Importance of Ca2+ influx by Na+/Ca2+ exchange under normal and sodium-loaded conditions in mammalian ventricles

Na(+)/Ca(2+) exchange (NCX) is a major Ca(2+) extrusion system in cardiac myocytes, but can also mediate Ca(2+) influx and trigger sarcoplasmic reticulum Ca(2+) release. Under conditions such as digitalis toxicity or ischemia/reperfusion, increased [Na(+)](i) may lead to a rise in [Ca(2+)](i) through NCX, causing Ca(2+) overload and triggered arrhythmias. Here we used an agent which selectively blocks Ca(2+) influx by NCX, KB-R7943 (KBR), and assessed twitch contractions and Ca(2+) transients in rat and guinea pig ventricular myocytes loaded with indo-1. KBR (5 muM) did not alter control steady-state twitch contractions or Ca(2+) transients at 0.5 Hz in rat, but significantly decreased them in guinea pig myocytes. When cells were Na(+)-loaded by perfusion of strophanthidin (50 muM), the addition of KBR reduced diastolic [Ca(2+)](i) and abolished spontaneous Ca(2+) oscillations. In guinea pig papillary muscles exposed to substrate-free hypoxic medium for 60 min, KBR (10 muM applied 10 min before and during reoxygenation) reduced both the incidence and duration of reoxygenation-induced arrhythmias. KBR also enhanced the recovery of developed tension after reoxygenation. It is concluded that (1) the importance of Ca(2+) influx via NCX for normal excitation-contraction coupling is species-dependent, and (2) Ca(2+) influx via NCX may be critical in causing myocardial Ca(2+) overload and triggered activities induced by cardiac glycoside or reoxygenation.