The cytosolic calcium transient modulates the action potential of rat ventricular myocytes.

duBell, William H.; Boyett, Mark R.; Spurgeon, Harold A.; Talo, A; Stern, Michael D.; Lakatta, Edward G.

doi:10.1113/jphysiol.1991.sp018554

Cited by 52 publications

(38 citation statements)

References 43 publications

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“…Together, these results suggested that [Ca 2ϩ ] i strongly modulates the murine ventricular action potential via the exchanger, as also reported for rat ventricular myocytes. 17 …”

Section: Mechanism Of Action Potential Remodelingmentioning

confidence: 99%

Familial Hypertrophic Cardiomyopathy-Linked Mutant Troponin T Causes Stress-Induced Ventricular Tachycardia and Ca ²⁺ -Dependent Action Potential Remodeling

Knollmann

Kirchhof

Sirenko

et al. 2003

Circulation Research

151

140

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Abstract-The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and high incidence of sudden death, despite causing little or no cardiac hypertrophy in patients. Transgenic mice expressing mutant human TnT (I79N-Tg) have increased cardiac contractility, but no ventricular hypertrophy or fibrosis. Enhanced cardiac function has been associated with myofilament Ca 2ϩ sensitization, suggesting altered cellular Ca 2ϩ handling. In the present study, we compare cellular Ca 2ϩ transients and electrophysiological parameters of 64 I79N-Tg and 106 control mice in isolated myocytes, isolated perfused hearts, and whole animals. Ventricular action potentials (APs) measured in isolated I79N-Tg hearts and myocytes were significantly shortened only at 70% repolarization. No significant differences were found either in L-type Ca 2ϩ or transient outward K ϩ currents, but inward rectifier K ϩ current (IK1) was significantly decreased. More critically, Ca 2ϩ transients of field-stimulated ventricular I79N-Tg myocytes were reduced and had slow decay kinetics, consistent with increased Ca 2ϩ sensitivity of I79N mutant fibers. AP differences were abolished when myocytes were dialyzed with Ca 2ϩ buffers or after the Na ϩ -Ca 2ϩ exchanger was blocked by Li ϩ . At higher pacing rates or in presence of isoproterenol, diastolic Ca 2ϩ became significantly elevated in I79N-Tg compared with control myocytes. Ventricular ectopy could be induced by isoproterenol-challenge in isolated I79N-Tg hearts and anesthetized I79N-Tg mice. Freely moving I79N-Tg mice had a higher incidence of nonsustained ventricular tachycardia (VT) during mental stress (warm air jets). We conclude that the TnT-I79N mutation causes stress-induced VT even in absence of hypertrophy and/or fibrosis, arising possibly from the combination of AP remodeling related to altered Ca is an autosomal-dominant disease resulting from mutations in genes encoding cardiac contractile proteins and is an important cause of sudden cardiac death. 1 Genotype/phenotype correlation studies suggest that the prognostic significance of most mutations is related to the degree of cardiac hypertrophy and fibrosis. 2,3 An exception to this are patients with cardiac troponin T (TnT) mutations such as TnT-I79N, 4 who often die suddenly at a young age, 5 even though cardiac hypertrophy and fibrosis are either mild or nonexistent. 6 Although it is generally assumed that these sudden deaths are caused be ventricular arrhythmias, such evidence has been difficult to obtain, 7 and no data exist for the TnT-I79N mutation.In vitro studies of skinned fibers reconstituted with mutant TnT protein show that FHC-linked troponin T mutations almost universally increase myofilament Ca 2ϩ sensitivity. 8 Because Ca 2ϩ binding to the troponin complex represents the largest component of dynamic Ca 2ϩ buffering during the cardiac cycle, 9 our modeling studies predict that the increased myofilament Ca 2ϩ sensitivity would significantly alter intracellular Ca 2ϩ transients. 10 Thus, T...

