Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: experimental studies.
B. O'Rourke, D. Kass, G. Tomaselli, S. K��b, R. Tunin, and E. Marb�n.
Circ. Res. 84 (5): 562--570 (March 1999)

Pacing-induced heart failure in the dog recapitulates many of the electrophysiological and hemodynamic abnormalities of the human disease; however, the mechanisms underlying altered Ca$^2+$ handling have not been investigated in this model. We now show that left ventricular midmyocardial myocytes isolated from dogs subjected to 3 to 4 weeks of rapid pacing have prolonged action potentials and Ca$^2+$ transients with reduced peaks, but durations approximately 3-fold longer than controls. To discriminate between action potential effects on Ca$^2+$ kinetics and direct changes in Ca$^2+$ regulatory processes, voltage-clamp steps were used to examine the time constant for cytosolic Ca$^2+$ removal (tauCa). tauCa was prolonged by just 35\% in myocytes from failing hearts after fixed voltage steps in physiological solutions (tauCa control, 216+/-25 ms, n=17; tauCa failing, 292+/-23 ms, n=22; P<0.05), but this difference was markedly accentuated when Na$^+$/Ca$^2+$ exchange was eliminated (tauCa control, 282+/-30 ms, n=13; tauCa failing, 576+/-83 ms, n=11; P<0. 005). Impaired sarcoplasmic reticular (SR) Ca$^2+$ uptake and a greater dependence on Na$^+$/Ca$^2+$ exchange for cytosolic Ca$^2+$ removal was confirmed by inhibiting SR Ca$^2+$ ATPase with cyclopiazonic acid, which slowed Ca$^2+$ removal more in control than in failing myocytes. beta-Adrenergic stimulation of SR Ca$^2+$ uptake in cells from failing hearts sufficed only to accelerate tauCa to the range of unstimulated controls. Protein levels of SERCA2a, phospholamban, and Na$^+$/Ca$^2+$ exchanger revealed a pattern of changes qualitatively similar to the functional measurements; SERCA2a and phospholamban were both reduced in failing hearts by 28\%, and Na$^+$/Ca$^2+$ exchange protein was increased 104\% relative to controls. Thus, SR Ca$^2+$ uptake is markedly downregulated in failing hearts, but this defect is partially compensated by enhanced Na$^+$/Ca$^2+$ exchange. The alterations are similar to those reported in human heart failure, which reinforces the utility of the pacing-induced dog model as a surrogate for the human disease.

