"..., Symposium on Pediatric Allergy
The Beta Adrenergic Theory of Bronchial Asthma Harold S. Nelson, M.D., Colonel, MC*
When Coca and Cooke first applied the term "atopy" to the hereditary state of man characterized clinically by hay fever and asthma, they considered hypersensitivity to commonly encountered environmental antigens to be a characteristic feature of the condition. 9 Subsequently it became clear that there were patients who had bronchial asthma which was clinically indistinguishable from allergically triggered asthma, yet in whom by history and skin testing there was no evidence of allergy. Furthermore, the presence of immediate hypersensitivity to environmental antigens did not appear to fully explain the occurrence of asthma, since many patients with an equal degree of sensitivity by skin testing would, on exposure to the antigen, experience only allergic rhinitis. The occurrence of asthma in the absence of allergy and the development of asthma in only about 25 per cent of atopic patients34 resulted in a search for some abnormality other than the immunologic in patients with bronchial asthma. An attempt to explain the pathogenesis of asthma which currently enjoys widespread popularity and has stimulated a great deal of recent investigation is the Beta Adrenergic Theory of Bronchial Asthma. 52 The concept that asthma is due to a functional imbalance of the autonomic nervous system is not new. As early as 1915, Eppinger and Hess suggested that asthma might be caused by excessive cholinergic activity. 14 In 1961 Szentivanyi, Fishel, and Talmage began a systematic study of the Bordetella Pertussis induced hypersensitivity state of certain strains of rats and mice. This is characterized by: hypersensitivity to histamine; decreased sensitivity to catecholamines; enhanced antibody formation, particularly of reagin-like antibody; and marked eosinophilia. 52 The similarity of these abnormalities to human bronchial asthma is evident. The demonstration that the Pertussis-induced hypersensitivity state was produced by impaired function of the beta adren*Chief, Allergy, Immunology Service, Fitzsimons Army Medical Center, Denver, Colorado The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Pediatric Clinics of North America- Vol. 22, No.1, February 1975
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ergic effector system led to the proposal that bronchial asthma in humans might be due to a similar beta adrenergic defect. 52
BASIC TENETS OF THE BETA ADRENERGIC THEORY OF BRONCHIAL ASTHMA The Beta Adrenergic Theory 46 • ''" proposes that: 1. The fundamental abnormality of bronchial asthma is hyperreactivity of the bronchial tree to a broad spectrum of immunologic, psychic, infectious, chemical, and physical stimuli which act either directly or through cholinergic reflexes. 2. This hyperreactivity results from diminished responsiveness of the beta adrenergic receptors of the tracheobronchial tree, including those of the bronchial smooth muscles which normally exert a homeostatic bronchodilating effect against these bronchoconstrictive stimuli. 3. Impairment of the beta adrenergic receptors in the skin, nose, and lymphoid tissue accounts for the occurrence of the other atopic conditions: atopic dermatitis, vasomotor rhinitis, and enhanced IgE production.
SUBDIVISIONS OF THE ADRENERGIC NERVOUS SYSTEM Under the stimulus of the beta adrenergic theory of bronchial asthma, workers in the field of allergy have accumulated impressive evidence of impaired adrenergic functioning in patients with bronchial asthma. To properly evaluate their findings, a review of the subdivisions of the adrenergic nervous system is in order (Table I). In 1948 Ahlquist proposed a division of adrenergic receptors into alpha receptors, primarily excitatory, and beta receptors, primarily inhibitory, in their effects.' Lands and co-workers further differentiated beta-1 receptors Table 1.
Response to Adrenergic Stimulation ALPHA ADRENERGIC
TISSUE
Bronchial smooth muscle Blood vessels Heart
Eosinophil Muscle Liver Adipose
Tissue cAMP
BETA ADRENERGIC RESPONSE
RESPONSE
Relaxation (beta 2)
Constriction
Dilatation (skeletal muscles) (beta 2) Cardioacceleration (beta 1) Augmented contractility (beta 1) Eosinopenia (beta 2) Glycogenolysis (beta 2) Glycogenolysis (beta 2) Free fatty acid mobilization (beta 1) Increased (beta 1 and 2)
Constriction (skin and viscera)
Decreased
THE BETA ADRENERGIC THEORY OF BRONCHIAL ASTHMA
55
mediating cardiac stimulation from beta-2 receptors mediating smooth muscle relaxation in the bronchi and blood vessels supplying skeletal muscles. 26 The beta adrenergic receptor has been associated with adenyl cyclase, a cell membrane localized enzyme, which converts ATP to cyclic 3'5' adenosine monophosphate (cAMP), the second messenger which induces the beta adrenergic responsesY The alpha adrenoreceptor has not been as firmly established, but ATPase, which diverts ATP from conversion to cAMP, has been suggested. 11 This competition for the same substrate would be consistent with the often antagonistic effects of alpha and beta adrenergic stimulation.
STUDIES OF ADRENERGIC RESPONSIVENESS IN ATOPIC SUBJECTS In normal subjects the tracheobronchial tree exhibits cholinergic (vagal) tone which can be reduced by atropine. Beta adrenergic stimulation produces bronchodilatation while alpha adrenergic stimulation appears to have little effect on bronchial caliber. 7 It has been known for many years that the airway of the asthmatic is unusually sensitive to the bronchoconstrictor effects of acetylcholine or methacholine. 23 Furthermore, methacholine sensitivity has been shown to increase with viral infections43 and with immunization with influenza42 and live measles vaccine.25 The latter findings suggest that viral infections, which are known to be frequently associated with exacerbations of asthma36 · 38 may do this by increasing the degree of autonomic imbalance in the lungs. Methacholine sensitivity does not appear to depend on the presence of clinical asthma, since increased sensitivity to methacholine has been demonstrated as long as 21 years after the last documented attack of asthma53 and several workers have reported methacholine supersensitivity preceding the first attack of asthma. 33 • 53 Unfortunately, enhanced sensitivity to methacholine merely indicates an imbalance of autonomic modulation of bronchial tone and does not localize the defect. Investigators have therefore turned to other tissues, where beta adrenergic responsiveness can be more discretely studied, but which also have less immediate relevance to bronchial asthma. A number of investigators have examined the metabolic and cardiovascular responses to administered catecholamines as a measure of beta adrenergic responsiveness. ,From Table 1 it is evident that impairment of beta adrenergic responses to catecholamines would result in less than the normal rise in serum free fatty acids, glucose, and lactate. The mean blood pressure would rise due to deficient dilatation of the vessels supplying the skeletal muscles. The pulse rate would change little or become slower, since not only would there be less direct cardioacceleration, but also reflex slowing of the heart would occur secondary to the rise in mean blood pressure. A review of Table 2 will show that all of these altered responses to catecholamine administration have been reported in patients with bronchial asthma. In each study often only one or two of several measured responses were abnormal, and then
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Table 2.
