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

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. 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. 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.