Inactivation of sodium channels underlies reversible neuropathy during critical illness in rats
Kevin R. Novak, … , Jaffar Khan, Mark M. Rich
Kevin R. Novak, … , Jaffar Khan, Mark M. Rich
Published April 1, 2009
Citation Information: J Clin Invest. 2009;119(5):1150-1158. https://doi.org/10.1172/JCI36570.
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Research Article Neuroscience

Inactivation of sodium channels underlies reversible neuropathy during critical illness in rats

Abstract

Neuropathy and myopathy can cause weakness during critical illness. To determine whether reduced excitability of peripheral nerves, rather than degeneration, is the mechanism underlying acute neuropathy in critically ill patients, we prospectively followed patients during the acute phase of critical illness and early recovery and assessed nerve conduction. During the period of early recovery from critical illness, patients recovered from neuropathy within days. This rapidly reversible neuropathy has not to our knowledge been previously described in critically ill patients and may be a novel type of neuropathy. In vivo intracellular recordings from dorsal root axons in septic rats revealed reduced action potential amplitude, demonstrating that reduced excitability of nerve was the mechanism underlying neuropathy. When action potentials were triggered by hyperpolarizing pulses, their amplitudes largely recovered, indicating that inactivation of sodium channels was an important contributor to reduced excitability. There was no depolarization of axon resting potential in septic rats, which ruled out a contribution of resting potential to the increased inactivation of sodium channels. Our data suggest that a hyperpolarized shift in the voltage dependence of sodium channel inactivation causes increased sodium inactivation and reduced excitability. Acquired sodium channelopathy may be the mechanism underlying acute neuropathy in critically ill patients.

Authors

Kevin R. Novak, Paul Nardelli, Tim C. Cope, Gregory Filatov, Jonathan D. Glass, Jaffar Khan, Mark M. Rich

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Figure 3

Amplitude of action potentials is reduced in dorsal root axons 3 days after induction of sepsis.

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Amplitude of action potentials is reduced in dorsal root axons 3 days af...
(A) Representative dorsal root axon action potentials from untreated and septic rats, showing the range of amplitudes in each group. While the largest action potentials from axons in septic rats were normal in amplitude, half the axons had action potentials that were smaller than those normally found in untreated rats. The horizontal line represents 0 mV. In untreated rats, 53% of axons had action potentials that exceeded 0 mV. In septic rats only 27% of axons had action potentials that exceeded 0 mV. Scale bars: 20 mV (vertical); 0.5 ms (horizontal). (B) Left: Action potential amplitude for axons from all untreated and septic rats (P < 0.01 by the Kolmogorov-Smirnov test, n = 60 axons from untreated rats and 33 axons from septic rats). Right: Action potential amplitude when resting potentials were matched between –50 and –55 mV. The difference in action potential amplitudes is unchanged when resting potential is matched (P < 0.01, n = 13 axons from untreated rats and n = 13 axons from septic rats).