Parasympathetic and sympathetic regulation

There are general differences between the parasympathetic and sympathetic branches of the autonomic nervous system, which can be contrasted. Parasympathetic control is essential to life and is considered a more discrete, finely regulated system than sympathetic control. Parasympathetic effects control the day-to-day bodily functions of digestion, bladder and rectal discharge, and basal secretion of bronchial mucus. Overstimulation of the parasympathetic branch would render the body incapable of violent action, resulting in what is termed the SLUD syndrome: salivation, lacrimation, urination, and defecation. These reactions are definitely counterproductive to fleeing or fighting!

By contrast, the sympathetic branch reacts as a general alarm system and does not exercise discrete controls. This is sometimes characterized as a “fight-or-flight” system: heart rate and blood pressure increase, blood flow shifts from the periphery to muscles and the heart, blood sugar increases, and bronchi dilate. The organism prepares for maximal physical exertion. The sympathetic branch is not essential to life; animal models with sympathectomy can survive but are unable to cope with violent stress.

Neurotransmitters

Another general feature of the autonomic nervous system, including sympathetic and parasympathetic branches, is the mechanism of neurotransmitter control of nerve impulses. Nerve impulse propagation is electrical and chemical (electrochemical). A nerve impulse signal is carried along a nerve fiber by electrical action potentials, caused by ion exchanges (sodium, potassium). At gaps in the nerve fiber between neurons (synapses), the electrical transmission is replaced by a chemical neurotransmitter. This is the chemical transmission of the electrical impulse, which occurs at the ganglionic synapses and at the end of the nerve fiber, termed the neuroeffector site. Identification of the chemical transmitters dates back to Loewi’s experiments in 1921 and is fundamental to understanding autonomic drugs and their classifications. The usual neurotransmitters in the PNS, including the ganglionic synapses and terminal sites in the autonomic branches, are shown in Figure 5-1 (Ach and norepinephrine).

The neurotransmitter conducting the nerve impulse at skeletal muscle sites is Ach, and this site is referred to as the neuromuscular junction, or the myoneural junction. In the parasympathetic branch, the neurotransmitter is also Ach at both the ganglionic synapse and the terminal nerve site, referred to as the neuroeffector site. In the sympathetic branch, Ach is the neurotransmitter at the ganglionic synapse; however, norepinephrine is the neurotransmitter at the neuroeffector site. There are two exceptions to this pattern, both in the sympathetic branch. Sympathetic fibers to sweat glands release Ach instead of norepinephrine, and preganglionic sympathetic fibers directly innervate the adrenal medulla, where the neurotransmitter is Ach. Sympathetic fibers that have Ach at the neuroeffector sites are cholinergic (for Ach) sympathetic fibers. “Cholinergic sympathetic” would be an apparent contradictory combination of terms if not for the exceptions to the rule of norepinephrine as the sympathetic neurotransmitter. For example, sweating can be caused by giving a cholinergic drug such as pilocarpine, although this effect is under sympathetic control. “Breaking out in a sweat,” along with sweaty palms and increased heart rate resulting from circulating epinephrine, are common effects of stress or fright mediated by sympathetic discharge.

Although it is an oversimplification, an easy way to learn the various neurotransmitters initially is to remember that Ach is the neurotransmitter everywhere (skeletal muscle, all ganglionic synapses, and parasympathetic terminal nerve sites) except at sympathetic terminal nerve sites, where norepinephrine is the neurotransmitter. The exceptions provided by sympathetic fibers releasing Ach can be remembered as exceptions to the general rule.

Efferent and afferent nerve fibers

The autonomic system is generally considered an efferent system—that is, impulses in the sympathetic and parasympathetic branches travel from the brain and spinal cord out to the various neuroeffector sites, such as the heart, gastrointestinal tract, and lungs. Afferent nerves run alongside the sympathetic and parasympathetic efferent fibers and carry impulses from the periphery to the cord. The afferent fibers convey impulses resulting from visceral stimuli and can form a reflex arc of stimulus input–autonomic output analogous to the well-known somatic reflex arcs, such as the knee-jerk reflex. The mechanism of a vagal reflex arc mediating bronchoconstriction is discussed further in Chapter 7, in conjunction with drugs used to block the parasympathetic impulses.

