Synchronous occurrence of spontaneous localized calcium release from the sarcoplasmic reticulum generates action potentials in rat cardiac ventricular myocytes at normal resting membrane potential.

Capogrossi, M. C.; Houser, Steven R.; Bahinski, Anthony; Lakatta, Edward G.

doi:10.1161/01.res.61.4.498

Cited by 115 publications

(81 citation statements)

References 17 publications

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“…The NCX inward current that is ignited by multifocal spontaneous Ca 2+ release is often sufficient to depolarize the surface membrane to the level required to activate Na + channels (41), and to generate a spontaneous AP (Fig. 4A).…”

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confidence: 99%

The Emergence of a General Theory of the Initiation and Strength of the Heartbeat

2006

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Abstract. Sarcoplasmic reticulum (SR) Ca2+ cycling, that is, the Ca 2+ clock, entrained by externally delivered action potentials has been a major focus in ventricular myocyte research for the past 5 decades. In contrast, the focus of pacemaker cell research has largely been limited to membrane-delimited pacemaker mechanisms (membrane clock) driven by ion channels, as the immediate cause for excitation. Recent robust experimental evidence, based on confocal cell imaging, and supported by numerical modeling suggests a novel concept: the normal rhythmic heart beat is governed by the tight integration of both intracellular Ca 2+ and membrane clocks. In pacemaker cells the intracellular Ca 2+ clock is manifested by spontaneous, rhythmic submembrane local Ca 2+ releases from SR, which are tightly controlled by a high degree of basal and reserve PKA-dependent protein phosphorylation. The Ca 2+ releases rhythmically activate Na + / Ca 2+ exchange inward currents that ignite action potentials, whose shape and ion fluxes are tuned by the membrane clock which, in turn, sustains operation of the intracellular Ca 2+ clock. The idea that spontaneous SR Ca 2+ releases initiate and regulate normal automaticity provides the key that reunites pacemaker and ventricular cell research, thus evolving a general theory of the initiation and strength of the heartbeat.

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Section: +mentioning

confidence: 99%

The Emergence of a General Theory of the Initiation and Strength of the Heartbeat

2006

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“…36 -38 Thus, spontaneous Ca 2+ oscillations are not due to transmembrane potential changes but, given the correct initiating conditions, cause traveling Ca 2+ waves, depolarizations, and nondriven action potentials. 4 , 8 , 37 , 39 Although several investigators have identified the nature of the sarcolemmal currents that may underlie these depolarizations, 40 to date no specific antiarrhythmic agents directed toward these underlying currents (e.g., I ti ) have been developed. Thus, we propose that, at least for Purkinje cells from infarcted heart, agents directed toward eliminating aberrant spontaneous Ca 2+ release, which leads to micro Ca 2+ transients, cell-wide waves, and action potentials, may be effective antiarrhythmic agents.…”

Section: Implications Of Findingsmentioning

confidence: 99%

2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart

Boyden

Dun²,

Barbhaiya³

et al. 2004

Heart Rhythm

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Objectives/Background-Studies from several laboratories have implicated intracellular Ca 2+ dynamics in the modulation of electrical activity. We have reported that abnormal Ca 2+ wave activity is the underlying cause of afterdepolarization-induced electrical activity in subendocardial Purkinje cells that survive in the 48-hour infarcted canine heart. These cells form the focus of arrhythmias at this time postcoronary artery occlusion.Methods-We studied the effects of agonists and antagonists on the abnormal Ca 2+ release activity of Purkinje cell aggregates dispersed from the subendocardium 48 hours postcoronary artery occlusion (IZPCs). Studies were completed using epifluorescent microscopy of Fluo-3 loaded Purkinje cells.Results-Similar to our previous report, highly frequent traveling micro Ca 2+ transients(μCaiTs) and cell-wide Ca 2+ waves were seen in IZPCs in the absence of any drug. Isoproterenol (ISO) increased μCaiTs and cell-wide Ca 2+ waves in Purkinje cells dispersed from the normal heart (NZPCs). In IZPCs, ISO increased cell-wide wave frequency but had no effect on the already highly frequent micro Ca 2+ wave transient activity, suggesting that ISO lowers the threshold of cell-wide generators responding to micro Ca 2+ transients. Drugs that block inward sodium or calcium currents (verapamil, tetrodotoxin) had no effect on Ca 2+ activity in Purkinje cells. Antagonists of intracellular Ca 2+ release channels [ryanodine, JTV519(K201)] greatly suppressed spontaneous Ca 2+ release events in IZPCs. 2APB, an agent that blocks IP 3 receptors, greatly reduced the frequency of Ca 2+ events in IZPCs.Conclusions-In arrhythmogenic Purkinje cells that survive in the infarcted heart, agents that block or inhibit intracellular Ca 2+ release channel activity reduced Ca 2+ waves and could be antiarrhythmic.

