The first evidence for chemical neurotransmission was provided by a simple yet dramatic study by Otto Loewi in 1920 in which he showed that the slowing of the heart rate produced by stimulation of the vagal parasympathetic nerves was due to the release of acetylcholine (see Chapter 7). Transmission at the synaptic junctions between preganglionic and postganglionic neurons and between the postganglionic neurons and the autonomic effectors are chemically mediated. The principal transmitter agents involved are acetylcholine and norepinephrine. The autonomic neurons that are cholinergic (ie, release acetylcholine) are (1) all preganglionic neurons, (2) all parasympathetic postganglionic neurons, (3) sympathetic postganglionic neurons that innervate sweat glands, and (4) sympathetic postganglionic neurons that end on blood vessels in some skeletal muscles and produce vasodilation when stimulated (sympathetic vasodilator nerves). The remaining sympathetic postganglionic neurons are noradrenergic (ie, release norepinephrine). The adrenal medulla is essentially a sympathetic ganglion in which the postganglionic cells have lost their axons and secrete both norepinephrine and epinephrine directly into the bloodstream.
Table 13–1 shows the types of cholinergic and adrenergic receptors at various junctions within the ANS. The junctions in the peripheral autonomic motor pathways are logical sites for pharmacologic manipulation of visceral function. The transmitter agents are synthesized, stored in the nerve endings, and released near the neurons, muscle cells, or gland cells where they bind to various ion channels or G-protein-coupled receptors (GPCR) to initiate their characteristic actions. The neurotransmitters are then removed from the area by reuptake or metabolism. Each of these steps can be stimulated or inhibited, with predictable consequences. Table 13–2 lists how various drugs can affect neurotransmission in autonomic neurons and effector sites.
TABLE 13–1Responses of some effector organs to autonomic nerve activity. ||Download (.pdf) TABLE 13–1 Responses of some effector organs to autonomic nerve activity.
| || ||Sympathetic Nervous System |
|Effector Organs ||Parasympathetic Nervous System ||Receptor Type ||Response |
Radial muscle of iris
Sphincter muscle of iris
Contraction for near vision
|α1 || |
Atria and ventricle
AV node and Purkinje fibers
Decreased heart rate
Decreased atrial contractility
Decreased conduction velocity
Increased heart rate
Increased conduction velocity
Skin, splanchnic vessels
|Systemic veins ||— ||α1, α2/ β2 ||Constriction/Dilation |
|Bronchial smooth muscle ||Contraction ||β2 ||Relaxation |
|Stomach and Intestine |
Motility and tone
α1, α2, β2
|Gallbladder ||Contraction ||β2 ||Relaxation |
|Urinary bladder |
|Uterus (pregnant) ||— ||α1/ β2 ||Contraction/Relaxation |
|Male sex organs ||Erection ||α1 ||Ejaculation |
|Liver ||— ||α1, β2 ||Glycogenolysis |
|Salivary glands ||Profuse, watery secretion ||α1/β ||Thick, viscous secretion/Amylase secretion |
|Lacrimal glands ||Secretion || ||— |
|Adipose tissue ||— ||β3 ||Lipolysis |
TABLE 13–2Examples of drugs that affect processes involved in autonomic neurotransmission. ||Download (.pdf) TABLE 13–2 Examples of drugs that affect processes involved in autonomic neurotransmission.