Terminology of drugs affecting the nervous system

Terminology of drugs and drug effects on the nervous system can be confusing and may seem inconsistent. The confusion is due to the fact that drugs and drug effects are derived from the type of nerve fiber (parasympathetic or sympathetic) or, alternatively, the type of neurotransmitter and receptor (Ach and norepinephrine). The following terms are based on the anatomy of the nerve fibers, to describe stimulation or inhibition:

Additional terms are used, based on the type of neurotransmitter and receptor. Cholinergic refers to Ach, and adrenergic is derived from adrenaline, another term for epinephrine, which is similar to norepinephrine and can stimulate sympathetic neuroeffector sites. Because Ach is the neurotransmitter at more sites than just parasympathetic sites, and because receptors exist on smooth muscle or blood cells without any nerve fibers innervating them, these terms denote a wider range of sites than the anatomically based terms such as parasympathomimetic. Cholinergic can refer to a drug effect at a ganglion, a parasympathetic nerve ending site, or the neuromuscular junction. Adrenergic describes receptors on bronchial smooth muscle or on blood cells, where there are no sympathetic nerves. For this reason, cholinergic and adrenergic are not strictly synonymous with parasympathetic and sympathetic. Cholinergic (cholinomimetic) refers to a drug causing stimulation of a receptor for Ach. Anticholinergic refers to a drug blocking a receptor for Ach. Adrenergic (adrenomimetic) refers to a drug stimulating a receptor for norepinephrine or epinephrine. Antiadrenergic refers to a drug blocking a receptor for norepinephrine or epinephrine. Cholinoceptor is an alternative term for cholinergic receptor, and adrenoceptor is an alternative term for adrenergic receptor.

Muscarinic and nicotinic receptors and effects

Two additional terms are used to refer to stimulation of receptor sites for Ach; they are derived from the action in the body of two substances, the alkaloids muscarine and nicotine. Receptor sites that are stimulated by these two chemicals are illustrated in Figure 5-4.

Subtypes of muscarinic receptors

Parasympathetic receptors and cholinergic receptors in general with or without corresponding nerve fibers are classified further into subtypes. These differences among cholinergic or muscarinic (M) receptors are based on different responses to different drugs, or recognition through use of DNA probes. Five muscarinic receptor subtypes have been identified: M₁, M₂, M₃, M₄, and M₅. They are all G protein–linked (see Chapter 2). As G protein–linked receptors, these five subtypes of muscarinic receptors share a structural feature common to such receptors—a long, “serpentine” polypeptide chain that crosses the cell membrane seven times (illustrated for G protein receptors in Chapter 2). Table 5-2 summarizes the muscarinic receptor subtypes, with their predominant location and the type of G protein with which they are coupled. Additional details about muscarinic receptor location and function in the pulmonary system are presented in the final section of this chapter, which summarizes nervous control and receptors in the lung.

Direct-acting cholinergic agents

Direct-acting cholinergic agents are structurally similar to Ach. As shown in Figure 5-3, direct-acting cholinergic agents mimic Ach, binding and activating muscarinic or nicotinic receptors directly. Examples of this group include methacholine, carbachol, bethanechol, and pilocarpine. Methacholine has been used in bronchial challenge tests by inhalation to assess the degree of airway reactivity in asthmatics and others. The parasympathetic effect is bronchoconstriction. Methacholine is a useful diagnostic agent to detect differences in degree of airway reactivity between asthmatics with hyperreactive airways and nonasthmatic individuals.

