Myocardial calcium cycling defect in furazolidone cardiomyopathy

1991 ◽  
Vol 69 (12) ◽  
pp. 1833-1840 ◽  
Author(s):  
Peter James O'Brien ◽  
Hua Shen ◽  
Janice E. Weiler ◽  
S. Mehdi Mirsalimi ◽  
Richard J. Julian
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Ruthenium Red ◽  
Channel Activity ◽  
Release Channel ◽  
Calcium Sequestration ◽  
Pump Activity ◽  
Highly Correlated ◽  
Sarcoplasmic Reticulum Calcium

We have previously demonstrated that in furazolidone-induced congestive heart failure in turkeys the specific Ca2+-ATPase activity of myocardial sarcoplasmic reticulum (SR) is 60% increased in compensation for a 50% depression in net Ca2+-sequestration activity. This study tested the hypothesis that SR Ca2+-uptake and Ca2+-ATPase activities were uncoupled in this cardiomyopathy because of increased Ca2+-release channel activity. A novel microassay was used to monitor Ca2+ transport by myocardial homogenates using the fluorescent Ca2+ dye indo 1 to indicate extravesicular ionized Ca2+. The method is applied to cyropreserved biopsy specimens of myocardium and requires only 50 mg tissue. Both SR Ca2+-pump and SR Ca2+-channel activity were estimated using the channel-inhibitor ruthenium red (RR) and the mitochondrial inhibitor sodium azide. The specificity of the RR inhibition was confirmed using ryanodine. Cardiomyopathy was induced in 2-week-old turkey pouits by the addition of 0.07% furazolidone to their feed for 4 weeks. Compared with controls, myocardial maximal Ca2+-channel activity relative to maximal Ca2+-pump activity was 22% greater and duration of Ca2+-channel activity was 100% increased. However, the heart failure birds had 43 and 53% decreases in absolute maximal Ca2+-pumping and Ca2+-channel activities, respectively. The abnormal Ca2+-channel activity resulted in 200% greater time before initiation of net Ca2+ sequestration and 700% greater final myocardial Ca2+ concentrations. For all birds, the Ca2+-accumulating activity was highly correlated with Ca2+-release activity (all p < 0.05). These data indicate that in this animal model of congestive heart failure there is defective SR Ca2+-channel function resulting in abnormal Ca2+ homeostasis. However, this defect can only partially explain our previous finding of furazolidone-induced uncoupling of Ca2+ uptake from Ca2+-ATPase activities. The consequent myocardial Ca2+ overload predisposes the heart to fatigue and irreversible failure.Key words: sarcoplasmic reticulum, calcium sequestration, furazolidone cardiomyopathy, indo 1 spectrofluorometry.

Sarcoplasmic reticulum calcium leak and cardiac arrhythmias

2007 ◽  
Vol 35 (5) ◽  
pp. 952-956 ◽  
Author(s):  
M.G. Chelu ◽  
X.H.T. Wehrens
Keyword(s):  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Arrhythmias ◽  
Ventricular Arrhythmias ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Incomplete Closure ◽  
Sarcoplasmic Reticulum Calcium

Ventricular arrhythmias deteriorating into sudden cardiac death are a major cause of mortality worldwide. The recent linkage of a genetic form of cardiac arrhythmia to mutations in the gene encoding RyR2 (ryanodine receptor 2) has uncovered an important role of this SR (sarcoplasmic reticulum) calcium release channel in triggering arrhythmias. Mutant RyR2 channels give rise to spontaneous release of calcium (Ca2+) from the SR during diastole, which enhances the probability of ventricular arrhythmias. Several molecular mechanisms have been proposed to explain the gain-of-function phenotype observed in mutant RyR2 channels. Despite considerable differences between the models discussed in the present review, each predicts spontaneous diastolic Ca2+ leak from the SR due to incomplete closure of the RyR2 channel. Enhanced SR Ca2+ leak is also observed in common structural diseases of the heart, such as heart failure. In heart failure, defective channel regulation in the absence of inherited mutations may also increase SR Ca2+ leak and initiate cardiac arrhythmias. Therefore inhibition of diastolic Ca2+ leak through SR Ca2+ release channels has emerged as a new and promising therapeutic target for cardiac arrhythmias.

