Autonomic Nervous System Abnormalities and Asthma 1 ROBERT F. LEMANSKE, JR. and MICHAEL A. KALINER
Background The constitutional basis for the development of allergic disease is no doubt complex with both genetic and environmental factors playing important etiologic roles. Nonetheless, considerable attention has been focused on the beta-adrenergic blockade theory of asthma, initially proposed by Szentivanyi in the late 1960s (1), as a unifying concept to partially explain many of the abnormalities seen in patients with asthma, and possibly, in other atopic diseases as well. The theory was advanced based on the observation that the injection of living or killed Bordetella pertussis organisms into certain strains of mice and rats modified the normal responses of these animals in such a way as to mimic many of the clinical abnormalities seen in asthmatic patients. Animals so treated developed hypersensitivity to endogenously released or exogenously administered histamine, serotonin, bradykinin, and acetylcholine; hypersensitivity to less specific stimuli such as cold, changes in atmospheric pressure, and respiratory irritants; enhanced antibody formation with reagin-likeactivity; and finally, marked eosinophilia. Moreover, associated with the development of these abnormalities was a concomitant reduction in the animals' sensitivityto catecholamines and, in some cases, even a reversal of normal adrenergic activity. These results suggested that a relationship between autonomic nervous system dysfunction and various physiologic and immunologic abnormalities seen in asthmatic patients may exist. As a corollary conclusion, the data implied that a diminished responsiveness to beta-adrenergic stimulation might potentially increase impulse transmission or receptor stimulation along alpha-adrenergic or cholinergic pathways (figure 1). The following discussion will review the data that has accumulated regarding the potential relevance of autonomic nervous system aberrations in humans, with particular emphasis on asthma. Autonomic Nervous System Abnormalities in Asthma Since its initial formulation, the beta-adrenergic theory has been the subject of intense study by many investigators. Early support for the theory came from in vivo observations (2-6) demonstrating a decreased rise in blood sugar, lactate, pyruvate, pulse rate, and urine cyclicadenosine 3',5'-monophosphate (cyclic AMP) in response to beta-adrenergic stimulation in asthmatic patients compared to normal individuals. Interestingly, Makino and coworkers (7) were able to demonstrate that the reductions in beta-adrenergic responsiveness observed in their patient population correlated with the degree of bronchial respon-
SUMMARY Autonomic nervous system function has been studied both in vifro and in vivo using a variety of methodologies. In asthmatic patients, beta-adrenergic hypol'1lsponsiveness and alphaadrenergic and cholinergic hyperresponslveness can be frequently demonstrated. These observations have provided support for the beta blockade theory of asthma, advanced In the late 1960s by Andor Szentlvanyi's experiments involving sensitized rodents. However, In addition to asthma, aberrations in autonomic nervous system function have been noted in other Individuals including cystic fibrosis patients and their parents, patients with emphysema and bronchitis, and in patients (allergic rhinitis and atopic dermatitis) who have demonstrable IgE antibody responses to a variety of antigens. Thus, although these defects are not specific for asthma, It Is noteworthy that these conditions share many clinical features; the ultimate phenotypic expression of these abnormalities may depend on both genetic and environmental factors that have yet to be defined. AM REV RE5PIR DIS 1990; 141:5157-5161
sivenessto acetylcholine. The concept that irritability of the airways was due to betaadrenergic blockade received further support from the observation of McNeill (8) that the beta-adrenergic blocking drug, propranolol, caused acute bronchoconstriction in asthmatic subjects, whereas it had no effect on the airway responses of normal persons to histamine or cholinergic aerosols (9). Recent work using inhaled propranolol has confirmed these findings (10). These in vivo observations were soon extended to in vitro studies that focused on isolated human leukocytes as a model system to further characterize beta-adrenergic responsiveness in various groups of patients (11-26). Beta-adrenergic receptors in human leukocytes are of the beta-2 type, as are found in human airway smooth muscle (27). This similarity, the relative ease of obtaining human blood samples, and the potential to elucidate further possible cellular or biochemical abnormalities responsible for the observed defects led to the extensive use of leukocytes in research directed along these lines of investigation. The results of investigations utilizing these methods have produced some interesting observations. Lymphocytes obtained from asthmatics possess reduced numbers of beta-adrenergic receptors (11, 16), and generate less cyclic AMP in response to beta-adrenergic stimulation (13),while granulocytes are functionally impaired in their ability to inhibit the release of lysosomal enzymes following stimulation with beta-adrenergic agents (15). Lymphocyte beta receptor numbers (28) and cyclic AMP responsiveness (29) correlate with airway response to acetylcholine, as do pupillary alpha and cholinergic responsiveness (see below) (30). Reduced leukocyte beta-adrenergic responsiveness may be more common in patients with exercise-induced asthma (31). These results all support the beta-adrenergic theory of asthma. More recent investigators, however, have demonstrated that these results may be a
reflection of the adrenergic agents concomitantly used to treat these patients (19-21,32). Interestingly, chronic beta-adrenergic therapy may alter leukocyte but not airway beta-adrenergic responsiveness (33), which may be restored by prednisone and ketotifen (34).Thus, decreasesin measurable leukocyte beta-adrenergic responsiveness may be the result of the therapy rather than an underlying defect in autonomic nervous system (ANS) function. Other investigators have found normal beta-adrenergic receptors on asthmatic granulocytes (12)as wellas normal beta-adrenergic receptor-adenylate cyclasecoupling (23).Normal leukocyte beta-receptor numbers and function in asthmatics may be present despite abnormal in vivo beta-adrenergic responsiveness (35). Similar differences have been reported for alpha-adrenergic responses in asthma (36) and cystic fibrosis (37). As extensions of these studies, investigators using the in vivo assessment of beta-adrenergic (38), alpha-adrenergic (39), and cholinergic (40)responsiveness in groups of allergic patients have demonstrated an array of abnormalities unrelated to disease severity or concomitant drug administration. The systems employed for measurement of each of these ANS components were relatively unique and involved evaluation of changes in blood pressure following isoproterenol infusions, measurements of pupillary size in response to alpha-adrenergic and cholinergic stimulation, and measurement of cutaneous blood flow in response to alpha-adrenergic stimulation. The experimental protocol to evaluate betaadrenergic sensitivity involvedthe intravenous administration of isoproterenol in increasing concentrations from 6 to 21 ng/kg body
I From the Departments of Medicine and Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin, and the Laboratory of Clinical Investigation, National Institute of Allergyand Infectious Disease, National Institutes of Health, Bethesda, Maryland.
