Activation of ischemia- and reperfusion-sensitive abdominal visceral C fiber afferents. Role of hydrogen peroxide and hydroxyl radicals.

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Abstract
Abdominal ischemia and reperfusion evoke reflex excitation of the cardiovascular system and generate reactive oxygen species. We have shown previously that the reactive oxygen species hydrogen peroxide (H2O2) elicits reflex excitation of the cardiovascular system after serosal application to abdominal organs. However, it is not known if ischemia-sensitive afferents respond to reactive oxygen species or if scavengers such as dimethylthiourea (DMTU) inhibit the response of these afferents to ischemia or reperfusion. Therefore, to provide more information on the neurophysiological mechanisms underlying the activation of these afferents, we studied their responses to H2O2 applied to the receptive field during recordings of single-unit activity of ischemia-insensitive or -sensitive abdominal visceral C fiber afferents in anesthetized cats. Additionally, we recorded single-unit activity of ischemia and reperfusion-sensitive afferents before and after treatment with DMTU (10 mg/kg), which scavenges H2O2 and hydroxyl radicals or the iron chelator deferoxamine (DEF, 10 mg/kg), which inhibits hydroxyl radical formation. Application of 44 mumol H2O2 to afferent endings increased the discharge frequency in nine of 11 ischemia-sensitive units, from 0.01 +/- 0.01 to 0.67 +/- 0.16 impulses per second. In contrast, only one of 10 ischemia-insensitive C fibers responded to H2O2 application. In an additional 13 ischemia-sensitive C fibers, DMTU significantly (p < 0.05) attenuated ischemia-induced increases in discharge frequency from 0.42 +/- 0.18 to 0.24 +/- 0.1 impulses per second (ischemia versus DMTU + ischemia, respectively). In eight additional C fibers, we found that reperfusion after 5 minutes of ischemia was associated with an increase in discharge activity from a baseline activity of 0.02 +/- 0.01 to 0.44 +/- 0.07 impulses per second. DMTU significantly attenuated the reperfusion-induced increases in discharge frequency from 0.08 +/- 0.04 to 0.18 +/- 0.06 impulses per second. DEF significantly (p < 0.05) attenuated the increased discharge activity from 0.39 +/- 0.07 to 0.10 +/- 0.04 impulses per second (ischemia versus DEF + ischemia, respectively) in an additional 11 ischemia-sensitive C fibers. In contrast, iron-saturated DEF did not attenuate ischemia- and reperfusion-induced increases in impulse activity. Thus, ischemia-sensitive but not ischemia-insensitive abdominal visceral afferents respond to H2O2. Furthermore, ischemia- and reperfusion-sensitive afferents decreased their impulse activity to a repeated period of ischemia or reperfusion after DMTU or DEF treatment. These data suggest that reactive oxygen species, particularly H2O2 and hydroxyl radicals, activate abdominal visceral C fibers in the cat during brief periods of ischemia and reperfusion.