Persistent depolarizing inhibition

Position in the classification of inhibition processes

Inhibition is a temporary active process that regulates the level of excitation. In the central nervous system and internal organs, processes of excitation and inhibition constantly replace each other. Historically, peripheral inhibition (discovered by the Weber brothers, A. and E. Weber, in 1847 using the effect of the vagus nerves, n. vagus, on the heart) and central inhibition (first investigated by I.M. Sechenov in 1862) are distinguished.

According to their electrophysiological nature, three types of inhibition are distinguished:

• Hyperpolarizing inhibition — a decrease in tissue excitability under the action of inhibitory neurotransmitters on postsynaptic membranes.
• Persistent depolarizing inhibition — impairment of the membrane's return to the resting state.
• Stabilizing inhibition — the impossibility of excitation due to a blockade of sodium permeability of membranes without changing the resting potential (under the action of biologically active substances).

How does persistent depolarizing inhibition occur?

The process can occur as an independent functional process or as a result of the interaction of two excitations. The main characteristics of the mechanism:

• Conditions of occurrence — high excitation frequency.
• Neurotransmitter accumulation — the accumulation of an excitatory neurotransmitter prevents the potential of the postsynaptic membrane from returning to the resting state.
• Charge change — physiologically, the difference between the current membrane charge and the critical level of depolarization (CLD) increases.
• Membrane specificity — the process can also occur under the action of inhibitory neurotransmitters due to the specific properties of cell membranes.

By its nature, this type of inhibition is analogous to the phenomena of parabiosis or accommodation.

Clinical significance: depolarizing block

With an increase in the dose of agents acting on cholinergic synapses, an excess of acetylcholine causes persistent depolarization of the postsynaptic membrane.

The consequence of this is a depolarizing block of neuromuscular transmission and a cholinergic crisis, which manifests as:

• Amplification of M-cholinomimetic symptoms (parasympathetic effects).
• Paradoxical increase in muscle weakness (myasthenia gravis symptoms).

It is important to note that the released endogenous acetylcholine does not eliminate this block. On the contrary, it enhances the depolarization of the postsynaptic membrane, thereby deepening the neuromuscular block.

Diagnostics and the "dual block" phenomenon

Edrophonium is used for the differential diagnosis of a cholinergic crisis (anticholinesterase overdose) and a myasthenic crisis (exacerbation of the disease or lack of medication). It is a peripherally acting quaternary amine administered intravenously. The effect occurs in 30–60 seconds and lasts 5–15 minutes. In a cholinergic crisis, the administration of edrophonium does not increase skeletal muscle tone and may increase muscle weakness, which quickly resolves due to the short duration of action of the drug.

With frequent repeated administrations of suxamethonium, the desensitization phenomenon may occur:

• Desensitization (N_m-cholinergic receptors) — a change in the sensitivity of the endplate.
• Change of block type — the depolarizing block is replaced by an antidepolarizing (nondepolarizing) one.

The clinical significance of this phenomenon lies in the fact that only in the phase of the antidepolarizing block are anticholinesterase agents able to reduce the myoparalytic effect.

Class and exam questions

What else to study on this topic

• Hyperpolarizing and stabilizing inhibition
• Parabiosis and accommodation
• Cholinergic and myasthenic crises
• Neuromuscular transmission and types of muscle blocks

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