Doxorubicin-induced late cardiotoxicity: delayed impairment of Ca2+-handling mechanisms in the sarcoplasmic reticulum in the rat

2000 ◽  
Vol 78 (4) ◽  
pp. 329-338 ◽  
Author(s):  
Akihito Chugun ◽  
Kyosuke Temma ◽  
Toshifumi Oyamada ◽  
Natsuyo Suzuki ◽  
Yoshinori Kamiya ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Left Atrial ◽  
Force Frequency ◽  
Ventricular Muscle ◽  
Doxorubicin Treatment ◽  
Time To Peak ◽  
Atrial Muscle ◽  
Late Cardiotoxicity ◽  
Cardiac Functions ◽  
Rat Hearts

Doxorubicin treatment causes delayed development of cardiotoxicity. Whether the doxorubicin-induced impairment of cardiac functions reverses or progresses with time after the cessation of the treatment was examined. The rats were injected with doxorubicin (2.5 mg/kg, i.v., once a week for 3 weeks) and sacrificed at 1 (1W), 13 (13W), or 18 (18W) weeks after the final doxorubicin administration. The time to peak of twitch contraction observed at 2-Hz stimulation was not altered in left atrial or ventricular muscle preparations isolated from 1W rats, but it was prolonged in those from 13W and 18W rats. The reduction of the magnitude of postrest contraction and the alteration of force-frequency relationships in left atrial muscle preparations in 1W rats were not significant, but were intensified in the 13W and 18W groups. Alterations in the postrest contraction and the force-frequency relationships in ventricular muscle preparations isolated from doxorubicin-treated rat hearts were weaker, but the pattern of alteration was similar to that observed in left atrial muscle preparations. Caffeine-induced contraction observed in skinned fibers that were isolated from the 1W rats was not altered, but it was reduced in the 18W rats. The Ca2+ sensitivity of contractile proteins was not altered in doxorubicin-treated rat hearts in any of the groups. The Kd values estimated from a [3H]ryanodine binding study were not altered, but the Bmax values were significantly lower in the 13W and 18W groups than those observed in control rats. These results suggest that the dysfunction of the sarcoplasmic reticulum progresses after the completion of doxorubicin treatment and contributes to the doxorubicin-induced late cardiotoxicity.Key words: doxorubicin, late cardiotoxicity, rat heart, sarcoplasmic reticulum.

Characteristics of the second inward current in cells isolated from rat ventricular muscle

1983 ◽  
Vol 219 (1217) ◽  
pp. 447-469 ◽  
Keyword(s):  
Single Cells ◽  
External Solution ◽  
Maximum Level ◽  
Charge Carriers ◽  
Ventricular Muscle ◽  
Inward Current ◽  
Adult Rat ◽  
Time To Peak ◽  
Rat Hearts ◽  
Steady Level

The second inward current ( I si ) in single cells isolated from ventricular muscle of adult rat hearts was measured in response to step depolarizations under voltage-clamp conditions. The major ion carrying this current was Ca, and I si was reduced or abolished by Mn, Ni, Cd, nifedipine, nimodipine and D600. Sr and Ba could substitute for Ca as charge carriers, and reduced the rate of apparent inactivation of I si . These effects of Sr and Ba, together with the relation between the steady level of apparent inactivation and membrane potential in Ca containing solution, were taken as evidence that inactivation was at least in part dependent on internal Ca. The reduction of external Na to 11% of normal caused a reduction in peak I si when Ca was present in the external solution, but did not reduce I si when Ca was replaced by Sr. It therefore seems unlikely that Na is a major charge carrier I si under the conditions of our experiments. The time-to-peak and rate of apparent inactivation of I si were faster than in previous studies that used multicellular preparations. Both the kinetics and peak amplitude of I si were markedly dependent on temperature ( Q 10 close to 3). Contraction of the cells, which was monitored optically, was initiated within 3 ms of the peak I si , reached a maximum level after approximately 40–50 ms, and was about 100 ms in duration.

Ca2+ and Na+ in rat myocytes showing different force-frequency relationships

1991 ◽  
Vol 261 (5) ◽  
pp. C739-C750 ◽  
Author(s):  
J. E. Frampton ◽  
S. M. Harrison ◽  
M. R. Boyett ◽  
C. H. Orchard
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Time Course ◽  
Cell Types ◽  
Stimulation Frequency ◽  
Force Frequency ◽  
Rat Hearts ◽  
Rate Of Decline ◽  
Frequency Relationship ◽  
Positive Force ◽  
In Cells

Intracellular [Ca2+] ([Ca2+]i), intracellular Na+ activity (aiNa), and contraction have been monitored in single myocytes isolated from the ventricles of rat hearts. Some of these cells showed an increase in the size of the twitch as stimulation frequency was increased (positive force-frequency relationship), while others showed a decrease in the strength of contraction as the frequency of stimulation was increased (negative force-frequency relationship). In cells that showed a positive force-frequency relationship, increasing stimulation frequency resulted in increases in aiNa, diastolic [Ca2+]i, systolic [Ca2+]i, and the amount of Ca2+ that could be released from the sarcoplasmic reticulum by caffeine. The rate of decline of the [Ca2+]i transient and the twitch also increased as stimulation frequency was increased. In cells that showed a negative force-frequency relationship, increasing stimulation frequency had less effect on aiNa and had either no effect or decreased systolic [Ca2+]i with no change in the amount of Ca2+ that could be released from the sarcoplasmic reticulum using caffeine. The rate of relaxation of the [Ca2+]i transient and the twitch again increased as stimulation frequency increased. The pattern and time course of mechanical restitution was the same in both cell types. Although these data are essentially descriptive, it is consistent with the hypothesis that the final contractile response observed during changes of stimulation frequency may be dependent on how the Ca2+ loading of the preparation varies with stimulation frequency.

