Pediatric Annals

Autonomic Mechanisms in Asthma and Other Allergic Diseases

Richard J Summers, MD; Richard Evans, III, MD

Abstract

In recent years, recognition of a possible imbalance in the normal homeostatic mechanisms of the autonomic nervous system in the atopic disorders - allergic rhinitis, allergic asthma, and atopic dermatitis - has resulted in several exciting revelations concerning the pathophysiology of these entities. The effects of various pharmacologic agents on the clinical manifestations that result from stimulation of the sympathetic and parasympathetic nervous systems have allowed investigators to further delineate the relative importance of these two major divisions of the autonomic nervous system in producing and preventing the signs and symptoms of the immediate hypersensitivity reaction.

In fact, it is now possible to discuss the malfunction of these systems on a cellular level. The final answer concerning the exact pathogenesis of these dynamic, multifactorial disorders does require further scientific research; it is important to realize that what is widely accepted today may be completely disproved tomorrow.

The symptoms of an allergic patient are the consequence of a series of events that are first elicited by the reaction of allergen and the reaginic antibody, immunoglobulin E (IgE), on the surface of tissue mast cells and circulating basophils, with the subsequent release of chemical mediators (Figure 1). In order to understand this complex series of events, one must consider each phase of this reaction. Reception, cellular response, mediator release, and target organ stimulation are the major phenomena involved.

Ishizaka, K., and Ishizaka, T. Identification of gamma E antibodies as a carrier of reaginic activity. /. Immunol. 99 (1967), 1187.

Orange, R. P., Austen, W. G., and Austen, K. F. Immunological release of histamine and slow-reacting substance of anaphylaxis from human lung. I. Modulation by agents influencing cellular levels of cyclic 3', 5'-adenosine monophosphate. J. Exp. Med. 134, (1971), 136 S.

Comroe, J. H. Physiology of Respiration, Second Edition. Chicago: Year Book Medical Publications, 1974, Chapters 8 and 11, pp. 72, 142.

Ash, A. S. F., and Schild, H. L. Receptors mediating some actions of histamine. Br. J. Pharmacol. 27 (1966), 427.

Black, J. W., et al. Definition and antagonism of histamine H^sub 2^-receptors. Nature 236 (1972), 385.

Black, J. W. Histamine receptors. In Klinge, E., (ed). Receptors and Cellular Pharmacology. Proceedings of the Sixth International Congress of Pharmacology. Volume 1. Helsinski, Finland: Finnish Pharmacological Society, 1975.

Plaut, M., and Lichtenstein, L. M. Cellular and chemical basis of the allergic inflammatory response: component parts and control mechanisms. In Middleton, E., Jr., Reed, C. R., and Ellis, E. F., (eds.). Allergy: Principles and Practice. St. Louis: The C V. Mosby Co., 1978. pp. 119-122.

Benveniste, J. Platelet-activating factor, a new mediator of anaphylaxis and immune complex deposition from rabbit and human basophils. Nature 249 (1974), 581.

Orange, R. P. The formation of slow reacting substance of anaphylaxis human lung tissues. In Brent, L., and Holborow, ]. (eds.). Progress in Immunology ?, Volume 4. Amsterdam: NorthHolland Publishing Co., 1974.

Hedqvist, P., and Mathe, A. A. Lung function and the role of prostaglandins. In Lichtenstein, L. L., and Austen, K. F. (eds.). Asthmo: Physiology, lmmunopharmacology and Treatment. New York Academic Press, 1977, pp. 131-146.

Nakamo, )., and Rodgers, R. L. The prostaglandins: Biochemistry, physiology, and clinical pharmacology in asthma and other lung disorders. In Weiss, E. B., and Segal, M. S. (eds.). Bronchial Asthma: Mechanisms and Therapeutics. Boston: Urde, Brown & Company, 1976, pp. 191-192.

TABLE 1

SELECTED RESPONSES MEDIATED BY a- or ^-ADRENOCEPTORS

TABLE 2

SUBTYPES OF β-ADRENOCEPTORS IN MAMMALIAN TISSUES

TABLE 3

SYMPATHOMIMETIC AMINES

TABLE 4

REGULATION OF CYCLIC NUCLEOTIDE LEVELS

TABLE 5

CHEMICAL MEDIATORS OF IMMEDIATE HYPERSENSITIVITY

TABLE 6

SELECTED EFFECTS OF H1- AND H2-RECEPTOR STIMULATION

TABLE 7

SELECTED PHARMACOLOGIC ACTIONS OF PROSTAGLANDINS…

In recent years, recognition of a possible imbalance in the normal homeostatic mechanisms of the autonomic nervous system in the atopic disorders - allergic rhinitis, allergic asthma, and atopic dermatitis - has resulted in several exciting revelations concerning the pathophysiology of these entities. The effects of various pharmacologic agents on the clinical manifestations that result from stimulation of the sympathetic and parasympathetic nervous systems have allowed investigators to further delineate the relative importance of these two major divisions of the autonomic nervous system in producing and preventing the signs and symptoms of the immediate hypersensitivity reaction.