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Evidence of Impaired Beta Adrenergic Responses in Patients with Bronchial Asthma and Atopy
I. Increased bronchial sensitivity to methacholine and histamine.'' II. Decreased responsiveness to catecholamines: A. Metabolic: Less rise in blood glucose, 13 • 16 • 22 • 29 • 32 • lactate,'"· 37 and free fatty acids. 21 B. Cardiovascular: Higher diastolic and mean blood pressure 19 and slower pulse rate. 24 • 32 C. Eosinophils: Diminished eosinopenic response." Abnormal second stage of aggregation." D. Platelets: E. Leukocytes: Decreased generation of cAMP. 2 • 18 • 30 • 44 F. Cyclic AMP: Less rise in plasma and urinary excretion. 5 • 4 ' III. Abnormal responses in the skin in patients with atopic dermatitis: A. Enhanced sweat gland response to acetylcholine'' B. Failure of isoproterenol to inhibit DNA synthesis.'
often only in patients with severe asthma. In one study no abnormal responses could be demonstrated. 27 The circulating elements of the blood provide a readily available tissue. It is not surprising that a number of investigators have studied beta adrenergic responses of eosinophils, platelets, and leukocytes and their enzyme systems. Eosinophilia in the blood, tissues, and secretions is a characteristic feature of both allergic and nonallergic bronchial asthma. 12 A possible explanation for this hypereosinophilia was provided by the discovery that the fall in eosinophils induced by epinephrine is a beta adrenergic response, blocked by propranolol,41 and that patients with bronchial asthma had a diminished eosinopenic response to epinephrine compared to normal controlsY Platelets, on exposure to epinephrine, undergo a biphasic aggregation, the second portion of which is under beta adrenergic control.5° This beta adrenergic phase of platelet aggregation has been reported to be abnormal in patients with bronchial asthma by some investigators,t 7 • 50 but others have been unable to confirm this finding. 20 • 35 There have been several studies of leukocyte adenyl cyclase activity with general agreement that the leukocytes of patients with bronchial asthma stimulate less well with isoproterenol as measured by cAMP generation. 2 • 18 • 30• 44 This impaired adenyl cyclase response appears to be corrected by corticosteroid therapy,30 and has also been reported to fluctuate with the state of the asthma, being demonstrable during exacerbations but absent during remission.•• It has been noted, however, that the leukocyte adenyl cyclase activity is not invariably abnormal, even in the presence of significant bronchial asthma. 2 • 18 • 44 Normally some of the cAMP generated in response to beta adrenergic stimulation escapes from the cells, giving rise to elevated plasma levels and increased urinary excretion. 3 Whereas urinary excretion rose twofold following epinephrine in normal individuals, patients with asthma showed no significant increase,5 and the rise in plasma cAMP following epinephrine was found to be significantly less in asthmatic than in normal subjects. 48
THE BETA ADRENERGIC THEORY OF BRONCHIAL AsTHMA
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While an abnormality of leukocytes is not normally considered a clinical feature of atopy, involvement of the skin, manifest by atopic dermatitis, is. A number of workers have sought and found evidence suggesting impaired beta adrenergic responsiveness in the skin of atopic individuals, both with and without eczema. The sweat glands of atopic subjects showed increased sweating following stimulation with acetylcholine 54 but, unlike the normal skin, there was no further increase in the response to acetylcholine following exogenous beta adrenergic blockade. 21 These studies were interpreted as suggesting a pre-existing beta adrenergic blockade in the atopic skin, with already maximal responsiveness to acetylcholine, and therefore no enhancement of this response with the administration of propranolol. Catecholamine-induced inhibition of DNA synthesis in the skin has been shown to be a beta-2 adrenergic response. 8 Both normal and involved skin from patients with eczema failed to show this normal DNA inhibition on exposure to catecholamines in vivo; 8 however, the same authors found normal responsiveness of the adenyl cyclase of atopic skin to beta adrenergic stimulation. 28 Thus it remains to be demonstrated that the defect in atopic skin, manifest as failure of catecholamines to inhibit DNA synthesis, represents a beta adrenergic defect.