Sarcoplasmic reticulum Ca-release channel and ATP-synthesis activities are early myocardial markers of heart failure produced by rapid ventricular pacing in dogs

1994 ◽  
Vol 72 (9) ◽  
pp. 999-1006 ◽  
Author(s):  
Peter James O'Brien ◽  
Gordon W. Moe ◽  
Linda M. Nowack ◽  
Etienne A. Grima ◽  
Paul W. Armstrong
Keyword(s):  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Rate Constant ◽  
Atp Synthesis ◽  
Ca Channel ◽  
Ventricular Pacing ◽  
Channel Activity ◽  
Release Channel ◽  
Ca Uptake ◽  
Rapid Ventricular Pacing

The contraction–relaxation cycle of the heart is dependent on a cycle of ATP production and utilization and a cycle of Ca uptake and Ca release by the sarcoplasmic reticulum (SR). Heart failure (HF) is associated with abnormalities of myocardial Ca and ATP cycling, but the time course of their development is unknown. This study tested the hypothesis that, compared with ATP-utilizing and Ca-uptake activities, decreases in ATP-synthesis and Ca-release activities occurred earlier in the development of HF and persisted longer during recovery from HF. HF was induced by right ventricular pacing of dogs at 250 beats/min. Dogs were studied after 1 week of pacing (n = 8, early HF), at HF (n = 11, severe HF), and 4 weeks after cessation of pacing (n = 9) and were compared with dogs not subjected to pacing. At early HF, there were decreased activities (p < 0.05) of the SR Ca-release channel (rate constant from 199 ± 36 × 10−4 to 90 ± 16 × 10−4 s−1), mitochondrial ATP synthesis (from 11.2 ± 2.4 to 7.0 ± 2.2 international units (IU)/g), and creatine kinase (CK) from 2028 ± 266 to 1811 ± 79 IU/g). The decreased Ca-channel activity was due to a 32% decrease in maximal activity (rate constant from 249 ± 50 × 10−4 to 170 ± 29 × 10−4 s−1) and to a 2-fold increase (from 19.1 ± 12.4 to 42.0 ± 14.2%) in inhibition of maximal channel activity (p < 0.05). At severe HF, Ca-uptake (rate constant from 407 ± 41 × 10−4 to 296 ± 77 × 10−4 s−1) and ATP-utilization activities also became depressed (from 27.2 ± 3.3 to 20.3 ± 1.9 IU/g), and CK further decreased to 1321 ± 241 IU/g (p < 0.05). Four weeks after cessation of pacing, only total Ca-cycling (sum of Ca uptake and Ca release), Ca-uptake, and CK activities were significantly recovered (p < 0.05). Left ventricular ejection fraction was significantly correlated with total Ca cycling (n = 12, r = 0.68, p < 0.02), Ca-channel inhibition (n = 12, r = −0.60, p < 0.04), and basal ATPase (n = 11, r = 0.69, p < 0.02). We conclude that biochemical measurements of ATP- and Ca-cycling activities correlate with myocardial performance, and that compared with ATP-utilization and Ca-uptake activities, inhibition of ATP synthesis and Ca release occurs earlier in the development of HF and persists longer during recovery from HF.Key words: Ca-release channel, sarcoplasmic reticulum, rapid ventricular pacing, congestive heart failure, Ca ATPase pump, mitochondria.

scholarly journals Interfering with calcium release suppresses I gamma, the "hump" component of intramembranous charge movement in skeletal muscle.

1991 ◽  
Vol 97 (5) ◽  
pp. 845-884 ◽  
Author(s):  
L Csernoch ◽  
G Pizarro ◽  
I Uribe ◽  
M Rodríguez ◽  
E Ríos
Keyword(s):  
Skeletal Muscle ◽  
Time Course ◽  
Calcium Release ◽  
Time Derivative ◽  
Ruthenium Red ◽  
Total Charge ◽  
Charge Movement ◽  
Release Channel ◽  
Release Flux ◽  
Highly Correlated

Four manifestations of excitation-contraction (E-C) coupling were derived from measurements in cut skeletal muscle fibers of the frog, voltage clamped in a Vaseline-gap chamber: intramembranous charge movement currents, myoplasmic [Ca2+] transients, flux of calcium release from the sarcoplasmic reticulum (SR), and the intrinsic optical transparency change that accompanies calcium release. In attempts to suppress Ca release by direct effects on the SR, three interventions were applied: (a) a conditioning pulse that causes calcium release and inhibits release in subsequent pulses by Ca-dependent inactivation; (b) a series of brief, large pulses, separated by long intervals (greater than 700 ms), which deplete Ca2+ in the SR; and (c) intracellular application of the release channel blocker ruthenium red. All these reduced calcium release flux. None was expected to affect directly the voltage sensor of the T-tubule; however, all of them reduced or eliminated a component of charge movement current with the following characteristics: (a) delayed onset, peaking 10-20 ms into the pulse; (b) current reversal during the pulse, with an inward phase after the outward peak; and (c) OFF transient of smaller magnitude than the ON, of variable polarity, and sometimes biphasic. When the total charge movement current had a visible hump, the positive phase of the current eliminated by the interventions agreed with the hump in timing and size. The component of charge movement current blocked by the interventions was greater and had a greater inward phase in slack fibers with high [EGTA] inside than in stretched fibers with no EGTA. Its amplitude at -40 mV was on average 0.26 A/F (SEM 0.03) in slack fibers. The waveform of release flux determined from the Ca transients measured simultaneously with the membrane currents had, as described previously (Melzer, W., E. Ríos, and M. F. Schneider. 1984. Biophysical Journal. 45:637-641), an early peak followed by a descent to a steady level during the pulse. The time at which this peak occurred was highly correlated with the time to peak of the current suppressed, occurring on average 6.9 ms later (SEM 0.73 ms). The current suppressed by the above interventions in all cases had a time course similar to the time derivative of the release flux; specifically, the peak of the time derivative of release flux preceded the peak of the current suppressed by 0.7 ms (SEM 0.6 ms). The magnitude of the current blocked was highly correlated with the inhibitory effect of the interventions on Ca2+ release flux.(ABSTRACT TRUNCATED AT 400 WORDS)

