Hyperglycaemic hypoxia alters after‐potential and fast K+ conductance of rat axons by cytoplasmic acidification.

Schneider, Uwe; Quasthoff, Stefan; Mitrović, Nenad; Grafe, Peter

doi:10.1113/jphysiol.1993.sp019700

Cited by 35 publications

(23 citation statements)

References 49 publications

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“…The apparent lack of time-dependent inward rectification to hyperpolarizing currents with hypoxia may simply have been due to the depolarization. We have no evidence for a specific effect of anoxia on inward rectification, as has been reported by Duchen (1990) (Strupp et al 1991;Schneider et al 1992Schneider et al ,1993b (Schneider et al 1993a). In the present study, the effects of these two hexoses were explored on the electrotonus during hypoxia.…”

Section: Effects Of Hypoxiamentioning

confidence: 52%

“…Cytoplasmic acidification inactivates fast axonal K+ channels (Schneider et al 1993b), but these channels have not previously been held to be major determinants of the resting potential. To pursue this matter further, we required a technique that would (a) reveal changes in both nodal and internodal channels contributing to the resting potential, (b) provide stable recordings for long periods of hypoxia, and (c) would avoid undefined pathophysiology due to mechanical damage.…”

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confidence: 99%

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The effects of hyperglycaemic hypoxia on rectification in rat dorsal root axons.

Grafe¹,

Bostock²,

Schneider³

1994

The Journal of Physiology

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1. Electrotonic responses to 150 ms current pulses were recorded from isolated rat dorsal roots incubated for at least 3 h with either normal (5 mM) or high (25 mM) D-glucose solutions, and with either normal (25 mM) or low (5 mM) bicarbonate concentrations. 2. On replacement of 02 by N2 for 50 min, all the roots depolarized, but the changes in electrotonus differed systematically. With normal glucose, the depolarization was accompanied by an increase in input conductance. In contrast, for the hyperglyeaemic roots the depolarization was slower and accompanied by a fall in input conductance which was exacerbated in low bicarbonate concentrations. 3. The changes induced by hyperglycaemic hypoxia in low bicarbonate could be mimicked by exposure of the roots either to 100% CO2 or to a combination of 3 mm tetraethylammonium chloride and 3 mm 4-aminopyridine, to block both fast and slow potassium channels. 4. These results indicate that the primary mechanism of hypoxic depolarization of these sensory axons is altered by hyperglycaemia. In normoglycaemia, the changes in electrotonus are consistent with an increase in axonal potassium conductance. The block of potassium channels seen in hyperglycaemic hypoxia is attributed to intra-axonal acidification by anaerobic glycolysis and may contribute to the pathogenesis of diabetic neuropathy.

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Section: Effects Of Hypoxiamentioning

confidence: 52%

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confidence: 99%

The effects of hyperglycaemic hypoxia on rectification in rat dorsal root axons.

Grafe¹,

Bostock²,

Schneider³

1994

The Journal of Physiology

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“…This, with the enhanced resting supernormality, is consistent with these channels being rendered relatively ineffective, requiring a longer polarizing current than usual to restore their voltage dependence. Ischaemia can block K¤ channels, but this has been demonstrated only when axons are hyperglycaemic as well as hypoxic (Schneider et al 1993;Grafe et al 1994). The block is due to intracellular acidosis, and a comparable phenomenon would explain the present findings, despite the fact that the subjects were not hyperglycaemic and that the effects were seen following release of ischaemia rather than during ischaemia.…”

Section: Post-ischaemic Effects Of Polarizing Currents On Supernormalitymentioning

confidence: 99%

“…The switch to anaerobic glycolysis could lead to intracellular acidosis, and ultimately to secondary effects on ion channel function (e.g. inactivation of fast K¤ channels), particularly in the presence of hyperglycaemia (Schneider et al 1993). Finally, some conductances are sensitive to intracellular ATP (KATP channels, see Jonas et al 1991; inward rectification, see Kusaka & Puro, 1997).…”

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Changes in excitability indices of cutaneous afferents produced by ischaemia in human subjects

