THE AUTONOMIC NERVOUS SYSTEM I. Introduction The autonomic nervous

THE AUTONOMIC NERVOUS SYSTEM I. Introduction The autonomic nervous system controls the function of the heart, blood vessels, viscera, and smooth muscle, and serves to maintain a stable internal environment despite exposure to a constantly changing external environment. There are several differences between the control mediated by the autonomic nervous system, compared to that mediated by the somatic neurons which innervate skeletal muscle. A. B. Activity of somatic nerves is under voluntary control; activity of autonomic neurons is generally involuntary. The target organ of somatic neurons, skeletal muscle, is quiescent in the absence of neuronal stimulation; the target organs of autonomic neurons usually show spontaneous activity which is modulated by stimulation. Autonomic neurons are organized into ganglia and plexi. Sensory information is carried by afferent autonomic pathways to CNS, where the controlling and integrating centers for most autonomic functions are located. Efferent pathways carry information from CNS to ganglia located outside the CNS, and from the ganglia on to the visceral effector organs. C. The autonomic nervous system is composed of 2 divisions, the parasympathetic and sympathetic nervous systems. The sympathetic preganglionic axons leave the intermediate spinal cord with the ventral roots from the first thoracic segment to the 3rd lumbar segment. The parasympathetic preganglionic axons originate in the midbrain, medulla, and sacral part of the spinal cord. Many end organs are innervated by both sympathetic and parasympathetic fibers that usually act in an antagonist manner to control organ function. The adrenal medulla, the central portion of the adrenal gland, is a part of the sympathetic system and contains secretory (chromaffin) cells that release catecholamines (mainly epinephrine) in response to neuronal stimulation. Classically, the sympathetic system is considered to be dominant during times of stress, when the organism is in a "fight or flight" situation. The sympathetic system can be stimulated to undergo widespread discharge in times of stress, causing increased heart rate and blood pressure, dilation of pupils and bronchioles, increased concentration of blood sugar and shifting of the blood from skin and viscera to skeletal muscle, increasing the ability of the organism to respond. The parasympathetic system dominates when the organism is restoring or conserving energy during rest or sleep. The parasympathetic system usually undergoes discharge at discrete sites. In general, sympathetic ganglia innervate many targets, while parasympathetic ganglia lie close to their targets, and a given parasympathetic ganglion only innervates one effector organ. Introduction to Autonomic Nervous System/Ganglionic Blocker Page 53 Preganglionic axons of sympathetic neurons using ACh as a neurotransmitter form synapses on ganglionic neurons that have ganglionic nicotinic AChR. The ganglionic neurons send postganglionic fibers to their target organs, where they usually release norepinephrine. There are two exceptions to this general rule. Most sweat glands are innervated by cholinergic sympathetic fibers (although sweating palms are caused by adrenergic sympathetic fibers). There are also cholinergic sympathetic fibers in the skeletal muscle vasculature, but these are thought to have negligible physiological significance. Preganglionic axons of parasympathetic neurons also use ACh as a neurotransmitter and form nicotinic synapses on ganglionic neurons. The postganglionic fibers of these neurons also use ACh as a neurotransmitter and form cholinergic synapses via the muscarinic (mAChR) on the target organ. In addition to the release of either ACh or norepinephrine, most postganglionic autonomic nerve terminals contain and are able to release peptides and other neuroactive substances such as purines. While it is believed that these compounds may act either as "cotransmitters" or as "neuromodulators," the precise physiological role of these substances remains to be elucidated. II. Effects of Autonomic Stimulation on Organ Function A. Heart: Parasympathetic activity slows the heart rate by hyperpolarization and slowing of the diastolic depolarization in the sino-atrial node and reduces contractile force in the atria by shortening the atrial action potential. Sympathetic activity increases heart rate by increasing rate of diastolic depolarization and increases contractile force by increasing Ca++ influx during the action potential. Note that while the sympathetic nervous system