In fact, it is now possible to discuss the malfunction of these systems on a cellular level. The final answer concerning the exact pathogenesis of these dynamic, multifactorial disorders does require further scientific research; it is important to realize that what is widely accepted today may be completely disproved tomorrow.

The symptoms of an allergic patient are the consequence of a series of events that are first elicited by the reaction of allergen and the reaginic antibody, immunoglobulin E (IgE), on the surface of tissue mast cells and circulating basophils, with the subsequent release of chemical mediators (Figure 1). In order to understand this complex series of events, one must consider each phase of this reaction. Reception, cellular response, mediator release, and target organ stimulation are the major phenomena involved.

Figure 1. Immediate hypersensitivity. Specific IgE molecules are fixed by their crystallizable fragment (Fc) portions to Fc receptor sites on the mast cell membrane. Specific antibody reactivity resides in the opposite end of the IgE antibody, the antigen-binding fragment (F[Ab]2) portions. Bridging of two antibody molecules by two antigenic determinant sites of a specific antigen, as shown here, initiates a physicochemical reaction that leads to release of chemical mediators from the mast cell.

Figure 1. Immediate hypersensitivity. Specific IgE molecules are fixed by their crystallizable fragment (Fc) portions to Fc receptor sites on the mast cell membrane. Specific antibody reactivity resides in the opposite end of the IgE antibody, the antigen-binding fragment (F[Ab]2) portions. Bridging of two antibody molecules by two antigenic determinant sites of a specific antigen, as shown here, initiates a physicochemical reaction that leads to release of chemical mediators from the mast cell.

IMMUNOLOGIC AND PHARMACOLOGIC RECEPTORS

The concept of receptors is used here to describe the interaction of the cell surface with its environment. Immunologic and pharmacologic receptors are important in asthma and other allergic diseases.

Immunologic receptors on the surface of mediator-containing mast cells and basophils specifically bind IgE. This binding capacity is characteristic of IgE. Even though this new class of immunoglobulin was discovered only recently, the ability of allergic sera to passively bind to human tissue has been recognized for more than 50 years.

Immunoglobulin E is synthesized by plasma cells in germinal centers of the gastrointestinal and respiratory mucosa. It is present in small amounts (nanograms/ml.) in the serum and has a very strong binding affinity for tissue mast cells and circulating basophils. There are between 100,000 and 500,000 receptors for IgE on the surface of human basophils. Binding of two molecules of IgE with a specific allergen will initiate a series of reactions, including, apparently, activation of a proesterase enzyme, calcium-ion influx into the cell, and an energy-dependent stage involving glycolysis. This leads to the release of potent chemical mediators such as histamine and slow-reacting substance of anaphylaxis (SRS-A), which will be discussed in more detail below.

Table

TABLE 1SELECTED RESPONSES MEDIATED BY a- or ^-ADRENOCEPTORS

TABLE 1

SELECTED RESPONSES MEDIATED BY a- or ^-ADRENOCEPTORS

The subsequent generation and release of chemical mediators can be modulated by stimulation of pharmacologic receptors on the cell surface. These include a- and ßadrenergic receptors, cholinergic receptors, and prostaglandin receptors. These receptors appear to regulate the release of mediators by influencing the intracellular level of the cyclic nucleotides, cyclic adenosine monophosphate (c-AMP), and cyclic guanosine monophosphate (c-GMP), (Figure 2).

The physiologic activity of adrenergic and cholinergic receptors is not limited to the IgE-dependent reaction culminating in mediator release. The receptors are also present throughout different organ systems. Selected α- and β1-adrenergic responses found in respiratory smooth muscle and the circulatory system are shown in Table 1. The balancing effect of β1 and β2-adrenergic receptors can modulate smooth-muscle tone. β-adrenergic receptors may be subtyped in mammalian tissues to β1- and β2-receptor responses. Examples of these subtypes are seen in Table 2. Note that β2 receptor stimulation results in relaxation of respiratory smooth muscle and β1 receptor activation influences cardiac rate and contraction.

