Protons regulate the excitability properties of rat myelinated sensory axons in vitro through block of persistent sodium currents

Abstract

Little information is available on the pH sensitivity of the excitability properties of mammalian axons. Computer-assisted threshold tracking in humans has helped to define clinically relevant changes of nerve excitability in response to hyperventilation and ischaemia, but in vivo studies cannot directly differentiate between the impact of pH and other secondary factors. In this investigation, we applied an excitability testing protocol to a rat saphenous skin nerve in vitro preparation. Changes in extracellular pH were induced by altering pCO(2) in the perfusate, and excitability properties of large myelinated fibres were measured in the pH range from 6.9 to 8.1. The main effect of protons on nerve excitability was a near linear increase in threshold which was accompanied by a decrease in strength-duration time constant reflecting mainly a decrease in persistent sodium current. In the recovery cycle, late subexcitability following 7 conditioning stimuli was substantially reduced at acid pH, indicating a block of slow but not of fast potassium channels. Changes in threshold electrotonus were complex, reflecting the combined effects of pH on multiple channel types. These results provide the first systematic data on pH sensitivity of mammalian nerve excitability properties, and may help in the interpretation of abnormal clinical excitability measurements. AbstractLittle information is available on the pH sensitivity of the excitability properties of mammalian axons. Computer-assisted threshold tracking in humans has helped to define clinically relevant changes of nerve excitability in response to hyperventilation and ischaemia, but in vivo studies cannot directly differentiate between the impact of pH and other secondary factors. In this investigation we applied an excitability testing protocol to a rat saphenous skin-nerve preparation in vitro. Changes in extracellular pH were induced by altering pCO 2 in the perfusate, and excitability properties of large myelinated fibres were measured in the pH range from 6.9 to 8.1.The main effect of protons on nerve excitability was a near linear increase in threshold which was accompanied by a decrease in strength-duration time constant reflecting mainly a decrease in persistent sodium current. In the recovery cycle late subexcitability following 7 conditioning stimuli was substantially reduced at acid pH, indicating a block of slow but not of fast potassium channels. Changes in threshold electrotonus were complex, reflecting the combined effects of pH on multiple channel types.These results provide the first systematic data on pH sensitivity of mammalian nerve excitability properties, and may help in the interpretation of abnormal clinical excitability measurements.

Why Are Sensory Axons More Vulnerable for Ischemia than Motor Axons?

“…Threshold fluctuations have been associated with tissue acidosis in patients with diabetes mellitus [42] and in patients with critical illness polyneuropathy multiple excitability indices of membrane potential were related to respiratory acidosis [43]. However, it is unlikely that our observed changes resulted from changes of pH, since acidosis has been associated with threshold increase and SDTC decrease [44].…”

Why Are Sensory Axons More Vulnerable for Ischemia than Motor Axons?

“…Threshold fluctuations have been associated with tissue acidosis in patients with diabetes mellitus [42] and in patients with critical illness polyneuropathy multiple excitability indices of membrane potential were related to respiratory acidosis [43]. However, it is unlikely that our observed changes resulted from changes of pH, since acidosis has been associated with threshold increase and SDTC decrease [44].…”

Transient impairment of the axolemma following regional anaesthesia by lidocaine in humans

“…Care was taken that the solution was titrated to the same pH as the standard lidocaine solution (Maurer et al . ). Serial ultrasound scans (see Fig.…”

Why Are Sensory Axons More Vulnerable for Ischemia than Motor Axons?

“…Threshold fluctuations have been associated with tissue acidosis in patients with diabetes mellitus [42] and in patients with critical illness polyneuropathy multiple excitability indices of membrane potential were related to respiratory acidosis [43]. However, it is unlikely that our observed changes resulted from changes of pH, since acidosis has been associated with threshold increase and SDTC decrease [44].…”

Transient impairment of the axolemma following regional anaesthesia by lidocaine in humans

“…Care was taken that the solution was titrated to the same pH as the standard lidocaine solution (Maurer et al . ). Serial ultrasound scans (see Fig.…”

Why Are Sensory Axons More Vulnerable for Ischemia than Motor Axons?

“…Threshold fluctuations have been associated with tissue acidosis in patients with diabetes mellitus [42] and in patients with critical illness polyneuropathy multiple excitability indices of membrane potential were related to respiratory acidosis [43]. However, it is unlikely that our observed changes resulted from changes of pH, since acidosis has been associated with threshold increase and SDTC decrease [44].…”

Transient impairment of the axolemma following regional anaesthesia by lidocaine in humans

“…Care was taken that the solution was titrated to the same pH as the standard lidocaine solution (Maurer et al . ). Serial ultrasound scans (see Fig.…”