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LEMANSKE AND KALINER
TABLE 1 BETA-ADRENERGIC RESPONSIVENESS Plasma Cyclic AMP Response t
Pulse Pressure Response'
Group
Imbalance
Fig. 1. In normal individuals, autonomic nervous system stimulat ion via beta-adrenergic pathways is balanced by opposing alpha-adrenergic and/or cholinergic responses. In patients with asthma. this relationship may be disturbed as manifested by alpha-adrenerg ic or cholinerg ic hyperresponsiveness or beta-adrenergic hyporesponsiveness.
weight X min with sequential blood pressure determinations until a predetermined increase in pulse pressure (22 mm Hg) was achieved (38). Before and immediately after each isoproterenol infusion, blood was drawn for radioimmunoassay of cyclic AMP. The mean dose of isoproterenol needed to increase the pulse pressure for 22 mm Hg or greater in pat ients with allergic asthma or allergic rhinitis and two control populations [skin test negative controls (normals) and skin test positive, history negative controls (preallergyj] is depicted in table 1 (41). The normal control subjects were significantly more sensitive to intravenously administered isoproterenol than were the other three groups . In fact, 22 of the 25 control subjects responded to 9 ng/kg body weight x min or less, whereas 12 of 16 asthmatic subjects, 4 of the 8 patients with allergic rhinitis, and 4 of 7 preallergic subjects needed 12 ng/kg body weight x min of isoproterenolor more. There was no significant difference between the isoproterenol required by the groups with allergic asthma, allergic rhinitis, and preallergy. Concentrations of isoproterenol (table 1) required to increase plasm a cyclic AMP levels by 500/0 were also significantly lower in the normal controls compared to the other three groups of individuals. Therefore, the existence of beta-adrenergic hyporeactivity in asthmatic subjects was reconfirmed using several in vivo responses to isoproterenol. By studying patients with milder forms of allergic asthma, the possibility of concomitant drug administration interfering with the results wasavoided. Of interest in these studies, however, was that both allergic rhinitis and preallergic subjects showed comparable degrees of beta-adrenergic hyporeactivity as the asthmatic subjects. Thus, beta-adrenergic hyperresponsiveness seemed more closely associated with the atopic state. To evaluate mechanisms by which betaadrenergic responsivenesscould be attenuated in these groups of patients, the presence of autoantibodies to the beta-adrenergic receptor was studied. If such antibodies were present, they could potentially interfere with normal agonist-receptor interaction as has been
Normal controls Allergic asthma Allergic rhinitis Preallergy
Subjects Tested (n)
25 17 8 7
Isoproterenol Needed (nglkg body wt'min)
8.04 14.25 12.75 11.10
± ± ± ±
0.48 1.21 1.58 1.26
p Valuet
< 0.0001 < 0.0005 < 0.01
SUbjects Tested (n)
13 10 5 5
Isoproterenol Needed (nglkg body wt·min)
8.08 11.70 11.00 10.80
± ± ± ±
0.62 1.51 1.00 1.33
p Valuet
< 0.025 < 0.05 < 0.05
Data from Kaliner and colleagues (41), used w ith perm ission. • Pulse pressure response to intravenously administered isop roterenol (range 6 to 21 ng/kg body weight 'm in) was ascertained . The concentration (mean ± SEM ) increasing the pulse pressure by 22 mm Hg or greater was des ignated as the endpo int (56). t Plasma cyc lic adenosine monophosphate (AMP) responses to intravenous isoprotere nol were ascertained by radioimmunoassay in samples taken at the end of each infusion of isoproterenol. The concentration (mean ± SEM) that increased the cycl ic AMP level by 50% was designated as the endpoint. p value of each group compared with normal controls by Student's I test for unpaired samples.
