AUTONOMIC NERVOUS SYSTEM AND NEUROHUMORAL TRANSMISSION

Even though the first practitioners of anesthesia had essentially no knowledge of adrenergic or cholinergic transmission, it would be difficult to administer anesthetics today without a thorough understanding of the autonomic nervous system and its neurotransmitters. These concepts are required in part because neuraxial blocks and general anesthetics are known to profoundly alter the ability of the body to respond to fluid losses and stress. Many modern surgical and neurovascular techniques require strict control of arterial and venous pressures, and this control is performed through interventions that alter autonomic tone.

The first hint of involuntary control of glandular and vascular function occurred in the 17th and 18th centuries. Robert Whytt (1714–1766) was the first to describe the reflex nature of many involuntary activities,^[43] and Thomas Willis^[44] (1621–1675) had described the sympathetic chain as early as 1657. He called it the intercostal nerve because it received segmental branches from the spinal cord at each level.

Pourfour du Petit (1664–1741) observed that there was a corresponding miosis and retraction of the nictitating membrane when this nerve was unilaterally cut in the neck of a cat.^[45] Winslow gave the intercostal nerve the name of grand sympathique, stressing that this nerve brought the various organs of the body into sympathy,^[46] a term that was originally coined by the Greek physician Soranus (98–138) in the first century AD (sym, "together," and pathos, "feeling"). Claude Bernard (1813–1878) observed vasoconstriction and pupillary dilation that followed stimulation of the same intercostal (now called the sympathetic) nerve and then described the vasomotor nerves arising between the cervical and lumbar enlargements of the spinal cord.^[47]

In 1889, John N. Langley (1852–1925) began his classic work on sympathetic transmission in autonomic ganglia. He blocked synaptic transmission in the ganglia by painting them with nicotine and then mapped the distribution of the presynaptic and postsynaptic autonomic nerves.^[48] He observed the similarity between the effects of injection of adrenal gland extracts and stimulation of the sympathetic nerves.^[49] The active principle of adrenal medullary extracts was called epinephrine by John J. Abel^[50] (1837–1938) in 1897. Abel was one of the first pharmacologists in the United States, and with his discovery of the hormone epinephrine, he uncovered one of the most commonly used lifesaving agents in the anesthesiologist's pharmacopoeia. Although epinephrine is a highly practical agent used by paramedics, emergency room physicians, intensivists, and anesthesiologists, Abel considered himself a "pure scientist." In one of his writings, ^[51] he made the following comments about the life of an investigator:

The investigator should freely dare to attack problems not because they give promise of immediate value to the human race, but because they make an irresistible appeal of an inner beauty. ... From this point of view the investigator is a man whose inner life is free in the best sense of the word. In short, there should be in research work a cultural character, an artistic quality, elements that give to painting, music, and poetry their high place in the life of man.

Thomas R. Elliott (1877–1961) postulated that sympathetic nerve impulses release a substance similar to epinephrine and considered this substance to be a chemical step in the process of neurotransmission.^[52] George Barger (1878–1939) and Henry H. Dale (1875–1968) then studied the pharmacologic activity of a large series of synthetic amines related to epinephrine and called these drugs sympathomimetic.^[53] The different effects on end organs produced by adrenal extracts and sympathetic stimulation were analyzed by Walter B. Cannon^[54] (1871–1945) and by Ulf Svante von Euler^[55] (1905–1983). In a series of papers, these authors demonstrated that the sympathetic nerves released norepinephrine, whereas the adrenal gland released both epinephrine and norepinephrine.

In 1907, Walter E. Dixon^[56] (1871–1931) observed that the alkaloid muscarine had the same effect as stimulation of the vagus nerves on various end organs. He proposed that the nerve liberated a muscarine-like chemical that acted as a chemical mediator. In 1914, Henry H. Dale ^[57] investigated the pharmacologic properties of acetylcholine and was impressed that its effects reproduced the same effects as stimulation of the craniosacral fine myelinated fibers that Walter H. Gaskell^[58] (1847–1914) had called the bulbosacral involuntary nerves and had by then been called parasympathetic by Langley.