A large number of sympathomimetic amines are capable of stimulating adrenergic receptors. Table 3 illustrates the relative activity of many of these agents and their approximate duration of effect.

It should be noted that isoetharine, metaproterenol, and terbutaline are more selective β2 stimulants. Generally, the selective β2 stimulants can be clinically used by inhalation with fewer side effects as bronchodilators than isoproterenol. They are also better tolerated orally than ephedrine. Furthermore, these agents appear to be safer because of less cardiac stimulation. Tachyphylaxis* is not generally found with the selective β2 agents, and these medications are sufficiently resistant to intestinal and liver enzymes to be active after oral administration.

Stimulation of cholinergic receptors is also important in the homeostasis of respiratory smooth-muscle tone. Acetylcholine is released as a result of stimulation of stretch, irritant, or temperature-sensitive receptors, which are more easily activated in allergic persons. Acetylcholine and other cholinomimetic agents act mainly on the primary cholinergic receptor at the parasympathetic neuroeffector junction. As mentioned, these agents also enhance antigen-induced mediator release by increasing intracellular c-GMP. This parasympathetic system, which has its effector limb in the vagus nerve, has overwhelming control of the pulmonary airways. The bronchoconstricting action of acetylcholine is blocked by atropine and a new investigative agent, SCH-1000.

Figure 2. Pharmacologic control of immunologic mediator release. Stimulatbn of β-adrenergic receptors on mast cell elicits an increase in the level of cyclic AMP within the cell, and this is associated with a decrease in the release of chemical mediators. A decrease in tissue level of cyclic AMP, induced by a adrenergic receptor stimulatbn, is accompanied by an increase m release of mediators. Prostaglandins can bring about either an increase or a decrease of cyclic AMP, depending on which agent is given, with a resultant inverse effect in each case on mediator release. Stimulation of the cholinergic receptor is associated with an increase in cyclic GMP, resulting in increased mediator release.

Figure 2. Pharmacologic control of immunologic mediator release. Stimulatbn of β-adrenergic receptors on mast cell elicits an increase in the level of cyclic AMP within the cell, and this is associated with a decrease in the release of chemical mediators. A decrease in tissue level of cyclic AMP, induced by a adrenergic receptor stimulatbn, is accompanied by an increase m release of mediators. Prostaglandins can bring about either an increase or a decrease of cyclic AMP, depending on which agent is given, with a resultant inverse effect in each case on mediator release. Stimulation of the cholinergic receptor is associated with an increase in cyclic GMP, resulting in increased mediator release.

Table

TABLE 2SUBTYPES OF β-ADRENOCEPTORS IN MAMMALIAN TISSUES

TABLE 2

SUBTYPES OF β-ADRENOCEPTORS IN MAMMALIAN TISSUES

Thus, it is evident that selective stimulation of the above receptors has contributed a large volume of knowledge toward our understanding of asthma and allergic disorders. This knowledge provides an excellent foundation for further research in this area.

CELLULAR RESPONSE

The cyclic nucleotides - cyclic 3′,5′-adenosine monophosphate (c-AMP) and cyclic 3',5'-guanosine monophosphate (c-GMP) - are the "second messengers," which modulate the cellular response after receptor stimulation. These nucleotides function through opposing actions symbolized by the dualism of the ancient Oriental concept of yin and yang. Alterations in the formation and destruction of these nucleotides occur through stimulation of adrenergic and cholinergic receptors. The pathogenesis of allergic disease may be secondary to changes in the levels of these two cyclic nucleotides.

Cyclic AMP is formed by enzymatic catalysis of adenosine triphosphate by adenyl cyclase. Phosphodiesterase then degrades c-AMP to 5' AMP, (Figure 2). Cyclic AMP is felt to be important in stabilizing intracellular, mediator-containing granules. Cyclic nucleotides affect many different organ systems, including respiratory smooth muscle and the circulatory system.

Table

TABLE 3SYMPATHOMIMETIC AMINES

TABLE 3

SYMPATHOMIMETIC AMINES

Stimulation of the "β-receptor," adenyl cyclase, by β-adrenergic agents such as isoproterenol, will result in an increased production of c-AMP. As previously mentioned, the β-receptor can also be selectively stimulated to produce an increase in c-AMP in target organs with predominantly β1, or β2 effects (Table 2). Other factors that regulate cyclic nucleotide levels are listed in Table 4. The therapeutic implications of the factors that enhance c-AMP production will be discussed by other authors in this series of articles in Pediatric Annals.

