Ca 2+ wave incidence observed with istaroxime remains present, suggesting that istaroxime‐dependent relief on phospholamban‐dependent sarcoplasmic reticulum Ca 2+ ATPase 2A inhibition is not the unique mechanism underlying the low arrhythmogenic profile of this drug. Conclusions Our results indicate that, different from ouabain, istaroxime can reach a significant inotropic effect without leading to calcium/calmodulin‐dependent kinase II–dependent cardiomyocyte death. Additionally, we provide novel insights regarding the low arrhythmogenic impact of istaroxime on cardiac Ca 2+ handling.

Defibrillation depresses heart sarcoplasmic reticulum calcium pump: a mechanism of postshock dysfunction

1998 ◽  
Vol 274 (1) ◽  
pp. H98-H105 ◽  
Author(s):  
Douglas L. Jones ◽  
Njanoor Narayanan
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Atp Hydrolysis ◽  
Myocardial Dysfunction ◽  
Cardiac Contractility ◽  
Membrane Vesicles ◽  
Intracellular Ca ◽  
Current Densities ◽  
Langendorff Hearts ◽  
Pumping Function ◽  
Sarcoplasmic Reticulum Calcium

Presently, the only therapy for ventricular fibrillation is delivery of high-voltage shocks. Despite “successful defibrillation,” patients may have poor cardiac contractility, the mechanisms of which are unknown. Intracellular Ca2+ handling by the sarcoplasmic reticulum (SR) plays a major role in contractility. We tested the hypothesis that defibrillation shocks interfere with Ca2+ transport function of cardiac SR. Rats anesthetized with pentobarbital sodium had bilateral electrodes implanted subcutaneously for transthoracic shocks. A series of 10 shocks, 10 s apart, at 0–250 V was delivered from a trapezoidal defibrillator. The hearts were rapidly removed, SR-enriched membrane vesicles were isolated, and ATP-dependent Ca2+ uptake and Ca2+-stimulated ATP hydrolysis were determined. There was a marked, shock-related decline in Ca2+ uptake, whereas adenosinetriphosphatase activity remained unaltered. The polypeptide compositions were similar in control and shocked SR. In Langendorff hearts, shocks also decreased contractility and slowed relaxation. These data indicate that shocks with current densities similar to defibrillation depress Ca2+-pumping function of cardiac SR because of uncoupling of ATP hydrolysis and Ca2+ transport. Shock-induced impairment of Ca2+ pump function may underlie postshock myocardial dysfunction.

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.

Effects of E. coli sepsis and myocardial depressant factor on interval-force relations in dog ventricle

1993 ◽  
Vol 264 (5) ◽  
pp. H1402-H1410 ◽  
Author(s):  
P. Jha ◽  
H. Jacobs ◽  
D. Bose ◽  
R. Wang ◽  
J. Yang ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Steady State ◽  
Sarcoplasmic Reticulum ◽  
Calcium Metabolism ◽  
Calcium Content ◽  
Left Ventricular ◽  
Muscle Preparation ◽  
E Coli ◽  
Calcium Availability ◽  
Fractional Release

We examined whether depressed left ventricular (LV) contractility during Escherichia coli sepsis in dogs was due to a decrease in the fractional release of calcium from the sarcoplasmic reticulum (SR) or a reduction in calcium content in this organelle. To indirectly assess SR calcium availability in a right ventricular (RV) trabecular muscle preparation, we utilized functional indexes of cellular myocardial calcium metabolism, which included rapid-cooling contracture (RCC), an indicator of SR calcium content, and postrest contraction (PRC), an index of calcium availability from the release compartment of the SR. Measurements were made during steady-state stimulation at 0.5 and 1.5 Hz, during which time rest intervals of 30-240 s were periodically imposed. SR calcium availability was measured in RV trabeculae of dogs subjected to 4 h of E. coli sepsis and was compared with calcium availability measured in nonseptic dogs. We further characterized a filterable cardiodepressant substance (FCS), which has been previously shown to be associated with LV depression in this model, to determine whether it produced changes in calcium metabolism similar to those found in sepsis. The results showed that calcium availability from the SR of septic dogs was not impaired. Furthermore, FCS was found in the 10,000- to 30,000-mol wt fraction of plasma and produced changes in PRC in canine trabeculae that were similar to those produced during sepsis. We conclude that, as assessed by PRC and RCC, SR calcium content and release are not impaired in sepsis.

scholarly journals Cellular mechanisms of reduced sarcoplasmic reticulum Ca2+content in L-thyroxin-induced rat ventricular hypertrophy

2008 ◽  
Vol 29 (4) ◽  
pp. 430-436 ◽  
Author(s):  
Lai-jing SONG ◽  
Guan-lei WANG ◽  
Jie LIU ◽  
Qin-ying QIU ◽  
Jing-hua OU ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ventricular Hypertrophy ◽  
Cellular Mechanisms

The effect of N-acetylcysteine on cardiac contractility to dobutamine in rats with streptozotocin-induced diabetes

2005 ◽  
Vol 519 (1-2) ◽  
pp. 118-126 ◽  
Author(s):  
Xing Cheng ◽  
Zhengyuan Xia ◽  
Joyce M. Leo ◽  
Catherine C.Y. Pang
Keyword(s):  
Cardiac Contractility ◽  
Streptozotocin Induced Diabetes

Phospholamban-to-SERCA2 ratio controls the force-frequency relationship

1999 ◽  
Vol 276 (3) ◽  
pp. H779-H785 ◽  
Author(s):  
Markus Meyer ◽  
Wolfgang F. Bluhm ◽  
Huaping He ◽  
Steven R. Post ◽  
Frank J. Giordano ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Transgenic Mice ◽  
Cardiac Myocytes ◽  
Cardiac Contractility ◽  
Adult Rabbit ◽  
Force Frequency ◽  
Papillary Muscles ◽  
Inhibitory Protein ◽  
Frequency Relationship ◽  
Myocyte Contractility

The force-frequency relationship (FFR) describes the frequency-dependent potentiation of cardiac contractility. The interaction of the sarcoplasmic reticulum Ca2+-adenosinetriphosphatase (SERCA2) with its inhibitory protein phospholamban (PLB) might be involved in the control of the FFR. The FFR was analyzed in two systems in which the PLB-to-SERCA2 ratio was modulated. Adult rabbit cardiac myocytes were transduced with adenovirus encoding for SERCA2, PLB, and β-galactosidase (control). After 3 days, the relative PLB/SERCA2 values were significantly different between groups (SERCA2, 0.5; control, 1.0; PLB, 4.5). SERCA2 overexpression shortened relaxation by 23% relative to control, whereas PLB prolonged relaxation by 39% and reduced contractility by 47% (0.1 Hz). When the stimulation frequency was increased to 1.5 Hz, myocyte contractility was increased by 30% in control myocytes. PLB-overexpressing myocytes showed an augmented positive FFR (+78%), whereas SERCA2-transduced myocytes displayed a negative FFR (−15%). A more negative FFR was also found in papillary muscles from SERCA2 transgenic mice. These findings demonstrate that the ratio of phospholamban to SERCA2 is an important component in the control of the FFR.

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