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“…Together, these results suggested that [Ca 2ϩ ] i strongly modulates the murine ventricular action potential via the exchanger, as also reported for rat ventricular myocytes. 17 …”

Section: Mechanism Of Action Potential Remodelingmentioning

confidence: 99%

Familial Hypertrophic Cardiomyopathy-Linked Mutant Troponin T Causes Stress-Induced Ventricular Tachycardia and Ca ²⁺ -Dependent Action Potential Remodeling

Knollmann

Kirchhof

Sirenko

et al. 2003

Circulation Research

151

140

View full text Add to dashboard Cite

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“…Janvier & Boyett, 1996), and as a result of the modulation of these Ca 2+ -dependent mechanisms, the profile of the action potential (e.g. Du Bell et al 1991).…”

mentioning

confidence: 99%

Streptomycin and intracellular calcium modulate the response of single guinea‐pig ventricular myocytes to axial stretch

Belus

White

2003

The Journal of Physiology

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Isolation of guinea-pig ventricular myocytesGuinea-pigs (weight approximately 300 g) were killed by cervical dislocation following stunning; all procedures conformed with the UK Animals (Scientific Procedures) Act 1986. Left ventricular myocytes were isolated using methods based on those of Frampton et al. (1991). Briefly, hearts were removed and mounted on a Langendorff apparatus and perfused with a Hepes-based isolation solution of the following composition (mM): NaCl 130; KCl 5.4; NaH 2 PO 4 0.4; MgCl 2 .6H 2 O 1.4; CaCl 2 1.8; Hepes 10; glucose 10; taurine 20; creatine 10; with 1 % bovine serum albumin (pH 7.3) to clear blood from the coronary circulation. Perfusion was then continued with Ca 2+ -free isolation solution Streptomycin and intracellular calcium modulate the response of single guinea-pig ventricular myocytes to axial stretch Alexandra Belus and Ed White School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UKWe tested the hypothesis that both stretch-activated channels (SACs) and intracellular calcium ([Ca 2+ ] i ) are important in the electrical response of single guinea-pig ventricular myocytes to axial stretch. Myocytes were attached to carbon fibre transducers and stretched, sarcomere length increased by approximately 9 %, and there was a prolongation of the action potential duration. Streptomycin, a blocker of SACs, had no effect upon the shortening, [Ca 2+ ] i transients or action potentials of electrically stimulated, unstretched myocytes, at a concentration of 50 mM, but at 40 mM, prevented any stretch-induced increase in action potential duration. Under action potential clamp, stretch elicited a current with a linear current-voltage relationship that was inward at membrane potentials negative to its reversal potential of _30 mV, in 10 of 24 cells tested, and was consistent with the activation of non-specific, cationic SACs. This current was not seen in any stretched cells that were exposed to 40 mM streptomycin. However, exposure of cells to 5 mM BAPTA-AM, in order to reduce [ Journal of Physiology(1.8 mM CaCl 2 replaced with 0.1 mM EGTA) for 4 min, followed by 5 min perfusion with isolation solution containing 50 mM Ca 2+ , 1 mg ml _1 collagenase (type II; Worthington Biochemical Corporation, NJ, USA) and 0.1 mg ml _1 protease (type XIV; Sigma Chemical Co.). The left ventricle was then separated from the rest of the heart, minced, and gently shaken at 37°C in the collagenase-containing isolation solution. Cells were filtered from this solution at 5 min intervals and resuspended in isolation solution containing 1.8 mM Ca 2+ .To ] i were measured simultaneously. A video image of the cell was monitored using an edge detection system (Crescent Electronics, UT, USA) and the change in cell length following stimulation was used as our measure of contractility. Cells were loaded with the Ca 2+ -sensitive fluorescent indicator fura-2 AM (Molecular Probes, OR, USA) by incubation for 10 min at 22-24° C in 1.8 mM Ca 2+ isolation solution containing 3-5 mM fura-2 AM. The ratio of fl...

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“…68,69 This happens apparently via the increased Na ϩ /Ca 2ϩ -exchanger inward current that is boosted by augmentation of the calcium transients. 65 In rat myocytes, the Na ϩ /Ca 2ϩ -exchanger current is proportional to [Ca 2ϩ ] i. 70 The present study demonstrates that stretch influences the APs of the rat atrial myocytes.…”

Section: Electrical Activity Of the Myocyte During Stretchmentioning

confidence: 58%

“…Since calcium transient modulates the AP 65 and vice versa, 66 the changes in [Ca 2ϩ ] i during stretch should change the shape of the APs of the myocytes. It is known that inotropic interventions, such as stretch, increase the late duration of the APs 67 in cardiac myocytes with a short plateau.…”