EVIDENCE IN CONFLICT WITH THE BET A ADRENERGIC THEORY Alpha Adrenergic Hyperactivity Difficult to reconcile with the theory that bronchial asthma is due entirely to impaired beta adrenergic responsiveness is the evidence suggesting alpha adrenergic hyperactivity in some asthmatic patients. It has been reported that phentolamine, an alpha adrenergic blocking agent, largely restores the impaired leukocyte adenyl cyclase response to isoproterenol characteristically seen in asthmatics. 2 • 31 Moreover, the leukocytes of patients with bronchial asthma have been reported to show elevated activity of ATPase, an enzyme which has been associated with alpha adrenergic responses. 10 Some investigators have shown in the presence of beta adrenergic blockade a bronchoconstricting effect in asthmatics with phenylephrine, an alpha adrenergic agent. 45 In vitro this alpha adrenergic bronchoconstriction can be increased up to 1000fold by the addition of endotoxin. 49 This has suggested to some workers that alpha adrenergic bronchoconstrictor responses could become hyperactive and contribute to the bronchoconstriction in some patients with asthma. Humoral Transfer of Abnormal Responses in Bronchial Asthma A number of investigators have reported that the plasma or serum from patients with bronchial asthma conferred abnormal responsiveness on normal tissues. Of the abnormal responses alluded to earlier, the failure of catecholamines to inhibit DNA synthesis reported in patients with atopic dermatitis28 and the abnormal second phase of platelet
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aggregation which was found in patients with bronchial asthma50 were reported to be passively transferrable by a serum factor. Also, patients with bronchial asthma have been shown to have impaired degradation of macroaggregated albumin both in vivo and in vitro. Degradation normally occurs through the cooperative action of leukocytes and serum. When normal leukocytes were added to serum from patients with asthma, the rate of degradation was decreased to that seen when both cells and plasma were from asthmatics.n Finally, it has been reported that monkeys infused with serum from patients with asthma developed up to a twenty-fold increase in bronchial sensitivity to inhaled methacholine. In this report the serum factor was shown to be heat labile, suggesting the possibility that IgE was involved. 15 At present, there is no good evidence of what relationship these intriguing but unconfirmed findings may have to the pathogenesis of bronchial asthma.
The Relation of Medications to the Abnormal Responses in Bronchial Asthma Often the abnormal responses reported in patients with bronchial asthma were seen only in patients with severe symptoms, and hence likely to have required regular and prolonged use of bronchodilator medication, particularly sympathomimetic amines. It could therefore be difficult to differentiate to what extent the abnormal responses represent changes induced by medication rather than defects related to the pathogenesis of the asthma. Several investigators have included in their studies groups of normal individuals who ingested sympathomimetic amines for varying periods. In each case they were unable to demonstrate in these normal individuals the induction of the particular abnormal response under study. One group administered ephedrine for 2 weeks without affecting the rise in cyclic AMP excretion following epinephrine, 4 and also reported that ingestion of ephedrine for 7 to 30 days by normal individuals did not affect epinephrine-induced hyperglycemia. 16 "Tedral" taken for 2 weeks was reported not to affect the leukocyte adenyl cyclase response to isoproterenoJ.4 4 There are other studies, however, which indicate that even 1 week of ephedrine, in normal pharmacologic doses, can induce alterations in the response to epinephrine infusions similar to those which have been reported in patients with bronchial asthma. 39 • 40 These have included abnormalities in the glucose, lactate, free fatty acid, mean blood pressure, and heart rate responses to epinephrine. The explanation for these conflicting findings is not clear but it suggests, as has been repeatedly stressed by others, that recent medication must be considered in evaluating the response of patients with bronchial asthma to catecholamines. Induced Beta Adrenergic Blockade in Normal Individuals Added evidence supporting the theory that beta adrenergic blockade underlies bronchial asthma would come from the induction of the basic features of the disease in normal individuals by exogenous beta adrenergic blockade. The administration of a potent beta adrenergic blocking agent, propranolol, to patients with bronchial asthma can produce a
THE BETA ADRENERGIC THEORY OF BRONCHIAL ASTHMA
59
marked increase in the bronchial sensitivity to methacholine or even frank wheezing. 55 On the other hand, the administration of propranolol to normal individuals in doses sufficient to block the pulse rate increase due to isoproterenol did not induce the characteristic bronchial hypersensitivity to histamine and methacholine seen in patients with asthma. 55 Furthermore, a similar degree of induced beta adrenergic blockade did not produce any evidence in normal controls of another condition frequently encountered in patients with bronchial asthma-exercise-induced bronchospasm- even when they were given an exercise load which was followed by an average 24 per cent fall in the FEV-1 in a group of patients with asthma. 5 6
SUMMARY The Beta Adrenergic Theory offers an attractive unitarian explanation for many of the features of bronchial asthma. The autonomic imbalance produced by the postulated impairment of beta adrenergic responsiveness, leaving relatively unopposed cholinergic bronchoconstrictive reflexes, could explain the bronchial hyperreactivity which is the hallmark of the disease. Furthermore, the bronchial sensitivity to methacholine and histamine, the relative refractoriness to epinephrine, the peripheral and sputum eosinophilia, the hereditary nature of asthma, and even the aggravation of asthma by infection and the increased production of lgE could be explained by the theory. Investigators have reported impressive evidence of decreased beta adrenergic response to catecholamines in a wide variety of tissues, including decreased activity of the beta adrenergic receptor adenyl cyclase in leukocytes, and decreased plasma levels and urinary excretion of the secondary messenger of adrenergic stimulation, cyclic AMP. Nevertheless, certain facts prevent complete acceptance of the theory: many of the defects are demonstrable only in patients with severe asthma, while those with mild but definite asthma may have normal responses; some of the abnormal responses can be induced by medication which the patients may have been taking; and finally, it has not been possible to produce, by inducing beta blockade in normal men, two of the characteristic features of asthma, methacholine sensitivity and exercise-induced bronchospasm. Therefore, although the Beta Adrenergic Theory offers an attractive explanation for many of the features of bronchial asthma and is supported by an increasing body of circumstantial evidence, it still remains unproven and further studies will be required to determine whether, indeed, impaired adenyl cyclase response to catecholamines is the common underlying defect in patients with bronchial asthma.
