KB-R7943 Block of Ca Influx Via Na/Ca Exchange Does Not Alter Twitches or Glycoside Inotropy but Prevents Ca Overload in Rat Ventricular Myocytes

Background—The Na/Ca exchange (NCX) extrudes Ca from cardiac myocytes, but it can also mediate Ca influx, load the sarcoplasmic reticulum with Ca, and trigger Ca release from the sarcoplasmic reticulum. In ischemia/ reperfusion or digitalis toxicity, increased levels of intracellular [Na] ([Na]i) may raise levels of intracellular [Ca ] ([Ca]i) via NCX, leading to cell injury and arrhythmia. Methods and Results—We used KB-R7943 (KBR) to selectively block Ca influx via NCX to study the role of NCX-mediated Ca influx in intact rat ventricular myocytes. Removing extracellular Na caused [Ca]i to rise, due to Ca influx via NCX, and this was blocked by 90% with 5 mmol/L KBR. However, KBR did not alter [Ca]i decline due to NCX. Thus, we used 5 mmol/L KBR to selectively block Ca entry but not efflux via NCX. Under control conditions, 5 mmol/L KBR did not alter steady-state twitches, Ca transients, Ca 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]i and abolished the spontaneous Ca 21 oscillations, but it did not prevent inotropy. Conclusions—In rat ventricular myocytes, Ca influx via NCX is not important for normal excitation-contraction coupling. Furthermore, the inhibition of Ca efflux alone (as [Na]i rises) may be sufficient to cause glycoside inotropy. In contrast, Ca overload and spontaneous activity at high [Na]i was blocked by KBR, suggesting that net Ca 21 influx (not merely reduced efflux) via NCX is involved in potentially arrhythmogenic Ca overload. (Circulation. 2000;101:1441-1446.)