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

1. The effects of hyperglycaemic hypoxia (a condition possibly involved in the pathogenesis of diabetic neuropathy) on the depolarizing after‐potential and the potassium conductance of myelinated rat spinal root axons were investigated using electrophysiological recordings from intact spinal roots and from excised, inside‐out axonal membrane patches. 2. Isolated spinal roots were exposed to hypoxia in solutions containing normal or high glucose concentrations. The depolarizing after‐potential of compound action potentials was only enhanced in spinal roots exposed to hyperglycaemic (25 mM D‐glucose) hypoxia. A maximal effect was seen in bathing solutions with low buffering power. 3. The depolarizing after‐potential was also enhanced by cytoplasmic acidification after replacement of 10‐30 mM chloride in the bathing solution by propionate. 4. Multi‐channel current recordings from excised, inside‐out axonal membrane patches were used to study the effects of cytoplasmic acidification on voltage‐dependent K+ conductances with fast (F channels) and intermediate (I channels) kinetics of deactivation. 5. F channels were blocked by small changes in cytoplasmic pH (50% inhibition at pH 6.9). I channels were much less sensitive to intra‐axonal acidification. 6. In conclusion, our data show that hyperglycaemic hypoxia enhances the depolarizing after‐potential in peripheral rat axons. The underlying mechanism seems to be an inhibition of a fast, voltage‐dependent axonal K+ conductance by cytoplasmic acidification. This alteration in membrane conductance may contribute to positive symptoms in diabetic neuropathy.