Sodium channel function and the excitability of human cutaneous afferents during ischaemia

Abstract

The changes in excitability of cutaneous afferents in the median nerve of healthy subjects were compared during 13 min of ischaemia and during 13 min continuous depolarizing DC. In addition, intermittent polarizing currents were used to compensate for or to accentuate the threshold change produced by ischaemia. Measurements were made alternately of the ischaemic (or current-induced) changes in threshold, refractoriness and, in some experiments, supernormality. The strength-duration time constant (tau(SD)) was calculated from the thresholds to test stimuli of different duration. During ischaemia for 13 min, the threshold decreased steadily by 34 % over the initial 8 min, reached a plateau and increased slightly over the final few minutes. However, with continuous depolarizing DC, the threshold decreased linearly with the applied current, by 55 % with strong current ramps. Intermittent injection of hyperpolarizing DC was used to compensate for the ischaemic threshold change, but the compensating current increased progressively and did not reach a plateau as had occurred with the ischaemic threshold change. During ischaemia, tau(SD) increased to a plateau, following the threshold more closely than the current required to compensate for threshold. Refractoriness, on the other hand, increased more steeply than the applied compensating current. There were similar discrepancies in the relationships of tau(SD) and refractoriness to supernormality. The smaller-than-expected threshold change during ischaemia could result from limitations on the change in excitability produced by ischaemic metabolites acting on the gating and/or permeability of Na(+) channels. Intermittent depolarizing DC was applied during the ischaemic depolarization to determine whether it would reduce or accentuate the discrepancies noted during ischaemia alone. The extent of the threshold change was greater than with ischaemia alone, and there was a greater change in tau(SD) and a proportionately smaller change in refractoriness. It is concluded that ischaemia produces factors that can block Na(+) channels and/or alter their gating. Without these processes, the ischaemic change in threshold would be much greater than that actually recorded, probably sufficient to produce prominent ectopic impulse activity.

Figure 1. Changes in amplitude and excitability indices during ischaemia and continuous depolarizing DC for 13 min

The data in A illustrate changes during ischaemia (means ± s.e.m., n = 8). Threshold decreased during ischaemia but, like τ_SD, reached a plateau after ∼8 min. Refractoriness continued to increase steadily throughout the 13 min. The data in B illustrate changes during a continuous depolarizing DC ramp, to a maximum of 30 % of resting I_1.0 (means ± s.e.m., n = 6). There were continuous changes in each index of excitability without plateau, no decrease in maximal amplitude and no increase in latency. For the same change in threshold (indicated by the dashed horizontal line), there was a much greater increase in refractoriness and a slightly smaller increase in τ_SD in A than in B (see arrows and the large symbols). Note the decrease in the maximal sensory potential during ischaemia (A) but not during DC (B). The horizontal filled bars indicate the period of ischaemia (A) and depolarizing DC (B). All data were normalized to a pre-ischaemic control level of unity before averaging.

Figure 2. Comparison of the changes in amplitude, threshold and refractoriness produced by ischaemia and a continuous DC ramp in two subjects

In both subjects, continuous depolarizing DC to a maximum of 80 % of resting I_1.0 (○) produced a much greater decrease in threshold but a smaller increase in refractoriness than ischaemia (•). In subject 2, there was a prominent increase in refractoriness, which reached a plateau at > 600 %. Note the absence of a change in the maximal sensory potential during the DC. Data were recorded in different experiments and were normalized to a pre-ischaemic control level of unity before averaging.

Figure 3. Compensation for the change in threshold during ischaemia

A, the change in threshold during ischaemia for 13 min in the absence (○) and presence (•) of intermittent hyperpolarizing DC of 30 ms duration to compensate for the threshold change (mean data for 5 subjects ± s.e.m.). Here and in Figs 7A and 8A, threshold data were normalized to a pre-ischaemic control level of unity. B, the intermittent compensating current (•), effective in controlling the threshold change except at the onset of ischaemia and on its release. C, superimposition of threshold and compensating current, after the latter was scaled, as detailed in the text, and inverted. Threshold underwent a proportionately smaller change than the current required to compensate for the threshold change. In this and subsequent figures, the horizontal filled bar indicates the period of ischaemia.

Figure 6. The change in supernormality during ischaemia

A, the change in supernormality from the experiments in Figs 3–5 (means ± s.e.m.). In B-D, supernormality was scaled (much as was the compensating current in Figs 3–5) and plotted on the same axes as threshold, refractoriness and τ_SD (after inversion in B). There were proportionately smaller changes in threshold (B), and τ_SD (D) but greater change in refractoriness (C).

Figure 4. The change in refractoriness during ischaemia

A, the change in refractoriness during ischaemia for 13 min (mean data for 5 subjects ± s.e.m. from the experiments in Fig. 3). B, the intermittent compensating current of 30 ms duration (same data as in Fig. 3B). C, superimposition of refractoriness and compensating current, after the latter was scaled, as detailed in the text. Refractoriness underwent a proportionately greater change than the current required to compensate for the threshold change.

Figure 5. The change in strength-duration time constant (τ_SD) during ischaemia

A, the change in τ_SD during ischaemia for 13 min (mean data for 5 subjects ± s.e.m. from the experiments in Fig. 3). B, the intermittent compensating current of 30 ms duration (same data as in Fig. 3B). C, superimposition of τ_SD and compensating current, after the latter was scaled, as detailed in the text. τ_SD underwent a proportionately smaller change than the current required to compensate for the threshold change.

Figure 7. The effect of intermittent depolarizing DC on different parameters of axonal excitability during ischaemia

Mean data for five subjects (±s.e.m.) during ischaemia (•) and ischaemia plus intermittent depolarizing DC (○). With the additional DC there was a greater threshold decrease (A), a greater increase in refractoriness (B), and a greater increase in τ_SD (C). D, relationship between refractoriness and excitability (i.e. the reciprocal of threshold) during ischaemia for the data in A and B. The relationships were initially reasonably linear, and linear regression lines were fitted, up to the points indicated by the large symbols. There was proportionately less refractoriness for the data with additional intermittent depolarizing DC even though there was a greater absolute increase in refractoriness in B. E and F illustrate the relationship between the cumulative increase in refractoriness and excitability (ischaemia: thick line; ischaemia + DC: thin line). The data began to differ when the excitability increased by 16 % (i.e. when the threshold decreased to 86 %).

Figure 8. Comparison between the changes produced by ischaemia (•), a continuous DC ramp (○) and ischaemia plus continuous DC (▵) for one subject

The data in Fig. 2 (for subject 2) are superimposed on the changes produced by ischaemia plus continuous depolarizing DC. Ischaemia + DC produced the greatest decrease in threshold (A) and the greatest increases in refractoriness (B) and τ_SD (C). D and E, the relationships between the change in refractoriness and excitability indicate that for the same change in excitability the change in refractoriness was greatest for ischaemia alone. Linear regression lines were fitted up to the large symbols indicated by the arrows in D. E shows the same data as in D on expanded axes.