scholarly journals Expression of active p21-activated kinase-1 induces Ca2+flux modification with altered regulatory protein phosphorylation in cardiac myocytes

2009 ◽  
Vol 296 (1) ◽  
pp. C47-C58 ◽  
Author(s):  
Katherine A. Sheehan ◽  
Yunbo Ke ◽  
Beata M. Wolska ◽  
R. John Solaro
Keyword(s):  
Troponin I ◽  
Ventricular Myocytes ◽  
Regulatory Protein ◽  
Cardiac Contractility ◽  
Tension Development ◽  
Cell Shortening ◽  
Time To Peak ◽  
Fiber Tension ◽  
Intracellular Ca ◽  
P21 Activated Kinase

p21-Activated kinase-1 (Pak1) is a serine-threonine kinase that associates with and activates protein phosphatase 2A in adult ventricular myocytes and, thereby, induces increased Ca2+sensitivity of skinned-fiber tension development mediated by dephosphorylation of myofilament proteins (Ke Y, Wang L, Pyle WG, de Tombe PP, Solaro RJ. Circ Res 94: 194–200, 2004). We test the hypothesis that activation of Pak1 also moderates cardiac contractility through regulation of intracellular Ca2+fluxes. We found no difference in field-stimulated intracellular Ca2+concentration ([Ca2+]i) transient amplitude and extent of cell shortening between myocytes expressing constitutively active Pak1 (CA-Pak1) and controls expressing LacZ; however, time to peak shortening was significantly faster and rate of [Ca2+]idecay and time of relengthening were slower. Neither caffeine-releasable sarcoplasmic reticulum (SR) Ca2+content nor fractional release was different in CA-Pak1 myocytes compared with controls. Isoproterenol application revealed a significantly blunted increase in [Ca2+]itransient amplitude, as well as a slowed rate of [Ca2+]idecay, increased SR Ca2+content, and increased cell shortening, in CA-Pak1 myocytes. We found no significant change in phospholamban phosphorylation at Ser16or Thr17in CA-Pak1 myocytes. Analysis of cardiac troponin I revealed a significant reduction in phosphorylated species that are primarily attributable to Ser23/24in CA-Pak1 myocytes. Nonstimulated, spontaneous SR Ca2+release sparks were significantly smaller in amplitude in CA-Pak1 than LacZ myocytes. Propagation of spontaneous Ca2+waves resulting from SR Ca2+overload was significantly slower in CA-Pak1 myocytes. Our data indicate that CA-Pak1 expression has significant effects on ventricular myocyte contractility through altered myofilament Ca2+sensitivity and modification of the [Ca2+]itransient.

Voltage-independent changes in L-type Ca2+current uncoupled from SR Ca2+ release in cardiac myocytes

2000 ◽  
Vol 279 (4) ◽  
pp. H2024-H2031 ◽  
Author(s):  
Andrzej M. Janczewski ◽  
Edward G. Lakatta ◽  
Michael D. Stern
Keyword(s):  
Cardiac Myocytes ◽  
Ventricular Myocytes ◽  
Abrupt Increase ◽  
Time To Peak ◽  
Time Integral ◽  
Marked Disparity ◽  
Release Flux ◽  
Intracellular Ca ◽  
Combined Actions ◽  
Continuous Presence