|Transmission Process ||Drug ||Site of Drug Action ||Drug Action |
|Neurotransmitter synthesis || |
Membrane of cholinergic nerve terminals
Cytoplasm of noradrenergic nerve terminals
Blocks choline uptake; slows synthesis
Inhibits tyrosine hydroxylase; blocks synthesis
|Neurotransmitter storage mechanism || |
Vesicles in cholinergic nerve terminals
Vesicles in noradrenergic nerve terminals
Prevents storage of acetylcholine
Prevents storage of norepinephrine
|Neurotransmitter release mechanism ||Norepinephrine, dopamine, acetylcholine, prostaglandins ||Receptors on cholinergic and adrenergic nerve terminals ||Modulates transmitter release |
|Neurotransmitter reuptake mechanism ||Cocaine, tricyclic antidepressants ||Adrenergic nerve terminals ||Inhibits uptake; prolongs transmitter’s action on postsynaptic receptors |
|Inactivation of neurotransmitter ||Edrophonium, neostigmine, physostigmine, ||Acetylcholinesterase in cholinergic synapses ||Inhibits enzyme; prolongs and intensifies actions of acetylcholine |
|Adrenoceptor activation || |
β2: Albuterol, ritodrine, salmeterol, terbutaline
Sympathetic postganglionic nerve-effector organ junctions (eg, blood vessels, hair follicles, and radial muscle)
Sympathetic postganglionic nerve-effector organ junctions (eg, heart, bronchial smooth muscle, and uterine smooth muscle)
Binds to and activates α-adrenoceptors; ↑ IP3/DAG cascade (α1) or ↓ cAMP (α2)
Binds to and activates β-adrenoceptors; ↑ cAMP
|Adrenoceptor blockade || |
α1: Prazosin, terazosin
β1, β2: Propranolol
β1 > β2: Atenolol, esmolol
Sympathetic postganglionic nerve-effector organ junctions (eg, blood vessels)
Sympathetic postganglionic nerve-effector organ junctions (eg, heart and bronchial smooth muscle)
Binds to and blocks α-adrenoceptors
Binds to and blocks β-adrenoceptors
|Nicotinic receptor activation ||Nicotine ||Receptors on autonomic ganglia ||Binds to nicotinic receptors; opens Na+, K+ channels in postsynaptic membrane |
|Nicotinic receptor blockade ||Hexamethonium, trimethaphan ||Receptors on autonomic ganglia ||Binds to and blocks nicotinic receptors |
|Muscarinic receptor activation ||Bethanecol ||Cholinergic receptors on smooth muscle, cardiac muscle, and glands ||Binds to and activates muscarinic receptors; ↑ IP3/DAG cascade or ↓ cAMP |
|Muscarinic receptor blockade ||Atropine, ipratropium, scopolamine, tropicamide ||Cholinergic receptors on smooth muscle, cardiac muscle, and glands ||Binds to and blocks muscarinic receptors |
The processes involved in the synthesis and breakdown of acetylcholine were described in Chapter 7. Acetylcholine does not usually circulate in the blood, and the effects of localized cholinergic discharge are generally discrete and of short duration because of the high concentration of acetylcholinesterase at cholinergic nerve endings. This enzyme rapidly breaks down the acetylcholine, terminating its actions.
Transmission in autonomic ganglia is mediated primarily by the actions of acetylcholine on nicotinic cholinergic receptors that are blocked by hexamethonium (Figure 13–4). These are called NN receptors to distinguish them from the nicotinic cholinergic receptors (NM) that are located at the neuromuscular junction and are blocked by D-tubocurare. Nicotinic receptors are examples of ligand-gated ion channels; binding of an agonist to nicotinic receptors opens N+ and K+ channels to cause depolarization.
Schematic of excitatory and inhibitory postsynaptic potentials (EPSP and IPSP) recorded via an electrode in an autonomic ganglion cell. In response to acetylcholine release from the preganglionic neuron, two EPSPs were generated in the postganglionic neuron due to nicotinic (N) receptor activation. The first EPSP was below the threshold for eliciting an action potential, but the second EPSP was suprathreshold and evoked an action potential. This was followed by an IPSP, probably evoked by muscarinic (M2) receptor activation. The IPSP is then followed by a slower, M1-dependent EPSP, and this can be followed by an even slower peptide-induced EPSP. (Used with permission from Katzung BG, Maters SB, Trevor AJ: Basic & Clinical Pharmacology, 11th ed. New York, NY: McGraw-Hill; 2009.)
The responses produced in postganglionic neurons by stimulation of their preganglionic innervation include both a rapid depolarization called a fast excitatory postsynaptic potential (EPSP) that generates action potentials and a prolonged excitatory postsynaptic potential (slow EPSP). The slow response may modulate and regulate transmission through the sympathetic ganglia. The initial depolarization is produced by acetylcholine acting on the NN receptor. The slow EPSP is produced by acetylcholine acting on a muscarinic receptor on the membrane of the postganglionic neuron.