The final proof of neurotransmission by acetylcholine through chemical mediation was provided through the elegant experiments of Otto Loewi (1873–1961). He stimulated the neural innervation of the frog heart and then allowed the perfusion fluid to come in contact with a second isolated heart preparation.^[59] The resulting bradycardia provided evidence that some substance was released from the donor nerves that slowed the heart rate of the second organ.^[59] Loewi and Navrail presented evidence that this substance was acetylcholine, as Dale had suggested. Loewi and Dale were jointly awarded the Nobel Prize in 1936 for their work on chemical neurotransmission.

Theodore Tuffier (1857–1929) first demonstrated the relevance of the sympathetic nervous system to the practice of anesthesia in 1900. In a series of experiments on dogs, he demonstrated the sympatholysis that occurs after spinal anesthesia.^[60] Further studies on the sympathectomy resulting from neuraxial block were performed by G. Smith and W. Porter in 1915. ^[61] Working with cats, they concluded that the fall in blood pressure was secondary to sympathetic paralysis of the vasomotor fibers

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Reversal of neuromuscular blockade rests on a fundamental understanding of two types of cholinergic receptors, muscarinic and nicotinic, originally described in 1914 by Dale.^[57] Physostigmine was isolated from the West African calabar bean by T. R. Fraser (1841–1920) in 1863,^[63] and he also demonstrated that atropine blocked its muscarinic side effects. Jacob Pal^[64] (1863–1936) discovered the effect of physostigmine to reverse the paralytic effect of curare in 1900. Neostigmine, synthesized in 1931,^[65] given alone during reversal of neuromuscular blockade had produced cardiac arrest in several cases before it was learned that a proper dose of antimuscarinic drug should be administered beforehand. ^{[66] [67] [68]} Atropine was isolated from the plant Atropa belladonna by A. Mein^[69] in 1831 and blocked peripheral and central nervous system muscarinic receptors. Glycopyrrolate was synthesized in 1960 as an antimuscarinic agent that did not pass the blood-brain barrier.^[70] Glycopyrrolate is more titratable, has fewer central nervous system side effects, and has gradually replaced atropine as the preferred anticholinergic during reversal of neuromuscular blockade.

Crucial to the control of arterial blood pressure and heart rate in the perioperative period was the realization that there was more than one type of adrenergic receptor. In 1948, Ahlquist proposed the designations of α- and β-adrenergic receptors,^[71] and various subtypes of these two main classes have been characterized since then. Esmolol was introduced in 1985 as a short-acting β-adrenergic antagonist that effectively controls heart rate during anesthesia.^[72] Labetalol is a unique agent that was introduced in 1976 and antagonizes α- and β-adrenergic receptors.^[73] Agonist activity at the α₂ -adrenergic receptor, using agents such as clonidine and dexmedetomidine,^[74] may have an expanded role in the practice of anesthesia in the future. The α₂ -adrenergic agonist effects produce sedation and analgesia through a central effect and, because they do not induce respiratory depression, may have some advantages over opioids as sedatives in awake subjects.^[75]

Manipulation of blood pressure can be achieved by intravenous nitrates, such as nitroglycerin and nitroprusside, which act directly on smooth muscle to allow rapid and more precise control of hemodynamics. Nitroglycerin was synthesized in 1846 by the Italian chemist Ascanio Sobrero (1812–1888) by combining nitric acid and glycerol. The first practical use of the drug was made by Alfred Nobel (1833–1896), who mixed the agent with silica to make dynamite, a highly successful explosive used in building tunnels and canals. A portion of the vast wealth of Nobel was directed by his will to be distributed annually in the form of Nobel Prizes beginning in 1901.^{[76] [77]} William Murrell^[78] (1853–1912) reported the use of sublingual nitroglycerin in 1879 to treat angina. Intravenous use of the nitrovasodilators during anesthesia was not feasible until the development of continuous arterial monitoring, but for the past 30 years, these agents have been popular for rapid control of hypertensive crisis in the operating room.^[79] The mechanism of action of nitrates on smooth muscle, by the release of nitric oxide, was demonstrated by Ferid Murad in 1986.^[80] Nitric oxide, considered a toxic gas by Priestley who discovered it and by Humphry Davy who breathed it, has been shown to be a useful inhalation agent when used in a very low dose of 5 to 10 ppm in cases of life-threatening pulmonary hypertension.^[81]