To determine the effect of voltage-independent alterations of L-type Ca2+ current ( I Ca) on the sarcoplasmic reticular (SR) Ca2+ release in cardiac myocytes, we measured I Ca and cytosolic Ca2+ transients (Cai 2+; intracellular Ca2+ concentration) in voltage-clamped rat ventricular myocytes during 1) an abrupt increase of extracellular [Ca2+] (Cao 2+) or 2) application of 1 μM FPL-64176, a Ca2+channel agonist, to selectively alter I Ca in the absence of changes in SR Ca2+ loading. On the first depolarization in higher Cao 2+, peak I Ca was increased by 46 ± 6% ( P < 0.001), but the increases in the maximal rate of rise of Cai 2+(dCai 2+/d t max, where t is time; an index of SR Ca2+ release flux) and the Cai 2+ transient amplitude were not significant. Rapid exposure to FPL-64176 greatly slowed inactivation of I Ca, increasing its time integral by 117 ± 8% ( P < 0.001) without significantly increasing peak I Ca, dCai 2+/d t max, or amplitude of the corresponding Cai 2+ transient. Prolongation of exposure to higher Cao 2+ or FPL-64176 did not further increase peak I Ca but greatly increased dCai 2+/d t max, Cai 2+ transient amplitude, and the gain of Ca2+ release (dCai 2+/d t max/ I Ca), evidently due to augmentation of the SR Ca2+ loading. Also, the time to peak dCai 2+/d t maxwas significantly increased in the continuous presence of higher Cao 2+ (by 37 ± 5%, P < 0.001) or FPL-64176 (by 63 ± 5%, P < 0.002). Our experiments provide the first evidence of a marked disparity between an increased peak I Ca and the corresponding SR Ca2+ release. We attribute this to saturation of the SR Ca2+ release flux as predicted by local control theory. Prolongation of the SR Ca2+ release flux, caused by combined actions of a larger I Ca and maximally augmented SR Ca2+ loading, might reflect additional Ca2+ release from corbular SR.

Rate-dependent changes in cell shortening, intracellular Ca(2+) levels and membrane potential in single, isolated rainbow trout (Oncorhynchus mykiss) ventricular myocytes

2000 ◽  
Vol 203 (3) ◽  
pp. 493-504 ◽  
Author(s):  
C.L. Harwood ◽  
F.C. Howarth ◽  
J.D. Altringham ◽  
E. White
Keyword(s):  
Membrane Potential ◽  
Sarcoplasmic Reticulum ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Stimulation Frequency ◽  
Cell Shortening ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Rate Dependent ◽  
Intracellular Ca ◽  
Action Potential Configuration

The effects of increasing stimulation frequency (from 0.2 to 1.4 Hz) on the contractility, intracellular Ca(2+) concentration ([Ca(2+)](i)) and membrane potential of single ventricular myocytes isolated from the heart of rainbow trout (Oncorhynchus mykiss) were measured. Cell shortening, expressed as a percentage of resting cell length, was our index of contractility. The fluorescent Ca(2+) indicator Fura-2 was used to monitor changes in [Ca(2+)](i). Action potentials and L-type Ca(2+) currents (I(Ca)) were recorded using the whole-cell patch-clamp technique. Experiments were performed at 15 degrees C. Increasing the stimulation frequency caused a significant increase in diastolic [Ca(2+)](i) and a significant decrease in diastolic cell length and membrane potential. During systole, there was a significant fall in the amplitude of the [Ca(2+)](i) transient, cell shortening and action potential with a decrease in the duration of the action potential at both 20 % and 90 % repolarisation. Caffeine was used to assess the Ca(2+) content of the sarcoplasmic reticulum. We observed that sarcoplasmic reticulum Ca(2+) load was greater at 1.0 Hz than at 0.6 Hz, despite a smaller electrically evoked [Ca(2+)](i) transient. The amplitude of I(Ca) was found to decrease with increased stimulation frequency. At 0.6 Hz, electrically evoked [Ca(2+)](i) transients in the presence of 10 mmol l(−)(1) caffeine or 10 micromol l(−)(1) ryanodine and 2 micromol l(−)(1) thapsigargin were reduced by approximately 15 %. We have described the changes in contractility, [Ca(2+)](i) and action potential configuration in a fish cardiac muscle system. Under the conditions tested (0.6 Hz, 15 degrees C), we conclude that the sarcoplasmic reticulum contributes at least 15 % of the Ca(2+) associated with the [Ca(2+)](i) transient. The rate-dependent decrease in contraction amplitude appears to be associated with the fall in the amplitude of the [Ca(2+)](i) transient. This, in turn, may be influenced by changes in the action potential configuration via mechanisms such as altered Ca(2+) efflux and Ca(2+) influx. In support of our conclusions, we present evidence that there is a rate-dependent decrease in Ca(2+) influx via I(Ca) but that the Ca(2+) load of the sarcoplasmic reticulum is not reduced at increased contraction frequencies.