The release of acetylcholine from postganglionic fibers acts on muscarinic cholinergic receptors, which are blocked by atropine. Muscarinic receptors are GPCR and are divided into subtypes M1–M5, but M2 and M3 are the main subtypes found in autonomic target organs. M2 receptors are located in the heart; binding of an agonist to these receptors opens K+ channels and inhibits adenylyl cyclase. M3 receptors are located on smooth muscle and glands; binding of an agonist to these receptors leads to the formation of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) and an increase in intracellular Ca2+.
Compounds with muscarinic actions include congeners of acetylcholine and drugs that inhibit acetylcholinesterase. Clinical Box 13–2 describes some of the signs and therapeutic strategies for the treatment of acute intoxication from organophosphate cholinesterase inhibitors. Clinical Box 13–3 describes an example of cholinergic poisoning resulting from digestion of toxic mushrooms.
The processes involved in the synthesis, reuptake, and breakdown of norepinephrine were described in Chapter 7. Norepinephrine spreads farther and has a more prolonged action than acetylcholine. Norepinephrine, epinephrine, and dopamine are all found in plasma. The epinephrine and some of the dopamine come from the adrenal medulla, but most of the norepinephrine diffuses into the bloodstream from sympathetic nerve endings. Metabolites of norepinephrine and dopamine also enter the circulation.
The norepinephrine released from sympathetic postganglionic fibers binds to adrenoceptors. These are also GPCR and are divided into several subtypes: α1, α2, β1, β2, and β3. Table 13–1 shows some of the locations of these receptor subtypes on smooth muscles, cardiac muscle, and glands on autonomic effector targets. Binding of an agonist to α1-adrenoceptors activates the Gq-coupling protein, which leads to formation of IP3 and DAG and an increase in intracellular Ca2+. Binding of an agonist to α2-adrenoceptors causes dissociation of the inhibitory G-protein Gi to inhibit adenylyl cyclase and decrease cyclic adenosine monophosphate (cAMP). Binding of an agonist to β-adrenoceptors activates the Gs-coupling protein to activate adenylyl cyclase and increase cAMP.
There are several diseases or syndromes that result from dysfunction of sympathetic innervation of specific body regions. Clinical Box 13–4 describes Horner syndrome, which is due to interruption of sympathetic nerves to the face. Clinical Box 13–5 describes a vasospastic condition (Raynaud phenomenon) in which blood flow to the fingers and toes is transiently reduced, typically when a sensitive individual is exposed to stress or cold.
CLINICAL BOX 13–2 Organophosphates: Pesticides and Nerve Gases
The World Health Organization estimates that 1–3% of agricultural workers worldwide suffer from acute pesticide poisoning; it accounts for significant morbidity and mortality, especially in developing countries. Like organophosphate pesticides (eg, parathion and malathion), nerve gases (eg, soman and sarin) used in chemical warfare and terrorism inhibit acetylcholinesterase at peripheral and central cholinergic synapses, prolonging the actions of acetylcholine at these synapses. The organophosphate cholinesterase inhibitors are readily absorbed by the skin, lung, gut, and conjunctiva, making them very dangerous. They bind to the enzyme and undergo hydrolysis, resulting in a phosphorylated active site on the enzyme. The covalent phosphorous-enzyme bond is very stable and hydrolyzes at a very slow rate. The phosphorylated enzyme complex may undergo a process called aging in which one of the oxygen-phosphorous bonds breaks down, which strengthens the phosphorous-enzyme bond. This process takes only 10 min to occur after exposure to soman. The earliest signs of organophosphate toxicity are usually indicative of excessive activation of autonomic muscarinic receptors; these include miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea. CNS signs of toxicity include cognitive disturbances, convulsions, seizures, and even coma; these signs are often accompanied by nicotinic effects such as depolarizing neuromuscular blockade. THERAPEUTIC HIGHLIGHTS
The muscarinic cholinergic receptor antagonist atropine is often given parenterally in large doses to control signs of excessive activation of muscarinic cholinergic receptors. When given soon after exposure to the organophosphate and before aging has occurred, nucleophiles such as pralidoxime are able to break the bond between the organophosphate and the acetylcholinesterase. Thus, this drug is called a “cholinesterase regenerator.” If pyridostigmine is administered in advance of exposure to a cholinesterase inhibitor, it binds to the enzyme and prevents binding by the toxic organophosphate agent. The protective effects of pyridostigmine dissipate within 3–6 h, but this provides enough time for clearance of the organophosphate from the body. Since the drug cannot cross the blood-brain barrier, protection is limited to peripheral cholinergic synapses. A mixture of pyridostigmine, carbamate, and atropine can be administered prophylactically to soldiers and civilians who are at risk for exposure to nerve gases. Benzodiazepines can be used to abort the seizures caused by exposure to organophosphates.
