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.