Indirect-acting cholinergic agents

Indirect-acting cholinergic agonists inhibit the cholinesterase enzyme, as seen in Figure 5-3. Because cholinesterase usually inactivates the Ach neurotransmitter, inhibiting this enzyme results in accumulation of endogenous Ach at the neuroeffector junction of parasympathetic nerve endings or the neuromuscular junction. More Ach is made available to attach to receptor sites and to stimulate cholinergic responses. If Ach receptors have been blocked, this increase in neurotransmitter can reverse the blockage by competing with the blocking drug for the receptors. Nerve transmission can then resume, either at the parasympathetic terminal site or at the neuromuscular junction.

The drug echothiophate (Phospholine), listed in Table 5-3, stimulates autonomic muscarinic receptors in the iris sphincter and ciliary muscle of the eye to produce pupillary constriction (miosis) and lens thickening. An increase in the neurotransmitter Ach at the neuromuscular junction makes drugs such as neostigmine useful in reversing neuromuscular blockade caused by paralyzing agents such as pancuronium or doxacurium (see Chapter 18). Neostigmine and edrophonium are also useful in increasing muscle strength in a neuromuscular disease such as myasthenia gravis, in which the cholinergic receptor is blocked by autoantibodies. The drug edrophonium (Tensilon) is used in the Tensilon test to determine whether muscle weakness is caused by overdosing with an indirect-acting cholinergic agent (causing ultimate receptor fatigue and blockade) or undertreatment with insufficient drug. Because edrophonium is short-acting (5 to 15 minutes, depending on the dose), it is useful as a diagnostic agent, rather than as a maintenance treatment in neuromuscular disease.

When using indirect-acting cholinergic agents such as neostigmine to increase nerve function at the neuromuscular junction, Ach activity at parasympathetic sites such as salivary and nasopharyngeal glands also increases. These undesirable muscarinic effects can be blocked by pretreatment with a parasympatholytic or antimuscarinic drug such as atropine or its derivatives.

Atropine as a prototype parasympatholytic agent

Atropine is usually considered the prototype parasympatholytic, and there is renewed interest in the use of aerosolized analogues of atropine in respiratory care; this is discussed more fully in Chapter 7. Atropine occurs naturally as the levo isomer in Atropa belladonna, the nightshade plant, and in Datura stramonium, or jimsonweed. The drug is referred to as a belladonna alkaloid.

Atropine is a competitive antagonist to Ach at muscarinic receptor sites (glands, gastrointestinal tract, heart, and eyes) and can form a reversible bond with these cholinergic receptors. It is nonspecific for muscarinic receptor subtypes and blocks M₁, M₂, and M₃ receptors. Atropine blocks salivary secretion and causes dry mouth. In the respiratory system, atropine decreases secretion by mucous glands and relaxes bronchial smooth muscle by blocking parasympathetically maintained basal tone. Atropine blocks vagal innervation of the heart to produce increased heart rate. There is no effect on blood vessels because these do not have parasympathetic innervation, only the Ach receptors. Vascular resistance would not increase with atropine. If a parasympathomimetic were given, atropine would block the dilating effect on blood vessel receptor sites. Pupillary dilation (mydriasis) occurs as a result of blockade of the circular iris muscle, and the lens is flattened (cycloplegia) by blockade of the ciliary muscle. In the gastrointestinal tract, atropine decreases acid secretion, tone, and mobility. Bladder wall smooth muscle is relaxed, and voiding is slowed. Sweating is inhibited by atropine, which blocks Ach receptors on sweat glands. Sweat glands are innervated by sympathetic cholinergic fibers.

At usual clinical doses, atropine exerts a low level of CNS stimulation, with a slower sedative effect in the brain. Scopolamine, another classic antimuscarinic agent, can produce drowsiness and amnesia. In larger doses, atropine can cause toxic effects in the CNS, including hallucinations.

The anticholinergic (antimuscarinic) effect on the vestibular system can inhibit motion sickness. Scopolamine was used for this, and antihistamine drugs such as dimenhydrinate (Dramamine) that have anticholinergic effects are commonly used to prevent motion sickness. The dry mouth and drowsiness that also occur with a drug such as dimenhydrinate are typical antimuscarinic effects.