CLINICAL BOX 13–3 Mushroom Poisoning
Of more than 5000 species of mushrooms found in the United States, approximately 100 are poisonous and ingestion of about 12 of these can result in death. Estimates are an annual incidence of five cases per 100,000 individuals in the United States; worldwide databases are not available. Mushroom poisoning or mycetism is divided into rapid-onset (15–30 min after ingestion) and delayed-onset (6–12 h after ingestion) types. In rapid-onset cases caused by mushrooms of the Inocybe genus, the symptoms are due to excessive activation of muscarinic cholinergic synapses. The major signs of muscarinic poisoning include nausea, vomiting, diarrhea, urinary urgency, vasodilation, sweating, and salivation. Ingestion of mushrooms such as the Amanita muscaria exhibit signs of the antimuscarinic syndrome rather than muscarinic poisoning because they also contain alkaloids that block muscarinic cholinergic receptors. The classic symptoms of this syndrome are being “red as a beet” (flushed skin), “hot as a hare” (hyperthermia), “dry as a bone” (dry mucous membranes, no sweating), “blind as a bat” (blurred vision and cycloplegia), and “mad as a hatter” (confusion and delirium). The delayed-onset type of mushroom poisoning occurs after ingestion of Amanita phalloides, Amanita virosa, Galerina autumnalis, and Galerina marginata. These mushrooms cause abdominal cramping, nausea, vomiting, and profuse diarrhea; but the major toxic effects are due to hepatic injury (jaundice and bruising) and associated central effects (confusion, lethargy, and coma). These mushrooms contain amatoxins that inhibit RNA polymerase. There is a 60% mortality rate associated with ingestion of these mushrooms. THERAPEUTIC HIGHLIGHTS
The rapid-onset type muscarinic poisoning can be treated effectively with atropine. Individuals who exhibit the antimuscarinic syndrome can be treated with physostigmine, which is a cholinesterase inhibitor with a 2–4 h duration of action that acts centrally and peripherally. If agitated, these individuals may require sedation with a benzodiazepine or an antipsychotic agent. The delayed-onset of toxicity due to ingestion of mushrooms containing amatoxins does not respond to cholinergic drugs. Treatment of amatoxin ingestion includes intravenous administration of fluids and electrolytes to maintain adequate hydration. Administering a combination of a high-dose of penicillin G and silibinin (a flavonolignan found in certain herbs with antioxidant and hepatoprotective properties) has been shown to improve survival. If necessary, vomiting can also be induced by using activated charcoal to reduce the absorption of the toxin.
