Nodes of Ranvier in acrylamide neuropathy: voltage clamp and electron microscopic analysis of rat sciatic nerve fibres at proximal levels.

Adult male rats were injected with acrylamide monomer (50 mg/kg i.p., 3 times/week). The animals developed hind limb paresis and distal motor nerve conduction velocity decreased. Three of 14 examined isolated myelinated sciatic nerve fibres showed a reduced excitability. In the remaining fibres the action potentials were normal. Potential clamp analysis of nodes of Ranvier in the single fibres revealed large delayed nodal K currents in 6 cases. Four of these 6 fibres exhibited a markedly increased membrane capacitance and in 2 fibres an increased Na permeability was found. Electron microscopic examination of sciatic nerves revealed comparatively subtle internodal and nodal-paranodal alterations in large myelinated fibres. Internodally, focal aggregates of tubulovesicular profiles could be found and some Schwann cells were hypertrophic. Paranodally, axonal evaginations penetrated in between the terminating myelin lamellae. Some paranodes had a very thin myelin covering and/or exhibited varying degrees of myelin sheath retraction. In the nodal axon domains lacking an axolemmal undercoating and partly non-undercoated axolemmal protrusions could be found. Similar physiological and morphological alterations occur in the rat sciatic nerve above a neuroma. Therefore, the presently observed proximal changes may, to some extent, represent non-specific alterations, secondary to a target deprivation caused by the distal axon degeneration typical for acrylamide neuropathy.

Reversible and irreversible nodal dysfunction in diabetic neuropathy.

Acute reversible diabetic nerve dysfunction has been associated with a reversible myo-inositol-related (Na+ + K+)-ATPase defect, while poorly reversible chronic nerve dysfunction correlates with progressive axoglial dysjunction of peripheral nerve. The causal relationships between biochemical and neuroanatomical abnormalities and those of nodal membrane function are not known. Nodal clamp examinations were carried out in the sciatic nerve of diabetic BB-rats to elucidate the events underlying diabetic nerve dysfunctions and how these relate to metabolic and structural defects of diabetic nerve. With increasing duration of diabetes, there was a progressive decline in nodal action potentials attributable to decreased Na+ permeability and a decrease in the membranous Na+ gradient. Vigorous insulin therapy in short-term (6-week) diabetic BB-rats normalized the Na+-permeability defect and the membranous Na+ gradient. These defects did not reverse in long-term (24-week) diabetic animals subjected to the same treatment. This poorly reversible nodal dysfunction accounts for the not readily reversible conduction defect in chronic diabetes and is probably directly related to irreversible axoglial dysjunction.

Experimental uremic neuropathy. Part 2. Sodium permeability decrease and inactivation in potential clamped nerve fibers.

Potential recordings and potential clamp of isolated myelinated fibers from the sciatic nerve of acutely uremic rats showed a marked decrease in excitability related to a decrease in the specific Na permeability (P Na) of the nodal membrane. Mean value of the available P Na in the resting node of the uremic rats was 24% of the P Na in a control group. This change explained the decreased nerve conduction velocity in the acutely uremic rat. The Na current reversal potential was decreased in some fibers, reflecting an axoplasmic Na accumulation. The decrease in P Na was to a large extent caused by an increased inactivation, due to a negative shift (about 10 mV) of the steady state inactivation curve along the potential axis. The activation of P Na was similarly shifted (about 10 mV) to a more negative potential region. Such changes may be caused by elevated intracellular [Ca], suggesting a disturbance in Ca metabolism or an intracellular accumulation of cationic metabolites (which possibly have a similar effect) in rats with acute uremia.

Biochemical and electrophysiological characteristics of toxins isolated from the venom of the scorpion Centruroides sculpturatus.

Recent progress in biochemical, structural and physiological studies has revealed several interesting properties of the toxins from the American scorpion, Centruroides sculpturatus. These toxins, together with similar toxins from other species of scorpions, comprise a unique family of homologous proteins with phylogenetically related structural differences. There is now evidence from both binding and electrophysiological studies that two distinct classes of toxins are present in the venom of C. sculpturatus. One class of toxins markedly slows inactivation of the sodium permeability but has no demonstrable effect on activation, whereas the second class induces a transient shift in the voltage-dependence of activation. Both groups make inactivation incomplete.

Nitrogen narcosis and pressure reversal of anesthetic effects in node of Ranvier.

To compare sodium channel block by hyperbaric nitrogen with that induced by other anesthetics and to examine the basis for pressure antagonism to anesthetic condition block, voltage clamped nodes of Ranvier were exposed to nitrogen at pressures at 1-14 atm alone and in combination with helium to a total pressure of up to 100 atm. At 7 and 14 atm nitrogen, sodium currents were reversibly depressed without accompanying changes in the current-voltage relation. The curve relating steady-state inactivation (h infinity) to voltage was shifted in the hyperpolarizing direction, as is the case with other general anesthetic agents. The time constant of inactivation (tau h) was slightly decreased at depolarized potentials. The preceding companion paper demonstrated an opposite effect of hyperbaric helium on the properties of sodium inactivation. Addition of helium pressure in the presence of nitrogen at 14 atm did not increase peak sodium current with inactivation maximally removed, but it did shift the h infinity curve back toward control levels, thus increasing sodium current at points on the slope of the curve. It is proposed that these opposing shifts in steady-state inactivation levels are the basis for pressure antagonism to anesthetic conduction block. In the case of inert gases and volatile anesthetic agents, the antagonism may be direct but has not been shown to be so. In the case of the local anesthetic benzocaine, differences in the voltage dependence of anesthetic and pressure-induced changes in tau h indicate the antagonism is indirect.