Parasympatholytic (antimuscarinic) effects

If the basic effects of the parasympathetic system are known, the effects of an antagonist such as atropine can be deduced. For example, if parasympathetic (vagal) stimulation slows the heart rate, parasympatholytic should increase the heart rate by blocking that innervation. Box 5-1 lists the effects and uses of parasympatholytic agents.

Adrenergic neurotransmitter function

In the sympathetic branch of the autonomic nervous system, the usual neurotransmitter at the terminal nerve sites is norepinephrine, with the exceptions described previously (sweat glands and adrenal medulla). Figure 5-5 illustrates neurotransmitter function with norepinephrine. In the presynaptic neuron, tyrosine is converted to dopa and then to dopamine, which is converted by dopamine β-hydroxylase to norepinephrine, in the storage vesicles. An action potential in the nerve opens calcium channels, allowing an influx of calcium. Increased intracellular calcium leads to exocytosis of the vesicles containing norepinephrine, which attaches to receptors on the postsynaptic membrane. The exact physiologic effect depends on the site of innervation and the type of sympathetic receptor, which can also vary, as described subsequently.

The primary method of terminating the action of norepinephrine at the postsynaptic membrane is through a reuptake process, back into the presynaptic neuron. This is termed uptake-1. The neurotransmitter action can be ended by two other mechanisms as well: uptake into tissue sites around the nerve terminal, a process termed uptake-2 to distinguish it from reuptake into the nerve terminal itself, and diffusion of excess norepinephrine away from the receptor site, to be metabolized in the liver or plasma. In addition, norepinephrine can stimulate autoreceptors on the presynaptic neuron, which inhibits further neurotransmitter release. These autoreceptors have been identified as α₂-receptors (discussed later).

The distinction between two types of uptake processes is due to research published by Iversen in 1965.¹ The uptake-2 process is a mediated uptake of exogenous amines (chemicals such as norepinephrine) in nonneuronal tissues, such as cardiac muscle cells. Iversen and Salt² distinguished details of the uptake-2 process:

The last effect of uptake-2 inhibition by corticosteroids is discussed more fully in Chapter 11. Table 5-4 lists the physiologic effects of sympathetic activation. The effects listed in Table 5-4 are given for the same organs as listed in Table 5-1 for the parasympathetic system for comparison.

Enzyme inactivation

The enzymes that metabolize norepinephrine, epinephrine, and chemicals similar to these neurotransmitters are important for understanding differences in the action of the adrenergic bronchodilator group. Chemicals structurally related to epinephrine are termed catecholamines, and their general structure is outlined in Chapter 6 in the discussion of sympathomimetic (adrenergic) bronchodilators. Two enzymes are available that can inactivate catecholamines such as epinephrine: catechol O-methyltransferase (COMT) and monoamine oxidase (MAO). The action of both enzymes on epinephrine (Figure 5-6) is important because COMT is responsible for ending the action of catecholamine bronchodilators.

Sympathetic (adrenergic) receptor types

The effects of adrenergic receptors are mediated by coupling with G proteins, and they are identified as G protein–linked receptors. Adrenergic receptor subtypes, with examples of their location and the type of G protein with which they are coupled, are summarized in Table 5-5.

α and β receptors

! KEY POINT

Receptors at sympathetic end sites are subdivided into α and β receptors, with α receptors mediating excitatory effects (e.g., vasoconstriction) and β receptors mediating inhibitory effects (e.g., smooth muscle relaxation).