scholarly journals Lower sarcoplasmic reticulum Ca2+ threshold for triggering afterdepolarizations in diabetic rat hearts

Heart Rhythm ◽  
2019 ◽  
Vol 16 (5) ◽  
pp. 765-772 ◽  
Author(s):  
Iuliana Popescu ◽  
Guo Yin ◽  
Sathya Velmurugan ◽  
Jeffrey R. Erickson ◽  
Florin Despa ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Diabetic Rat ◽  
Rat Hearts

scholarly journals Electrically-Induced Ventricular Fibrillation Alters Cardiovascular Function and Expression of Apoptotic and Autophagic Proteins in Rat Hearts

2019 ◽  
Vol 20 (7) ◽  
pp. 1628 ◽  
Author(s):  
Andras Czegledi ◽  
Agnes Tosaki ◽  
Alexandra Gyongyosi ◽  
Rita Zilinyi ◽  
Arpad Tosaki ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Ventricular Fibrillation ◽  
Cardiac Death ◽  
Caspase 3 ◽  
Recovery Period ◽  
Heart Rhythm ◽  
Heart Tissue ◽  
Altered Expression ◽  
Cardiac Functions ◽  
Rat Hearts

Background: The pathological heart contractions, called arrhythmias, especially ventricular fibrillation (VF), are a prominent feature of many cardiovascular diseases leading to sudden cardiac death. The present investigation evaluates the effect of electrically stimulated VF on cardiac functions related to autophagy and apoptotic mechanisms in isolated working rat hearts. Methods: Each group of hearts was subjected to 0 (Control), 1, 3, or 10 min of spacing-induced VF, followed by 120 min of recovery period and evaluated for cardiac functions, including aortic flow (AF), coronary flow (CF), cardiac output (CO), stroke volume (SV), and heart rate (HR). Hearts were also evaluated for VF effects on infarcted zone magnitude and Western blot analysis was conducted on heart tissue for expression of the apoptotic biomarker cleaved-caspase-3 and the autophagy proteins: p62, P-mTOR/mTOR, LC3BII/LC3BI ratio, and Atg5-12 complexes. Results: Data revealed that VF induced degradation in AF, CF, CO, and SV, which prominently included-variable post-VF capacity for recovery of normal heart rhythm; increased extent of infarcted heart tissue; altered expression of cleaved-caspase-3 suggesting potential for VF-mediated amplification of apoptosis. VF influence on expression of p62, LC3BII/LC3BI, and Atg5-12 proteins was complex, possibly due to differential effects of VF-induced expression on proteins comprising the autophagic program. Conclusions: VF was observed to cause time-dependent changes in autophagy processes, which with additional analysis under ongoing investigations, likely to yield novel therapeutic targets for the prevention of VF and sudden cardiac death.

Abnormal contraction caused by expression of Gi-coupled receptor in transgenic model of dilated cardiomyopathy

2001 ◽  
Vol 280 (4) ◽  
pp. H1653-H1659 ◽  
Author(s):  
Anthony J. Baker ◽  
Charles H. Redfern ◽  
Mark D. Harwood ◽  
Paul C. Simpson ◽  
Bruce R. Conklin
Keyword(s):  
Transgenic Mice ◽  
Right Ventricular ◽  
Dilated Cardiomyopathy ◽  
Myocardial Function ◽  
Expression System ◽  
Contractile Force ◽  
Ventricular Muscle ◽  
Time To Peak ◽  
Contraction And Relaxation

Although increased Gi signaling has been associated with dilated cardiomyopathy in humans, its role is not clear. Our goal was to determine the effects of chronically increased Gi signaling on myocardial function. We studied transgenic mice that expressed a Gi-coupled receptor (Ro1) that was targeted to the heart and regulated by a tetracycline-controlled expression system. Ro1 expression for 8 wk resulted in abnormal contractions of right ventricular muscle strips in vitro. Ro1 expression reduced myocardial force by >60% (from 35 ± 3 to 13 ± 2 mN/mm2, P < 0.001). Nevertheless, sensitivity to extracellular Ca2+ was enhanced. The extracellular [Ca2+] resulting in half-maximal force was lower with Ro1 expression compared with control (0.41 ± 0.05 vs. 0.88 ± 0.05 mM, P < 0.001). Ro1 expression slowed both contraction and relaxation kinetics, increasing the twitch time to peak (143 ± 6 vs. 100 ± 4 ms in control, P < 0.001) and the time to half relaxation (124 ± 6 vs. 75 ± 6 ms in control, P < 0.001). Increased pacing frequency increased contractile force threefold in control myocardium ( P < 0.001) but caused no increase of force in Ro1-expressing myocardium. When stimulation was interrupted with rests, postrest force increased in control myocardium, but there was postrest decay of force in Ro1-expressing myocardium. These results suggest that defects in contractility mediated by Gi signaling may contribute to the development of dilated cardiomyopathy.

scholarly journals Doxorubicin-induced late cardiotoxicity: Delayed impairment of Ca2+-handling mechanisms in the sarcoplasmic reticulum in the rat

2000 ◽  
Vol 82 ◽  
pp. 196
Author(s):  
Kyosuke Temma ◽  
Akihito Chugun ◽  
Natsuyo Suzuki ◽  
Kazunori Kamiya ◽  
Yukio Hara ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Late Cardiotoxicity
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