Bernhard Meier, MD

• Professor of Medicine
• Chairman, Department of Cardiology
• University Hospital Bern
• Bern, Switzerland

More than 100 substances have been identified as potential neurotransmitters because they have met some (hence the "potential" qualifier) or all of these criteria erectile dysfunction drugs and melanoma purchase levitra super active 40mg visa. These substances can be subdivided into three major categories: small-molecule transmitters beer causes erectile dysfunction buy levitra super active with paypal, peptides impotence at 70 cheap generic levitra super active canada, and gaseous transmitters erectile dysfunction in 20s order 40mg levitra super active mastercard. The small-molecule neurotransmitters may be further subdivided into acetylcholine erectile dysfunction treatment garlic 40 mg levitra super active free shipping, amino acids erectile dysfunction early age buy levitra super active australia, biogenic amines, and purines. The first three groups of small-molecule transmitters contain what are considered the classic neurotransmitters. Remaining transmitters are substances that are more recent additions to the list of neurotransmitters, although many of them have been known as biologically important molecules in other contexts for a long time. Small-Molecule Neurotransmitters Acetylcholine In the peripheral nervous system, acetylcholine is the transmitter at neuromuscular junctions, at sympathetic and parasympathetic ganglia, and of the postganglionic fibers from all parasympathetic ganglia and a few sympathetic ganglia. After release, the action of acetylcholine is terminated by the enzyme acetylcholinesterase, which is highly concentrated in the synaptic cleft. The choline is then taken up by an Na+ symporter in the presynaptic membrane for the resynthesis of acetylcholine. The extracellular enzymatic degradation of acetylcholine is unusual for a neurotransmitter inasmuch as the synaptic action of other classic neurotransmitters is terminated via reuptake by a series of specialized transporter proteins. When applied to cells, it causes depolarization and is released from neurons, and specific receptors and transporters for it have been identified. In addition to being the main excitatory neurotransmitter, glutamate is a potent neurotoxin at high concentrations. The most notable are the spiny neurons of the striatum and the Purkinje cells of the cerebellar cortex. The inhibitory nature of Purkinje cells was especially surprising because they represent the entire output of the cerebellar cortex, and thus cerebellar cortical activity basically functions to suppress the activity of its downstream targets (cerebellar and vestibular nuclei). Glycine functions as an inhibitory neurotransmitter in a much more restricted territory. Glycinergic synapses are predominantly found in the spinal cord, where they represent approximately half of the inhibitory synapses. They are likewise present in the lower brainstem, cerebellum, and retina in significant numbers. Transport of the neurotransmitter into the cell is accomplished by symport with two Na+ and one Cl- ion. In contrast, GlyT2 is located on glycinergic nerve terminals and is largely restricted to the spinal cord, brainstem, and cerebellum. In noradrenergic neurons, another enzyme, dopamine -hydroxylase, converts dopamine to norepinephrine. Epinephrine is obtained by adding a methyl group to norepinephrine via phenylethanolamineN-methyl transferase. In serotoninergic neurons, serotonin is synthesized from the essential amino acid tryptophan. Tryptophan is first converted to 5-hydroxytryptophan by tryptophan 5-hydroxylase, which is then converted to serotonin by aromatic L-amino acid decarboxylase. Finally, in histaminergic neurons the conversion of histidine to histamine is catalyzed by histidine decarboxylase. The catecholamines are then degraded by two enzymes, monoamine oxidase and catechol Omethyltransferase. Biogenic Amines Many of the neurotransmitters in this category may be familiar because they have roles outside the nervous system, often as hormones. Noradrenergic neurons are primarily found in the locus coeruleus and nucleus subcoeruleus, which are located near each other in the dorsal part of the rostral pons. Targets of the nucleus subcoeruleus are more limited but still widespread and include the pons, medulla, and spinal cord. Similar to the noradrenergic fibers, serotoninergic fibers are distributed throughout most of the brain and spinal cord. Dopaminergic fibers arise from two main brainstem regions: the substantia nigra pars compacta, which projects to the striatum, and the ventral tegmental area, which projects more widely to the neocortex and subcortical areas, including the nucleus accumbens. Finally, adrenergic neurons are relatively few in number when compared with the other biogenic amine transmitters. The largest group, termed C1, has projections to the locus coeruleus and down to the thoracic and lumbar levels of the spinal cord, where they terminate in the autonomic nuclei of the intermediolateral and intermediomedial cell columns. Thus, these neurons are important for autonomic functions, particularly vasomotor ones, such as control of arterial pressure. The diffuse nature of the projection pattern of most of the amine systems is mirrored in their proposed functions. Activity in the different aminergic systems is believed to be important in setting global brain states. For example, these systems are involved in setting the level of arousal (sleep, waking), attention, and mood. Their involvement in pathways connected with the hypothalamus and other autonomic centers also indicates that they have important homeostatic functions. Peptides Peptide neurotransmitters consist of chains of between 3 and about 40 amino acids. It is now clear that many neurons that release classic neurotransmitters also release neuropeptides. As detailed later, understanding the interaction between coexisting classic and peptide transmitters has become an important area of research. In addition to being co-released with another transmitter, neuropeptides can also function as the sole or primary neurotransmitter at a synapse. In some ways neuropeptides are like the classic neurotransmitters: they are packaged into synaptic vesicles, their release is dependent on Ca++, and they bind to specific receptors on target neurons. However, there are also significant differences, ones that have led to alternative names for the intercellular communication mediated by neuropeptides, such as nonsynaptic, parasynaptic, and volume transmission. Neuropeptides are packaged into large electrondense vesicles that are scattered throughout the presynaptic terminal rather than in small electron-lucent vesicles docked at the active zone, where small-molecule transmitters are stored. For example, the separate storage of peptide and nonpeptide transmitters immediately raises the question of whether the two transmitters are co-released or differentially released in response to particular stimulation patterns. In fact, differential release of peptide and classic transmitters from the same cell has been demonstrated for several types of neurons and is probably a result of the differences in vesicle storage described earlier. In particular, the slower release and lack of rapid reuptake mean that neuropeptides can act for long durations, diffuse over a region of brain tissue, and affect all cells in that region (that have the appropriate receptors) rather than just acting at the specific synapse at which it was released. In fact, studies have shown that there is often a