In 1948, Ahlquist³ distinguished alpha (α) and beta (β) sympathetic receptors on the basis of differing responses to various adrenergic drugs, all of which were similar to norepinephrine with minor structural differences. These drugs included phenylephrine, norepinephrine, epinephrine, and isoproterenol. The two types of sympathetic receptors were distinguished as follows:

• α receptors: Generally excite, with the exception of the intestine and CNS receptors, where inhibition or relaxation occurs

• β receptors: Generally inhibit or relax, with the exception of the heart, where stimulation occurs

α-sympathetic receptors are found on peripheral blood vessels, and stimulation results in vasoconstriction. α-adrenergic agonists are frequently used for topical vasoconstriction of the nasal mucosa, to treat symptoms of nasal congestion caused by the common cold. β-adrenergic receptors are found on airway smooth muscle and in the heart. Drug activity of adrenergic stimulants (sympathomimetics) ranges along the spectrum seen in Figure 5-7.

As illustrated in Figure 5-7, phenylephrine is one of the purest α stimulants, and isoproterenol is an almost pure β stimulant. “Pure” reactions do not occur with any drug—that is, even phenylephrine may affect other sites. Epinephrine stimulates α and β sites equally, but norepinephrine has more of an α than β effect.

α₁ and α₂ receptors

! KEY POINT

α receptors are subdivided into α₁ receptors, which are excitatory, and α₂ receptors, which are inhibitory and are found on the presynaptic neuron to inhibit further neurotransmitter release.

α receptors have also been differentiated into α₁ and α₂ receptors. This classification has been made on a morphologic basis (location of the receptors) and a pharmacologic basis (differences in response to various drugs). The pharmacologic differentiation of α₁ and α₂ receptors is similar to the distinction between α and β receptors (Figure 5-8). This differentiation is based on a response continuum ranging from excitation (α₁) to inhibition (α₂) as different drugs are administered. For example, phenylephrine causes vasoconstriction, as previously mentioned, whereas clonidine (Catapres) causes a lowering of blood pressure and sympathetic activity. Both agents are considered to be α-receptor agonists. Other agents such as prazosin (Minipress) or labetalol (Normodyne) cause a lowering of blood pressure, but yohimbine causes an increase in blood pressure. Yet all these agents are considered α-receptor antagonists. Blockade of α₁-excitatory receptors by prazosin would prevent vasoconstriction and decrease blood pressure, whereas blockade of α₂-inhibitory receptors by yohimbine would prevent vasodilation and increase blood pressure.

Because different α agonists can cause opposite effects, and different α blockers do the same, α receptors were subdivided into the two types described. The location-based, or morphologic, differentiation of α₁ and α₂ receptors is more complex. In peripheral nerves, α₁ receptors are located on postsynaptic sites such as vascular smooth muscle, and α₂ receptors are presynaptic (Figure 5-9). Stimulation of these peripheral α₁ receptors causes excitation and vasoconstriction; activation of peripheral (presynaptic) α₂ receptors causes inhibition of further neurotransmitter release. Peripheral α₂ receptors perform a negative feedback control mechanism, referred to as autoregulation, which has been shown with sympathetic (adrenergic) neurons; they are referred to as autoreceptors (see Figure 5-5).⁵ Norepinephrine released from the nerve ending can activate α₁ (postsynaptic) and α₂ (presynaptic) receptors. Postsynaptic stimulation causes a cell response such as vasoconstriction, but presynaptic stimulation leads to inhibition of further neurotransmitter release. In the CNS, α₂ receptors are generally considered to be on postsynaptic sites; this is the reverse of their location peripherally, where they are presynaptic. These central postsynaptic α₂ receptors are the site of action for antihypertensive agents such as clonidine (Catapres) or methyldopa (Aldomet). These are discussed further and illustrated in Chapter 22.

To summarize, α₁ and β₁ receptors excite, and α₂ and β₂ receptors inhibit. This consistency of subscripts for (1) excitation versus (2) inhibition aids in remembering their effects.

Sympathetic innervation and effects

The sympathetic nervous system exerts its effects by direct and indirect means, as outlined in previous sections. Direct effects refer to direct innervation of tissue sites by nerve fibers. Indirect effects are mediated by the release of circulating catecholamines epinephrine and norepinephrine.