REFERENCES 1. Ahlquist, R. P.: Study of adrenotropic receptors. Am. j. PhysioL, 153:586-600,1948. 2. Alston, W. C., Patel, K. R, and Kerr, j. W.: Response of leukocyte adenyl cyclase to
60 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
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isoprenaline and effect of alpha-blocking drugs in extrinsic bronchial asthma. Brit. Med. J .. 1 :90-93. 1974. Ball, J. H., Kaminsky, N. 1., Hardman, J. G., Broadus, A. E., Sutherland, E. W., and Liddle, G. W.: Effects of catecholamines and adrenergic-blocking agents on plasma and urinary cyclic nucleotides in man. J. Clin. Invest., 51:2124-2129, 1972. Bernstein, R. A., Linarelli, L., Friday, G. A., Drash, A., and Fireman, P.: Effect of ephedrine sulfate on urinary cyclic adenosine monophosphate (AMP) in normals (abst.). J. Allerg., 51:89, 197 . Bernstein, R. A., Linarelli, L., Facktor, M. A., Friday, G. A., Drash, A. L., and Fireman, P.: Decreased urinary adenosine 3'5' monophosphate (cyclic AMP) in asthmatics. J. Lab. Clin. Med., 80:772-779, 1972. Busse, W. W., and Reed, C. E.: Abnormal degradation of macroaggregated albumen particles in patients with asthma. J. Allerg. Clin. lmmunol., 53:271-277, 1974. Carbezas, G. A., Graf, P. D., and Nadel, J. A.: Sympathetic versus parasympathetic nervous regulation of airways in dogs. J. Appl. Physiol., 31:651-655, 1971. Carr, R. H., Busse, W. W., and Reed, C. E.: Failure of catecholamines to inhibit epidermal mitosis in vitro. J. Allerg. Clin. Immunol., 51:255-262, 1973. Coca, A. F., and Cooke, R. A.: Classification of phenomena of hypersensitiveness. J. Immunol., 8:163-182, 1923. Coffey, R. G., and Middleton, E. Jr.: Leukocyte adenosine triphosphatase (ATPase) activity in asthma: Effect of corticosteroid therapy (abst.). J. Allerg. Clin. Immunol., 53:98, 1974. Coffey, R. G., Hadden, J. W., Hadden, E. M., and Middleton, E., Jr.: Stimulation of ATPase by norepinephrine: An alpha adrenergic receptor mechanism (abst.). Fed. Proc., 30:497, 1971. Cooke, R. A.: Infective asthma: Indication of its allergic nature. Am. J. Med. Sci., 183:309-317,1932. Cookson, D. U., and Reed, C. E.: A comparison of the effects of isoproterenol in the normal and asthmatic subject. Am. Rev. Resp. Dis., 88:636-643, 1963. Eppinger, H., and Hess, L.: Vagotonia. A clinical study in vegetative neurology. New York, Nervous and Mental Disease Publishing. Company, 1915, pp. 47-48. Fink, J. N., and Schueter, D. P.: Passive transfer of methacholine sensitivity (abst.). J. Allerg., 43:167-168, 1969. Fireman, P., Palm, C. R., Friday, G. A., and Drash, A. L.: Metabolic responses to epinephrine in asthmatic, eczematous, and normal subjects (abst.). J. Allerg., 45:117, 1970. Fishel, C. W., and Zwemer, R. J.: Aggregation of platelets from B. Pertussis-infected mice and atopically sensitive human individuals (abst.). Fed. Proc., 29:640, 1970. Gillespie, E., Valentine, M. D., and Lichtenstein, L. M.: Cyclic AMP metabolism in asthma: Studies with leukocytes and lymphocytes. J. Aller g. Clin. Immunol., 53:27-33, 1974. Grieco, M. H., Pierson, R. W., and Pi-sunyer, F. X.: Comparison of the circulatory and metabolic effects of isoproterenol, epinephrine, and metroxamine in normal and asthmatic subjects. Am. J. Med., 44:863-872, 1968. Harwell, W. B., Patterson, J. T., Lieberman, P., and Beachey, E.: Platelet aggregation in atopic and normal patients. J. Allerg. Clin. Immunol., 51:274-284, 1973. Hemels, H. G. W. M.: The effect of propranolol on the acetyl choline-induced sweat gland response in atopic and non-atopic subjects. Brit. J. Derm., 83:312-314, 1970. Inoue, S.: Effects of epinephrine on asthmatic children. J. Allerg., 40:337-348, 1967. Itkin, I. H.: Bronchial hypersensitivity to mecholyl and histamine in asthma subjects. J. AI!erg., 40:245-256, 1967. Kirkpatrick, C. H., and Keller, C.: Impaired responsiveness to epinephrine in asthma. Am. Rev., Resp. Dis., 96:692-699, 1967. Kumar, L., Newcomb, R. W., and Molk, L.: Effect of live measles vaccine on bronchial sensitivity of asthmatic children to metacholine (abst.). J. Allerg., 45:104, 1970. Lands, A. M., Arnold, A., McAuliff, J. P., Luduena, F. P., and Brown, T. G., Jr.: Differentiation of receptor systems activated by sympathomimetic amines. Nature (London), 214:597-598, 1967. Leeks, H. I., Wood, D. W., and Donsky, G.: The metabolic, circulatory, and bronchomotor responses of asthmatic children to epinephrine infusion. J. Allerg., 44:261-271, 1969. Lee, T. P., Storms, W., Busse, W., and Reed, C. E.: A study of atopic epidermis: Adenyl cyclase system and mitosis (abst.). J. AI!erg. Clin. lmmunol., 53:99, 1974. Lockey, S. D., Jr., Glennon, J. A., and Reed, C. E.: Comparison of some metabolic responses in normal and asthmatic subjects to epinephrine and glucagon. J. Allerg., 40:349-354, 1967. Logsdon, P. J., Middleton, E., Jr., and Coffey, R. G.: Stimulation of leukocyte adenyl cyclase by hydrocortisone and isoproterenol in asthmatic and nonasthmatic subjects. J. AI!erg. Clin. Immunol., 50:45-56, 1972.