M2-specific muscarinic cholinergic receptor-mediated inhibition of cardiac regulatory protein phosphorylation

1994 ◽  
Vol 266 (3) ◽  
pp. H1138-H1144 ◽  
Author(s):  
R. C. Gupta ◽  
J. Neumann ◽  
P. Boknik ◽  
A. M. Watanabe
Keyword(s):  
Guinea Pig ◽  
Protein Phosphorylation ◽  
Troponin I ◽  
Ventricular Myocytes ◽  
Regulatory Protein ◽  
Cholinergic Receptor ◽  
Protein Kinase Activity ◽  
Muscarinic Cholinoceptors ◽  
Dependent Protein ◽  
Muscarinic Cholinergic

Acetylcholine acting via muscarinic cholinoceptors decreased phosphorylation of phospholamban and troponin I without reducing adenosine 3',5'-cyclic monophosphate (cAMP) levels or cAMP-dependent protein kinase activity ratio in the presence of 10-100 nM isoproterenol in guinea pig ventricular myocytes. The effect of acetylcholine was more pronounced when adenosine deaminase (5 U/ml) was present and incubation period was short (10 s). Okadaic acid, an inhibitor of protein phosphatase activity, blocked the acetylcholine-mediated inhibition of isoproterenol-stimulated phosphorylation of phospholamban. It is suggested that acetylcholine reduces protein phosphorylation by a cAMP-independent mechanism in guinea pig ventricular myocytes.

Phosphorylation of phospholamban and troponin I in β-adrenergic-induced acceleration of cardiac relaxation

2000 ◽  
Vol 278 (3) ◽  
pp. H769-H779 ◽  
Author(s):  
Li Li ◽  
Jaime Desantiago ◽  
Guoxiang Chu ◽  
Evangelia G. Kranias ◽  
Donald M. Bers
Keyword(s):  
Troponin I ◽  
Ventricular Myocytes ◽  
Mechanical Load ◽  
Isometric Force ◽  
Relaxation Rates ◽  
Before And After ◽  
Intracellular Ca ◽  
Dependent Protein ◽  
Measured Relaxation ◽  
Cardiac Relaxation

Activation of cAMP-dependent protein kinase A (PKA) in ventricular myocytes by isoproterenol (Iso) causes phosphorylation of both phospholamban (PLB) and troponin I (TnI) and accelerates relaxation by up to twofold. Because PLB phosphorylation increases sarcoplasmic reticulum (SR) Ca pumping and TnI phosphorylation increases the rate of Ca dissociation from the myofilaments, both factors could contribute to the acceleration of relaxation seen with PKA activation. To compare quantitatively the role of TnI versus PLB phosphorylation, we measured relaxation rates before and after maximal Iso treatment for twitches of matched amplitudes in ventricular myocytes and muscle from wild-type (WT) mice and from mice in which the PLB gene was knocked out (PLB-KO). Because Iso increases contractions, even in the PLB-KO mouse, extracellular [Ca] or sarcomere length was adjusted to obtain matching twitch amplitudes (in the presence and absence of Iso). In PLB-KO myocytes and muscles (which were allowed to shorten), Iso did not alter the time constant (τ) of relaxation (∼29 ms). However, with increasing isometric force development in the PLB-KO muscles, Iso progressively but modestly accelerated relaxation (by 17%). These results contrast with WT myocytes and muscles where Iso greatly reduced τ of cell relaxation and intracellular Ca concentration decline (by 30–50%), independent of mechanical load. The Iso treatment used produced comparable increases in phosphorylation of TnI and PLB in WT. We conclude that the effect of β-adrenergic activation on relaxation is mediated entirely by PLB phosphorylation in the absence of external load. However, TnI phosphorylation could contribute up to 14–18% of this lusitropic effect in the WT mouse during maximal isometric contractions.

scholarly journals Decreased Ca2+ extrusion via Na+/Ca2+ exchange in epicardial left ventricular myocytes during compensated hypertrophy

2005 ◽  
Vol 288 (5) ◽  
pp. H2431-H2438 ◽  
Author(s):  
Mark R. Fowler ◽  
James R. Naz ◽  
Mark D. Graham ◽  
Gilles Bru-Mercier ◽  
Simon M. Harrison ◽  
...  
Keyword(s):  
Time Course ◽  
Ventricular Myocytes ◽  
Major Change ◽  
Left Ventricular ◽  
Spontaneously Hypertensive ◽  
Cellular Hypertrophy ◽  
Time To Peak ◽  
Intracellular Ca ◽  
The Face ◽  
Wistar Kyoto