*
noted in other conditions such as Graves' disease (42), myasthenia gravis (43), and certain types of insulin-resistant diabetes (44). Autoantibodies to beta receptors were detected by the ability of serum factors to precipitate solubilized canine lung beta-adrenergic receptors and to inhibit the binding of adrenergic ligands to beta receptors (45). Autoantibodies were searched for in 60 atopic (with and without asthma) and control subjects and they were detected in nine individuals: 3 of 19 apparently normal subjects, 1 of 9 preallergic subjects, 4 of 17 asthmatics, and none of 8 with allergic rhinitis. Seven cystic fibrosis patients were also evaluated and autoantibodies weredetected in one individual. Of sixsubjects (four with asthma, one with allergic rhinitis, and one with cystic fibrosis) with the greatest degree of beta-adrenergic hyporesponsiveness (needing 21 ng isoproterenol/kg body weight· min to increase pulse pressure by 22 mm Hg or more), four had autoantibodies to lung beta receptors. Of the 43 normal beta-adrenergic responders, only four had autoantibodies (46). The nine subjects with autoantibodies required significantly greater concentrations of isoproterenol to increase their pulse pressure to the desired endpoint than did a group of 51 individuals lacking autoantibodies. Thus, while not specific for asthma nor present in all patients, autoantibodies to beta receptors may be a factor in regulating beta-adrenergic responsiveness in some individuals. Alpha-adrenergic responsivity was also ascertained using two methods, each measuring the concentration of phenylephrine needed to elicit a predetermined response. In one test, the concentration of topical phenylephrine needed to induce mydriasis of 0.5 mm or larger in the dark was determined. In the other, the concentration of intradermal phenylephrine needed to reduce cutaneous blood flow by 50% was measured. The results obtained in the various populations are shown in table 2. Resting pupillary sizes in light and dark were the same in each group. However, the subjects with allergic asthma were significantly more sensitive in both tests than ei-
ther of the other allergicgroups or the normal controls. This finding indicated that allergic asthmatic subjects had hyperreactive alphaadrenergic responsiveness; this increased reactivity could not be attributed to age, sex, or eye color. Finally, the in vivo assessment of cholinergic responsiveness was also performed using pupillary responses to the topical administration of the cholinergic agonist, carbamylcholine chloride (0.1 to 1.5%). Increasing concentrations of carbachol were instilled in the conjunctival sac until the pupil constricted by 1.0 mm or greater. The mean concentration of carbachol needed to constrict the pupils in the various study populations is shown in table 3. Each of the allergic groups was significantly more responsive than the control groups. Thus, similar to beta-adrenergic responsiveness, cholinergic reactivity, using this assay system, appeared to be associated more with the atopic state rather than with asthma. Concomitant with cholinergic pupillary response determination, PD.o FEV 1 values for methacholine were measured. Of the 15 normal controls, 2 reacted to inhaled methacholine with bronchoconstriction, at 65 and 105 breath units, respectively. Only 1 of the 12 subjects with allergic rhinitis reacted (at 17 breath units) . All of the subjects with allergic asthma responded. Therefore, the cholinergic hyperreactivity noted in the pupillary responses of the group who had allergic rhinitis was not reproduced in the airways with inhaled methacholine. The patients who were examined for alphaand beta-adrenergic responsiveness as well as both tests of cholinergic responsiveness were compared. An inverse relationship between increased bronchial cholinergicresponsiveness and beta-adrenergic hyporesponsiveness was noted; however, these responses were found in allergicsubjects whether or not asthma was present. These correlations suggest that systemic cholinergic hypersensitivity accompanies the atopic state as does beta-adrenergic hyporesponsiveness and that additional factors are needed to produce bronchial lability.
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AUTONOMIC NERVOUS SYSTEM ABNORMALITIES AND ASTHMA
TABLE 2 ALPHA-ADRENERGIC RESPONSIVENESS Pupillary Response t
Cutaneous Response"
Group Normal controls Allergic asthma Allergic rhinitis Preallergy
Subjects Tested (n) 27 22 16
Phenylephrine Needed (ng) 32.06 4.37 23.74 Not
pValue:l:
< 0.005
± 7.53 ± 0.60 ± 9.37 done
< 0.02
SUbjects Tested (n) 57 22 24
8
Phenylephrine Needed (%) 2.55 1.59 2.33 2.50
± ± ± ±
0.08 0.17 0.10 0.16
p Value:l:
< 0.00001 < 0.001 < 0.005
Data Irom Kaliner and colleagues (41), used with permission. • Cutaneous reactivity to phenylephrine reflects the concentration 01 phenylephrine (mean ± SEM) needed to reduce cutaneous blood Ilow by 50%. t Pupillary responsiveness to phenylephrine was ascertained by measuring the concentration 01 phenylephrine (mean ± SEM) needed to dilate the pupils by 0.5 mm or greater in the dark. p value 01 each group compared with the allergic asthma group by Student's I test lor unpaired samples.
*
The relatively selective finding of alpha-adrenergic hyperreactivity in asthmatic subjects suggests that the presence of this abnormality may be one of the determinants of airway hyperresponsiveness. Finally, in regardto the nonadrenergic noncholinergic (NANC) system, its precise contribution to the pathogenesis of a variety of disease states that affect the lung has not been established. However, the potential role of the NANC system in modulating a number of processes previously felt to be the exclusive domain of either adrenergic or cholinergic pathways is currently being intensively evaluated (47). It is possible that aberrations in NAN C system function may also be present in various disease states as have been noted in both the adrenergic and cholinergic systems. Autonomic Nervous System Abnormalities in Other Disease States The ANS has justifiably been of interest with regard to its role in the pathogenesis of asthma and atopic disease. However, defects in ANS function have also been observed in patients with cystic fibrosis (25, 26, 48, 49), allergic
rhinitis (38, 40), chronic obstructive pulmonary disease (24), atopic dermatitis (50, 51), endogenous depression and psychomotor agitation (52). Interestingly, parents of children with cystic fibrosis (obligate heterozygotes) also have increased alpha and cholinergic responsiveness and diminished beta-adrenergic responsiveness; further, they also have a high prevalence of airway reactivity (53, 54). These results suggest that these various groups may represent different aspects of a broad spectrum of clinical manifestations associated with aberrations in ANS sensitivity. Although beyond the scope of this review, it should be noted that the coupling sequence of receptor to the various cyclases with the formation of cyclic nucleotides are only a few of the multiple membrane and cytosolicevents that occur following agonist interaction with various cell types. For example, the sequential methylation and/or phosphorylation of membrane phospholipids, calcium and other ionic fluxes, protein kinase activation, and the degradation of cyclicnucleotides by phosphodiesterases also play an important role in cell function. The relativeimportance of some of these events to ANS aberrations in a few diseases has been analyzed.