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@article{Orou_1999_562,
  abstract = {Pacing-induced heart failure in the dog recapitulates many of the
	electrophysiological and hemodynamic abnormalities of the human disease;
	however, the mechanisms underlying altered {C}a$^{2+}$ handling have
	not been investigated in this model. We now show that left ventricular
	midmyocardial myocytes isolated from dogs subjected to 3 to 4 weeks
	of rapid pacing have prolonged action potentials and {C}a$^{2+}$
	transients with reduced peaks, but durations approximately 3-fold
	longer than controls. To discriminate between action potential effects
	on {C}a$^{2+}$ kinetics and direct changes in {C}a$^{2+}$ regulatory
	processes, voltage-clamp steps were used to examine the time constant
	for cytosolic {C}a$^{2+}$ removal (tauCa). tauCa was prolonged by
	just 35\% in myocytes from failing hearts after fixed voltage steps
	in physiological solutions (tauCa control, 216+/-25 ms, n=17; tauCa
	failing, 292+/-23 ms, n=22; P<0.05), but this difference was markedly
	accentuated when {N}a$^{+}$/{C}a$^{2+}$ exchange was eliminated (tauCa
	control, 282+/-30 ms, n=13; tauCa failing, 576+/-83 ms, n=11; P<0.
	005). Impaired sarcoplasmic reticular (SR) {C}a$^{2+}$ uptake and
	a greater dependence on {N}a$^{+}$/{C}a$^{2+}$ exchange for cytosolic
	{C}a$^{2+}$ removal was confirmed by inhibiting SR {C}a$^{2+}$ ATPase
	with cyclopiazonic acid, which slowed {C}a$^{2+}$ removal more in
	control than in failing myocytes. beta-Adrenergic stimulation of
	SR {C}a$^{2+}$ uptake in cells from failing hearts sufficed only
	to accelerate tauCa to the range of unstimulated controls. Protein
	levels of SERCA2a, phospholamban, and {N}a$^{+}$/{C}a$^{2+}$ exchanger
	revealed a pattern of changes qualitatively similar to the functional
	measurements; SERCA2a and phospholamban were both reduced in failing
	hearts by 28\%, and {N}a$^{+}$/{C}a$^{2+}$ exchange protein was increased
	104\% relative to controls. Thus, SR {C}a$^{2+}$ uptake is markedly
	downregulated in failing hearts, but this defect is partially compensated
	by enhanced {N}a$^{+}$/{C}a$^{2+}$ exchange. The alterations are
	similar to those reported in human heart failure, which reinforces
	the utility of the pacing-induced dog model as a surrogate for the
	human disease.},
  added-at = {2009-06-03T11:20:58.000+0200},
  author = {O'Rourke, B. and Kass, D. A. and Tomaselli, G. F. and K��b, S. and Tunin, R. and Marb�n, E.},
  biburl = {https://www.bibsonomy.org/bibtex/2bddcddd25f6303c8efa5b85b7d9448cd/hake},
  description = {The whole bibliography file I use.},
  file = {Orou_1999_562.pdf:Orou_1999_562.pdf:PDF},
  interhash = {f29b180cb53c6442bd6722a9a2322f3b},
  intrahash = {bddcddd25f6303c8efa5b85b7d9448cd},
  journal = {Circ. Res.},
  keywords = {20th ATPase, Acids, Action Adrenergic, Animals, Antigens, Apoptosis, Blockers, Blotting, CD8, CHO Calcium Calcium, Calcium-Binding California, Cardiovascular, Cell Cells, Century, Channel Channels, Congestive, Contraction, Cultured, Decanoic Diazoxide, Dinucleoside Diuretics, Dogs, Electrophysiology, Emergency Enzyme Exchanger, Factors, Failure, Female, Flavoproteins, Forecasting, Fractions, Fusion, Gating, Glyburide, Gov't, Guinea Hamsters, Health Heart Heart, History, Humans, Hydroxy Inhibitors, Intracellular Inwardly Ion Ischemia, Ischemic Male, Medical Membrane Membranes, Mice, Mitochondria, Models, Myocardial Myocardial, Myocardium, National Non-P.H.S., Non-U.S. P.H.S., Patch-Clamp Phosphates, Pigs, Potassium Potentials, Preconditioning, Programs, Proteins, Rabbits, Rats, Receptors, Rectifying, Regional Research Reticulum, Sarcolemma, Sarcoplasmic Services, Sodium, Sodium-Calcium Subcellular Support, Tachycardia, Techniques, Thiazide, Time U.S. United {C}a$^{2+}$-Transporting},
  month = Mar,
  number = 5,
  pages = {562--570},
  pmid = {10082478},
  timestamp = {2009-06-03T11:21:24.000+0200},
  title = {Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced
	heart failure, I: experimental studies.},
  url = {http://circres.ahajournals.org/cgi/content/full/84/5/562},
  volume = 84,
  year = 1999
}