spatial mismatch between the presynaptic terminals that contain a particular neuropeptide and the sites of the receptors for that peptide. In sum, peptides released from a particular synapse probably affect the local neuronal population as a whole, whereas the co-released classic transmitters act in more of a point-to-point manner. Compounds that are not derived from the opium poppy but that exert direct effects by binding to opiate receptors are called opioids and form a clinically and functionally important class of neuropeptides. Operationally, opioids are defined as compounds whose effects are stereospecifically antagonized by a morphine derivative called naloxone. The three major classes of endogenous opioid peptides in mammals are enkephalins, endorphins, and dynorphins. Dynorphins and endorphins are somewhat longer peptides that contain one or the other of the enkephalin sequences at their N-terminal ends. Indeed, opioid peptides are among the most potent analgesic (pain-relieving) compounds known, and opiates are used therapeutically as powerful analgesics. Thus, low-frequency stimulation of the cell causes just the release of nonpeptide transmitter. In contrast, with higher-frequency stimulation of the presynaptic neuron, there is a more global increase in [Ca++] throughout the nerve terminal that leads to release of neuropeptide as well as neurotransmitter. When neuropeptides are co-released with other transmitters, they may act synergistically or antagonistically. The interactions, however, are not simply a one-to-one synergism or antagonism at a particular synapse because of the differing Substance P is a peptide consisting of 11 amino acids. It is present in specific neurons in the brain, in primary sensory neurons, and in plexus neurons in the wall of the gastrointestinal tract. The wall of the gastrointestinal tract is richly innervated with neurons that form networks or plexuses (see also Chapter 33). The intrinsic plexuses of the gastrointestinal tract exert primary control over its motor and secretory activities. These enteric neurons contain many of the neuropeptides, including substance P, that are found in the brain and spinal column. Substance P is involved in pain transmission and has a powerful effect on smooth muscle. Substance P is probably the transmitter used at synapses made by primary sensory neurons (their cell bodies are in the dorsal root ganglia) with spinal interneurons in the dorsal horn of the spinal column, and thus it is an example of a peptide acting as a primary transmitter at a synapse. Gas Neurotransmitters this is the newest category of neurotransmitter to be defined and stretches the usual definition of synaptic transmission even further than neuropeptides do. Gas neurotransmitters are neither packaged into synaptic vesicles nor released by exocytosis. Instead, gas neurotransmitters are highly permeant and simply diffuse from synaptic terminals to neighboring cells after synthesis, their synthesis being triggered by depolarization of the nerve terminal (the influx of Ca++ activates synthetic enzymes). Moreover, there are no specific reuptake mechanisms, nor do they undergo enzymatic destruction, so their action appears to be ended by diffusion or binding to superoxide anions or various scavenger proteins. It is thought that we now have a relatively complete catalog of the genes for these receptors. What this work has revealed is that there is a tremendous diversity of actual and potential receptor subtypes that are or could be used by the nervous system. Moreover, knowledge of the gene sequences has enabled an understanding of the relationship of different receptor proteins to each other and to other important proteins. This knowledge, combined with the results of biochemical, crystallographic, and other types of studies, has led to a much deeper understanding of the structural and functional workings of receptor proteins. In particular, various receptors can be grouped into families based on gene sequences, and members of each family share various structural and functional features. Almost all classic neurotransmitters and neuropeptides have at least one metabotropic-type receptor. Ionotropic receptors are protein complexes that both have an extracellular binding site for the transmitter and form an ion channel (pore) through the cell membrane. The receptor is made up of several protein subunits, usually three to five, each of which typically has a series of membrane-spanning domains, some of which contribute to the wall of the ion channel. Binding of the neurotransmitter alters (usually increases) the probability of the ion channel being in the open state and thus typically results in postsynaptic events that are rapid in both onset and decay, with a duration of several milliseconds. Neurotransmitter Receptors the multitude of neurotransmitters used in the nervous system provides it with a specific and flexible interneuronal communications system. These characteristics are even further enhanced by the variety of receptors for each neurotransmitter. Receptors for a particular neurotransmitter were traditionally distinguished primarily by pharmacological differences in their sensitivity to particular agonists and antagonists. For example, acetylcholine receptors were split into muscarinic and nicotinic classes, depending on whether they bind muscarine or nicotine. Though useful, this classification scheme has several limitations: some receptors fail to be activated by agonists, and it fails to disclose all the various receptor subtypes for a particular transmitter. Note the differing membrane topologies of the individual subunits of these two classes of receptors: four transmembrane domains for cys-loop receptors and three plus a pore loop for glutamate receptors. In contrast to ionotropic receptors, metabotropic receptors mediate postsynaptic phenomena that have a slow onset and that may persist from hundreds of milliseconds to minutes. Because of the various biochemical cascades they initiate, they have great potential to cause changes in the neuron beyond just generating a postsynaptic potential. Acetylcholine Receptors Acetylcholine receptors were originally classified on a pharmacological basis (being sensitive to nicotine or muscarine) into two major groups. This grouping corresponds to groupings based on structural and molecular biological studies. Nicotinic receptors are members of the ionotropic cys-loop family, and muscarinic receptors are part of the metabotropic family of receptor proteins. Being members of the cys-loop family, acetylcholine receptors are pentamers constructed from a series of subunit types called, some of which contain multiple members. Furthermore, the junctional receptors all use the 1 subunit, whereas centrally located receptors use one of the subunits between 2 and 10. As noted, the differing subunits result in receptors with differing pharmacological sensitivities and channel kinetics and selectivity. All are metabotropic receptors; however, they are coupled to different G proteins and can thus have distinct effects on the cell. Each set of G proteins is coupled to different enzymes and second messenger pathways (see Chapter 3 for details of these pathways). In addition, each of these receptors has a Cl- channel, which opens while the receptor portion is bound. Therefore, the probability of these channels opening and the average time a channel stays open are controlled by the concentration of the neurotransmitter for which the receptor is specific. Glycine receptors are pentamers and may be heteromers of and subunits (3: 2 ratio) or homomers.