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31. Logsdon, P. J., Carnright, D. U., Middleton, E., Jr., and Coffey, R. G.: The effect of phentolamine on adenylate cyclase and on isoproterenol stimulation in leukocytes from asthmatic and non-asthmatic subjects. J. Allerg. Clin. Immunol., 52:148-157, 1973. 32. Maselli, R., Meltzer, E. 0., and Ellis, E. F.: Pharmacologic effects of epinephrine in asthmatic children (abst.). J. Allerg., 45:117, 1970. 33. Masuda, T., Naito, A., Kinoshita, M., Harada, S., Sasagawa, S., Araki, H., and Makino, S.: Acetylcholine inhalation test in atopic dermatitis. J. Allerg., 40:193-201, 1967. 34. Maternowski, C.]., and Mathews, K. P.: The prevalence of ragweed pollinosis in foreign and native students at a midwestern university and its implications concerning methods for determining the inheritance of atopy. J. Allerg., 33:130-140, 1962. 35. McDonald, J. R., Tan, E. M., Stevenson, D. D., and Vaughan, J. H.: Platelet aggregation in asthmatic and normal subjects (abst.). J. Allerg. Clin. Immunol., 53:105-6, 1974. 36. Mcintosh, K., Ellis, E. F., Hoffman, L. S., Lybass, R. G., Eller, J J., and Fulginiti, V. A.: The association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children. J. Pediat., 82:578-590, 1973. 37. Middleton, E., Jr., and Finke, S. R.: Metabolic response to epinephrine in bronchial asthma. J. Allerg., 42:288-99, 1968. 38. Minor, T. E., Dick, E. C., DeMeo, A. N., Ouellette, J. ]., Cohen, M., and Reed, C. E.: Viruses as precipitants of asthmatic attacks in children. ].A.M.A., 227:292-298, 1974. 39. Nelson, H. S.: The effect of ephedrine on the response to epinephrine in normal men. J. Allerg. Clin. lmmunol., 51:191-198, 1973. 40. Nelson, H. S., Branch, L. B., Black, J. W., Pfeutze, B., Spaulding, H. S., Summers, R., and Wood, D.: S ubsensitivity to epinephrine following the administration of epinephrine and ephedrine to normal individuals. J. Allerg. Clin. Immunol., in press. 41. Ohman, J. L., Jr., Lawrence, M., and Lowell, F. C.: Effect of propranolol on the eosinopenic responses of cortisol, isoproterenol, and aminophylline. J. Allerg. Clin. Immunol., 50:151-56, 1972. 42. Ouellette, J. ]., and Reed, C. E.: Increased response of asthmatic subjects to methacholine after influenza vaccine. J. Allerg., 36:558-563, 1965. 43. Parker, C. D., Bilbo, R. E., and Reed, C. E.: Methacholine aerosol as test for bronchial asthma. Arch. Int. Med., 115:452-458, 1965. 44. Parker, C. W., and Smith, J. W.: Alterations in cyclic adenosine monophosphate metabolism in human bronchial asthma. J. Clin. Invest., 52:48-59, 1973. 45. Patel, K. R., and Kerr, J. W.: The airways response to phenylephrine after blockade of alpha and beta receptors in extrinsic bronchial asthma. Clin. Allerg., 3:439-48, 1973. 46. Reed, C. E.: Beta adrenergic blockade, bronchial asthma and atopy. J. Allerg., 42:238242, 1968. 47. Reed, C. E., Cohen, M., and Enta, T.: Reduced effect of epinephrine on circulating eosinophils in asthma and after beta-adrenergic blockade or Bordetella Pertussis vaccine. J. Allerg., 46:90-102, 1970. 48. Schwartz, H. J., and White, L. W.: Urinary and plasma cyclic AMP responses to epinephrine in asthmatic and normal subjects (abst.). J. Allerg. Clin. Immunol., 51 :88-89, 1973. 49. Simonsson, B. G., Svedmyr, N., Skoogh, B. E., Andersson, R., and Bergh, N. P.: In vivo and in vitro studies on alpha-receptors in human airways. Potentiation with bacterial endotoxin. Scand. J. Resp. Dis., 53:227-236, 1972. 50. Solinger, A., Bernstein, I. L., and Glueck, H. L.: The effect of epinephrine on platelet aggregation in normal and atopic subjects. J. Allerg., 51:29-34, 1973. 51. Sutherland, E. W., and Rail, T. W.: The relation of adenosine 3'5'-phosphate and phosphorylase to the actions of catecholamines and other hormones. Pharmacal. Rev., 12:265-299, 1960. 52. Szentivanyi, A.: The beta adrenergic theory of the atopic abnormality in bronchial asthma. J. Allerg., 42:203-232, 1968. 53. Townley, R. G., Ryo, U. Y., and Kang, B.: Bronchial sensitivity to methacholine in asthmatic subjects free of symptoms for one to twenty-one years (abst.). J. Allerg., 47:91-2, 1971. 54. Warndorff, J. A.: The response of the sweat gland to acetylcholine in atopic subjects. Brit. J. Derm., 83:306-11, 1970. 55. Zaid, G., and Beall, G. N.: Bronchial response to beta-adrenergic blockade. N. Eng. J. Med.,275:580-584, 1966. 56. Zaid, G., Beall, G. N., and Heimlich, E. M.: Bronchial response to exercise following betaadrenergic blockade. J. Allerg., 42: I 77-181, 1968. Fitzsimons Army Medical Center Denver, Colorado 80240
The Beta Adrenergic Theory of Bronchial Asthma Harold S. Nelson, M.D., Colonel, MC*
When Coca and Cooke first applied the term "atopy" to the hereditary state of man characterized clinically by hay fever and asthma, they considered hypersensitivity to commonly encountered environmental antigens to be a characteristic feature of the condition. 9 Subsequently it became clear that there were patients who had bronchial asthma which was clinically indistinguishable from allergically triggered asthma, yet in whom by history and skin testing there was no evidence of allergy. Furthermore, the presence of immediate hypersensitivity to environmental antigens did not appear to fully explain the occurrence of asthma, since many patients with an equal degree of sensitivity by skin testing would, on exposure to the antigen, experience only allergic rhinitis. The occurrence of asthma in the absence of allergy and the development of asthma in only about 25 per cent of atopic patients34 resulted in a search for some abnormality other than the immunologic in patients with bronchial asthma. An attempt to explain the pathogenesis of asthma which currently enjoys widespread popularity and has stimulated a great deal of recent investigation is the Beta Adrenergic Theory of Bronchial Asthma. 52 The concept that asthma is due to a functional imbalance of the autonomic nervous system is not new. As early as 1915, Eppinger and Hess suggested that asthma might be caused by excessive cholinergic activity. 14 In 1961 Szentivanyi, Fishel, and Talmage began a systematic study of the Bordetella Pertussis induced hypersensitivity state of certain strains of rats and mice. This is characterized by: hypersensitivity to histamine; decreased sensitivity to catecholamines; enhanced antibody formation, particularly of reagin-like antibody; and marked eosinophilia. 52 The similarity of these abnormalities to human bronchial asthma is evident. The demonstration that the Pertussis-induced hypersensitivity state was produced by impaired function of the beta adren*Chief, Allergy, Immunology Service, Fitzsimons Army Medical Center, Denver, Colorado The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Pediatric Clinics of North America- Vol. 22, No.1, February 1975
