NUCLEAR-MAGNETIC-RESONANCE STUDIES OF CATIONIC AND ENERGETIC ALTERATIONS WITH OXIDANT STRESS IN THE PERFUSED HEART - MODULATION WITH PYRUVATE AND LACTATE
S. Yanagida et al., NUCLEAR-MAGNETIC-RESONANCE STUDIES OF CATIONIC AND ENERGETIC ALTERATIONS WITH OXIDANT STRESS IN THE PERFUSED HEART - MODULATION WITH PYRUVATE AND LACTATE, Circulation research, 77(4), 1995, pp. 773-783
The postischemic generation of oxygen-derived free radicals may contri
bute to myocardial reperfusion injury by affecting sarcolemmal ion tra
nsport. Recent evidence indicates that exposure to reactive oxygen int
ermediates induces rapid increases in myocardial cytosolic free Ca2+ (
Ca-i(2+)). The mechanism is undetermined but may involve disturbances
in Na+ homeostasis. We tested this hypothesis by interleaving Na-23 an
d P-31 nuclear magnetic resonance (NMR) measurements of Na-i(+) and hi
gh-energy phosphates in glucose-perfused rat hearts exposed to hydroxy
l radicals generated from H2O2 and Fe3+. In separate experiments, K-i(
+) and Ca-i(2+) were measured with K-39 and F-19 NMR, respectively. Th
e hearts rapidly exhibited contracture. Threefold Nac, increases and s
ubstantial K-i(+) depletion were observed. Glycolytic inhibition was i
ndicated by rapid sugar phosphate accumulation and cellular energy dep
letion. Notably, however, severe functional and energetic deterioratio
n and substantial elevation of Ca-i(2+), occurred before substantial N
a-i(+) accumulation or K-i(+) depletion was observed. Further experime
nts investigated the ability of pyruvate to scavenge H2O2 and to prote
ct the myocardium from oxidant stress. Pyruvate (1 or 2.5 mmol/L) dram
atically attenuated functional and energetic alterations and alteratio
ns in Na-i(+) and K-i(+), whereas acetate (2.5 mmol/L) offered no prot
ection. Unlike pyruvate, lactate (5 mmol/L) has little or no capacity
to scavenge H2O2 but has similar protective effects. In conclusion, py
ruvate effectively protects against H2O2/Fe3+, largely by direct H2O2
scavenging. Protection with lactate may involve intracellular pyruvate
augmentation. Without exogenous pyruvate or lactate, myocardial Na+ h
omeostasis can be substantially altered by oxidant stress, possibly vi
a cellular energy depletion. Excess Na-i(+) accumulation may, in turn,
hasten metabolic and functional deterioration, but a causal link with
the initial alterations in function or Ca-i(2+) was not supported.