%0 Journal Article %1 Sato_2000_1441 %A Satoh, H. %A Ginsburg, K. S. %A Qing, K. %A Terada, H. %A Hayashi, H. %A Bers, D. M. %D 2000 %J Circulation %K /&/ Animals; Calcium, Contraction, Exchanger, Glycosides, Male; Myocardial Myocardium, Rats, Rats; Reticulum, Sarcoplasmic Sodium-Calcium Sprague-Dawley; Thiourea, analogs antagonists cytology/metabolism; derivatives/pharmacology drug effects; inhibitors; metabolism; pharmacology; %N 12 %P 1441--1446 %T KB-R7943 block of Ca$^2+$ influx via Na$^+$/Ca$^2+$ exchange does not alter twitches or glycoside inotropy but prevents Ca$^2+$ overload in rat ventricular myocytes. %U http://circ.ahajournals.org/cgi/content/full/101/12/1441 %V 101 %X BACKGROUND: The Na$^+$/Ca$^2+$ exchange (NCX) extrudes Ca$^2+$ from cardiac myocytes, but it can also mediate Ca$^2+$ influx, load the sarcoplasmic reticulum with Ca$^2+$, and trigger Ca$^2+$ release from the sarcoplasmic reticulum. In ischemia/reperfusion or digitalis toxicity, increased levels of intracellular Na$^+$ (Na$^+$(i)) may raise levels of intracellular Ca$^2+$ (Ca$^2+$(i)) via NCX, leading to cell injury and arrhythmia. METHODS AND RESULTS: We used KB-R7943 (KBR) to selectively block Ca$^2+$ influx via NCX to study the role of NCX-mediated Ca$^2+$ influx in intact rat ventricular myocytes. Removing extracellular Na$^+$ caused Ca$^2+$(i) to rise, due to Ca$^2+$ influx via NCX, and this was blocked by 90\% with 5 micromol/L KBR. However, KBR did not alter Ca$^2+$(i) decline due to NCX. Thus, we used 5 micromol/L KBR to selectively block Ca$^2+$ entry but not efflux via NCX. Under control conditions, 5 micromol/L KBR did not alter steady-state twitches, Ca$^2+$ transients, Ca$^2+$ load in the sarcoplasmic reticulum, or rest potentiation, but it did prolong the late low plateau of the rat action potential. When Na$^+$/K$^+$ ATPase was inhibited by strophanthidin, KBR reduced diastolic Ca$^2+$(i) and abolished the spontaneous Ca$^2+$ oscillations, but it did not prevent inotropy. CONCLUSIONS: In rat ventricular myocytes, Ca$^2+$ influx via NCX is not important for normal excitation-contraction coupling. Furthermore, the inhibition of Ca$^2+$ efflux alone (as Na$^+$(i) rises) may be sufficient to cause glycoside inotropy. In contrast, Ca$^2+$ overload and spontaneous activity at high Na$^+$(i) was blocked by KBR, suggesting that net Ca$^2+$ influx (not merely reduced efflux) via NCX is involved in potentially arrhythmogenic Ca$^2+$ overload.

@article{Sato_2000_1441, abstract = {BACKGROUND: The {N}a$^{+}$/{C}a$^{2+}$ exchange (NCX) extrudes {C}a$^{2+}$ from cardiac myocytes, but it can also mediate {C}a$^{2+}$ influx, load the sarcoplasmic reticulum with {C}a$^{2+}$, and trigger {C}a$^{2+}$ release from the sarcoplasmic reticulum. In ischemia/reperfusion or digitalis toxicity, increased levels of intracellular [{N}a$^{+}$] ([{N}a$^{+}$](i)) may raise levels of intracellular [{C}a$^{2+}$] ([{C}a$^{2+}$](i)) via NCX, leading to cell injury and arrhythmia. METHODS AND RESULTS: We used KB-R7943 (KBR) to selectively block {C}a$^{2+}$ influx via NCX to study the role of NCX-mediated {C}a$^{2+}$ influx in intact rat ventricular myocytes. Removing extracellular {N}a$^{+}$ caused [{C}a$^{2+}$](i) to rise, due to {C}a$^{2+}$ influx via NCX, and this was blocked by 90\% with 5 micromol/L KBR. However, KBR did not alter [{C}a$^{2+}$](i) decline due to NCX. Thus, we used 5 micromol/L KBR to selectively block {C}a$^{2+}$ entry but not efflux via NCX. Under control conditions, 5 micromol/L KBR did not alter steady-state twitches, {C}a$^{2+}$ transients, {C}a$^{2+}$ load in the sarcoplasmic reticulum, or rest potentiation, but it did prolong the late low plateau of the rat action potential. When {N}a$^{+}$/{K}$^{+}$ ATPase was inhibited by strophanthidin, KBR reduced diastolic [{C}a$^{2+}$](i) and abolished the spontaneous {C}a$^{2+}$ oscillations, but it did not prevent inotropy. CONCLUSIONS: In rat ventricular myocytes, {C}a$^{2+}$ influx via NCX is not important for normal excitation-contraction coupling. Furthermore, the inhibition of {C}a$^{2+}$ efflux alone (as [{N}a$^{+}$](i) rises) may be sufficient to cause glycoside inotropy. In contrast, {C}a$^{2+}$ overload and spontaneous activity at high [{N}a$^{+}$](i) was blocked by KBR, suggesting that net {C}a$^{2+}$ influx (not merely reduced efflux) via NCX is involved in potentially arrhythmogenic {C}a$^{2+}$ overload.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Satoh, H. and Ginsburg, K. S. and Qing, K. and Terada, H. and Hayashi, H. and Bers, D. M.}, biburl = {https://www.bibsonomy.org/bibtex/2000df6cba3c6a10866e289ecb42c56c4/hake}, description = {The whole bibliography file I use.}, file = {Sato_2000_1441.pdf:Sato_2000_1441.pdf:PDF}, institution = {Third Department of Internal Medicine, and Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan. satoh36@hama-med.ac.jp}, interhash = {b181aa88b37d9defc24bfef7ddbe347a}, intrahash = {000df6cba3c6a10866e289ecb42c56c4}, journal = {Circulation}, keywords = {/&/ Animals; Calcium, Contraction, Exchanger, Glycosides, Male; Myocardial Myocardium, Rats, Rats; Reticulum, Sarcoplasmic Sodium-Calcium Sprague-Dawley; Thiourea, analogs antagonists cytology/metabolism; derivatives/pharmacology drug effects; inhibitors; metabolism; pharmacology;}, month = Mar, number = 12, pages = {1441--1446}, pdf = {Sato_2000_1441.pdf}, pmid = {10736290}, timestamp = {2009-06-03T11:21:28.000+0200}, title = {KB-R7943 block of {C}a$^{2+}$ influx via {N}a$^{+}$/{C}a$^{2+}$ exchange does not alter twitches or glycoside inotropy but prevents {C}a$^{2+}$ overload in rat ventricular myocytes.}, url = {http://circ.ahajournals.org/cgi/content/full/101/12/1441}, volume = 101, year = 2000 }