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ergic effector system led to the proposal that bronchial asthma in humans might be due to a similar beta adrenergic defect. 52
BASIC TENETS OF THE BETA ADRENERGIC THEORY OF BRONCHIAL ASTHMA The Beta Adrenergic Theory 46 • ''" proposes that: 1. The fundamental abnormality of bronchial asthma is hyperreactivity of the bronchial tree to a broad spectrum of immunologic, psychic, infectious, chemical, and physical stimuli which act either directly or through cholinergic reflexes. 2. This hyperreactivity results from diminished responsiveness of the beta adrenergic receptors of the tracheobronchial tree, including those of the bronchial smooth muscles which normally exert a homeostatic bronchodilating effect against these bronchoconstrictive stimuli. 3. Impairment of the beta adrenergic receptors in the skin, nose, and lymphoid tissue accounts for the occurrence of the other atopic conditions: atopic dermatitis, vasomotor rhinitis, and enhanced IgE production.
SUBDIVISIONS OF THE ADRENERGIC NERVOUS SYSTEM Under the stimulus of the beta adrenergic theory of bronchial asthma, workers in the field of allergy have accumulated impressive evidence of impaired adrenergic functioning in patients with bronchial asthma. To properly evaluate their findings, a review of the subdivisions of the adrenergic nervous system is in order (Table I). In 1948 Ahlquist proposed a division of adrenergic receptors into alpha receptors, primarily excitatory, and beta receptors, primarily inhibitory, in their effects.' Lands and co-workers further differentiated beta-1 receptors Table 1.
Response to Adrenergic Stimulation ALPHA ADRENERGIC
TISSUE
Bronchial smooth muscle Blood vessels Heart
Eosinophil Muscle Liver Adipose
Tissue cAMP
BETA ADRENERGIC RESPONSE
RESPONSE
Relaxation (beta 2)
Constriction
Dilatation (skeletal muscles) (beta 2) Cardioacceleration (beta 1) Augmented contractility (beta 1) Eosinopenia (beta 2) Glycogenolysis (beta 2) Glycogenolysis (beta 2) Free fatty acid mobilization (beta 1) Increased (beta 1 and 2)
Constriction (skin and viscera)
Decreased
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mediating cardiac stimulation from beta-2 receptors mediating smooth muscle relaxation in the bronchi and blood vessels supplying skeletal muscles. 26 The beta adrenergic receptor has been associated with adenyl cyclase, a cell membrane localized enzyme, which converts ATP to cyclic 3'5' adenosine monophosphate (cAMP), the second messenger which induces the beta adrenergic responsesY The alpha adrenoreceptor has not been as firmly established, but ATPase, which diverts ATP from conversion to cAMP, has been suggested. 11 This competition for the same substrate would be consistent with the often antagonistic effects of alpha and beta adrenergic stimulation.
STUDIES OF ADRENERGIC RESPONSIVENESS IN ATOPIC SUBJECTS In normal subjects the tracheobronchial tree exhibits cholinergic (vagal) tone which can be reduced by atropine. Beta adrenergic stimulation produces bronchodilatation while alpha adrenergic stimulation appears to have little effect on bronchial caliber. 7 It has been known for many years that the airway of the asthmatic is unusually sensitive to the bronchoconstrictor effects of acetylcholine or methacholine. 23 Furthermore, methacholine sensitivity has been shown to increase with viral infections43 and with immunization with influenza42 and live measles vaccine.25 The latter findings suggest that viral infections, which are known to be frequently associated with exacerbations of asthma36 · 38 may do this by increasing the degree of autonomic imbalance in the lungs. Methacholine sensitivity does not appear to depend on the presence of clinical asthma, since increased sensitivity to methacholine has been demonstrated as long as 21 years after the last documented attack of asthma53 and several workers have reported methacholine supersensitivity preceding the first attack of asthma. 33 • 53 Unfortunately, enhanced sensitivity to methacholine merely indicates an imbalance of autonomic modulation of bronchial tone and does not localize the defect. Investigators have therefore turned to other tissues, where beta adrenergic responsiveness can be more discretely studied, but which also have less immediate relevance to bronchial asthma. A number of investigators have examined the metabolic and cardiovascular responses to administered catecholamines as a measure of beta adrenergic responsiveness. ,From Table 1 it is evident that impairment of beta adrenergic responses to catecholamines would result in less than the normal rise in serum free fatty acids, glucose, and lactate. The mean blood pressure would rise due to deficient dilatation of the vessels supplying the skeletal muscles. The pulse rate would change little or become slower, since not only would there be less direct cardioacceleration, but also reflex slowing of the heart would occur secondary to the rise in mean blood pressure. A review of Table 2 will show that all of these altered responses to catecholamine administration have been reported in patients with bronchial asthma. In each study often only one or two of several measured responses were abnormal, and then
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Table 2.
