TY - JOUR
T1 - Modulation of release of reactive oxygen species by the contracting diaphragm
AU - Stofan, Daniel A.
AU - Callahan, Leigh A.
AU - DiMarco, Anthony F.
AU - Nethery, David E.
AU - Supinski, Gerald S.
PY - 2000
Y1 - 2000
N2 - Recent reports have demonstrated that superoxide is released by the contracting diaphragm (1, 2). Moreover, extracellular scavengers of superoxide (i.e., exogeneously administered superoxide dismutase) reduce diaphragm fatigue rate, arguing that superoxide released from contracting muscles may have functionally significant effects (1, 3). The mechanism by which free radical formation and release occurs has not, however, been- determined, and all past studies of this phenomenon have been conducted at a single muscle length (the length of maximum force generation, Lo) and at a single level Of carbon dioxide. The purpose of the present study was twofold: (1) to examine the effect of blockade of two free radical-generating pathways (i.e., to block cyclooxygenase with indomethacin and xanthine oxidase with oxypurinol) on superoxide release by the contracting diaphragm, and (2) to examine the effect of altering muscle length, carbon dioxide levels, and stimulation frequency on superoxide release during contraction. Studies were performed using an isolated, arterially perfused, rat diaphragm preparation in which superoxide release was assessed in real time by measuring arteriovenous cytochrome c reduction gradients across this muscle. We found that superoxide release during contraction was: (1) not altered by indomethacin administration, (2) partially reduced by oxypurinol administration, (3) reduced by decreasing muscle length, (4) reduced by increasing carbon dioxide concentrations, and (5) reduced by decreasing stimulation frequency. The first two findings indicate that xanthine oxidase pathways contribute to free radical formation under these circumstances but cyclooxygenase does not. The last three findings suggest that these common physiologic alterations have significant effects on free radical release by contracting muscle.
AB - Recent reports have demonstrated that superoxide is released by the contracting diaphragm (1, 2). Moreover, extracellular scavengers of superoxide (i.e., exogeneously administered superoxide dismutase) reduce diaphragm fatigue rate, arguing that superoxide released from contracting muscles may have functionally significant effects (1, 3). The mechanism by which free radical formation and release occurs has not, however, been- determined, and all past studies of this phenomenon have been conducted at a single muscle length (the length of maximum force generation, Lo) and at a single level Of carbon dioxide. The purpose of the present study was twofold: (1) to examine the effect of blockade of two free radical-generating pathways (i.e., to block cyclooxygenase with indomethacin and xanthine oxidase with oxypurinol) on superoxide release by the contracting diaphragm, and (2) to examine the effect of altering muscle length, carbon dioxide levels, and stimulation frequency on superoxide release during contraction. Studies were performed using an isolated, arterially perfused, rat diaphragm preparation in which superoxide release was assessed in real time by measuring arteriovenous cytochrome c reduction gradients across this muscle. We found that superoxide release during contraction was: (1) not altered by indomethacin administration, (2) partially reduced by oxypurinol administration, (3) reduced by decreasing muscle length, (4) reduced by increasing carbon dioxide concentrations, and (5) reduced by decreasing stimulation frequency. The first two findings indicate that xanthine oxidase pathways contribute to free radical formation under these circumstances but cyclooxygenase does not. The last three findings suggest that these common physiologic alterations have significant effects on free radical release by contracting muscle.
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M3 - Article
C2 - 10712339
AN - SCOPUS:0034066957
SN - 1073-449X
VL - 161
SP - 891
EP - 898
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 3 I
ER -