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“…In single cardiac myocytes, the synchronous occurrence of spontaneous localized Ca2' release from the sarcoplasmic reticulum can generate "abnormal automaticity" even at a normal resting membrane potential. 46 The argument has been made that endocardial preparations from 1-day-old infarction in dogs demonstrate triggered activity arising from DADs at 360 C, whereas abnormal automaticity may become operative when the temperature is increased to 390 C.6 The ionic mechanism responsible for such a dramatic shift in the arrhythmogenic mechanism is not clear. In the present study, raising the temperature of the tissue bath from 370 to 390 C accelerated the rate of sustained rhythmic activity.…”

Section: Discussionmentioning

confidence: 99%

Effects of caffeine and ryanodine on delayed afterdepolarizations and sustained rhythmic activity in 1-day-old myocardial infarction in the dog.

1990

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Caffeine and ryanodine are known to modulate oscillatory release of Ca2' from the sarcoplasmic reticulum. The effects of caffeine and ryanodine on delayed afterdepolarizations (DADs) and sustained rhythmic activity in subendocardial Purkinje fibers surviving 1-day-old myocardial infarction in the dog were studied with standard microelectrode techniques. In preparations that showed sustained rhythmic activity, a high concentration of caffeine (10 mM) and ryanodine (10`and 10-6 M) slowed and terminated the sustained rhythmic activity and markedly suppressed DADs. An increase in the temperature of the tissue bath from 370 to 390 C did not change these results. In quiescent normal and infarcted preparations, a low concentration of caffeine (0.5 mM) differentially induced DADs in ischemic but not in normal Purkinje fibers, increased the amplitude of existing DADs, and brought subthreshold DADs to threshold potential that caused triggered activity. Our results are consistent with the hypothesis that triggered activity arising from DADs characterizes the sustained rhythmic activity in endocardial preparations 1 day after infarction and indicate an important role for the sarcoplasmic reticulum in the genesis of DADs and triggered activity in this model. (Circulation 1990;81:1393-1400 Subendocardial Purkinje fibers surviving 1 day after myocardial infarction in the dog show varying degrees of partial depolarization and spontaneous rhythmic activity.1-4 Two different mechanisms, abnormal automaticity3,5-7 and triggered activity arising from a delayed afterdepolarization (DAD),4 have been proposed to account for the arrhythmia. During sustained rhythmic activity, abnormal automaticity at a reduced membrane potential will be difficult to discern from triggered activity arising from DADs. In earlier studies of 1-day-old ischemic endocardial preparations in the dog, the sustained rhythmic activity was considered the result of abnormal automaticity.1-3 However, when the initiation and termination of these rhythms were studied in detail, most were found to be caused by triggered activity arising from DADs.

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Synchronous occurrence of spontaneous localized calcium release from the sarcoplasmic reticulum generates action potentials in rat cardiac ventricular myocytes at normal resting membrane potential.

Cited by 115 publications

References 17 publications

The Emergence of a General Theory of the Initiation and Strength of the Heartbeat

The Emergence of a General Theory of the Initiation and Strength of the Heartbeat

2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart

Effects of caffeine and ryanodine on delayed afterdepolarizations and sustained rhythmic activity in 1-day-old myocardial infarction in the dog.

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