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Evidence of Impaired Beta Adrenergic Responses in Patients with Bronchial Asthma and Atopy
I. Increased bronchial sensitivity to methacholine and histamine.'' II. Decreased responsiveness to catecholamines: A. Metabolic: Less rise in blood glucose, 13 • 16 • 22 • 29 • 32 • lactate,'"· 37 and free fatty acids. 21 B. Cardiovascular: Higher diastolic and mean blood pressure 19 and slower pulse rate. 24 • 32 C. Eosinophils: Diminished eosinopenic response." Abnormal second stage of aggregation." D. Platelets: E. Leukocytes: Decreased generation of cAMP. 2 • 18 • 30 • 44 F. Cyclic AMP: Less rise in plasma and urinary excretion. 5 • 4 ' III. Abnormal responses in the skin in patients with atopic dermatitis: A. Enhanced sweat gland response to acetylcholine'' B. Failure of isoproterenol to inhibit DNA synthesis.'
often only in patients with severe asthma. In one study no abnormal responses could be demonstrated. 27 The circulating elements of the blood provide a readily available tissue. It is not surprising that a number of investigators have studied beta adrenergic responses of eosinophils, platelets, and leukocytes and their enzyme systems. Eosinophilia in the blood, tissues, and secretions is a characteristic feature of both allergic and nonallergic bronchial asthma. 12 A possible explanation for this hypereosinophilia was provided by the discovery that the fall in eosinophils induced by epinephrine is a beta adrenergic response, blocked by propranolol,41 and that patients with bronchial asthma had a diminished eosinopenic response to epinephrine compared to normal controlsY Platelets, on exposure to epinephrine, undergo a biphasic aggregation, the second portion of which is under beta adrenergic control.5° This beta adrenergic phase of platelet aggregation has been reported to be abnormal in patients with bronchial asthma by some investigators,t 7 • 50 but others have been unable to confirm this finding. 20 • 35 There have been several studies of leukocyte adenyl cyclase activity with general agreement that the leukocytes of patients with bronchial asthma stimulate less well with isoproterenol as measured by cAMP generation. 2 • 18 • 30• 44 This impaired adenyl cyclase response appears to be corrected by corticosteroid therapy,30 and has also been reported to fluctuate with the state of the asthma, being demonstrable during exacerbations but absent during remission.•• It has been noted, however, that the leukocyte adenyl cyclase activity is not invariably abnormal, even in the presence of significant bronchial asthma. 2 • 18 • 44 Normally some of the cAMP generated in response to beta adrenergic stimulation escapes from the cells, giving rise to elevated plasma levels and increased urinary excretion. 3 Whereas urinary excretion rose twofold following epinephrine in normal individuals, patients with asthma showed no significant increase,5 and the rise in plasma cAMP following epinephrine was found to be significantly less in asthmatic than in normal subjects. 48
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While an abnormality of leukocytes is not normally considered a clinical feature of atopy, involvement of the skin, manifest by atopic dermatitis, is. A number of workers have sought and found evidence suggesting impaired beta adrenergic responsiveness in the skin of atopic individuals, both with and without eczema. The sweat glands of atopic subjects showed increased sweating following stimulation with acetylcholine 54 but, unlike the normal skin, there was no further increase in the response to acetylcholine following exogenous beta adrenergic blockade. 21 These studies were interpreted as suggesting a pre-existing beta adrenergic blockade in the atopic skin, with already maximal responsiveness to acetylcholine, and therefore no enhancement of this response with the administration of propranolol. Catecholamine-induced inhibition of DNA synthesis in the skin has been shown to be a beta-2 adrenergic response. 8 Both normal and involved skin from patients with eczema failed to show this normal DNA inhibition on exposure to catecholamines in vivo; 8 however, the same authors found normal responsiveness of the adenyl cyclase of atopic skin to beta adrenergic stimulation. 28 Thus it remains to be demonstrated that the defect in atopic skin, manifest as failure of catecholamines to inhibit DNA synthesis, represents a beta adrenergic defect.
EVIDENCE IN CONFLICT WITH THE BET A ADRENERGIC THEORY Alpha Adrenergic Hyperactivity Difficult to reconcile with the theory that bronchial asthma is due entirely to impaired beta adrenergic responsiveness is the evidence suggesting alpha adrenergic hyperactivity in some asthmatic patients. It has been reported that phentolamine, an alpha adrenergic blocking agent, largely restores the impaired leukocyte adenyl cyclase response to isoproterenol characteristically seen in asthmatics. 2 • 31 Moreover, the leukocytes of patients with bronchial asthma have been reported to show elevated activity of ATPase, an enzyme which has been associated with alpha adrenergic responses. 10 Some investigators have shown in the presence of beta adrenergic blockade a bronchoconstricting effect in asthmatics with phenylephrine, an alpha adrenergic agent. 45 In vitro this alpha adrenergic bronchoconstriction can be increased up to 1000fold by the addition of endotoxin. 49 This has suggested to some workers that alpha adrenergic bronchoconstrictor responses could become hyperactive and contribute to the bronchoconstriction in some patients with asthma. Humoral Transfer of Abnormal Responses in Bronchial Asthma A number of investigators have reported that the plasma or serum from patients with bronchial asthma conferred abnormal responsiveness on normal tissues. Of the abnormal responses alluded to earlier, the failure of catecholamines to inhibit DNA synthesis reported in patients with atopic dermatitis28 and the abnormal second phase of platelet
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aggregation which was found in patients with bronchial asthma50 were reported to be passively transferrable by a serum factor. Also, patients with bronchial asthma have been shown to have impaired degradation of macroaggregated albumin both in vivo and in vitro. Degradation normally occurs through the cooperative action of leukocytes and serum. When normal leukocytes were added to serum from patients with asthma, the rate of degradation was decreased to that seen when both cells and plasma were from asthmatics.n Finally, it has been reported that monkeys infused with serum from patients with asthma developed up to a twenty-fold increase in bronchial sensitivity to inhaled methacholine. In this report the serum factor was shown to be heat labile, suggesting the possibility that IgE was involved. 15 At present, there is no good evidence of what relationship these intriguing but unconfirmed findings may have to the pathogenesis of bronchial asthma.