Table

TABLE 4REGULATION OF CYCLIC NUCLEOTIDE LEVELS

TABLE 4

REGULATION OF CYCLIC NUCLEOTIDE LEVELS

An increased level of intracellular c-AMP is associated with decreased mediator release and relaxation of respiratory smooth muscle. Conversely, a decreased level of intracellular c-AMP is associated with an increase in the amount of mediator released. Recently prolonged usage of /3-agonist drugs, such as isoproterenol, has resulted in decreased c-AMP levels and possibly increased wheezing in asthmatics. Aspirin therapy has also been found to decrease lymphocyte c-AMP levels.

Since the finding of c-GMP in urine in 1963, it has been found that increased levels of this cyclic nucleotide may lead to an increased respiratory-smooth-muscle contractile response in atopic patients. A three-tofive-fold increase in c-GMP, followed by mediator release, may be stimulated by acetylcholine, a-adrenergic agonists, histamine; serotonin; oxytocin, bradykinin; phosphatidylserine; and prostaglandin Vl201 (Table 4). Although it has been demonstrated that adenylate cyclase has a direct stimulatory effect on c-AMP generation, a similar direct effect for guanylate cyclase on c-GMP has not been demonstrated.

CHEMICAL MEDIATORS

The important role of mediator-containing mast cells in the pathophysiology of asthma and other allergic diseases is suggested by the location of these cells in the respiratory and gastrointestinal mucosa, the presence of an IgE-triggering mechamism on the surface of these cells, and the ability of the cells to generate and release potent chemical mediators. The chemical mediators are capable of eliciting most of the tissue responses characteristic of allergic reactions (Table 5).

Table

TABLE 5CHEMICAL MEDIATORS OF IMMEDIATE HYPERSENSITIVITY

TABLE 5

CHEMICAL MEDIATORS OF IMMEDIATE HYPERSENSITIVITY

Following is a brief description of the currently recognized chemical mediators of immediate hypersensitivity: histamine, eosinophil chemotactic factor of anaphylaxis, platelet-activating factors, neutrophil chemotactic factor, slow-reacting substance of anaphylaxis, and prostaglandins.

Histamine (β-imidazolylethylamine) is widely distributed in the human body. It is found in high concentrations in the respiratory tissues. Histamine is contained within the granules of tissue mast cells and circulating basophils. Histamine is capable of eliciting increased vascular dilatation (manifest in the skin by a flare) and increased vascular permeability (manifest in the skin by wheal formation). It also elicits bronchial smoothmuscle contraction, stimulates eosinophil Chemotaxis, and probably plays a role in mucus secretion.

Relatively large concentrations of histamine are required in vitro in order to elicit human bronchial- smooth-muscle contraction. Intravenous administration of histamine in vivo is not associated with bronchospasm in normal persons. Asthmatic patients, on the other hand, are very sensitive to the inhalation or subcutaneous injection of histamine.

Histamine acts through two distinct receptors that have been defined as H1- and H2receptors (Table 6). Activation of Hj-receptors causes contraction of human bronchi and increased vascular permeability. The classic antihistamines such as diphenhydramine (Benadryl) are H, antagonists, blocking the H, receptors and thus preventing the above effects.

H2-receptor stimulation by histamine results in increased gastric secretion and other actions noted in Table 6. These effects can be blocked by the newer H2-blocking agents, burimamide, metiamide, and Cimetidine.

The H2-receptor responses are activated by an increase in c-AMP. The mechanism of activation of Hi-receptor responses is still not completely understood although activation of H1 receptors raises intracellular c-GMP.

Eosinophil chemotactic factor of anaphyIaxis (ECFA) was discovered in 1971 by Kay, Stechschulte, and Austen. The mediator is a tetrapeptide with a molecular weight of approximately 375. It is specifically chemotactic for eosinophils. Eosinophils also demonstrate diminished chemotactic responsiveness after interaction with ECFA. It seems likely that this deactivation represents a mechanism by which the specifically attracted eosinophils are then held at a site for the purpose of exerting some regulatory function. Eosinophils contain a large amount of arylsulphatase enzyme, which is capable of inactivating one of the other mediators - slow-reacting substance of anaphylaxis.