Großkreutz

Lin

Mogyoros

et al. 1999

The Journal of Physiology

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Relatively brief periods of ischaemia paralyse the electrogenic Na¤-K¤ pump, increase [K¤]ï and produce membrane depolarization. In sensory axons, the axonal depolarization can lead to hyperexcitability sufficient to result in ectopic activity. This is less likely in motor axons, probably because the former express a threshold conductance, thought to be mediated by persistent Na¤ channels (Bostock & Rothwell, 1997). Following release of ischaemic compression, heightened activity of the electrogenic Na¤-K¤ pump leads to axonal hyperpolarization. Paradoxically, ectopic activity can then be quite intense, particularly in sensory axons, and this is probably due, in part, to activation of an inwardly rectifying conductance that is again expressed more on sensory axons than on motor axons ).The changes in axonal excitability during ischaemia and after its release can be reproduced reasonably well by longlasting depolarizing and hyperpolarizing currents (Baker & Bostock, 1989), suggesting that the change in membrane potential is largely sufficient to explain some of the effects of ischaemia. However, it is likely that there is more to the excitability changes produced by ischaemia than the change in membrane potential. In a short communication on voltageclamped rat axons, Brismar (1981) reported that anoxia decreased maximal Na¤ permeability and shifted the relationship between Na¤ channel inactivation and membrane potential to more negative potentials, so that more Na¤ channels were inactivated at rest. In addition, ischaemia can have complex effects, both direct and indirect, on other 1. The present study was undertaken to determine whether mechanisms other than membrane depolarization contribute to the changes in excitability of cutaneous afferents of the median nerve under ischaemic conditions. 2. In six healthy subjects, axonal excitability was measured as the reciprocal of the threshold for a compound sensory action potential (CSAP) of 50% maximal amplitude. Refractoriness and supernormality were measured as threshold changes 2 and 7 ms, respectively, after supramaximal conditioning stimuli. The strength-duration time constant (ôSD) was calculated from the thresholds for unconditioned CSAPs using test stimuli of 0·1 and 1·0 ms duration. Changes in these indices were measured when subthreshold polarizing currents lasting 10 or 100 ms were applied, before, during and after ischaemia for 13 min. 3. At rest, the change in supernormality produced by polarizing currents was greater with the longer polarizing current, indicating that it took up to 100 ms to charge the internodal capacitance. 4. Refractoriness and its dependence on excitability increased more than expected during ischaemia. Supernormality was abolished during ischaemia, and reached a maximum after ischaemia but was then barely altered by polarizing current. ôSD had a similar relationship to excitability before, during and after ischaemia. 5. By contrast, during continuous depolarizing current for 8 min to mimic the depolarization produced by ischaemia, ...

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“…Previous extracellular studies on whole nerves showed that inward rectification is decreased in peripheral nerves exposed to hyperglycaemic hypoxia, a common complication of diabetes mellitus [23,24,25]. Recent findings by indirect electrophysiological methods indicate that inward rectification could be altered in human diabetic neuropathy [8] as well as in experimental diabetes [9] -(for a review see [7]).…”

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Intra-axonal recording from large sensory myelinated axons: Demonstration of impaired membrane conductances in early experimental diabetes

Križ

Padjen

2003

Diabetologia

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Aim/hypothesis. Diabetic neuropathy is accompanied by a range of positive (paresthaesia, dysesthaesia, pain) and negative (hypesthaesia, anesthaesia) neurological symptoms suggesting widespread alterations in axonal excitability. The nature and the mechanisms underlying these alterations in axonal excitability are not well understood. The aim of this study was to examine the extent of changes in membrane properties of an identified neuronal structure -the large myelinated sensory axons in early experimental diabetes in rats. Methods. Intra-axonal microelectrode recordings from large sensory myelinated axons from the isolated sural nerve in short-term streptozotocin-induced diabetic rats were used to study membrane properties using standard current-clamp technique.Results. In addition to decreased conduction velocity we found several differences in physiological properties of sensory axons from diabetic rats: decreased resting membrane potential, decreased single action potential amplitude associated with slower rate of rise and decrease in inward rectification associated with slight alteration in outwardly rectifying conductances indicating impaired potassium conductances. Conclusion/Interpretation. These results extend previous indirect evidence that potassium and sodium ionic conductances, most notably the inward rectifier (IR, I h ), are altered in large sensory axons of diabetic rats. . The pathogenesis of diabetic neuropathies and consequently their treatment remain elusive, in spite of a number of hypotheses advanced in the past decades. These hypotheses deal with several major areas, such as metabolic, ischaemia and oxidative stress, non-specific glycosylation, and disturbances in trophic factors [1,2,3,4]. The histopathological findings of advanced diabetic neuropathy (DN) are characterized by axonal degeneration, demyelination and atrophy that are associated with highly diverse disturbances of peripheral nerve function [2,5,6]. Different positive and negative neurological signs associated with DN suggest modification in axonal membrane excitability. Indeed, one of the earliest detectable physical signs of early DN is a decrease in conduction velocity as signsThe peripheral neuropathy associated with diabetes is one of the most common polyneuropathies, and at least 50% of diabetic patients will develop a form of

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Hyperglycaemic hypoxia alters after‐potential and fast K+ conductance of rat axons by cytoplasmic acidification.

Cited by 35 publications

References 49 publications

The effects of hyperglycaemic hypoxia on rectification in rat dorsal root axons.

The effects of hyperglycaemic hypoxia on rectification in rat dorsal root axons.

Changes in excitability indices of cutaneous afferents produced by ischaemia in human subjects

Intra-axonal recording from large sensory myelinated axons: Demonstration of impaired membrane conductances in early experimental diabetes

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