Reflex stimulation of the vagus nerve by inhalation of smoke outcome erectile dysfunction without treatment purchase 40mg levitra super active with visa, dust impotence lack of sleep 40mg levitra super active free shipping, cold air erectile dysfunction aafp cheap 40mg levitra super active free shipping, or other irritants can also result in airway constriction and coughing new erectile dysfunction drugs 2012 buy cheap levitra super active 40mg line. These agents act directly on airway smooth muscle to cause constriction and an increase in airway resistance erectile dysfunction statistics australia purchase 40 mg levitra super active overnight delivery. Inhalation of methacholine erectile dysfunction causes ppt purchase generic levitra super active from india, a derivative of acetylcholine, is used to diagnose airway hyperresponsiveness, which is one of the cardinal features of certain asthma phenotypes. Although everyone is capable of responding to methacholine, airway obstruction develops in individuals with asthma at much lower concentrations of inhaled methacholine. Conductance (L/sec/cm H2O) Measurement of Expiratory Flow Measurement of expiratory flow rates and expiratory volumes is an important clinical tool for evaluating and monitoring respiratory diseases. Results from individuals with suspected lung disease are compared with results predicted from normal healthy volunteers. Predicted or normal values vary with age, sex, ethnicity, height, and to a lesser extent, weight (Table 22. Abnormalities in values indicate abnormal pulmonary function and can be used to predict abnormalities in gas exchange. These values can detect the presence of abnormal lung function long before respiratory symptoms develop, and they can be used to determine disease severity and the response to therapy. Increasing lung volume increases the caliber of the airways because it creates a positive transairway pressure. As a result, resistance to airflow decreases with increasing lung volume and increases with decreasing lung volume. Other factors that increase airway resistance include airway mucus, edema, and contraction of bronchial smooth muscle, all of which decrease the caliber of the airways. When scuba diving, gas density rises and results in an increase in airway resistance; this increase can cause problems for individuals with asthma and obstructive pulmonary disease. Breathing a low-density gas such as an oxygen-helium mixture results in a decrease in airway resistance and has been exploited in the treatment of status asthmaticus, a condition associated with increased airway resistance due to a combination of bronchospasm, airway inflammation, and hypersecretion of mucus. A ratio less than 70% suggests Neurohumoral Regulation of Airway Resistance In addition to the effects of disease, airway resistance is regulated by various neural and humoral agents. In thespirogramthat is reportedin clinical settings, exhaledvolume increases from thebottomofthetracetothetop(A). A flow-volume curve or loop is created by displaying the instantaneous flow rate during a forced maneuver as a function of the volume of gas. Expiratory flow rates are displayed above the horizontal line, and inspiratory flow rates are displayed below the horizontal line. Determinants of Maximal Flow the shape of the flow-volume loop reveals important information about normal lung physiology that can be altered by disease. Inspection of the flow-volume loop reveals that the maximum inspiratory flow is the same or slightly greater than the maximum expiratory flow. This opposes the force generated by the inspiratory muscles and reduces maximum inspiratory flow. However, airway resistance decreases with increasing lung volume as the airway caliber increases. This is known as expiratory flow limitation and can be demonstrated by asking an individual to perform three forced expiratory maneuvers with increasing effort. However, the flow rates at lower lung volumes converge; this indicates that with modest effort, maximal expiratory flow is achieved. For this reason, expiratory flow rates at lower lung volumes are said to be effort independent and flow limited because maximal flow is achieved with modest effort, and no amount of additional effort can increase the flow rate beyond this limit. In contrast, events early in the expiratory maneuver are said to be effort dependent; that is, increasing effort generates increasing flow rates. In general the first 20% of the flow in the expiratory flow-volume loop is effort dependent. Flow Limitation and the Equal Pressure Point Why is expiratory flow limited and reasonably effort independent Factors that limit expiratory flow are important because many lung diseases affect these factors and thus affect the volume and speed with which air is moved into and out of the lung. Flow limitation occurs when the airways, which are intrinsically floppy distensible tubes, become compressed. The airways become compressed when the pressure outside the airway exceeds the pressure inside the airway. The airways are shown as tapered tubes because the total or collective airway crosssectional area decreases from the alveoli to the trachea. Because there is no flow, the pressure inside the airways is zero and the pressure across the airways (Pta, transairway pressure) is +30 cm H2O [Pta = Pairway - Ppl = 0 - (-30 cm H2O)]. This positive transpulmonary and transairway pressure holds the alveoli and airways open. When an active exhalation begins and the expiratory muscles contract, pleural pressure rises to +60 cm H2O (in this example). Alveolar pressure also rises, in part because of the increase in pleural pressure (+60 cm H2O) and in part because of the elastic recoil pressure of the lung at that lung volume (which in this case is 30 cm H2O). Because alveolar pressure exceeds atmospheric pressure, gas begins to flow from the alveolus to the mouth when the glottis opens. As gas flows out of the alveoli, the transmural pressure across the airways decreases. This occurs for three reasons: (1) there is a resistive pressure drop caused by the frictional pressure loss associated with flow (expiratory airflow resistance); (2) as the cross-sectional area of the airways decreases toward the trachea, gas velocity increases and this acceleration of gas flow further decreases the pressure; and (3) as lung volume decreases, the elastic recoil pressure decreases. Thus as air moves out of the lung, the driving pressure for expiratory gas flow decreases. In addition, the mechanical tethering that holds the airways open at high lung volumes diminishes as lung volume decreases. There is a point between the alveoli and the mouth at which the pressure inside the airways equals the pressure that surrounds the airways. Airways toward the mouth but still inside the chest wall become compressed because the pressure outside is greater than the pressure inside (dynamic