Table

TABLE 6SELECTED EFFECTS OF H1- AND H2-RECEPTOR STIMULATION

TABLE 6

SELECTED EFFECTS OF H1- AND H2-RECEPTOR STIMULATION

Factors capable of activating platelets are released from human cell suspensions and from human lung fragments by IgE dependent mechanisms. This phenomenon was first demonstrated by Benveniste in 1972. Platelet-activating factors (PAF) have a molecular weight of approximately 1,000 daltons and cause aggregation of human platelets, with subsequent release of serotonin. The role of serotonin, however, in human immediate hypersensitivity reaction is unknown. The fact that PAF is released from the mast cell and the effect this factor has on platelets demonstrates a definite link between immediate hypersensitivity and the coagulation mechanism.

Neutrophil chemotactic factor (NCF-A) has recently been recognized in extracts of human leukemic basophils and human lung fragments. This factor is released by IgE-dependent mechanisms. NCF-A most probably contributes to the accumulation of neutrophils found at the site of allergic tissue reactions.

Slow-reacting substance of anaphylaxis (SRS-A) is not preformed but is synthesized after the antigen-IgE antibody reaction on the cell surface. SRS-A is found in highest concentrations approximately 30 minutes after the antigen-antibody reaction. The molecular weight is approximately 500. Although neutrophilic and mononuclear cells can generate SRS-A, the tissue mast cell appears to be the major source of this factor. SRS-A is capable of inducing prolonged contraction of human bronchial smooth muscle in vitro and will alter in- vivo airway function of asthmatic patients. It is also capable of increasing vascular permeability. The compound is a sulfurcontaining liquid and is specifically inactivated by the enzyme arylsulphatase. This enzyme is found in large amounts in human eosinophils and lung tissue.

Prostaglandins are biologically active lipid substances that were first synthesized by Goldberg in 1933, and named prostaglandins by von Euler in 1935. Von Euler described the chemical, which was present in human seminal plasma, as an active smooth-muscle stimulator and vasodepressor. Since then, astounding strides have been made toward understanding the many effects of these substances on various organ systems (Table 7). In asthma and allergic diseases, prostaglandins are secondary mediators of the immediate hypersensitivity reaction.

Table

TABLE 7SELECTED PHARMACOLOGIC ACTIONS OF PROSTAGLANDINS

TABLE 7

SELECTED PHARMACOLOGIC ACTIONS OF PROSTAGLANDINS

The prostanoic-acid- derived prostaglandins are formed by the action of various synthetases on the most prevalent precursor, arachidonic acid. During the process of forming the primary prostaglandins PGE2 and PGF2Ot other biologically active prostaglandins are formed. These include the prostaglandin endoperoxides (PGG2 and PGH2) and thromboxane (TxA2).

The prostaglandins are synthesized de novo. Chemical and mechanical stimuli, as well as anaphylaxis, lead to prostaglandin release. The prostaglandins exert a primary effect on the respiratory system. Prostaglandin E1 causes a decrease in pulmonary vascular resistance, whereas PGE2 has an opposite effect. Prostaglandins E1 and E2 cause bronchorelaxation in normals, while PGE2 causes bronchoconstriction in asthmatics.

Prostaglandins are felt to be important for maintenance of bronchomotor tone. Therefore, a derangement of prostaglandin homeostasis may be present in asthma. However, this cannot be the only cause of asthma, since medications that decrease prostaglandin synthase, (such as indomethacin), do not prevent the induction of wheezing by PGF2a. Although prostaglandin synthase antagonists do not prevent wheezing, PGEi and PGE2 elicit a 10-fold greater bronchodilation response than isoproterenol. These two prostaglandins also prevent the release of histamine and slow-reacting substance in animals.

At the present time, clinical usage of the prostaglandins is not justified, since there are better bronchodilators, with fewer side effects, available. In the future, more potent derivatives, with less toxicity, may be developed to aid in the treatment of asthma.

From this detailed discussion one can readily realize that there is a complex interaction of immunologic and nonimmunologic factors involving the autonomic nervous system in patients with allergic diseases of the immediate type. In a patient with allergy one rarely is faced with either pure IgE-mediated disease or with pure nonimmunologic disease. Usually the allergic reaction entails varying combinations of both.

