招聘講演（11）

Biology of Neurotransmission in Health and Disease: Interaction with Muscle Relaxants.

J. A. Jeevendra Martyn, M.D., F.R.C.A., F.C.C.M.

Professor of Anaesthesia, Harvard Medical School

Anesthetist, Massachusetts General Hospital

Anesthetist-in-Chief, Shriners Hospitals for Children, Boston

Neuromuscular transmission occurs by a fairly simple and straightforward mechanism. The nerve synthesizes acetylcholine and stores it in small, uniformly sized packages called vesicles. Arrival of an action potential at the distal motor nerve ending leads to an instant opening of voltage gated Ca²⁺ -channels with a subsequent abrupt increase in intracellular calcium concentration, which triggers a cascade of intracellular signaling events leading to discharge of acetylcholine into the cleft separating nerve from muscle. Nicotinic acetylcholine receptors (nAChRs) in the endplate of the muscle, being activated by the released acetylcholine, respond by opening their channels for influx of sodium ions into the muscle to depolarize the muscle. The endplate potential created is propagated along the muscle membrane by the opening of the sodium channels present throughout the muscle membrane, leading to muscle contraction. Acetylcholine immediately detaches from the receptor and is destroyed by the nearby acetylcholinesterase located in the synaptic cleft.

Non-depolarising muscle relaxant drugs (NDMRs) act on the nAChRs, by preventing acetylcholine from binding to the receptor, thereby inhibiting depolarization of the receptor. Athough NDMRs are known to have effects on the presynaptic and postsynaptic nAChRs of the neuromuscular junction, recent evidence also demonstrates that this class of agents used in anaesthesia and intensive care can react with nicotinic and muscarinic acetylcholine receptors other than those at the neuromuscular junction, including those within the carotid body, vagus innervations of the heart, and in bronchial smooth muscle.

The muscle consists of three types of nAChRs. The fetal, immature, or extra-junctional muscle nAChR consists of two a1, and one of each b1, d, and g subunit (a1b1dg) and is present during decreased activity in muscle, as seen in the fetus before innervation, or after chemically or physically-induced immobilization; after lower or upper motor neuron injury, burns or sepsis – or after other events that cause increased muscle protein catabolism including sepsis or generalized inflammation. After innervation, the g-subunit is replaced by the e, which creates the adult, mature or junctional muscle nAChR (a1b1de) present throughout a healthy life. The third receptor in the muscle are the a7nAChRs and consists of 5 subunit of a7nAChRs and is produced pathological states enumerated above. The muscle nAChRs have two distinct agonist binding sites, one high affinity binding site between the a1 and d, and one low affinity binding site at the interface between a1 and e or g. The a7nAChR has five potential binding sites.

Immature receptors have a smaller single-channel conductance and a 2- to 10-fold longer mean channel open time than mature receptors. The changes in subunit composition may also alter the sensitivity or affinity, or both, of the receptor for specific ligands. Depolarising or agonist drugs such as suxamethonium and acetylcholine depolarize immature receptors more easily, fluxes: one-tenth to one-hundredth of doses necessary for mature receptors, can affect depolarization in immature receptors. Once depolarized, the immature channels also stay open for a longer time. Potency of nondepolarizing NDMRs is also decreased in the pathological states described above, demonstrated by a resistance to NDMRs. This resistance may be related to decreased affinity of the immature muscle a1b1dg and a7 nAChRs to NDMRs and to the upregulation of these receptors in the peri-junctional area. Resistance to NDMRs and hyperkalemia with succinylcholine can be seen in denervation, burns, immobilization, sepsis, and chronic use of NDMRs.

In pathological states described above the nAChRs are scattered over a large surface of the muscle. The nAChR channels opened by the agonist (suxamethonium) allow potassium to escape from the muscle and enter the blood. If a large part of the muscle surface consists of upregulated (immature) receptor channels, each of which stays open for a longer time, the amount of potassium that moves from muscle to blood can be very large. The resulting hyperkalaemia can cause dangerous disturbances in cardiac rhythm, including ventricular fibrillation. Moreover, it is difficult to prevent the hyperkalaemia by the prior administration of NDMRs because the extra-junctional upregulated nAChRs are not very sensitive to NDMRs in the usual doses. Larger than normal doses of non-depolarising NDMRs may attenuate the increase in blood potassium but cannot completely prevent it. Treatment of hyperkalemia consists of the use of calcium (gluconate or chloride) and use of insulin and dextrose, together with epinephrine.