TABLE 3 CHOLINERGIC RESPONSIVENESS Bronchial Response t
Pupillary Response"
Group Normal controls Allergic asthma Allergic rhinitis Preallergy
Subjects Tested (n) 57 19 25 8
Carbachol Needed (%) 0.78 0.66 0.67 0.66
± ± ± ±
0.03 0.05 0.04 0.08
p Value§
< 0.025 < 0.025 < 0.05
Subjects Tested (n)
Methacholine Needed:l: (breath units)
15 20 12
368 ± 4 25 ± 9 421 ± 4 Not done
p Value§
< 0.00001 NSII
Data from Kaliner and colleagues (41), used with permission. • Pupillary responses to topical carbachol were ascertained by measuring the concentration 01 carbachol (0.1% to 1.5%) needed 10 constrict the pupil by 1.0 mm or greater in Ihe light. Concentration 01 carbachol is expressed as mean ± SEM. t Bronchial responsiveness to inhaled (0.075 to 50 mg/ml) methacholine was ascertained by standardized bronchial challenge procedures. Breath unit = 1 breath of mglmJ methacholine. Results are expressed as mean cumulative breath units ± SEM. § P value of each group compared with normal controls by Studenfs I test lor unpaired samples. II NS = not significant.
*
Although diminished beta-adrenergic function has been noted in cystic fibrosis patients, the defect does not appear to be due to abnormalities in membrane methylation of phospholipids (55). However, in atopic dermatitis, decreased beta-adrenergic responses may be due, at least in part, to enhanced phosphodiesterase activity (50,51). Finally, recent evidence suggests that allergen challenge in allergic asthmatics may alter adenylate cyclase responsiveness (56). Conclusions The observations dealing with ANS dysfunction in allergic patients have now come full circle, and suggest that there is an array of abnormalities not only in allergic individuals, but also in patients with diseases that have overlapping manifestations. Whereas concomitantly administered catecholamines are certainly capable of affecting ANS responsiveness, carefully controlled studies have demonstrated abnormalities that appear to be fundamental in nature. The precise contribution of these abnormalities to various disease manifestations is unclear. However, it is reasonable to suggest that three levels of response critical in asthma may be influenced: (1) bronchial smooth muscle dilation and response to beta-adrenergic stimulation would be reduced, whereas cholinergically and even alpha-adrenergically mediated constriction would be augmented, (2) mast cell mediator release ordinarily suppressed by beta-adrenergic stimulation would be resistant to betaadrenergic agonists, whereas both cholinergic and alpha-adrenergic enhancement would be exaggerated, and (3) increased mucus secretion in response to alpha-adrenergic and cholinergicstimulation would be increased, whereas sodium and water fluxes into tracheobronchial secretions in response to beta-adrenergic stimulation would be reduced. To define more precisely the contribution ofANS dysfunction to various disease states, prospective analyses of each component of the ANS will be required. Studies in guinea pigs have suggested that the relative density of alpha-adrenergic to beta-adrenergic receptors is increased during the experimental production of asthma (57). Studies employing human lung tissue have supported these observations (58). Experiments in animal models (59) and observations in human children (60) suggest that the expression of allergy occurs during a period termed "allergic breakthrough," which may follow viral infections. Certainly viral upper respiratory infections are associated with alterations in airway autonomic responsiveness (61),and it is plausible to suggest that systemic alterations in ANS responsiveness may contribute to allergic breakthrough. Proof will require carefully conducted prospective analyses . A number of cautions are in order. As previously mentioned, the exact relationship between leukocyte autonomic responsiveness and systemic autonomic responsiveness is unclear. Moreover, leukocytes and platelets must
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be isolated prior to study with inherent procedural artifacts possibly introduced (62). The influence of donor age (63, 64), atopy (19-21), allergen exposure (65), pharmaceuticals (66), the presence of subpopulations of cell types (67-69), and innumerable other biologic variations may profoundly alter the results of both in vivo and in vitro studies. Notwithstanding these problems, the study ofANS responsiveness has provided intriguing avenues of exploration in evaluating mechanisms responsible for the development of allergic disease and airway hyperresponsiveness.
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AUTONOMIC NERVOUS SYSTEM ABNORMALITIES AND ASTHMA
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JA. Bronchial hyperreactivity. Am Rev Respir Dis 1980; 121:389-97. 62. Coutts SM, Nehring RE, JariwalaNU. Purification of rat peritoneal mast cells: occupation of IgE-receptors by IgE prevents loss of the receptors. J Immunol 1980; 124:2309-14. 63. Schocken DD, Roth GS. Reduced ~-adrenergic receptor concentrations in aging man. Nature 1977; 267:854-7. 64. Abrass IB. Scarpace PJ. Human lymphocytes beta-adrenergic receptors are unaltered with age. J Gerontology 1981; 36:298-302. 65. Meurs H, Kauffman HF, Timmermans A, deMonchy JGR, Koeter GH, deVries K. Specific immunological modulation of lymphocyte adenylate cyclase in asthmatic patients after allergenic bronchial provocation. Int Arch Allergy Appl Immunol 1986; 81:224-9.