Sympathetic nerve fibers form ganglionic synapses outside the lung. Postganglionic sympathetic nerve fibers from the cervical and upper thoracic ganglia form plexuses at the hilar region of the lung and enter the lung mingled with parasympathetic nerves. Histochemical and ultrastructural studies show a relatively high density of sympathetic nerve fibers to submucosal glands and bronchial arteries but few or no nerve fibers to airway smooth muscle in human lung.⁷ Figure 5-10 illustrates sympathetic innervation and effects mediated directly by nerve action and indirectly by circulating epinephrine in the human lung.

Parasympathetic innervation and effects

The lung is supplied by vagus nerves, with the recurrent laryngeal nerve (part of the thoracic vagus) innervating the trachea; other branches of the vagus enter the lung at the hilum and innervate the intrapulmonary airways. In the trachea and remaining airways, parasympathetic nerves supply airway smooth muscle and glands. The vagus nerves in the lung release Ach and are termed cholinergic. Ach couples with muscarinic Ach receptors on airway smooth muscle to cause bronchoconstriction and on submucosal glands to stimulate secretion. The action of Ach is limited by the enzyme acetylcholinesterase, or cholinesterase, which breaks down Ach.

Cholinergic nerve fibers in the lung are densest in the hilar region and decrease toward the airway periphery. Cholinergic muscarinic receptors also decrease in density in distal airways. Electrical stimulation of vagus nerves in dog studies caused more contraction in the intermediate bronchi than in the main bronchi or trachea.¹⁵

Muscarinic receptors in the airway

The genes for five subtypes of Ach, or muscarinic, receptors have been identified, designated M₁ through M₅. Only four of these subtypes, M₁ to M₄, have been identified by chemical (ligand)-binding studies pharmacologically. Three of these muscarinic receptor subtypes have been identified in human lung: M₁, M₂, and M₃. Their location is illustrated in Figure 5-11, and the function of each is discussed.

M₁ receptors.

M₁ receptors are present at the parasympathetic ganglion, on the postjunctional membrane. Usually, Ach ganglionic receptors are nicotinic, as described previously. However, the M₁ receptor may facilitate nicotinic receptor activity and nerve transmission, with an overall excitatory effect.

M₂ receptors.

M₂ receptors are localized to the presynaptic membrane of postganglionic parasympathetic nerve endings. These receptors are thought to be autoregulatory receptors whose stimulation by Ach inhibits further Ach release from the nerve ending, thereby limiting the cholinergic stimulation. This is analogous to the α₂ receptor inhibiting further release of norepinephrine from sympathetic nerve endings, identifying it as an autoreceptor as discussed previously (see section on Cholinergic Neurotransmitter Function). Stimulation of prejunctional M₂ receptors in human airways in vitro results in strong inhibition of cholinergic parasympathetic-induced bronchoconstriction. Pilocarpine, a direct-acting cholinergic agonist (parasympathomimetic), is a selective stimulant of M₂ receptors.¹⁶ Inhalation of pilocarpine blocks cholinergic reflex bronchoconstriction caused by sulfur dioxide in nonasthmatic human subjects, verifying that M₂ receptor stimulation can block cholinergic bronchoconstriction.¹⁷

In asthmatic subjects, pilocarpine does not inhibit bronchoconstriction. This suggests the possibility of M₂ receptor dysfunction in asthma, resulting in increased cholinergic bronchoconstriction. If M₂ receptors fail to provide their normal inhibition of Ach release and bronchial contraction, this may explain why blockade of β receptors can cause such severe bronchoconstriction in asthmatics. The normal balance of Ach inhibition by M₂ receptors is lacking, and β blockade by drugs such as propranolol leaves Ach stimulation of airway smooth muscle unchecked.

M₃ receptors.