innervates all regions of the heart, there is very little parasympathetic innervation of the ventricles. B. Smooth Muscle in General: Parasympathetic activity causes contraction or increased rhythmic activity of smooth muscle. Sympathetic activity causes relaxation or decreased rhythmic activity of smooth muscle. Exception: Sympathetic activity contracts vascular smooth muscle except in skeletal muscle arteries and veins, where both contraction and dilation can occur. (This seemingly contradictory statement will be explained later, after you learn about the different types of adrenergic receptors.) Introduction to Autonomic Nervous System/Ganglionic Blocker Page 54 TABLE 1 Effect of Stimulation and Parasympathetic Systems Organ Sympathetic Heart S-A Node Atria A-V Node Ventricles Eye Iris Ciliary Muscle Lacrimal Glands Lungs Sweat Glands Liver GI Tract Mydriasis Relaxation (for far vision) -----------------------------Bronchial dilation Secretion Glycogen breakdown Inhibition of peristalsis and secretion Inhibition of peristalsis Some secretion Vasoconstriction Miosis Contraction (for near vision) Secretion Bronchial constiction ----------------------------------------------------------Stimulation of peristalsis and secretion Contraction Secretion -----------------------------Increased rate Increased contractility Increased conduction velocity Increased contractility Decreased rate Decreased contractility Decreased conduction velocity ------------------------------ Effect Parasympathetic Colon and Bladder Salivary Glands Arterioles (except skeletal muscle) Veins Vasoconstriction -----------------------------These effects are usually observed following stimulation of the respective systems. The actual effect observed will depend on the overall neurogenic tone at the time of stimulation. In an untreated individual, arterioles, veins, and sweat glands have mainly sympathetic tone, and the heart, eye, salivary glands, GI tract, and bladder have mainly parasympathetic tone. C. Exocrine Glands in General: Parasympathetic activity usually stimulates secretion. Sympathetic activity can either reduce, stimulate, or have no effect on secretion, depending on the particular gland. D. Eye: Iris: Parasympathetic activity causes miosis (pupillary constriction) by causing contraction of the iris sphincter muscle. Sympathetic activity causes mydriasis (pupillary dilation) by causing contraction of the iris dilator muscle. Lens accommodation: Parasympathetic activity stimulates contraction of the ciliary muscle causing increased curvature of the lens for near vision. Sympathetic activity causes relaxation of the ciliary muscle, decreasing curvature of the lens for far vision. Introduction to Autonomic Nervous System/Ganglionic Blocker Page 55 III. Synaptic Transmission in Autonomic Ganglion A. Sympathetic Ganglion Synaptic transmission in the mammalian superior cervical ganglion has been extensively studied. Stimulation of the preganglionic fibers leads to a complex series of changes in the membrane potential of the postganglionic neuron: (1) an initial large depolarization (EPSP) due to activation of the ganglionic nicotinic AChR of the postganglionic neuron; (2) a small hyperpolarization (slow IPSP) due to the activity of an interneuron; (3) a small depolarization (slow EPSP), due to activation of mAChR on the postganglionic neuron. The fast EPSP is responsible for transmission through the ganglion; the PSPs serve to modulate synaptic transmission. B. Parasympathetic Ganglia Much less is known about synaptic transmission in parasympathetic ganglia. Electrophysiological studies of parasympathetic ganglia in amphibian heart suggest the presence of a fast EPSP due to activation of nAChR, and a slow IPSP, due to activation of mAChR. Thus, while transmission through parasympathetic ganglia may be simpler than that through sympathetic ganglia, the main pathway for synaptic transmission in each case uses ACh. There are many similarities between synaptic transmission at neuromuscular junctions and autonomic ganglia. The synthesis, storage and release of ACh take place in preganglionic cholinergic terminals of autonomic ganglia via processes similar to those already described at the neuromuscular junction. The nerve terminal contains many synaptic vesicles which release ACh by exocytosis. As at the neuromuscular junction, none of the drugs affecting these processes are used clinically to affect autonomic neurotransmission. The postsynaptic ganglionic AChR are also localized to the subsynaptic membrane; after denervation, the postsynaptic neurons become supersensitive to ACh and new receptors appear in nonsynaptic regions. Activation of the receptors causes a transient increase in membrane permeability to Na+ which desensitizes in the continued presence of agonists. While there are thus a number of similarities between the nicotinic receptor in skeletal muscle and in autonomic ganglia, the two receptors differ markedly in their specificity for ligand binding. Introduction to Autonomic Nervous System/Ganglionic Blocker Page 56 IV. Ganglionic Stimulating Drugs There are 2 classes of ganglionic stimulants. 