%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.

@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 }