M₃ receptors are present on submucosal glands and airway smooth muscle and possibly on surface goblet cells. Stimulation of M₃ receptors causes bronchoconstriction of smooth muscle and exocytosis and glandular secretion from submucosal mucous glands. M₃ receptors may also be present on airway epithelial cells, to increase ciliary beat. Antagonism of M₃ receptors is the basis for a class of bronchodilator agents, the anticholinergic bronchodilators (see Chapter 7).

Nonadrenergic, noncholinergic inhibitory nerves

There is evidence of a branch of nerves that are neither parasympathetic (cholinergic) nor sympathetic (adrenergic), which can cause relaxation of airway smooth muscle. These nerves have been termed nonadrenergic, noncholinergic (NANC) inhibitory nerves.²⁰ They are also referred to as simply nonadrenergic inhibitory nerves because adrenergic activity relaxes airway smooth muscle, and this is an additional but nonadrenergic neural method of relaxing such smooth muscle. Evidence of NANC inhibitory nerves is based on the following type of experimentation. When parasympathetic (cholinergic) receptors are blocked with an antagonist, such as atropine, and sympathetic (adrenergic) receptors are also blocked with a β blocker, such as propranolol, electrical field stimulation of the lung produces relaxation of bronchial smooth muscle. Katzung²¹ provides a more detailed description and evidence of this methodology. Figure 5-12 illustrates this inhibitory system that is neither adrenergic nor cholinergic and its possible neurotransmitter substances. A nonadrenergic inhibitory nervous system found in the gastrointestinal tract is primarily responsible for the relaxation of peristalsis and the internal anal sphincter. In the gastrointestinal tract, this system develops in conjunction with the parasympathetic branch. Embryologically, the gastrointestinal and respiratory tracts share a common origin, and the separation of the trachea and gut occurs around the 4th or 5th week of gestation. This common origin adds plausibility to the presence of a nonadrenergic inhibitory system in the lungs similar to that in the gastrointestinal tract.

The exact neurotransmitter responsible for relaxation responses mediated by NANC inhibitory nerves is under investigation; however, the neurotransmitter vasoactive intestinal peptide (VIP) is the current front-runner.²² VIP can relax mammalian airway smooth muscle. Another possible neurotransmitter causing airway smooth muscle relaxation is NO. The enzyme responsible for NO synthesis, nitric oxide synthase (NOS), has been found in nerve terminals around airway smooth muscle, and NO produces effects similar to those caused by NANC inhibitory nerve activation. Ricciardolo²³ believed that NANC inhibition is mediated by NO, with the help of VIP. An NANC inhibitory neurotransmitter substance has not as yet been definitively identified.

Nonadrenergic, noncholinergic excitatory nerves

The existence of nonadrenergic, noncholinergic excitatory nervous control of airway smooth muscle has also been shown using electrical field stimulation (EFS) techniques. This system is also referred to as simply noncholinergic excitatory nervous control because cholinergic activity contracts airway smooth muscle, and this is an additional but noncholinergic neural method of exciting and constricting such smooth muscle. Stimulation of NANC excitatory nerves causes bronchial contraction. Sensory afferent nerves termed C-fibers are present in the airways and around bronchial blood vessels and submucosal glands and within the airway epithelium. These afferent fibers follow vagal nerve tracts into the CNS, as shown in Figure 5-13.

Sensory C-fiber nerves contain substance P, which is a tachykinin (a family of small peptide mediators). Substance P is also referred to as a neuropeptide. Sensory C-fibers can be stimulated by noxious substances such as capsaicin, found in chili peppers. When stimulated, C-fibers conduct impulses to the CNS that result in reflexes of cough and parasympathetically induced bronchoconstriction. Sensory C-fibers also release their neuropeptides, such as substance P, at the local site of the nerve fiber. Substance P and other tachykinins cause bronchoconstriction in the airways and vasodilation, increased vascular permeability, mucous gland secretion, and enhanced mucociliary activity. The NANC excitatory C-fiber system has been considered as a possible cause of the hyperreactive airway seen in asthma. The presence of C-fibers is less marked in human airways than in rodent species.