Hypertension-induced cardiac hypertrophy alters the amplitude and time course of the systolic Ca2+ transient of subepicardial and subendocardial ventricular myocytes. The present study was designed to elucidate the mechanisms underlying these changes. Myocytes were isolated from the left ventricular subepicardium and subendocardium of 20-wk-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY; control). We monitored intracellular Ca2+ using fluo 3 or fura 2; caffeine (20 mmol/l) was used to release Ca2+ from the sarcoplasmic reticulum (SR), and Ni2+ (10 mM) was used to inhibit Na+/Ca2+ exchange (NCX) function. SHR myocytes were significantly larger than those from WKY hearts, consistent with cellular hypertrophy. Subepicardial myocytes from SHR hearts showed larger Ca2+ transient amplitude and SR Ca2+ content and less Ca2+ extrusion via NCX compared with subepicardial WKY myocytes. These parameters did not change in subendocardial myocytes. The time course of decline of the Ca2+ transient was the same in all groups of cells, but its time to peak was shorter in subepicardial cells than in subendocardial cells in WKY and SHR and was slightly prolonged in subendocardial SHR cells compared with WKY subendocardial myocytes. It is concluded that the major change in Ca2+ cycling during compensated hypertrophy in SHR is a decrease in NCX activity in subepicardial cells; this increases SR Ca2+ content and hence Ca2+ transient amplitude, thus helping to maintain the strength of contraction in the face of an increased afterload.

scholarly journals Mepivacaine reduces calcium transients in isolated murine ventricular cardiomyocytes

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Matias Mosqueira ◽  
Güçlü Aykut ◽  
Rainer H. A. Fink
Keyword(s):  
Electrical Stimulation ◽  
Adult Mouse ◽  
Ventricular Myocytes ◽  
Cellular Level ◽  
Significant Inhibition ◽  
Biophysical Parameters ◽  
Time To Peak ◽  
Reverse Mode ◽  
Intracellular Ca ◽  
Single Ventricular Myocytes

Abstract Background The potential mechanism of mepivacaine’s myocardial depressant effect observed in papillary muscle has not yet been investigated at cellular level. Therefore, we evaluated mepivacaine’s effects on Ca2+ transient in isolated adult mouse cardiomyocytes. Methods Single ventricular myocytes were enzymatically isolated from wild-type C57Bl/6 mice and loaded with 10 μM fluorescent Ca2+ indicator Fluo-4-AM to record intracellular Ca2+ transients upon electrical stimulation. The mepivacaine effects at half-maximal inhibitory concentration (IC50) was determined on calibrated cardiomyocytes’ Ca2+ transients by non-parametric statistical analyses on biophysical parameters. Combination of mepivacaine with NCX blockers ORM-10103 or NiCl2 were used to test a possible mechanism to explain mepivacaine-induced Ca2+ transients’ reduction. Results A significant inhibition at mepivacaine’s IC50 (50 μM) on Ca2+ transients was measured in biophysical parameters such as peak (control: 528.6 ± 73.61 nM vs mepivacaine: 130.9 ± 15.63 nM; p < 0.05), peak area (control: 401.7 ± 63.09 nM*s vs mepivacaine: 72.14 ± 10.46 nM*s; p < 0.05), slope (control: 7699 ± 1110 nM/s vs mepivacaine: 1686 ± 226.6 nM/s; p < 0.05), time to peak (control: 107.9 ± 8.967 ms vs mepivacaine: 83.61 ± 7.650 ms; p < 0.05) and D50 (control: 457.1 ± 47.16 ms vs mepivacaine: 284.5 ± 22.71 ms; p < 0.05). Combination of mepivacaine with NCX blockers ORM-10103 or NiCl2 showed a significant increase in the baseline of [Ca2+] and arrhythmic activity upon electrical stimulation. Conclusion At cellular level, mepivacaine blocks Na+ channels, enhancing the reverse mode activity of NCX, leading to a significant reduction of Ca2+ transients. These results suggest a new mechanism for the mepivacaine-reduction contractility effect.