A list of nonimmunologic triggers of symptoms of allergic diseases would include respiratory viral infections, exercise, emotional stress, temperature change, barometric pressure change, heredity, air pollution, and certain drugs. The allergic child will have some symptoms produced by the interaction of specific IgE bound to mast cells with a specific antigen, resulting in mediator release. The mediators then act on target organs in either the nose, lungs, or skin. These mediators may also stimulate irritant receptors, which then act through the central nervous system. This in turn leads to parasympathetic (vagalefferent) stimulation, which causes cholinergic effects. These two systems (i.e., the immunologic or IgE-mediated and the nonimmunologic or cholinergic or parasympathetic) are modulated by the cyclic nucleotides as second messengers operative in the intracellular response.

Symptomatic improvement with ßadrenergic agents is apparently a consequence of receptor stimulation associated with activation of adenyl cyclase and increased c-AMP production. This results in decreased cellular mediator release, ß-adrenergic agents may also effect symptomatic improvement by inhibition of vagal influence at the parasympathetic ganglion level and by blocking vagal-efferent stimulation of the target organs. Anticholinergic medications not only block vagal-efferent stimulation of the target organs but also block vagal enhancement of IgE-antigen interaction on the mast-cell surface.

It is evident that the pathophysiologic mechanisms at work in the production of allergic symptoms are much better understood now than they were at the beginning of the 20th century. With comprehensive knowledge of the phenomena of receptor stimulation, cellular response, mediator release, and target-organ activation, one can choose wisely the appropriate pharmacologic agents to optimally treat the patient with allergic disease.

GENERAL REFERENCES

Ishizaka, K., and Ishizaka, T. Identification of gamma E antibodies as a carrier of reaginic activity. /. Immunol. 99 (1967), 1187.

Orange, R. P., Austen, W. G., and Austen, K. F. Immunological release of histamine and slow-reacting substance of anaphylaxis from human lung. I. Modulation by agents influencing cellular levels of cyclic 3', 5'-adenosine monophosphate. J. Exp. Med. 134, (1971), 136 S.

Comroe, J. H. Physiology of Respiration, Second Edition. Chicago: Year Book Medical Publications, 1974, Chapters 8 and 11, pp. 72, 142.

Ash, A. S. F., and Schild, H. L. Receptors mediating some actions of histamine. Br. J. Pharmacol. 27 (1966), 427.

Black, J. W., et al. Definition and antagonism of histamine H^sub 2^-receptors. Nature 236 (1972), 385.

Black, J. W. Histamine receptors. In Klinge, E., (ed). Receptors and Cellular Pharmacology. Proceedings of the Sixth International Congress of Pharmacology. Volume 1. Helsinski, Finland: Finnish Pharmacological Society, 1975.

Plaut, M., and Lichtenstein, L. M. Cellular and chemical basis of the allergic inflammatory response: component parts and control mechanisms. In Middleton, E., Jr., Reed, C. R., and Ellis, E. F., (eds.). Allergy: Principles and Practice. St. Louis: The C V. Mosby Co., 1978. pp. 119-122.

Benveniste, J. Platelet-activating factor, a new mediator of anaphylaxis and immune complex deposition from rabbit and human basophils. Nature 249 (1974), 581.

Orange, R. P. The formation of slow reacting substance of anaphylaxis human lung tissues. In Brent, L., and Holborow, ]. (eds.). Progress in Immunology ?, Volume 4. Amsterdam: NorthHolland Publishing Co., 1974.

Hedqvist, P., and Mathe, A. A. Lung function and the role of prostaglandins. In Lichtenstein, L. L., and Austen, K. F. (eds.). Asthmo: Physiology, lmmunopharmacology and Treatment. New York Academic Press, 1977, pp. 131-146.

Nakamo, )., and Rodgers, R. L. The prostaglandins: Biochemistry, physiology, and clinical pharmacology in asthma and other lung disorders. In Weiss, E. B., and Segal, M. S. (eds.). Bronchial Asthma: Mechanisms and Therapeutics. Boston: Urde, Brown & Company, 1976, pp. 191-192.

TABLE 1

SELECTED RESPONSES MEDIATED BY a- or ^-ADRENOCEPTORS

TABLE 2

SUBTYPES OF β-ADRENOCEPTORS IN MAMMALIAN TISSUES

TABLE 3

SYMPATHOMIMETIC AMINES

TABLE 4

REGULATION OF CYCLIC NUCLEOTIDE LEVELS

TABLE 5

CHEMICAL MEDIATORS OF IMMEDIATE HYPERSENSITIVITY

TABLE 6

SELECTED EFFECTS OF H1- AND H2-RECEPTOR STIMULATION

TABLE 7

SELECTED PHARMACOLOGIC ACTIONS OF PROSTAGLANDINS

10.3928/0090-4481-19790801-07

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