%0 Journal Article %1 Schl_2000_774 %A Schlotthauer, K. %A Bers, D. M. %D 2000 %J Circ. Res. %K 11055973 Acid, Action Animals, Caffeine, Calcium, Cations, Chlorides, Electric Gov't, Heart Membrane Myocardium, Niflumic Non-U.S. P.H.S., Patch-Clamp Potentials, Rabbits, Research Reticulum, Sarcoplasmic Sodium, Stimulation, Support, Techniques, U.S. Ventricles, %N 9 %P 774--780 %T Sarcoplasmic reticulum Ca$^2+$ release causes myocyte depolarization. Underlying mechanism and threshold for triggered action potentials. %U http://circres.ahajournals.org/cgi/content/full/87/9/774 %V 87 %X Spontaneous sarcoplasmic reticulum (SR) Ca$^2+$ release causes delayed afterdepolarizations (DADs) via Ca$^2+$-induced transient inward currents (I:(ti)). However, no quantitative data exists regarding (1) Ca$^2+$ dependence of DADs, (2) Ca$^2+$ required to depolarize the cell to threshold and trigger an action potential (AP), or (3) relative contributions of Ca$^2+$-activated currents to DADs. To address these points, we evoked SR Ca$^2+$ release by rapid application of caffeine in indo 1-AM-loaded rabbit ventricular myocytes and measured caffeine-induced DADs (cDADs) with whole-cell current clamp. The SR Ca$^2+$ load of the myocyte was varied by different AP frequencies. The cDAD amplitude doubled for every 88+/-8 nmol/L of DeltaCa$^2+$(i) (simple exponential), and the DeltaCa$^2+$(i) threshold of 424+/-58 nmol/L was sufficient to trigger an AP. Blocking Na$^+$-Ca$^2+$ exchange current (I(Na/Ca)) by removal of Na(o) and Ca$^2+$(o) (or with 5 mmol/L Ni$^2+$) reduced cDADs by >90\%, for the same DeltaCa$^2+$(i). In contrast, blockade of Ca$^2+$-activated Cl$^-$ current (I(Cl(Ca))) with 50 micromol/L niflumate did not significantly alter cDADs. We conclude that DADs are almost entirely due to I(Na/Ca), not I(Cl(Ca)) or Ca$^2+$-activated nonselective cation current. To trigger an AP requires 30 to 40 micromol/L cytosolic Ca$^2+$ or a Ca$^2+$(i) transient of 424 nmol/L. Current injection, simulating I(ti)s with different time courses, revealed that faster I:(ti)s require less charge for AP triggering. Given that spontaneous SR Ca$^2+$ release occurs in waves, which are slower than cDADs or fast I(ti)s, the true DeltaCa$^2+$(i) threshold for AP activation may be approximately 3-fold higher in normal myocytes. This provides a safety margin against arrhythmia in normal ventricular myocytes.

@article{Schl_2000_774, abstract = {Spontaneous sarcoplasmic reticulum (SR) {C}a$^{2+}$ release causes delayed afterdepolarizations (DADs) via {C}a$^{2+}$-induced transient inward currents (I:(ti)). However, no quantitative data exists regarding (1) {C}a$^{2+}$ dependence of DADs, (2) {C}a$^{2+}$ required to depolarize the cell to threshold and trigger an action potential (AP), or (3) relative contributions of {C}a$^{2+}$-activated currents to DADs. To address these points, we evoked SR {C}a$^{2+}$ release by rapid application of caffeine in indo 1-AM-loaded rabbit ventricular myocytes and measured caffeine-induced DADs (cDADs) with whole-cell current clamp. The SR {C}a$^{2+}$ load of the myocyte was varied by different AP frequencies. The cDAD amplitude doubled for every 88+/-8 nmol/L of Delta[{C}a$^{2+}$](i) (simple exponential), and the Delta[{C}a$^{2+}$](i) threshold of 424+/-58 nmol/L was sufficient to trigger an AP. Blocking {N}a$^{+}$-{C}a$^{2+}$ exchange current (I(Na/Ca)) by removal of [Na](o) and [{C}a$^{2+}$](o) (or with 5 mmol/L {N}i$^{2+}$) reduced cDADs by >90\%, for the same Delta[{C}a$^{2+}$](i). In contrast, blockade of {C}a$^{2+}$-activated {C}l$^{-}$ current (I(Cl(Ca))) with 50 micromol/L niflumate did not significantly alter cDADs. We conclude that DADs are almost entirely due to I(Na/Ca), not I(Cl(Ca)) or {C}a$^{2+}$-activated nonselective cation current. To trigger an AP requires 30 to 40 micromol/L cytosolic {C}a$^{2+}$ or a [{C}a$^{2+}$](i) transient of 424 nmol/L. Current injection, simulating I(ti)s with different time courses, revealed that faster I:(ti)s require less charge for AP triggering. Given that spontaneous SR {C}a$^{2+}$ release occurs in waves, which are slower than cDADs or fast I(ti)s, the true Delta[{C}a$^{2+}$](i) threshold for AP activation may be approximately 3-fold higher in normal myocytes. This provides a safety margin against arrhythmia in normal ventricular myocytes.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Schlotthauer, K. and Bers, D. M.}, biburl = {https://www.bibsonomy.org/bibtex/246235d42a5c15124672ef572c9430294/hake}, description = {The whole bibliography file I use.}, file = {Schl_2000_774.pdf:Schl_2000_774.pdf:PDF}, interhash = {b9b5b0f8c49df9c085922ec7ad001f36}, intrahash = {46235d42a5c15124672ef572c9430294}, journal = {Circ. Res.}, key = 280, keywords = {11055973 Acid, Action Animals, Caffeine, Calcium, Cations, Chlorides, Electric Gov't, Heart Membrane Myocardium, Niflumic Non-U.S. P.H.S., Patch-Clamp Potentials, Rabbits, Research Reticulum, Sarcoplasmic Sodium, Stimulation, Support, Techniques, U.S. Ventricles,}, month = Oct, number = 9, pages = {774--780}, pmid = {11055973}, timestamp = {2009-06-03T11:21:28.000+0200}, title = {Sarcoplasmic reticulum {C}a$^{2+}$ release causes myocyte depolarization. Underlying mechanism and threshold for triggered action potentials.}, url = {http://circres.ahajournals.org/cgi/content/full/87/9/774}, volume = 87, year = 2000 }