CLINICAL BOX 13–4 Horner Syndrome
Horner syndrome is a rare disorder resulting from interruption of preganglionic or postganglionic sympathetic innervation to the face. The problem can result from injury to the nerves, injury to the carotid artery, a stroke or lesion in the brainstem, or a tumor in the lung. In most cases the problem is unilateral, with symptoms occurring only on the side of the damage. The hallmark of Horner syndrome is the triad of anhidrosis (reduced sweating), ptosis (drooping eyelid), and miosis (constricted pupil). Symptoms also include enophthalmos (sunken eyeball) and vasodilation. THERAPEUTIC HIGHLIGHTS
There is no specific pharmacologic treatment for Horner syndrome, but drugs affecting noradrenergic neurotransmission can be used to determine whether the source of the problem is interruption of the preganglionic or postganglionic innervation to the face. Since the iris of the eye responds to topical sympathomimetic drugs (ie, drugs that are direct agonists on adrenoceptors or drugs that increase the release or prevent reuptake of norepinephrine from the nerve terminal), the clinician can easily test the viability of the noradrenergic nerves to the eye. If the postganglionic sympathetic fibers are damaged, their terminals would degenerate and there would be a loss of stored catecholamines. If the preganglionic fibers are damaged, the postganglionic noradrenergic nerve would remain intact (but be inactive) and would still have stored catecholamines in its terminal. If a drug that causes release of catecholamine stores (eg, hydroxyamphetamine) is administered and the constricted pupil does not dilate, one would conclude that the noradrenergic nerve is damaged. If the eye dilates in response to this drug, the catecholamine stores are still able to be released, so the damage must be preganglionic. Administration of phenylephrine (α-adrenoceptor agonist) would dilate the pupil regardless of the site of injury as the drug binds to the receptor on the radial muscle of the iris.
CLINICAL BOX 13–5 Raynaud Phenomenon
Approximately 5% of men and 8% of women experience an episodic reduction in blood flow primarily to the fingers, often during exposure to cold or during a stressful situation. Vasospasms in the toes, tip of nose, ears, and penis can also occur. Smoking is associated with an increase in the incidence and severity of the symptoms of Raynaud phenomenon. The symptoms begin to occur between the age of 15 and 25; it is most common in cold climates. The symptoms often include a triphasic change in color of the skin of the digits. Initially, the skin becomes pale or white (pallor), cold, and numb. This can be followed by a cyanotic period in which the skin turns blue or even purple, during which time the reduced blood flow can cause intense pain. Once the blood flow recovers, the digits often turn deep red (rubor) and there can be swelling and tingling. Primary Raynaud phenomenon or Raynaud disease refers to the idiopathic appearance of the symptoms in individuals who do not have another underlying disease to account for the symptoms. In such cases, the vasospastic attacks may merely be an exaggeration of a normal response to cold temperature or stress. Secondary Raynaud phenomenon or Raynaud syndrome refers to the presence of these symptoms due to another disorder such as scleroderma, lupus, rheumatoid arthritis, Sjögren syndrome, carpel tunnel syndrome, and anorexia. Although initially thought to reflect an increase in sympathetic activity to the vasculature of the digits, this is no longer regarded as the mechanism underlying the episodic vasospasms. THERAPEUTIC HIGHLIGHTS
The first treatment strategy for Raynaud phenomenon is to avoid exposure to the cold, reduce stress, quit smoking, and avoid the use of medications that are vasoconstrictors (eg, β-adrenoceptor antagonists, cold medications, caffeine, and opioids). If the symptoms are severe, drugs may be needed to prevent tissue damage. These include calcium channel blockers (eg, nifedipine) and α-adrenoceptor antagonists (eg, prazosin). In individuals who do not respond to pharmacologic treatments, surgical sympathectomy has been done.
NONADRENERGIC & NONCHOLINERGIC TRANSMITTERS
In addition to the “classical neurotransmitters,” some autonomic fibers also release neuropeptides, although their exact functions in autonomic control have not been determined. The small granulated vesicles in postganglionic noradrenergic neurons contain adenosine triphosphate (ATP) and norepinephrine, and the large granulated vesicles contain neuropeptide Y (NPY). There is some evidence that low-frequency stimulation promotes release of ATP, whereas high-frequency stimulation causes release of NPY. Some visceral organs contain purinergic receptors, and evidence is accumulating that ATP is a mediator in the ANS along with norepinephrine.
Many sympathetic fibers innervating the vasculature of viscera, skin, and skeletal muscles release NPY and galanin in addition to norepinephrine. Vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), or substance P are co-released with acetylcholine from the sympathetic innervation to sweat glands (sudomotor fibers). VIP is co-localized with acetylcholine in many cranial parasympathetic postganglionic neurons supplying glands. Vagal parasympathetic postganglionic neurons in the gastrointestinal tract contain VIP and the enzymatic machinery to synthesize nitric oxide (NO).