Skeletal Muscle Sarcoplasmic Reticulum Ca 2+ -ATPase Gene Expression in Congestive Heart Failure

1997 ◽  
Vol 81 (5) ◽  
pp. 703-710 ◽  
Author(s):  
David G. Peters ◽  
Heather L. Mitchell ◽  
Sylvia A. McCune ◽  
Sonhee Park ◽  
Jay H. Williams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Skeletal Muscle ◽  
Congestive Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Atpase Gene

Lactate inhibits Ca2+-activated Ca2+-channel activity from skeletal muscle sarcoplasmic reticulum

1997 ◽  
Vol 82 (2) ◽  
pp. 447-452 ◽  
Author(s):  
Terence G. Favero ◽  
, Anthony C. Zable ◽  
, David Colter ◽  
Jonathan J. Abramson
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Single Channel ◽  
Channel Activity ◽  
Release Channel ◽  
Muscle Lactate ◽  
Tension Development ◽  
Contraction Coupling ◽  
Single Channel Activity ◽  
High Concentrations

Favero, Terence G., Anthony C. Zable, David Colter, and Jonathan J. Abramson. Lactate inhibits Ca2+-activated Ca2+-channel activity from skeletal muscle sarcoplasmic reticulum. J. Appl. Physiol. 82(2): 447–452, 1997.—Sarcoplasmic reticulum (SR) Ca2+-release channel function is modified by ligands that are generated during about of exercise. We have examined the effects of lactate on Ca2+- and caffeine-stimulated Ca2+ release, [3H]ryanodine binding, and single Ca2+-release channel activity of SR isolated from rabbit white skeletal muscle. Lactate, at concentrations from 10 to 30 mM, inhibited Ca2+- and caffeine-stimulated [3H]ryanodine binding to and inhibited Ca2+- and caffeine-stimulated Ca2+ release from SR vesicles. Lactate also inhibited caffeine activation of single-channel activity in bilayer reconstitution experiments. These findings suggest that intense muscle activity, which generates high concentrations of lactate, will disrupt excitation-contraction coupling. This may lead to decreases in Ca2+ transients promoting a decline in tension development and contribute to muscle fatigue.

Compensatory downregulation of myocardial Ca channel in SR from dogs with heart failure

1993 ◽  
Vol 264 (3) ◽  
pp. H926-H937 ◽  
Author(s):  
C. R. Cory ◽  
L. J. McCutcheon ◽  
M. O'Grady ◽  
A. W. Pang ◽  
J. D. Geiger ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ca Channel ◽  
Channel Activity ◽  
Binding Studies ◽  
Release Channel ◽  
Partial Restoration ◽  
Doberman Pinschers ◽  
Rapid Ventricular Pacing ◽  
45Ca Release ◽  
Terminal Cisternae

In this study we tested the hypothesis that the ryanodine-binding Ca-release channel activity and density of the sarcoplasmic reticulum (SR) terminal cisternae were decreased in congestive heart failure (CHF) that occurs spontaneously in doberman pinschers or experimentally with rapid ventricular pacing of mongrels. We used a novel, sensitive, and easy-to-perform microassay and demonstrated a 50% decrease in activity of the myocardial SR Ca pump and a 75% reduction in SR Ca-release channel activity in CHF. Decreases in Ca channel content were associated with increases in net Ca sequestration. 45Ca-release experiments from passively loaded SR terminal cisternae and ryanodine-binding studies confirmed a 53–68% downregulation of the Ca-release channel activity. As a consequence of release channel downregulation, there was partial restoration of net Ca sequestration activity in dogs with CHF and complete compensation in dogs with mild cardiac dysfunction. Deterioration of Ca cycling correlated with deterioration of myocardial performance, apparently due to decreased Ca-adenosinetriphosphatase (ATPase) pump and not Ca channel content. One-half the reduction in Ca-release activity could be attributed to decreased Ca sequestration and one-half to decreased Ca channel density. Downregulation of Ca channel content decreases the amplitude of the Ca cycle and maximizes the downregulation of Ca pumps that may occur. Although these adaptations may reduce cellular energy expenditure, they are likely to render the myocardium more susceptible to fatigue and failure.

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