Hypertonic perfusion inhibits intracellular Na and Ca accumulation in hypoxic myocardium

Much evidence supports the view that hypoxic/ischemic injury is largely due to increased intracellular Ca concentration ([Ca](i)) resulting from I) de creased intracellular pH (pH(i)), 2) stimulated Na/H exchange that increase s Na uptake and thus intracellular Na (Na-i), and 3) decreased Na gradient that decreases or reverses net Ca transport via Na/Ca exchange. The Na/H ex changer (NHE) is also stimulated by hypertonic solutions; however, hyperton ic media may inhibit NHE's response to changes in pH(i) (Cala PM and Maldon ado HM. J Gen Physiol 103: 1035-1054, 1994). Thus we tested the hypothesis that hypertonic perfusion attenuates acid-induced increases in Nai in myoca rdium and, thereby, decreases Cai accumulation during hypoxia. Rabbit heart s were Langendorff perfused with HEPES-buffered Krebs-Henseleit solution eq uilibrated with 100% O-2 or 100% Na. Hypertonic perfusion began 5 min befor e hypoxia or normoxic acidification (NH4Cl washout). Na-i, [Ca](i), pH(i), and high-energy phosphates were measured by NMR. Control solutions were 295 mosM, and hypertonic solutions were adjusted to 305, 325, or 345 mosM by a ddition of NaCl or sucrose. During 60 min of hypoxia (295 mosM), Na-i rose from 22 +/- 1 to 100 +/- 10 meq/kg dry wt while [Ca](i) rose from 347 +/- 1 1 to 1,306 +/- 89 nM. During hypertonic hypoxic perfusion (325 mosM), incre ases in Nai and [Ca](i) were reduced by 65 and 60%, respectively (P < 0.05) . Hypertonic perfusion also diminished Na uptake after normoxic acidificati on by 87% (P < 0.05). The data are consistent with the hypothesis that mild hypertonic perfusion diminishes acid-induced Na accumulation and, thereby, decreases Na/Ca exchange-mediated Ca-i accumulation during hypoxia.