Na + “Fuzzy Space”: Does It Exist, and Is It Important In Ischemic Injury?

Work is reviewed which provides evidence for the presence of a subsarcolemmal microdomain, in which the [Na + ] is influenced by Na + influx via the Na + channel and the activity of the Na pump. The sarcolemma adjacent to this microdomain, which has been referred to as “Na + fuzzy space,” appears to include Na‐Ca exchangers, and thus alterations of [Na + ] in this space may influence Ca 2+ influx and efflux, and thus Ca 2+ loading, more directly than do alterations of bulk cytoplasmic [Na + ]. The degree of Ca 2+ loading is an important determinant of contractility in heart muscle, and therefore alterations in fuzzy space [Na + ] may be important in mediating the positive inotropic effects of Na pump inhibitors, such as digitalis, and the negative inotropic effects of Na + channel blockers such as disopyramide. During ischemia, myocyte Ca 2+ overload can contribute to ATP depletion by activation of Ca 2+ ‐dependent ATPases and by induction of the mitochondrial permeability transition, and thus is an important contributor to myocyte dysfunction and injury. Hypoxia associated with ischemia can induce Na + influx via a persistent opening of the Na + channel. It is likely that this Na + influx elevates [Na + ] in the fuzzy space, and thus increases Ca 2+ influx via Na‐Ca exchange, and increases Ca 2+ loading. Inhibition of the persistent Na + current with a resulting decrease in Ca 2+ loading by drugs such as tetrodotoxin (TTX) and ranolazine may be a mechanism by which these agents produce a cardio‐protective effect during ischemia.