(Circulation. 1997;96:614-620.)
© 1997 American Heart Association, Inc.
Articles |
Lactate and PO2 Modulate Superoxide Anion Production in Bovine Cardiac Myocytes
Potential Role of NADH Oxidase
From the Department of Physiology, New York Medical College, Valhalla, NY.
Correspondence to Michael S. Wolin, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595.
Background Lactate increases lucigenin
chemiluminescence (CL)–detectable superoxide anion
(O2
-) generation in bovine vascular smooth
muscle and endothelium, and a microsomal
flavoprotein-containing NADH oxidase whose activity is regulated by
PO2 and cytosolic NAD(H) redox appears to be
the detected source of O2-
production. Little is known about the importance of this
O2--producing system in cardiac
myocytes.
Methods and Results In isolated bovine cardiac myocytes,
lactate (10 mmol/L) increased lucigenin-detectable
O2- levels to 
1.8 times baseline,
whereas pyruvate (10 mmol/L) and mitochondrial probes did not
increase the detection of O2-. A
nonmitochondrial NADH oxidase activity, found in microsomes containing
a cytochrome b558, was a major source of
O2- production in the
homogenate of myocytes, because NADH (0.1 mmol/L)
increased basal lucigenin CL >100-fold. NADPH oxidases, mitochondria,
and xanthine oxidase were minor sources of detectable
O2- production. However,
mitochondria released H2O2 in the presence of
5 mmol/L succinate and 30 µmol/L antimycin, based on its
detection as catalase-inhibitable luminol (+horseradish
peroxidase)–elicited CL. Diphenyliodonium (DPI), an
inhibitor of flavoprotein-containing oxidases,
significantly attenuated basal, lactate, and NADH-elicited lucigenin
CL. Hypoxia eliminated myocyte lucigenin CL, and posthypoxic
reoxygenation caused an 8.6-fold increase in the
detection of O2- that was potentiated by
lactate and inhibited by DPI.
Conclusions NADH oxidase activity linked to cytosolic
NAD(H) redox appears to be a key source of
O2- production in cardiac myocytes
that could contribute to oxidant signaling mechanisms and injury upon
exposure to changes in PO2 and metabolites
produced under hypoxia, such as lactate. These processes could
contribute to the previously observed potentiation of injury caused by
lactate in cardiac ischemia/reperfusion.
Key Words: free radicals • hypoxia • myocytes • oxygen
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