%0 Journal Article
%1 Orou_1999_562
%A O'Rourke, B.
%A Kass, D. A.
%A Tomaselli, G. F.
%A K��b, S.
%A Tunin, R.
%A Marb�n, E.
%D 1999
%J Circ. Res.
%K 20th ATPase, Acids, Action Adrenergic, Animals, Antigens, Apoptosis, Blockers, Blotting, CD8, CHO Calcium Calcium, Calcium-Binding California, Cardiovascular, Cell Cells, Century, Channel Channels, Congestive, Contraction, Cultured, Decanoic Diazoxide, Dinucleoside Diuretics, Dogs, Electrophysiology, Emergency Enzyme Exchanger, Factors, Failure, Female, Flavoproteins, Forecasting, Fractions, Fusion, Gating, Glyburide, Gov't, Guinea Hamsters, Health Heart Heart, History, Humans, Hydroxy Inhibitors, Intracellular Inwardly Ion Ischemia, Ischemic Male, Medical Membrane Membranes, Mice, Mitochondria, Models, Myocardial Myocardial, Myocardium, National Non-P.H.S., Non-U.S. P.H.S., Patch-Clamp Phosphates, Pigs, Potassium Potentials, Preconditioning, Programs, Proteins, Rabbits, Rats, Receptors, Rectifying, Regional Research Reticulum, Sarcolemma, Sarcoplasmic Services, Sodium, Sodium-Calcium Subcellular Support, Tachycardia, Techniques, Thiazide, Time U.S. United {C}a$^{2+}$-Transporting
%N 5
%P 562--570
%T Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced
	heart failure, I: experimental studies.
%U http://circres.ahajournals.org/cgi/content/full/84/5/562
%V 84
%X Pacing-induced heart failure in the dog recapitulates many of the
	electrophysiological and hemodynamic abnormalities of the human disease;
	however, the mechanisms underlying altered Ca$^2+$ handling have
	not been investigated in this model. We now show that left ventricular
	midmyocardial myocytes isolated from dogs subjected to 3 to 4 weeks
	of rapid pacing have prolonged action potentials and Ca$^2+$
	transients with reduced peaks, but durations approximately 3-fold
	longer than controls. To discriminate between action potential effects
	on Ca$^2+$ kinetics and direct changes in Ca$^2+$ regulatory
	processes, voltage-clamp steps were used to examine the time constant
	for cytosolic Ca$^2+$ removal (tauCa). tauCa was prolonged by
	just 35\% in myocytes from failing hearts after fixed voltage steps
	in physiological solutions (tauCa control, 216+/-25 ms, n=17; tauCa
	failing, 292+/-23 ms, n=22; P<0.05), but this difference was markedly
	accentuated when Na$^+$/Ca$^2+$ exchange was eliminated (tauCa
	control, 282+/-30 ms, n=13; tauCa failing, 576+/-83 ms, n=11; P<0.
	005). Impaired sarcoplasmic reticular (SR) Ca$^2+$ uptake and
	a greater dependence on Na$^+$/Ca$^2+$ exchange for cytosolic
	Ca$^2+$ removal was confirmed by inhibiting SR Ca$^2+$ ATPase
	with cyclopiazonic acid, which slowed Ca$^2+$ removal more in
	control than in failing myocytes. beta-Adrenergic stimulation of
	SR Ca$^2+$ uptake in cells from failing hearts sufficed only
	to accelerate tauCa to the range of unstimulated controls. Protein
	levels of SERCA2a, phospholamban, and Na$^+$/Ca$^2+$ exchanger
	revealed a pattern of changes qualitatively similar to the functional
	measurements; SERCA2a and phospholamban were both reduced in failing
	hearts by 28\%, and Na$^+$/Ca$^2+$ exchange protein was increased
	104\% relative to controls. Thus, SR Ca$^2+$ uptake is markedly
	downregulated in failing hearts, but this defect is partially compensated
	by enhanced Na$^+$/Ca$^2+$ exchange. The alterations are
	similar to those reported in human heart failure, which reinforces
	the utility of the pacing-induced dog model as a surrogate for the
	human disease.

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Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: experimental studies.
B. O'Rourke, D. Kass, G. Tomaselli, S. K��b, R. Tunin, and E. Marb�n.
Circ. Res. 84 (5): 562--570 (March 1999)

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Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: experimental studies.B. O'Rourke, D. Kass, G. Tomaselli, S. K��b, R. Tunin, and E. Marb�n. Circ. Res. 84 (5): 562--570 (March 1999)

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Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: experimental studies.
B. O'Rourke, D. Kass, G. Tomaselli, S. K��b, R. Tunin, and E. Marb�n.
Circ. Res. 84 (5): 562--570 (March 1999)