Neuromuscular transmission in diabetes: response to high-frequency activation

In searching for the cellular correlates of diabetic neuropathy, we examined the response to tetanic stimulation of diabetic neuromuscular junctions and of age-matched controls. The experiments were performed on the soleus nerve muscle preparation of the rat in which diabetes was induced by streptozotocin. Tetanic potentiation was substantially lower in diabetic rats. In addition, it was found that the diabetic neuromuscular junction is more resistant to high-frequency stimulation than normal age-matched controls, in which such stimulation causes a progressively increasing number of failures in synaptic transmission. Tetanic failures cannot be predicted from the stochastic properties of transmitter release and are due to propagation block of action potentials into the nerve terminals. The resistance of diabetic nerves to tetanic stimulation is a function of the duration of diabetes; the earliest significant difference between the number of tetanic failures in diabetic and normal age-matched controls was observed after 19 d of diabetes, and this difference grew with increased duration of diabetes. The resistance to tetanic stimulation in diabetic rats is reversed by insulin in vivo but not in vitro. Elevation in extracellular [K+] increases the number of tetanic failures in both diabetic and normal preparations. Furthermore, elevating extracellular [K+] to 8.5 mM brings the number of tetanic failures into the range of tetanic failures in normal nerves. This finding is consistent with the hypothesis that differences in extracellular [K+] accumulation during high-frequency stimulation are responsible for the diabetic nerve's relative resistance to high-frequency stimulation. The lower number of failures corrects only partially the impaired neuromuscular transmission in the diabetic state, and there is an overall reduction in tetanic potentiation in diabetes.