5161 66. Williams WR, Davies BH. Modulation of lymphocyte adrenergic receptors by hormones and antiasthmatic drugs. J Clin Lab Immunol 1985; 16: 131-6. 67. Niaudet P, Beaurain G, Bach M. Differences in effect of isoproterenol stimulation on levels of cyclic AMP in human Band T lymphocytes. Eur J Immunol 1976; 6:834-9. 68. Galant SP, Underwood SB, Lundak TC, Groncy CC, Mouratides D1. Heterogeneity of human lymphocyte subpopulations to pharmacologic stimulation. 1. Lymphocyte responsiveness to betaadrenergic agents. J Allergy Clin Immunol 1978; 62:349-55. 69. Bishopric NH, Cohen HJ, Lefkowitz RJ. Betaadrenergic receptors in lymphocyte subpopulations. J Allergy Clin Immunol 1980; 65:29-34.
Background The constitutional basis for the development of allergic disease is no doubt complex with both genetic and environmental factors playing important etiologic roles. Nonetheless, considerable attention has been focused on the beta-adrenergic blockade theory of asthma, initially proposed by Szentivanyi in the late 1960s (1), as a unifying concept to partially explain many of the abnormalities seen in patients with asthma, and possibly, in other atopic diseases as well. The theory was advanced based on the observation that the injection of living or killed Bordetella pertussis organisms into certain strains of mice and rats modified the normal responses of these animals in such a way as to mimic many of the clinical abnormalities seen in asthmatic patients. Animals so treated developed hypersensitivity to endogenously released or exogenously administered histamine, serotonin, bradykinin, and acetylcholine; hypersensitivity to less specific stimuli such as cold, changes in atmospheric pressure, and respiratory irritants; enhanced antibody formation with reagin-likeactivity; and finally, marked eosinophilia. Moreover, associated with the development of these abnormalities was a concomitant reduction in the animals' sensitivityto catecholamines and, in some cases, even a reversal of normal adrenergic activity. These results suggested that a relationship between autonomic nervous system dysfunction and various physiologic and immunologic abnormalities seen in asthmatic patients may exist. As a corollary conclusion, the data implied that a diminished responsiveness to beta-adrenergic stimulation might potentially increase impulse transmission or receptor stimulation along alpha-adrenergic or cholinergic pathways (figure 1). The following discussion will review the data that has accumulated regarding the potential relevance of autonomic nervous system aberrations in humans, with particular emphasis on asthma. Autonomic Nervous System Abnormalities in Asthma Since its initial formulation, the beta-adrenergic theory has been the subject of intense study by many investigators. Early support for the theory came from in vivo observations (2-6) demonstrating a decreased rise in blood sugar, lactate, pyruvate, pulse rate, and urine cyclicadenosine 3',5'-monophosphate (cyclic AMP) in response to beta-adrenergic stimulation in asthmatic patients compared to normal individuals. Interestingly, Makino and coworkers (7) were able to demonstrate that the reductions in beta-adrenergic responsiveness observed in their patient population correlated with the degree of bronchial respon-
SUMMARY Autonomic nervous system function has been studied both in vifro and in vivo using a variety of methodologies. In asthmatic patients, beta-adrenergic hypol'1lsponsiveness and alphaadrenergic and cholinergic hyperresponslveness can be frequently demonstrated. These observations have provided support for the beta blockade theory of asthma, advanced In the late 1960s by Andor Szentlvanyi's experiments involving sensitized rodents. However, In addition to asthma, aberrations in autonomic nervous system function have been noted in other Individuals including cystic fibrosis patients and their parents, patients with emphysema and bronchitis, and in patients (allergic rhinitis and atopic dermatitis) who have demonstrable IgE antibody responses to a variety of antigens. Thus, although these defects are not specific for asthma, It Is noteworthy that these conditions share many clinical features; the ultimate phenotypic expression of these abnormalities may depend on both genetic and environmental factors that have yet to be defined. AM REV RE5PIR DIS 1990; 141:5157-5161
sivenessto acetylcholine. The concept that irritability of the airways was due to betaadrenergic blockade received further support from the observation of McNeill (8) that the beta-adrenergic blocking drug, propranolol, caused acute bronchoconstriction in asthmatic subjects, whereas it had no effect on the airway responses of normal persons to histamine or cholinergic aerosols (9). Recent work using inhaled propranolol has confirmed these findings (10). These in vivo observations were soon extended to in vitro studies that focused on isolated human leukocytes as a model system to further characterize beta-adrenergic responsiveness in various groups of patients (11-26). Beta-adrenergic receptors in human leukocytes are of the beta-2 type, as are found in human airway smooth muscle (27). This similarity, the relative ease of obtaining human blood samples, and the potential to elucidate further possible cellular or biochemical abnormalities responsible for the observed defects led to the extensive use of leukocytes in research directed along these lines of investigation. The results of investigations utilizing these methods have produced some interesting observations. Lymphocytes obtained from asthmatics possess reduced numbers of beta-adrenergic receptors (11, 16), and generate less cyclic AMP in response to beta-adrenergic stimulation (13),while granulocytes are functionally impaired in their ability to inhibit the release of lysosomal enzymes following stimulation with beta-adrenergic agents (15). Lymphocyte beta receptor numbers (28) and cyclic AMP responsiveness (29) correlate with airway response to acetylcholine, as do pupillary alpha and cholinergic responsiveness (see below) (30). Reduced leukocyte beta-adrenergic responsiveness may be more common in patients with exercise-induced asthma (31). These results all support the beta-adrenergic theory of asthma. More recent investigators, however, have demonstrated that these results may be a