airway compression). As a consequence the transairway pressure now becomes negative [Pta = Paw - Ppl = 58 - (+60) = -2 cm H2O] just beyond the equal pressure point. No amount of effort will increase the flow further because the higher pleural pressure tends to collapse the airway at the equal pressure point, just as it also tends to increase the gradient for expiratory gas flow. It is also why airway resistance is greater during exhalation than during inspiration. In the absence of lung disease, the equal pressure point occurs in airways that contain cartilage, and thus they resist collapse. As lung volume decreases and as elastic recoil pressure decreases, the equal pressure point moves closer to the alveoli. Dynamic Compliance One additional measurement of dynamic lung mechanics should be mentioned, and this is the measurement of dynamic compliance. Dynamic compliance is always less than static compliance, and it increases during exercise. This is because during tidal volume breathing, a small change in alveolar surface area is insufficient to bring additional surfactant molecules to the surface, and thus the lung is less compliant. During exercise the opposite occurs; there are large changes in Inflation-deflation pressure-volume curve. Both of these respiratory activities are important for maintaining normal lung compliance. In contrast to the lung, the dynamic compliance of the chest wall is not significantly different from its static compliance. Changes in the mechanical properties of the lung or chest wall (or both) in the presence of disease result in an increase in the work of breathing. However, like other skeletal muscles they can fatigue, and respiratory failure may ensue. Respiratory muscle fatigue is the most common cause of respiratory failure, a process in which gas exchange is inadequate to meet the metabolic needs of the body. In restrictive lung diseases, such as pulmonary fibrosis, lung compliance is decreased and the pressure-volume curve is shifted to the right. With time or disease progression, these respiratory muscles can fatigue and result in respiratory failure. The work of breathing is also increased when deeper breaths are taken (an increase in tidal volume requires more elastic work to overcome) and when the respiratory rate increases (an increase in minute Ex p. Normal individuals and individuals with lung disease adopt respiratory patterns that minimize the work of breathing. For this reason, individuals with pulmonary fibrosis (increased elastic work) breathe more shallowly and rapidly, and those with obstructive lung disease (normal elastic work but increased resistive work) breathe more slowly and deeply. Individuals tend to adopt the respiratory rate at which the total workofbreathingisminimal(arrow)forthosewithoutlungdisease. Airway resistance varies with the inverse of the fourth power of the radius and is higher in turbulent than in laminar flow. Airway resistance decreases with increases in lung volume and with decreases in gas density. Pulmonary function tests (spirometry, flow-volume loop, body plethysmography) can detect abnormalities in lung function before individuals become symptomatic. Test results are compared with results obtained in normal individuals and vary with sex, ethnicity, age, and height. Restrictive lung diseases are characterized by decreases in lung volume, normal expiratory flow rates and resistance, and a marked decrease in lung compliance. The equal pressure point is the point at which the pressure inside and surrounding the airway is the same. Specifically, as lung volume and elastic recoil decrease, the equal pressure point moves toward the alveolus in normal individuals. Energy is expended during breathing to overcome the inherent mechanical properties of the lung. For individuals with increased airway resistance, work is minimized by breathing at lower frequencies. For individuals with restrictive lung diseases, work is minimized by shallow breathing at high frequencies. The dynamic compliance of the lung is always less than the static compliance and increases during exercise, sighing, and yawning. Define two types of dead space ventilation, and describe how dead space ventilation changes with tidal volume. Describe the composition of gas in ambient air, the trachea, and the alveolus, and understand how this composition changes with changes in oxygen fraction and barometric pressure. Understand the alveolar carbon dioxide equation and identify how it changes with alterations in alveolar ventilation. Compare the distribution of pulmonary blood flow to the distribution of ventilation. List and define the four categories of hypoxia and the six causes of hypoxic hypoxia. Distinguish the causes of hypoxic hypoxia on the basis of the response to 100% O2. Dead Space Ventilation: Anatomical and Physiological Anatomical Dead Space Dead space ventilation is ventilation to airways that do not participate in gas exchange. There are two types of dead space: anatomical dead space and physiological dead space. The ratio of the volume of the conducting airways (dead space) to tidal volume represents the fraction of each breath that is "wasted" in filling the conducting airways. Ventilation Ventilation is the process by which air moves in and out of the lungs. The incoming air is composed of a volume that fills the conducting airways (dead space ventilation) and a portion that fills the alveoli (alveolar ventilation). Minute (or total) ventilation (V E) is the volume of air that enters or leaves the lung per minute: Equation 23. As tidal volume increases, the fraction of the dead space ventilation decreases for the same exhaled minute ventilation. If dead space doubles, tidal volume must increase in order to maintain the same level of alveolar ventilation. The larger the tidal volume, the smaller the proportion of dead space ventilation. If the dead space increases, the individual must inspire a larger tidal volume to maintain normal levels of blood gases. This adds to the work of breathing and can contribute to respiratory muscle fatigue and respiratory failure. The composition of this gas mixture can be described in terms of either gas fractions or the corresponding partial pressure. Because ambient air is a gas, the gas laws can be applied, from which two important principles arise. The first is that when the components are viewed in terms of gas fractions (F), the sum of the individual gas fractions must equal one: Equation 23. Thus at sea level, where atmospheric pressure (also known as barometric pressure [Pb]) is 760 mm Hg, the partial pressures of the gases in air are as follows: Equation 23. This volume includes the anatomical dead space and the dead space secondary to perfused but unventilated alveoli. The physiological dead space is always at least as large as the anatomical dead space, and in the presence of disease, it may be considerably larger.