Myofilament response to Ca2+ and Na+/H+ exchanger activity in sex hormone-related protection of cardiac myocytes from deactivation in hypercapnic acidosis

2007 ◽  
Vol 292 (2) ◽  
pp. R837-R843 ◽  
Author(s):  
Tepmanas Bupha-Intr ◽  
Jonggonnee Wattanapermpool ◽  
James R. Peña ◽  
Beata M. Wolska ◽  
R. J. Solaro
Keyword(s):  
Cardiac Myocytes ◽  
Ventricular Myocytes ◽  
Specific Inhibitor ◽  
Hypercapnic Acidosis ◽  
Intact Cells ◽  
Cell Shortening ◽  
Female Sex Hormones ◽  
Ovx Rats ◽  
Intracellular Ca ◽  
Myofilament Activation

Compared to sham-operated controls, myofilaments from hearts of ovariectomized (OVX) rats demonstrate an increase in Ca2+ sensitivity with no change in maximum tension (Wattanapermpool J and Reiser PJ. Am J Physiol 277: H467–H473, 1999). To test the significance of this modification in intact cells, we compared intracellular Ca2+ transients and shortening of ventricular myocytes isolated from sham and 10-wk OVX rats. There was a decrease in the peak Ca2+ transient with prolonged 50% decay time in OVX cardiac myocytes without changes in the resting intracellular Ca2+ concentration. Percent cell shortening was also depressed, and relaxation was prolonged in cardiac myocytes from OVX rats compared with shams. Ovariectomy induced a sensitization of the myofilaments to Ca2+. Hypercapnic acidosis suppressed the shortening of OVX myocytes to a lesser extent than that detected in shams. Moreover, a larger compensatory increase in %cell shortening was obtained in OVX myocytes during prolonged acidosis. The elevated compensation in cell shortening was related to a higher amount of increase in the amplitude of the Ca2+ transient in OVX myocytes. However, these differences in Ca2+ transients and %cell shortening were no longer evident in the presence of 1 μM cariporide, a specific inhibitor of Na+/H+ exchanger type 1 (NHE1). Our results indicate that deprivation of female sex hormones modulates the intracellular Ca2+ concentration in cardiac myocytes, possibly via an increased NHE1 activity, which may act in concert with Ca2+ hypersensitivity of myofilament activation as a determinant of sex differences in cardiac function.

Subcellular properties of [Ca2+]itransients in phospholamban-deficient mouse ventricular cells

1998 ◽  
Vol 274 (5) ◽  
pp. H1800-H1811 ◽  
Author(s):  
Jörg Hüser ◽  
Donald M. Bers ◽  
Lothar A. Blatter
Keyword(s):  
Ventricular Myocytes ◽  
Marked Decrease ◽  
Regulatory Protein ◽  
Inhibitory Effect ◽  
Deficient Mouse ◽  
Wild Type ◽  
Contraction Coupling ◽  
Ventricular Cells ◽  
Pump Rate ◽  
Intracellular Ca

The regulatory protein phospholamban exerts a physiological inhibitory effect on the sarcoplasmic reticulum (SR) Ca2+ pump that is relieved with phosphorylation. We have studied the subcellular properties of intracellular Ca2+([Ca2+]i) transients in ventricular myocytes isolated from wild-type (WT) and phospholamban-deficient (PLB-KO) mice. In PLB-KO myocytes, steady-state twitch [Ca2+]itransients revealed an accelerated relaxation and the occurrence of highly localized failures of Ca2+release. The acceleration of SR Ca2+ uptake caused an increase in SR Ca2+ load with the frequent occurrence of spontaneous [Ca2+]iwaves and Ca2+ sparks. [Ca2+]iwaves in PLB-KO cells showed a marked decrease in spatial width and more frequently appeared to abort. Local Ca2+ release events (Ca2+ sparks) were larger and more variable in amplitude and [Ca2+]ideclined faster in PLB-KO myocytes. Increased local buffering and reduction in the refractoriness of SR Ca2+ release caused by the increased SR pump rate led to an overall enhancement of local [Ca2+]igradients and inhomogeneities in the [Ca2+]idistribution during spontaneous Ca2+ release, [Ca2+]iwaves, and excitation-contraction coupling.