reflection of the adrenergic agents concomitantly used to treat these patients (19-21,32). Interestingly, chronic beta-adrenergic therapy may alter leukocyte but not airway beta-adrenergic responsiveness (33), which may be restored by prednisone and ketotifen (34).Thus, decreasesin measurable leukocyte beta-adrenergic responsiveness may be the result of the therapy rather than an underlying defect in autonomic nervous system (ANS) function. Other investigators have found normal beta-adrenergic receptors on asthmatic granulocytes (12)as wellas normal beta-adrenergic receptor-adenylate cyclasecoupling (23).Normal leukocyte beta-receptor numbers and function in asthmatics may be present despite abnormal in vivo beta-adrenergic responsiveness (35). Similar differences have been reported for alpha-adrenergic responses in asthma (36) and cystic fibrosis (37). As extensions of these studies, investigators using the in vivo assessment of beta-adrenergic (38), alpha-adrenergic (39), and cholinergic (40)responsiveness in groups of allergic patients have demonstrated an array of abnormalities unrelated to disease severity or concomitant drug administration. The systems employed for measurement of each of these ANS components were relatively unique and involved evaluation of changes in blood pressure following isoproterenol infusions, measurements of pupillary size in response to alpha-adrenergic and cholinergic stimulation, and measurement of cutaneous blood flow in response to alpha-adrenergic stimulation. The experimental protocol to evaluate betaadrenergic sensitivity involvedthe intravenous administration of isoproterenol in increasing concentrations from 6 to 21 ng/kg body
I From the Departments of Medicine and Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin, and the Laboratory of Clinical Investigation, National Institute of Allergyand Infectious Disease, National Institutes of Health, Bethesda, Maryland.
5157
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LEMANSKE AND KALINER
TABLE 1 BETA-ADRENERGIC RESPONSIVENESS Plasma Cyclic AMP Response t
Pulse Pressure Response'
Group
Imbalance
Fig. 1. In normal individuals, autonomic nervous system stimulat ion via beta-adrenergic pathways is balanced by opposing alpha-adrenergic and/or cholinergic responses. In patients with asthma. this relationship may be disturbed as manifested by alpha-adrenerg ic or cholinerg ic hyperresponsiveness or beta-adrenergic hyporesponsiveness.
weight X min with sequential blood pressure determinations until a predetermined increase in pulse pressure (22 mm Hg) was achieved (38). Before and immediately after each isoproterenol infusion, blood was drawn for radioimmunoassay of cyclic AMP. The mean dose of isoproterenol needed to increase the pulse pressure for 22 mm Hg or greater in pat ients with allergic asthma or allergic rhinitis and two control populations [skin test negative controls (normals) and skin test positive, history negative controls (preallergyj] is depicted in table 1 (41). The normal control subjects were significantly more sensitive to intravenously administered isoproterenol than were the other three groups . In fact, 22 of the 25 control subjects responded to 9 ng/kg body weight x min or less, whereas 12 of 16 asthmatic subjects, 4 of the 8 patients with allergic rhinitis, and 4 of 7 preallergic subjects needed 12 ng/kg body weight x min of isoproterenolor more. There was no significant difference between the isoproterenol required by the groups with allergic asthma, allergic rhinitis, and preallergy. Concentrations of isoproterenol (table 1) required to increase plasm a cyclic AMP levels by 500/0 were also significantly lower in the normal controls compared to the other three groups of individuals. Therefore, the existence of beta-adrenergic hyporeactivity in asthmatic subjects was reconfirmed using several in vivo responses to isoproterenol. By studying patients with milder forms of allergic asthma, the possibility of concomitant drug administration interfering with the results wasavoided. Of interest in these studies, however, was that both allergic rhinitis and preallergic subjects showed comparable degrees of beta-adrenergic hyporeactivity as the asthmatic subjects. Thus, beta-adrenergic hyperresponsiveness seemed more closely associated with the atopic state. To evaluate mechanisms by which betaadrenergic responsivenesscould be attenuated in these groups of patients, the presence of autoantibodies to the beta-adrenergic receptor was studied. If such antibodies were present, they could potentially interfere with normal agonist-receptor interaction as has been
Normal controls Allergic asthma Allergic rhinitis Preallergy
Subjects Tested (n)
25 17 8 7
Isoproterenol Needed (nglkg body wt'min)
8.04 14.25 12.75 11.10
± ± ± ±
0.48 1.21 1.58 1.26
p Valuet
< 0.0001 < 0.0005 < 0.01
SUbjects Tested (n)
13 10 5 5
Isoproterenol Needed (nglkg body wt·min)
8.08 11.70 11.00 10.80
± ± ± ±
0.62 1.51 1.00 1.33
p Valuet
< 0.025 < 0.05 < 0.05
Data from Kaliner and colleagues (41), used w ith perm ission. • Pulse pressure response to intravenously administered isop roterenol (range 6 to 21 ng/kg body weight 'm in) was ascertained . The concentration (mean ± SEM ) increasing the pulse pressure by 22 mm Hg or greater was des ignated as the endpo int (56). t Plasma cyc lic adenosine monophosphate (AMP) responses to intravenous isoprotere nol were ascertained by radioimmunoassay in samples taken at the end of each infusion of isoproterenol. The concentration (mean ± SEM) that increased the cycl ic AMP level by 50% was designated as the endpoint. p value of each group compared with normal controls by Student's I test for unpaired samples.