True bronchial veins are present in the region of the lung hilus erectile dysfunction specialist doctor discount levitra super active 40mg fast delivery, and blood flows into the azygos impotence losartan trusted 40mg levitra super active, hemiazygos erectile dysfunction rings generic 40mg levitra super active fast delivery, or intercostal veins before entering the right atrium erectile dysfunction in middle age levitra super active 40 mg amex. The bronchopulmonary veins are formed through a network of tributaries from the bronchial and pulmonary circulatory vessels that anastomose and form vessels with an admixture of blood from both circulatory systems erectile dysfunction pills uk buy 40mg levitra super active with visa. Blood from these anastomosed vessels returns to the left atrium through pulmonary veins erectile dysfunction drugs from india purchase levitra super active 40 mg on line. Approximately two thirds of the total bronchial circulation is returned to the heart via the pulmonary veins and this anastomosis route. The bronchial circulation receives only approximately 1% of total cardiac output; in comparison, the pulmonary circulation receives almost 100%. In the presence of diseases such as cystic fibrosis, the bronchial arteries, which normally receive only 1% to 2% of cardiac output, increase in size (hypertrophy) and receive as much as 10% to 20% of the cardiac output. The erosion of inflamed tissue into these vessels as a result of bacterial infection is responsible for the hemoptysis (coughing up blood) that can occur in this disease. The autonomic nervous system has four distinct components: parasympathetic, sympathetic, nonadrenergic noncholinergic inhibitory, and nonadrenergic noncholinergic stimulatory. The parasympathetic innervation of the lung originates from the medulla in the brainstem (cranial nerve X, the vagus nerve). Preganglionic fibers from the vagal nuclei descend in the vagus nerve to ganglia adjacent to airways and blood vessels in the lung. Postganglionic fibers from the ganglia then complete the network by innervating smooth muscle cells, blood vessels, and bronchial epithelial cells (including goblet cells and submucosal glands). In the lungs, both preganglionic and postganglionic fibers Bronchial Circulation the bronchial circulation is a distinct system, separate from the pulmonary circulation in the lung, that provides systemic arterial blood to the trachea, upper airways, surface secretory cells, glands, nerves, visceral pleural surfaces, lymph nodes, pulmonary arteries, and pulmonary veins. Acetylcholine and substance P are neurotransmitters of excitatory motor neurons; dynorphin and vasoactive intestinal peptide are neurotransmitters of inhibitory motor neurons. Parasympathetic stimulation through the vagus nerve is responsible for the slightly constricted smooth muscle tone in a normal resting lung. Parasympathetic fibers also innervate the bronchial glands, and these fibers, when stimulated, increase the synthesis of mucus glycoprotein, which increases the viscosity of mucus. Parasympathetic innervation is greatest in the larger airways and most limited in the smaller conducting airways in the periphery. Whereas the response of the parasympathetic nervous system is very specific and local, the response of the sympathetic nervous system tends to be more general. Mucous glands and blood vessels are heavily innervated by the sympathetic nervous system; however, airway smooth muscle is not. Neurotransmitters of the adrenergic nerves include norepinephrine and dopamine, although dopamine has no influence on the lung. This disrupts the balanced response of increased water and increased viscosity between the sympathetic and parasympathetic pathways. In addition to those in the sympathetic and parasympathetic systems, afferent nerve endings are present in the epithelium and in smooth muscle cells in the lung. Central Control of Respiration Breathing is an automatic, rhythmic, and centrally regulated process with voluntary control. Regulation of respiration requires (1) generation and maintenance of a respiratory rhythm; (2) modulation of this rhythm by sensory feedback loops and reflexes that allow adaptation to various conditions while minimizing energy costs; and (3) recruitment of respiratory muscles that can contract appropriately for gas exchange. Muscles of Respiration the major muscles of respiration include the diaphragm, the external intercostal muscles, and the scalene muscles, all of which are skeletal muscles. Skeletal muscles provide the driving force for ventilation; the force of contraction increases when they are stretched and decreases when they are shortened. This increases the vertical dimension of the chest cavity and creates a pressure difference between the thorax and abdomen. In adults, the diaphragm can generate airway pressures of up to 150 to 200 cm H2O during maximal inspiratory effort. During quiet breathing (tidal breathing), the diaphragm moves approximately 1 cm; however, during deep-breathing maneuvers (vital capacity), the diaphragm can move as much as 10 cm. The diaphragm is innervated by the right and left phrenic nerves, whose origins are at the third to fifth cervical segments of the spinal cord (C3 to C5). This causes an increase in both the lateral and anteroposterior diameters of the thorax. Innervation of the external intercostal muscles originates from intercostal nerves that arise from the same level of the spinal cord (T1 and T2). Paralysis of these muscles has no significant effect on respiration because respiration is dependent primarily on the diaphragm. This is why individuals with injuries to the lower spinal cord can breathe on their own; it is only when the injury is above C3 that an individual is completely dependent on a ventilator. Accessory muscles of inspiration (the scalene muscles, which elevate the sternocleidomastoid muscles; the alae nasi, which cause nasal flaring; and small muscles in the neck and head) do not contract during normal breathing. However, they do contract vigorously during exercise, and when airway obstruction is significant, they actively pull up the rib cage. Because the upper airway must remain patent during inspiration, the pharyngeal wall muscles (genioglossus and arytenoid) are also considered muscles of inspiration. All the rib cage muscles are voluntary muscles that are supplied by intercostal arteries and veins and innervated by motor and sensory intercostal nerves. Exhalation during normal breathing is passive, but it becomes active during exercise and hyperventilation. The most important muscles of exhalation are those of the abdominal wall (rectus abdominis, internal and external oblique, and transversus abdominis) and the internal intercostal muscles, which oppose the external intercostal muscles. During normal breathing, this workload is low, and the inspiratory muscles have significant reserve. Respiratory muscles can be trained to do more work, but there is a limit to the work that they can perform. Respiratory muscle weakness can impair movement of the chest wall, and respiratory muscle fatigue is a major factor in the development of respiratory failure. Lung Embryology, Development, Aging, and Repair the epithelium of the lung arises as a pouch from the primitive foregut at approximately 22 to 26 days after fertilization of the ovum. Over the next 2 to 3 weeks, further branching occurs to create the irregular dichotomous branching pattern. Thus intrauterine events that occur before 16 weeks of gestation will affect the number of airways. A condition known as congenital diaphragmatic hernia is an example of a congenital lung disease. Growth of the lungs is similar and relatively proportional to growth in body length and stature. Although the growth rate of the lung slows after adolescence, the body and lung increase in size steadily until adulthood. Improvement in lung function occurs at all stages of growth