1. Nicotinic Drugs These drugs act as agonists which activate and then desensitize the AChR. Low concentrations of these drugs stimulate nicotinic receptors sympathetic and parasympathetic ganglia and in the adrenal medulla. Higher concentrations cause blockade in both types of ganglia. The final effect can thus be a summation of opposing effects. Because of their broad and somewhat unpredictable actions the ganglionic stimulants are not widely used clinically. However, because of the widespread consumption of nicotine from tobacco, its use in insecticides and its high level of toxicity, it is important. At low doses nicotine has sympathomimetic cardiovascular effects (increased heart rate and increased force of contraction, elevating blood pressure) and parasympathetic G.I. effects (increased intestinal tone of motility). In addition, nicotine is lipid soluble and can produce complex central effects, tremors, stimulation of respiration, and at high doses, convulsions. Nicotine is thought to be the second most widely used addicting drug used in the U.S.A. (caffeine is first). Abrupt cessation of smoking by a nicotine-dependent smoker can result in headaches, tremors, visual disorders, irritability, etc. A nicotine-containing gum and transdermal patches are available to help smokers reduce nicotine dependence gradually while breaking the smoking habit. Nursing women or people with cardiovascular problems should not use nicotine. 2. Muscarinic Drugs Drugs which stimulate mAChR (muscarine, pilocarpine, etc.) cause stimulation of sympathetic ganglia via the late EPSP. For most of these agents, these effects are usually masked by muscarinic effects on the cardiovascular system. There is, however, an experimental drug called McN-A-343, which appears to preferentially stimulate mAChR in the symapthetic ganglia and in the adrenal medulla and not mAChR in target organs such as the heart or vascular smooth muscle. (As will be discussed later, this is because there are pharmacologically distinct subtypes of muscarinic receptors). Thus, McN-A-343 can produce vasoconstriction which is blocked by atropine. Introduction to Autonomic Nervous System/Ganglionic Blocker Page 57 V. Ganglionic Blockers Hexamethonium, mecamylamine, pentolinium, TEA, and trimethaphan act as competitive antagonists – they block ganglionic transmission by binding to the AChR without a change in the membrane potential of the ganglionic cells. The prototype of the ganglionic blockers, hexamethonium, is the 6 carbon version of the depolarizing neuromuscular junction blocker decamethonium. Hexamethonium is a very weak blocker at the neuromuscular junction but much more potent at autonomic ganglia. The ganglionic blockers block both parasympathetic and sympathetic ganglia. Their actual effect depends therefore on whether the predominant autonomic tone in an untreated individual is parasympathetic or sympathetic. The effects on organs with predominantly sympathetic tone are: (1) (2) arterioles and veins – causes vasodilation sweat glands – decrease sweating The effects on organs with predominantly parasympathetic tone are: (1) (2) (3) (4) (5) heart – tachycardia eye – pupillary dilation and cycloplegia salivary glands – dry mouth GI tract – relaxation of intestinal muscle, constipation bladder – difficulty in emptying the bladder Ganglionic blockers in the past were used as hypotensive agents, but are now rarely used, except in emergency treatment of hypertensive crises and to produce controlled hypotension during certain surgical procedures. The hypotensive effects are due to the dilation of most arteries and veins in skin and viscera leading to a decrease in total systemic vascular resistance. The side effects of the ganglion blockers are due to their effects on other organs as described above: visual problems, constipation, etc. More severe reactions include marked hypotension and paralysis of the bowel and bladder. VI. Readings: (G & G, Ninth Edition) Chapter 6; Chapter 9: pp. 191-197; Chapter 24: pp. 565-566. Introduction to Autonomic Nervous System/Ganglionic Blocker Page 58