*
noted in other conditions such as Graves' disease (42), myasthenia gravis (43), and certain types of insulin-resistant diabetes (44). Autoantibodies to beta receptors were detected by the ability of serum factors to precipitate solubilized canine lung beta-adrenergic receptors and to inhibit the binding of adrenergic ligands to beta receptors (45). Autoantibodies were searched for in 60 atopic (with and without asthma) and control subjects and they were detected in nine individuals: 3 of 19 apparently normal subjects, 1 of 9 preallergic subjects, 4 of 17 asthmatics, and none of 8 with allergic rhinitis. Seven cystic fibrosis patients were also evaluated and autoantibodies weredetected in one individual. Of sixsubjects (four with asthma, one with allergic rhinitis, and one with cystic fibrosis) with the greatest degree of beta-adrenergic hyporesponsiveness (needing 21 ng isoproterenol/kg body weight· min to increase pulse pressure by 22 mm Hg or more), four had autoantibodies to lung beta receptors. Of the 43 normal beta-adrenergic responders, only four had autoantibodies (46). The nine subjects with autoantibodies required significantly greater concentrations of isoproterenol to increase their pulse pressure to the desired endpoint than did a group of 51 individuals lacking autoantibodies. Thus, while not specific for asthma nor present in all patients, autoantibodies to beta receptors may be a factor in regulating beta-adrenergic responsiveness in some individuals. Alpha-adrenergic responsivity was also ascertained using two methods, each measuring the concentration of phenylephrine needed to elicit a predetermined response. In one test, the concentration of topical phenylephrine needed to induce mydriasis of 0.5 mm or larger in the dark was determined. In the other, the concentration of intradermal phenylephrine needed to reduce cutaneous blood flow by 50% was measured. The results obtained in the various populations are shown in table 2. Resting pupillary sizes in light and dark were the same in each group. However, the subjects with allergic asthma were significantly more sensitive in both tests than ei-
ther of the other allergicgroups or the normal controls. This finding indicated that allergic asthmatic subjects had hyperreactive alphaadrenergic responsiveness; this increased reactivity could not be attributed to age, sex, or eye color. Finally, the in vivo assessment of cholinergic responsiveness was also performed using pupillary responses to the topical administration of the cholinergic agonist, carbamylcholine chloride (0.1 to 1.5%). Increasing concentrations of carbachol were instilled in the conjunctival sac until the pupil constricted by 1.0 mm or greater. The mean concentration of carbachol needed to constrict the pupils in the various study populations is shown in table 3. Each of the allergic groups was significantly more responsive than the control groups. Thus, similar to beta-adrenergic responsiveness, cholinergic reactivity, using this assay system, appeared to be associated more with the atopic state rather than with asthma. Concomitant with cholinergic pupillary response determination, PD.o FEV 1 values for methacholine were measured. Of the 15 normal controls, 2 reacted to inhaled methacholine with bronchoconstriction, at 65 and 105 breath units, respectively. Only 1 of the 12 subjects with allergic rhinitis reacted (at 17 breath units) . All of the subjects with allergic asthma responded. Therefore, the cholinergic hyperreactivity noted in the pupillary responses of the group who had allergic rhinitis was not reproduced in the airways with inhaled methacholine. The patients who were examined for alphaand beta-adrenergic responsiveness as well as both tests of cholinergic responsiveness were compared. An inverse relationship between increased bronchial cholinergicresponsiveness and beta-adrenergic hyporesponsiveness was noted; however, these responses were found in allergicsubjects whether or not asthma was present. These correlations suggest that systemic cholinergic hypersensitivity accompanies the atopic state as does beta-adrenergic hyporesponsiveness and that additional factors are needed to produce bronchial lability.
5159
AUTONOMIC NERVOUS SYSTEM ABNORMALITIES AND ASTHMA
TABLE 2 ALPHA-ADRENERGIC RESPONSIVENESS Pupillary Response t
Cutaneous Response"
Group Normal controls Allergic asthma Allergic rhinitis Preallergy
Subjects Tested (n) 27 22 16
Phenylephrine Needed (ng) 32.06 4.37 23.74 Not
pValue:l:
< 0.005
± 7.53 ± 0.60 ± 9.37 done
< 0.02
SUbjects Tested (n) 57 22 24
8
Phenylephrine Needed (%) 2.55 1.59 2.33 2.50
± ± ± ±
0.08 0.17 0.10 0.16
p Value:l:
< 0.00001 < 0.001 < 0.005
Data Irom Kaliner and colleagues (41), used with permission. • Cutaneous reactivity to phenylephrine reflects the concentration 01 phenylephrine (mean ± SEM) needed to reduce cutaneous blood Ilow by 50%. t Pupillary responsiveness to phenylephrine was ascertained by measuring the concentration 01 phenylephrine (mean ± SEM) needed to dilate the pupils by 0.5 mm or greater in the dark. p value 01 each group compared with the allergic asthma group by Student's I test lor unpaired samples.