development; however, once optimal size has been attained in early adulthood (20 to 25 years of age), lung function starts to decline with age. The decrease in lung function with age, estimated at less than 1% per year, appears to begin earlier and proceed faster in individuals who smoke or are exposed to toxic environmental factors. The major physiological insufficiencies caused by aging involve ventilatory capacity and responses, especially during exercise, and they result in abnormal ventilation with normal perfusion. In addition, gas diffusion decreases with age, probably as a result of a decrease in alveolar surface area. Age-related decreases in lung function and altered structure parallel biochemical observations of increased levels of elastin within the lung, which could explain some of the functional abnormalities. The lungs demonstrate anatomical and physiological unity; that is, each unit (bronchopulmonary segment) is structurally identical and functions just like every other unit. The upper airways (nose, sinuses, pharynx) condition inspired air for temperature, humidity, and atmospheric pressure, and they control, via the epiglottis, the flow of air into the lungs and food/fluids into the esophagus. Components of the lower airways (trachea, bronchi, bronchioles) are considered conducting airways in which air is transported to the gas-exchanging respiratory units composed of respiratory bronchioles, alveolar ducts, and alveoli. The pulmonary circulatory system has the ability to accommodate large volumes of blood at low pressure and brings deoxygenated blood from the right ventricle to the gas-exchanging units in the lung. The bronchial circulation arises from the aorta and provides nourishment (O2) to the lung parenchyma. Parasympathetic stimulation results in constriction of airway smooth muscles (airway narrowing) whereas sympathetic stimulation results in relaxation of airway smooth muscles (airway opening). The diaphragm is the major muscle of respiration, and its contraction creates a pressure difference (mechanoreceptor response) between the thorax and diaphragm (negative pressure in the chest), which induces inspiration. The respiratory center is located in the medulla and regulates respiration with input from sensory (mechanoreceptor and chemoreceptor) feedback loops. Molecular and physiological determinants of pulmonary developmental biology: a review. Lung inflammation and fibrosis: an alveolar macrophage-centered perspective from the 1970s to 1980s. Explain how surfactant affects lung compliance, and describe its importance in maintaining unequal alveolar volumes. Thus a negative pressure in the pleural space is a pressure that is lower than atmospheric pressure. Also in accordance with convention, pressures across surfaces such as the lungs or chest wall have been defined as the difference between the pressure inside and the pressure outside the surface. The pressure differences across the lung and across the chest wall are defined as the transmural (across a wall or surface) pressures. The mechanical properties of the lung and chest wall determine the ease or difficulty of this air movement. Lung mechanics is the study of the mechanical properties of the lung and chest wall (including the diaphragm, abdominal cavity, and anterior abdominal muscles). Lung mechanics is important for how the lungs work both normally and in the presence of disease, inasmuch as most lung diseases affect the mechanical properties of the lungs, chest wall, or both. In addition, death from lung disease is almost always due to respiratory muscle fatigue, which results from an inability of the respiratory muscles to overcome the altered mechanical properties of the lungs, chest wall, or both. Lung mechanics includes static mechanics (the mechanical properties of a lung whose volume is not changing with time) and dynamic mechanics (properties of a lung whose volume is changing with time). How a Pressure Gradient Is Created Air flows into and out of the lungs from areas of higher pres sure to areas of lower pressure. Before inspiration begins, the pleural pressure in normal individuals is approximately -3 to -5 cm H2O. Therefore, the pressure in the pleural space is negative in 447 Pressures in the Respiratory System In healthy people, the lungs and chest wall move together as a unit. Between these structures is the pleural space, which under normal conditions is best thought of as a potential (or virtual) space. Because the lungs and chest wall move together, changes in their respective volumes are equal during inspiration and exhalation. Volume changes in the lungs and chest wall are driven by changes in the surrounding pressure. This negative pressure is created by the inward elastic recoil pressure of the lung, and it acts to "pull the lung" away from the chest wall. The lung is not able, however, to pull away from the chest wall, inasmuch as the two function as a unit. Thus the inward elastic recoil pressure of the lung is balanced by the outward recoil of the chest wall. With the onset of inspiration, the muscles of the dia phragm and chest wall contract, which causes a downward movement of the diaphragm and an outward and upward movement of the rib cage. This negative pleural pressure is transmitted across the lung tissue and results in a decrease in alveolar pressure. As gas flows into the airways to the alveoli, the pressure gradient along the airways decreases, and flow stops when there is no longer a pressure gradient from atmospheric to alveolar pressure. The decrease in pleural pressure at the start of inspiration secondary to inspiratory muscle contraction is greater than the transmitted fall in alveolar pressure, and, as a result, transpulmonary pressure at the start of inspiration is positive (see Eq. Because pleural pressure is negative in relation to atmospheric pressure during quiet breathing, the transmural pressure across the chest wall is negative (see Eq. On exhalation, the diaphragm moves higher into the chest, pleural pressure increases. In the alveoli, the driving force for exhalation is the sum of the elastic recoil of the lungs and pleural pressure (see Chapter 22). During tidal volume breathing in normal individuals, the decrease in alveolar pressure at the start of inspiration is small (1 to 3 cm H2O). It is much larger in individuals with airway obstruction because of the larger pressure drop that occurs across obstructed airways. Airflow stops in the absence of a pressure gradient, which occurs whenever alveolar pressure and atmospheric pressure are equal. Positive(inrelationtoatmospheric)pressuresarerepresentedabove the horizontal dotted line, and negative pressures are represented belowit. The patient then inhales maximally and exhales forcefully and completely, and the volume of exhaled air is measured. Both methods are used clinically and provide valuable information about lung function and lung disease. The helium dilution technique is the older and simpler method, but it is often less accurate than body plethysmography, which requires sophisticated and expensive equipment. C1, known concentration of an inert gas; C2, new (previously unknown) concentrationofthegas;V1,knownvolumeofabox;V2,lungvolume (initiallyunknown). The answer lies in the properties of the lung paren chyma and in the interaction between the lungs and the chest wall. The lung contains elastic fibers that (1) stretch when stress is applied, which results in an increase in lung volume, and (2) recoil passively when this stress is released, which results in a decrease in lung volume. Similarly, chest wall volume can increase when the respiratory muscles are stretched and decrease when respiratory muscle length is shortened. Decreasing lung volume results in shortening of the expira tory muscles, which, in turn, results in a decrease in muscle force. The decrease in lung volume is also associated with an increase in the outward recoil pressure of the chest wall.

