Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading

Abstract

Background: Studies have shown that the rise in intracellular ionized calcium, [Ca2+]i, in hypoxic myocardium is driven by an increase in sodium, [Na+]i, but the source of Na+ is not known. Methods and Results: Inhibitors of the voltage-gated Na+ channel were used to investigate the effect of Na+ channel blockade on hypoxic Na+ loading, Na+-dependent Ca2+ loading, and reoxygenation hypercontracture in isolated adult rat cardiac myocytes. Single electrically stimulated (0.2 Hz) cells were loaded with either SBFI (to index [Na+],) or indo-1 (to index [Ca2+]i) and exposed to glucose-free hypoxia (Po2 <0.02 mm Hg). Both [Na+]; and [Ca2+]i increased during hypoxia when cells became inexcitable following ATP-depletion contracture. The hypoxic rise in [Na+]; and [Ca2+]i was significantly attenuated by 1 μmol/L R 56865. Tetrodotoxin (60 μmol/L), a selective Na+-channel blocker, also markedly reduced the rise in [Ca2+]; during hypoxia and reoxygenation. Reoxygenation-induced cellular hypercontracture was reduced from 83% (45 of 54 cells) under control conditions to 12% (4 of 32) in the presence of R 56865 (P