Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0848283 (rundown)
 502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rundown of ionic gradients is a central feature of white matter anoxic injury; however, little is known about the contribution of anions such as Cl-. We used the in vitro rat optic nerve to study the role of aberrant Cl- transport in anoxia/ischemia. After 30 min of anoxia (NaN3, 2 mm), axonal membrane potential (V(m)) decreased to 42 +/- 11% of control and to 73 +/- 11% in the presence of tetrodotoxin (TTX) (1 microm). TTX + 4,4'-diisothiocyanatostilbene-2,2' disulfonic acid disodium salt (500 microm), a broad spectrum anion transport blocker, abolished anoxic depolarization (95 +/- 8%). Inhibition of the K-Cl cotransporter (KCC) (furosemide 100 microm) together with TTX was also more effective than TTX alone (84 +/- 14%). The compound action potential (CAP) area recovered to 26 +/- 6% of control after 1 hr anoxia. KCC blockade (10 microm furosemide) improved outcome (40 +/- 4%), and TTX (100 nm) was even more effective (74 +/- 12%). In contrast, the Cl- channel blocker niflumic acid (50 microm) worsened injury (6 +/- 1%). Coapplication of TTX (100 nm) + furosemide (10 microm) was more effective than either agent alone (91 +/- 9%). Furosemide was also very effective at normalizing the shape of the CAPs. The KCC3a isoform was localized to astrocytes. KCC3 and weaker KCC3a was detected in myelin of larger axons. KCC2 was seen in oligodendrocytes and within axon cylinders. Cl- gradients contribute to resting optic nerve membrane potential, and transporter and channel-mediated Cl- fluxes during anoxia contribute to injury, possibly because of cellular volume changes and disruption of axo-glial integrity, leading to propagation failure and distortion of fiber conduction velocities.
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PMID:Aberrant chloride transport contributes to anoxic/ischemic white matter injury. 1273 53

Na(+)-K(+)-ATPase pump failure during either anoxia or ouabain perfusion induces rapid axonal depolarization by dissipating ionic gradients. In this study, we examined the interplay between cation and anion transporting pathways mediating axonal depolarization during anoxia or selective Na(+)-K(+)-ATPase inhibition. Compound resting membrane (V(m)) potential of rat optic nerve was measured in a grease gap at 37 degrees C. Chemical anoxia (2 mM NaCN or NaN(3)) or ouabain (1 mM) caused a loss of resting potential to 42 +/- 11% and 47 +/- 2% of control after 30 min, respectively. Voltage-gated Na(+)-channel blockade was partially effective in abolishing this depolarization. TTX (1 microM) reduced depolarization to 73 +/- 10% (chemical anoxia) and 68 +/- 4% (ouabain) of control. Quaternary amine Na(+) channel blockers QX-314 (1 mM) or prajmaline (100 microM) produced similar results. Residual ionic rundown largely representing co-efflux of K(+) and Cl(-) during chemical anoxia in the presence of Na(+)-channel blockade was further spared with DIDS (500 microM), a broad-spectrum anion transport inhibitor (95 +/- 8% of control after 30 min in anoxia + TTX vs. 73 +/- 10% in TTX alone). Addition of DIDS was slightly more effective than TTX alone in ouabain (74 +/- 5% DIDS + TTX vs. 68 +/- 4% in TTX alone, P < 0.05). Additional Na(+)-entry pathways such as the Na-K-Cl cotransporter were examined using bumetanide, which produced a modest albeit significant sparing of V(m) during ouabain-induced depolarization. Although cation-transporting pathways play the more important role in mediating pathological depolarization of central axons, anion-coupled transporters also contribute to a significant, albeit more minor, degree.
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PMID:Differential effects of Na-K-ATPase pump inhibition, chemical anoxia, and glycolytic blockade on membrane potential of rat optic nerve. 1577 66