Any sudden erectile dysfunction 18 years old cheap levitra super active american express, excessive output by one ventricle soon causes an increase in venous return to the second ventricle bisoprolol causes erectile dysfunction buy 40 mg levitra super active fast delivery. The consequent increase in diastolic fiber length in the second ventricle augments the output of that ventricle to correspond to the output of its mate impotence injections medications order levitra super active 40mg with visa. In this way erectile dysfunction treatment supplements buy 40mg levitra super active amex, the Frank-Starling mechanism maintains a precise balance between the output of the right and left ventricles impotence at 70 purchase levitra super active american express. If the two ventricles were not arranged in series in a closed circuit erectile dysfunction no xplode generic 40 mg levitra super active fast delivery, any small but maintained imbalance in output of the two ventricles would be catastrophic. Hence, venous return to the left ventricle (a function of right ventricular output) exceeds left ventricular output, and left ventricular diastolic volume and pressure rise. Only when the output of both ventricles is identical (points A and C) is equilibrium reached. Under such conditions, however, left atrial pressure (point C) exceeds right atrial pressure (point A). Thearrows indicate the half-times of inactivation of the calcium current, as obtained from kinetic analysis. At the new steady state, the force developed is more than five times greater than the force at the larger contraction interval. A return to the larger interval (20 seconds) has the opposite influence on the development of force. The rise in the force developed when the contraction interval is decreased is caused by a gradual increase in intracellular [Ca++]. Two mechanisms contribute to the rise in intracellular [Ca++]: an increase in the number of depolarizations per minute and an increase in the inward Ca++ current per depolarization. In the first mechanism, Ca++ enters the myocardial cell during each action potential plateau (see Chapters 13 and 16). As the interval between beats is diminished, the number of plateaus per minute increases. Although the duration of each action potential (and of each plateau) decreases as the interval between beats is reduced, the overriding effect of the increased number of plateaus per minute on the influx of Ca++ prevails, and intracellular [Ca++] increases. In the second mechanism, as the interval between beats is suddenly diminished, the inward rectifying calcium current (iCa) progressively increases with each successive beat until a new steady state is attained at the new basic cycle length. Both the increased magnitude and the slowed inactivation of iCa result in greater Ca++ influx into the myocyte during the later depolarizations than during the first depolarization. Transient changes in the intervals between beats also profoundly affect the strength of contraction. In the intact circulatory system, this response depends partly on the Frank-Starling mechanism. Inadequate time for ventricular filling just before the premature beat results in the weak premature contraction. The weakness of the premature beat is directly related to its degree of prematurity: the earlier the premature beat, the weaker its force of contraction. The curve that represents strength of contraction of a premature beat in relation to the coupling interval is called a mechanical restitution curve. Extrinsic Regulation of Myocardial Performance Although a completely isolated heart can adapt well to changes in preload and afterload, various extrinsic factors also influence the heart in an individual. Often, these extrinsic regulatory mechanisms may overwhelm the intrinsic mechanisms. The extrinsic regulatory factors may be subdivided into nervous and chemical components. Nervous Control Sympathetic nervous activity enhances atrial and ventricular contractility. Note that the duration of systole is reduced and the rate of ventricular relaxation is increased during the early phases of diastole; both these effects assist ventricular filling. For any given cardiac cycle length, the abbreviated systole allows more time for diastole and hence for ventricular filling. Sympathetic nervous activity also enhances myocardial performance by altering intracellular Ca++ dynamics (see Chapter 16). Consequently, protein kinases that promote the phosphorylation of various proteins are activated within the myocardial cells. Phosphorylation of phospholamban facilitates reuptake of Ca++ by the sarcoplasmic reticulum, and phosphorylation of troponin I reduces the sensitivity of contractile proteins to Ca++. During relaxation, the Ca++ that dissociates from the contractile proteins is taken up by the sarcoplasmic reticulum for subsequent release. However, there is a lag of approximately 500 to 800 msec before this Ca++ is available for release from the sarcoplasmic reticulum in response to the next depolarization. Thus the strength of the premature beat is reduced because the time during the preceding relaxation is insufficient to allow much of the Ca++ taken up by the sarcoplasmic reticulum to become available for release during the premature beat. Phosphorylation of specific sarcolemmal proteins also activates calcium channels in the membranes of myocardial cells. Activation of calcium channels increases the influx of Ca++ during the action potential plateau, and more Ca++ is released from the sarcoplasmic reticulum in response to each cardiac excitation. The overall effect of increased cardiac sympathetic activity in intact animals can best be appreciated in terms of Before stellate ganglion stimulation 100 Left ventricular pressure (mm Hg) 75 50 25 0 + dP/dt During stellate ganglion stimulation families of ventricular function curves. When the frequency of electrical stimulation applied to the left stellate ganglion increases, the ventricular function curves shift progressively to the left. The vagus nerves also depress the ventricular myocardium, but the effects are less pronounced than in the atria. In pumping heart preparations, the ventricular function curve shifts to the right during vagal stimulation, an indication of reduced contractility. The negative inotropic effect of vagus nerve stimulation, depicted as the reduced slope of the end-systolic pressure-volume relation, is opposed by a muscarinic receptor antagonist and diminished by a -adrenoceptor antagonist. The results indicate that vagus nerve stimulation reduces contractility in the heart and does so by at least two pathways. This direct inhibition diminishes the Ca++ conductance of the cell membrane, reduces phosphorylation of the calcium channel, and hence decreases myocardial contractility. Thus vagal activity can decrease ventricular contractility partly by antagonizing any stimulatory effects that concomitant sympathetic activity may be exerting on ventricular contractility. Chemical Control the adrenal medulla is essentially a component of the autonomic nervous system (see Chapters 11 and 43). The principal hormone secreted by the adrenal medulla is epinephrine; some norepinephrine is also released. The rate of secretion of these catecholamines by the adrenal medulla is regulated by mechanisms that control the activity of the sympathetic nervous system. Concentrations of