Mediators

(also transmitter substances), in biology, substances that transmit excitation from a nerve ending to a working organ and from one nerve cell to another.

The presumption that the transmission of excitation is due to the formation of some sort of chemical compound dates from the beginning of the 20th century. It was substantiated experimentally in 1921 in the works of O. Loewi, who showed that the vagus nerve’s effect on the heart is caused by the formation of what he called the vagus substance (later established to be acetylcholine) and that the effect of the sympathetic nerves is caused by a “sympathetic substance” (norepinephrine). Subsequent research by A. F. Samoilov and C. Sherrington showed that the transfer of excitation from motor nerve to striated muscle occurs with the participation of a mediator, acetylcholine. The next stage was the discovery of the chemical transmission of excitation from neuron to neuron in the peripheral nerve ganglia and the central nervous system.

Research with the electron microscope has shown that in the nerve endings of the central and peripheral synapses there are many vesicles (as large as 300 angstroms) containing acetylcholine. In nervous excitation, some of these vesicles burst. Their contents are discharged into the synaptic cleft and interact with sections of the postsynaptic membrane, the choline receptors, that are sensitive to acetylcholine. This causes a sharp increase in the permeability of the membrane. Potassium ions leave the cell and are distributed on its surface, while sodium ions penetrate the cell. The negative electrical charge inside the cell is lowered, and the cell membrane is depolarized, leading to the development of an excitatory postsynaptic potential. When the magnitude of this potential reaches a threshold, or critical, level, a spike (the electrical impulse of excitation) arises.

The acetylcholine that is discharged into the synaptic cleft is inactivated by the enzyme acetylcholinesterase, which hydrolyzes acetylcholine to the physiologically inactive choline and acetic acid. The normal ratio of potassium ions to sodium ions on both sides of the membrane is restored by the sodium-potassium pump—the active transport of ions against their electrochemical gradients.

The endings of all parasympathetic nerves and the endings of the sympathetic nerves of the sweat glands contain acetylcholine; the endings of all sympathetic nerves except those of the sweat glands contain norepinephrine. The effect of norepinephrine is realized through specific apparatuses called adrenoreceptors. Both acetylcholine and norepinephrine have also been discovered in neurons and nerve fibers.

Depending on the nature of the mediation, the various neural formations of the autonomic nervous system are classified as adrenergic and cholinergic. Certain biogenic amines, such as serotonin and histamine, probably participate in mediation, but this has not been proved. The question of the existence of special inhibitory mediators has also not been resolved conclusively. It is possible that any mediator can produce either excitation or inhibition, depending on the intensity and duration of the mediator’s effect and on the functional state of the system excited.

The role of mediator in the central nervous system may be played by dopamine, serotonin, gamma-aminobutyric acid, glycine, and possibly histamine, as well as by acetylcholine and epinephrine.

The effect of mediators is not limited to local reactions. Some of the mediators formed in the tissues, especially in the nerve tissues, are not used at the site of formation and are not inactivated but instead enter the tissue fluid and blood to produce various autonomic reactions that affect many body functions (seeNEUROHUMORAL REGULATION). Excess acetylcholine is destroyed by tissue and serum cholinesterases and is bonded to erythrocytes and tissue proteins. Norepinephrine, which undergoes complex chemical conversions, is partly excreted from the body and partly reclaimed from the blood by nerve endings or deposited around neurons, a phenomenon called reuptake.

The study of mediators has played an important role in the development of physiology (accounting for the discovery of humoral regulation), pharmacology (allowing the synthesis of preparations that intensify or reduce the activities of the central and autonomic nervous systems, such as tranquilizers and ganglion blocks), and many clinical disciplines (for example, neuropathology, psychiatry, and obstetrics).