(Circulation. 2000;101:1441.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
KB-R7943 Block of Ca2+ Influx Via Na+/Ca2+ Exchange Does Not Alter Twitches or Glycoside Inotropy but Prevents Ca2+ Overload in Rat Ventricular Myocytes
From the Third Department of Internal Medicine (H.S., K.Q., H.T.) and Photon Medical Research Center (H.H.), Hamamatsu University School of Medicine, Hamamatsu, Japan, Department of Physiology (K.S.G., D.M.B.), Loyola University Chicago, Maywood, Ill.
Correspondence to Hiroshi Satoh, MD, PhD, Third Department of Internal Medicine, Hamamatsu University School of Medicine, 3600 Handa-Cho, Hamamatsu 431-3192, Japan. E-mail satoh36{at}hama-med.ac.jp
Background—The Na+/Ca2+ exchange (NCX) extrudes Ca2+ from cardiac myocytes, but it can also mediate Ca2+ influx, load the sarcoplasmic reticulum with Ca2+, and trigger Ca2+ release from the sarcoplasmic reticulum. In ischemia/reperfusion or digitalis toxicity, increased levels of intracellular [Na+] ([Na+]i) may raise levels of intracellular [Ca2+] ([Ca2+]i) via NCX, leading to cell injury and arrhythmia.
Methods and Results—We used KB-R7943 (KBR) to selectively block Ca2+ influx via NCX to study the role of NCX-mediated Ca2+ influx in intact rat ventricular myocytes. Removing extracellular Na+ caused [Ca2+]i to rise, due to Ca2+ influx via NCX, and this was blocked by 90% with 5 µmol/L KBR. However, KBR did not alter [Ca2+]i decline due to NCX. Thus, we used 5 µmol/L KBR to selectively block Ca2+ entry but not efflux via NCX. Under control conditions, 5 µmol/L KBR did not alter steady-state twitches, Ca2+ transients, Ca2+ 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 [Ca2+]i and abolished the spontaneous Ca2+ oscillations, but it did not prevent inotropy.
Conclusions—In rat ventricular myocytes, Ca2+ influx via NCX is not important for normal excitation-contraction coupling. Furthermore, the inhibition of Ca2+ efflux alone (as [Na+]i rises) may be sufficient to cause glycoside inotropy. In contrast, Ca2+ overload and spontaneous activity at high [Na+]i was blocked by KBR, suggesting that net Ca2+ influx (not merely reduced efflux) via NCX is involved in potentially arrhythmogenic Ca2+ overload.
Key Words: myocytes • ion exchange • sarcoplasmic reticulum • arrhythmia
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