Brief rapid pacing depresses contractile function via Ca2+/PKC-dependent signaling in cat ventricular myocytes

2001 ◽  
Vol 280 (1) ◽  
pp. H90-H98 ◽  
Author(s):  
Yong Gao Wang ◽  
William J. Benedict ◽  
Jörg Hüser ◽  
Allen M. Samarel ◽  
Lothar A. Blatter ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Contractile Function ◽  
Calpain Inhibitor ◽  
Western Blots ◽  
Cell Shortening ◽  
Kinase C ◽  
Intracellular Ca ◽  
Rapid Pacing ◽  
Pkc Β ◽  
Sustained Inhibition

The purpose of this study is to determine the effects of brief rapid pacing (RP; ∼200–240 beats/min for ∼5 min) on contractile function in ventricular myocytes. RP was followed by a sustained inhibition of peak systolic cell shortening (−44 ± 4%) that was not due to changes in diastolic cell length, membrane voltage, or L-type Ca2+ current ( I Ca,L). During RP, baseline and peak intracellular Ca2+ concentration ([Ca2+]i) increased markedly. After RP, Ca2+ transients were similar to control. The effects of RP on cell shortening were not prevented by 1 μM calpain inhibitor I, 25 μMl- N 5-(1-iminoethyl)-orthinthine, or 100 μM N G-monomethyl-l-arginine. However, RP-induced inhibition of cell shortening was prevented by lowering extracellular [Ca2+] (0.5 mM) during RP or exposure to chelerythrine (2–4 μM), a protein kinase C (PKC) inhibitor, or LY379196 (30 nM), a selective inhibitor of PKC-β. Exposure to phorbol ester (200 nM phorbol 12-myristate 13-acetate) inhibited cell shortening (−46 ± 7%). Western blots indicated that cat myocytes express PKC-α, -δ, and -ε as well as PKC-β. These findings suggest that brief RP of ventricular myocytes depresses contractility at the myofilament level via Ca2+/PKC-dependent signaling. These findings may provide insight into the mechanisms of contractile dysfunction that follow paroxysmal tachyarrhythmias.

Pyruvate augments calcium transients and cell shortening in rat ventricular myocytes

1998 ◽  
Vol 274 (1) ◽  
pp. H8-H17 ◽  
Author(s):  
Bradley J. Martin ◽  
Hector H. Valdivia ◽  
Rolf Bünger ◽  
Robert D. Lasley ◽  
Robert M. Mentzer
Keyword(s):  
Ventricular Myocytes ◽  
Contractile Function ◽  
Rat Ventricular Myocytes ◽  
Cell Shortening ◽  
Transport Inhibitor ◽  
Monocarboxylate Transport ◽  
Nadh Ratio ◽  
Intracellular Ca ◽  
Ethanesulfonic Acid

Pyruvate has been shown to be a metabolic inotrope in the myocardium. In millimolar concentrations, it has been shown to increase both myocardial phosphorylation potential and the cytosolic [NAD+]-to-[NADH] ratio. To determine if changes in these parameters can alter intracellular Ca2+ concentration ([Ca2+]i) and hence contractile function, Ca2+ transients and cell shortening (CS) were measured in isolated rat ventricular myocytes superfused with a physiological N-2-hydroxyethylpiperazine- N′-2-ethanesulfonic acid buffer (11 mmol/l glucose) with and without additional pyruvate,l-lactate, acetate, or isoproterenol. The addition of 5 mmol/l pyruvate resulted in a 33% increase in CS and a 39% increase in systolic [Ca2+]i. These pyruvate effects were 70% of those observed with 100 nmol/l isoproterenol. The mitochondrial monocarboxylate transport inhibitor α-cyano-4-hydroxycinnamate (250 μmol/l) strongly inhibited pyruvate inotropy, suggesting a substantial obligatory coupling between pyruvate inotropism and its oxidation by the mitochondria. A possible role of the cytosolic [NAD+]-to-[NADH] ratio was assessed by comparing the effects of 20 mmol/ll-lactate to those of equimolar pyruvate. In contrast to 20 mmol/l pyruvate, excess l-lactate failed to appreciably increase CS or systolic [Ca2+]i. The findings imply that, at levels substantially above 5 mmol/l, a portion of pyruvate inotropism might be due to extreme cytosolic [NAD+]-to-[NADH] ratios. This study is the first evidence that augmented [Ca2+]itransients are most likely the mechanism of cardiac pyruvate inotropism.

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