*
The relatively selective finding of alpha-adrenergic hyperreactivity in asthmatic subjects suggests that the presence of this abnormality may be one of the determinants of airway hyperresponsiveness. Finally, in regardto the nonadrenergic noncholinergic (NANC) system, its precise contribution to the pathogenesis of a variety of disease states that affect the lung has not been established. However, the potential role of the NANC system in modulating a number of processes previously felt to be the exclusive domain of either adrenergic or cholinergic pathways is currently being intensively evaluated (47). It is possible that aberrations in NAN C system function may also be present in various disease states as have been noted in both the adrenergic and cholinergic systems. Autonomic Nervous System Abnormalities in Other Disease States The ANS has justifiably been of interest with regard to its role in the pathogenesis of asthma and atopic disease. However, defects in ANS function have also been observed in patients with cystic fibrosis (25, 26, 48, 49), allergic
rhinitis (38, 40), chronic obstructive pulmonary disease (24), atopic dermatitis (50, 51), endogenous depression and psychomotor agitation (52). Interestingly, parents of children with cystic fibrosis (obligate heterozygotes) also have increased alpha and cholinergic responsiveness and diminished beta-adrenergic responsiveness; further, they also have a high prevalence of airway reactivity (53, 54). These results suggest that these various groups may represent different aspects of a broad spectrum of clinical manifestations associated with aberrations in ANS sensitivity. Although beyond the scope of this review, it should be noted that the coupling sequence of receptor to the various cyclases with the formation of cyclic nucleotides are only a few of the multiple membrane and cytosolicevents that occur following agonist interaction with various cell types. For example, the sequential methylation and/or phosphorylation of membrane phospholipids, calcium and other ionic fluxes, protein kinase activation, and the degradation of cyclicnucleotides by phosphodiesterases also play an important role in cell function. The relativeimportance of some of these events to ANS aberrations in a few diseases has been analyzed.
TABLE 3 CHOLINERGIC RESPONSIVENESS Bronchial Response t
Pupillary Response"
Group Normal controls Allergic asthma Allergic rhinitis Preallergy
Subjects Tested (n) 57 19 25 8
Carbachol Needed (%) 0.78 0.66 0.67 0.66
± ± ± ±
0.03 0.05 0.04 0.08
p Value§
< 0.025 < 0.025 < 0.05
Subjects Tested (n)
Methacholine Needed:l: (breath units)
15 20 12
368 ± 4 25 ± 9 421 ± 4 Not done
p Value§
< 0.00001 NSII
Data from Kaliner and colleagues (41), used with permission. • Pupillary responses to topical carbachol were ascertained by measuring the concentration 01 carbachol (0.1% to 1.5%) needed 10 constrict the pupil by 1.0 mm or greater in Ihe light. Concentration 01 carbachol is expressed as mean ± SEM. t Bronchial responsiveness to inhaled (0.075 to 50 mg/ml) methacholine was ascertained by standardized bronchial challenge procedures. Breath unit = 1 breath of mglmJ methacholine. Results are expressed as mean cumulative breath units ± SEM. § P value of each group compared with normal controls by Studenfs I test lor unpaired samples. II NS = not significant.
*
Although diminished beta-adrenergic function has been noted in cystic fibrosis patients, the defect does not appear to be due to abnormalities in membrane methylation of phospholipids (55). However, in atopic dermatitis, decreased beta-adrenergic responses may be due, at least in part, to enhanced phosphodiesterase activity (50,51). Finally, recent evidence suggests that allergen challenge in allergic asthmatics may alter adenylate cyclase responsiveness (56). Conclusions The observations dealing with ANS dysfunction in allergic patients have now come full circle, and suggest that there is an array of abnormalities not only in allergic individuals, but also in patients with diseases that have overlapping manifestations. Whereas concomitantly administered catecholamines are certainly capable of affecting ANS responsiveness, carefully controlled studies have demonstrated abnormalities that appear to be fundamental in nature. The precise contribution of these abnormalities to various disease manifestations is unclear. However, it is reasonable to suggest that three levels of response critical in asthma may be influenced: (1) bronchial smooth muscle dilation and response to beta-adrenergic stimulation would be reduced, whereas cholinergically and even alpha-adrenergically mediated constriction would be augmented, (2) mast cell mediator release ordinarily suppressed by beta-adrenergic stimulation would be resistant to betaadrenergic agonists, whereas both cholinergic and alpha-adrenergic enhancement would be exaggerated, and (3) increased mucus secretion in response to alpha-adrenergic and cholinergicstimulation would be increased, whereas sodium and water fluxes into tracheobronchial secretions in response to beta-adrenergic stimulation would be reduced. To define more precisely the contribution ofANS dysfunction to various disease states, prospective analyses of each component of the ANS will be required. Studies in guinea pigs have suggested that the relative density of alpha-adrenergic to beta-adrenergic receptors is increased during the experimental production of asthma (57). Studies employing human lung tissue have supported these observations (58). Experiments in animal models (59) and observations in human children (60) suggest that the expression of allergy occurs during a period termed "allergic breakthrough," which may follow viral infections. Certainly viral upper respiratory infections are associated with alterations in airway autonomic responsiveness (61),and it is plausible to suggest that systemic alterations in ANS responsiveness may contribute to allergic breakthrough. Proof will require carefully conducted prospective analyses . A number of cautions are in order. As previously mentioned, the exact relationship between leukocyte autonomic responsiveness and systemic autonomic responsiveness is unclear. Moreover, leukocytes and platelets must
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LEMANSKE AND KALINER
be isolated prior to study with inherent procedural artifacts possibly introduced (62). The influence of donor age (63, 64), atopy (19-21), allergen exposure (65), pharmaceuticals (66), the presence of subpopulations of cell types (67-69), and innumerable other biologic variations may profoundly alter the results of both in vivo and in vitro studies. Notwithstanding these problems, the study ofANS responsiveness has provided intriguing avenues of exploration in evaluating mechanisms responsible for the development of allergic disease and airway hyperresponsiveness.
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