Section: Electrical Activity Of the Myocyte During Stretchmentioning

confidence: 99%

Mechanisms of Stretch-Induced Changes in [Ca ²⁺ ] _i in Rat Atrial Myocytes

Tavi

Han

Weckström

1998

Circulation Research

105

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Abstract-To study the effects of stretch on the function of rat left atrium, we recorded contraction force, calcium transients, and intracellular action potentials (APs) during stretch manipulations. The stretch of the atrium was controlled by intra-atrial pressure. The Frank-Starling behavior of the atrium was manifested as a biphasic increase of the contraction force after increasing the stretch level. The development of the contraction force after step increase of the stretch (intra-atrial pressure from 1 to 3 mm Hg) was accompanied by the increase in the amplitude of the calcium transients (PϽ0.05, nϭ4) and decrease in the time constant of the Ca 2ϩ transient decay. The APs of the individual myocytes were also affected by stretch; the duration of the AP was decreased at positive voltages (AP duration at 15% repolarization level, PϽ0.001; nϭ13) and increased at negative voltages (AP duration at 90% repolarization level, PϽ0.01; nϭ13). To study the mechanisms causing these changes we developed a mathematical model describing [Ca 2ϩ ] i and electrical behavior of single rat atrial myocytes. Stretch was simulated in the model by increasing the troponin (TnC) sensitivity and/or applying a stretch-activated (SA) calcium influx. We mimicked the Ca 2ϩ influx by introducing a nonselective cationic conductance, the SA channels, into the membrane. Neither of the 2 plausible mechanosensors (TnC or SA channels) alone could produce similar changes in the Ca 2ϩ transients or APs as seen in the experiments. The model simulated the effects of stretch seen in experiments best when both the TnC affinity and the SA conductance activation were applied simultaneously. The SA channel activation led to gradual augmentation of Ca 2ϩ transients, which modulated the APs through increased Na ϩ /Ca 2ϩ -exchanger inward current. The role of TnC affinity change was to modulate the Ca 2ϩ transients, stabilize the diastolic [Ca 2ϩ ] i , and presumably to produce the immediate increase of the contraction force after stretch seen in experiments. Furthermore, we found that the same mechanism that caused the normal physiological responses to stretch could also generate arrhythmogenic afterpotentials at high stretch levels in the model.

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The cytosolic calcium transient modulates the action potential of rat ventricular myocytes.

Cited by 52 publications

References 43 publications

Familial Hypertrophic Cardiomyopathy-Linked Mutant Troponin T Causes Stress-Induced Ventricular Tachycardia and Ca ²⁺ -Dependent Action Potential Remodeling

Familial Hypertrophic Cardiomyopathy-Linked Mutant Troponin T Causes Stress-Induced Ventricular Tachycardia and Ca ²⁺ -Dependent Action Potential Remodeling

Streptomycin and intracellular calcium modulate the response of single guinea‐pig ventricular myocytes to axial stretch

Mechanisms of Stretch-Induced Changes in [Ca ²⁺ ] _i in Rat Atrial Myocytes

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The cytosolic calcium transient modulates the action potential of rat ventricular myocytes.

Cited by 52 publications

References 43 publications

Familial Hypertrophic Cardiomyopathy-Linked Mutant Troponin T Causes Stress-Induced Ventricular Tachycardia and Ca 2+ -Dependent Action Potential Remodeling

Familial Hypertrophic Cardiomyopathy-Linked Mutant Troponin T Causes Stress-Induced Ventricular Tachycardia and Ca 2+ -Dependent Action Potential Remodeling

Streptomycin and intracellular calcium modulate the response of single guinea‐pig ventricular myocytes to axial stretch

Mechanisms of Stretch-Induced Changes in [Ca 2+ ] i in Rat Atrial Myocytes

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Product

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Familial Hypertrophic Cardiomyopathy-Linked Mutant Troponin T Causes Stress-Induced Ventricular Tachycardia and Ca ²⁺ -Dependent Action Potential Remodeling

Familial Hypertrophic Cardiomyopathy-Linked Mutant Troponin T Causes Stress-Induced Ventricular Tachycardia and Ca ²⁺ -Dependent Action Potential Remodeling

Mechanisms of Stretch-Induced Changes in [Ca ²⁺ ] _i in Rat Atrial Myocytes