catecholamines in blood thus rise under the same conditions that activate the sympathetic nervous system. However, the cardiovascular effects of circulating catecholamines are probably minimal under normal conditions. Moreover, the pronounced changes in myocardial contractility with exercise, for example, are mediated mainly by the norepinephrine released from cardiac sympathetic nerve fibers rather than by the catecholamines released from the adrenal medulla. A,Controlpressure-volume curves were calculated during occlusion of the inferior vena cava. The end-systolic pressure-volume relation, defined by the slope of the straight line, measured approximately 4mmHg/mL. B, During stimulation of the left vagus nerve, the slope of the end-systolic pressure-volume relation decreased to approximately 3mmHg/mL, an indication that contractility had decreased. Vagus nerve stimulation decreases left ventricular contractility in vivo in the humanandpigheart. Cardiac muscle taken from adrenalectomized animals and placed in a tissue bath is more likely to fatigue in response to stimulation than is cardiac muscle obtained from normal animals. In addition, the glucocorticoid hydrocortisone potentiates the cardiotonic effects of catecholamines. This potentiation is mediated in part by the ability of adrenocortical steroids to inhibit the extraneuronal catecholamine uptake mechanisms. Thyroid hormones increase cardiac protein synthesis, and this response leads to cardiac hypertrophy. Indeed, the positive inotropic effect of insulin is potentiated by -adrenergic receptor antagonists. The enhanced contractility cannot be explained satisfactorily by the concomitant augmentation of glucose transport into myocardial cells. This endogenous hormone is probably not important in normal regulation of the cardiovascular system, but it has been used clinically to enhance cardiac performance. The effects of glucagon on the heart and certain metabolic effects are similar to those of catecholamines. The catecholamines activate adenylate cyclase by interacting with -adrenergic receptors, but glucagon activates this enzyme by a different mechanism. The cardiovascular derangements in hypopituitarism are related principally to the associated deficiencies in adrenocortical and thyroid function. In hypophysectomized animals, growth hormone alone has little effect on the depressed heart, whereas thyroxine by itself restores adequate cardiac performance under basal conditions. However, when blood volume or peripheral resistance is increased, thyroxine alone does not restore adequate cardiac function, but the combination of growth hormone and thyroxine reestablishes normal cardiac performance. In certain animal models of heart failure, administration of growth hormone alone increases cardiac output and myocardial contractility. Blood Gases Changes in cardiac performance as a result of stimulation of central and peripheral chemoreceptors have been described previously in this chapter. The consequent reduction in total peripheral resistance increases cardiac output, as explained in Chapter 19. Mild hypoxia stimulates performance, but more severe hypoxia depresses performance because oxidative metabolism is limited. Increases in intracellular pH have the opposite effect; that is, they enhance sensitivity to Ca++. Aspects of local control are discussed in Chapter 17, in which the relative importance of these two control mechanisms is shown to vary in different tissues. The arterioles are involved in regulating the rate of blood flow throughout the body. These vessels offer the greatest resistance to the flow of blood pumped to the tissues by the heart, and thus these vessels are important in the maintenance of arterial blood pressure. When this smooth muscle contracts strongly, the endothelial lining folds inward and completely obliterates the vessel lumen. When the smooth muscle is completely relaxed, the vessel lumen is maximally dilated. In addition, the smooth muscle in these vessels is partially contracted (which accounts for the tone of these vessels). If all the resistance vessels in the body dilated simultaneously, arterial blood pressure would fall precipitously. Vascular smooth muscle controls total peripheral resistance, arterial and venous tone, and the distribution of blood flow throughout the body. In the following sections, intrinsic and extrinsic control of vascular smooth muscle tone, and thus perfusion of peripheral tissues, is reviewed. Filled (red) circles represent the flow rates obtained immediately after abrupt changes in perfusion pressure from the controllevel(thepointwherelinescross). Open (blue) circlesrepresent the steady-state flow rates obtained at the new perfusion pressure. Calculation of hydraulic resistance (pressure/flow) across the vascular bed during steady-state conditions shows that the resistance vessels constrict with an elevation in perfusion pressure but dilate with a reduction in perfusion pressure. This response to perfusion pressure is independent of the endothelium because it is identical in intact vessels and in vessels that have been stripped of their endothelium. According to the myogenic mechanism, vascular smooth muscle contracts in response to an increase in the pressure difference across the wall of a blood vessel (transmural pressure), and it relaxes in response to a decrease in transmural pressure. The signaling mechanisms that allow distention of a vessel to elicit contraction are unknown. However, because stretch of vascular smooth muscle has been shown to raise intracellular [Ca++], an increase in transmural pressure is believed to activate membrane calcium channels. Intrinsic or Local Control of Peripheral Blood Flow Autoregulation and Myogenic Regulation In certain tissues, blood flow is adjusted to the existing metabolic activity of the tissue. Furthermore, when tissue metabolism is steady, changes in perfusion pressure (arterial blood pressure) evoke changes in vascular resistance that tend to maintain a constant blood flow. When pressure is abruptly increased or decreased from a control pressure of 100 mm Hg, flow increases or decreases, respectively. However, even with pressure maintained at its new level, blood flow returns toward the control level within 30 to 60 seconds. Hence, the myogenic mechanism may play little role in regulating blood flow to tissues under normal conditions. However, when a person changes from a lying to a standing position, transmural pressure rises in the lower extremities, and the precapillary vessels constrict in response to this imposed stretch. Basal Vessel Tone Endothelium-Mediated Regulation As described in Chapter 17, the endothelium lining the vasculature produces a number of substances that can relax. Thus the endothelium plays an important role in regulating blood flow to specific vascular beds. Metabolic control of vascular resistance by the release of a vasodilator substance requires the existence of a basal vessel tone. Tonic activity in vascular smooth muscle is readily demonstrable, but in contrast to tone in skeletal muscle, the tone in vascular smooth muscle is independent of the nervous system. The following factors may be involved: (1) the myogenic response to the stretch imposed by blood pressure, (2) the high partial pressure of oxygen in arterial blood (PaO2), or (3) the presence of Ca++.

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