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

Background-The Na+/Ca2+ exchange (NCX) extrudes Ca2+ from cardiac myocytes, hut 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, l eading 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 ventri cular myocytes. Removing extracellular Na+ caused [Ca2+](i) to rise, due to Ca2+ influx via NCX, and this was blocked by 90% with 5 mu mol/L KBR. Howe ver, KBR did not alter [Ca2+](i) decline due to NCX. Thus, we used 5 mu mol /L KBR to selectively block Ca2+ entry but not efflux via NCX. Under contro l conditions, 5 mu mol/L KBR did not alter steady-state twitches, Ca2+ tran sients, 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) a nd abolished the spontaneous Ca2+ oscillations, but it did not prevent inot ropy. Conclusions-In rat ventricular myocytes, Ca2+ influx via NCX is not importa nt for normal excitation-contraction coupling. Furthermore, the inhibition of Ca2+ efflux alone (as [Na+](i) rises) may be sufficient to cause glycosi de inotropy. In contrast, Ca2+ overload and spontaneous activity at high [N a+](i) was blocked by KBR, suggesting that net Ca2+ influx (not merely redu ced efflux) via NCX is involved in potentially arrhythmogenic Ca2+ overload .