The Relation of Medications to the Abnormal Responses in Bronchial Asthma Often the abnormal responses reported in patients with bronchial asthma were seen only in patients with severe symptoms, and hence likely to have required regular and prolonged use of bronchodilator medication, particularly sympathomimetic amines. It could therefore be difficult to differentiate to what extent the abnormal responses represent changes induced by medication rather than defects related to the pathogenesis of the asthma. Several investigators have included in their studies groups of normal individuals who ingested sympathomimetic amines for varying periods. In each case they were unable to demonstrate in these normal individuals the induction of the particular abnormal response under study. One group administered ephedrine for 2 weeks without affecting the rise in cyclic AMP excretion following epinephrine, 4 and also reported that ingestion of ephedrine for 7 to 30 days by normal individuals did not affect epinephrine-induced hyperglycemia. 16 "Tedral" taken for 2 weeks was reported not to affect the leukocyte adenyl cyclase response to isoproterenoJ.4 4 There are other studies, however, which indicate that even 1 week of ephedrine, in normal pharmacologic doses, can induce alterations in the response to epinephrine infusions similar to those which have been reported in patients with bronchial asthma. 39 • 40 These have included abnormalities in the glucose, lactate, free fatty acid, mean blood pressure, and heart rate responses to epinephrine. The explanation for these conflicting findings is not clear but it suggests, as has been repeatedly stressed by others, that recent medication must be considered in evaluating the response of patients with bronchial asthma to catecholamines. Induced Beta Adrenergic Blockade in Normal Individuals Added evidence supporting the theory that beta adrenergic blockade underlies bronchial asthma would come from the induction of the basic features of the disease in normal individuals by exogenous beta adrenergic blockade. The administration of a potent beta adrenergic blocking agent, propranolol, to patients with bronchial asthma can produce a
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marked increase in the bronchial sensitivity to methacholine or even frank wheezing. 55 On the other hand, the administration of propranolol to normal individuals in doses sufficient to block the pulse rate increase due to isoproterenol did not induce the characteristic bronchial hypersensitivity to histamine and methacholine seen in patients with asthma. 55 Furthermore, a similar degree of induced beta adrenergic blockade did not produce any evidence in normal controls of another condition frequently encountered in patients with bronchial asthma-exercise-induced bronchospasm- even when they were given an exercise load which was followed by an average 24 per cent fall in the FEV-1 in a group of patients with asthma. 5 6
SUMMARY The Beta Adrenergic Theory offers an attractive unitarian explanation for many of the features of bronchial asthma. The autonomic imbalance produced by the postulated impairment of beta adrenergic responsiveness, leaving relatively unopposed cholinergic bronchoconstrictive reflexes, could explain the bronchial hyperreactivity which is the hallmark of the disease. Furthermore, the bronchial sensitivity to methacholine and histamine, the relative refractoriness to epinephrine, the peripheral and sputum eosinophilia, the hereditary nature of asthma, and even the aggravation of asthma by infection and the increased production of lgE could be explained by the theory. Investigators have reported impressive evidence of decreased beta adrenergic response to catecholamines in a wide variety of tissues, including decreased activity of the beta adrenergic receptor adenyl cyclase in leukocytes, and decreased plasma levels and urinary excretion of the secondary messenger of adrenergic stimulation, cyclic AMP. Nevertheless, certain facts prevent complete acceptance of the theory: many of the defects are demonstrable only in patients with severe asthma, while those with mild but definite asthma may have normal responses; some of the abnormal responses can be induced by medication which the patients may have been taking; and finally, it has not been possible to produce, by inducing beta blockade in normal men, two of the characteristic features of asthma, methacholine sensitivity and exercise-induced bronchospasm. Therefore, although the Beta Adrenergic Theory offers an attractive explanation for many of the features of bronchial asthma and is supported by an increasing body of circumstantial evidence, it still remains unproven and further studies will be required to determine whether, indeed, impaired adenyl cyclase response to catecholamines is the common underlying defect in patients with bronchial asthma.
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isoprenaline and effect of alpha-blocking drugs in extrinsic bronchial asthma. Brit. Med. J .. 1 :90-93. 1974. Ball, J. H., Kaminsky, N. 1., Hardman, J. G., Broadus, A. E., Sutherland, E. W., and Liddle, G. W.: Effects of catecholamines and adrenergic-blocking agents on plasma and urinary cyclic nucleotides in man. J. Clin. Invest., 51:2124-2129, 1972. Bernstein, R. A., Linarelli, L., Friday, G. A., Drash, A., and Fireman, P.: Effect of ephedrine sulfate on urinary cyclic adenosine monophosphate (AMP) in normals (abst.). J. Allerg., 51:89, 197 . Bernstein, R. A., Linarelli, L., Facktor, M. A., Friday, G. A., Drash, A. L., and Fireman, P.: Decreased urinary adenosine 3'5' monophosphate (cyclic AMP) in asthmatics. J. Lab. Clin. Med., 80:772-779, 1972. Busse, W. W., and Reed, C. E.: Abnormal degradation of macroaggregated albumen particles in patients with asthma. J. Allerg. Clin. lmmunol., 53:271-277, 1974. Carbezas, G. A., Graf, P. D., and Nadel, J. A.: Sympathetic versus parasympathetic nervous regulation of airways in dogs. J. Appl. Physiol., 31:651-655, 1971. Carr, R. H., Busse, W. W., and Reed, C. E.: Failure of catecholamines to inhibit epidermal mitosis in vitro. J. Allerg. Clin. Immunol., 51:255-262, 1973. Coca, A. F., and Cooke, R. A.: Classification of phenomena of hypersensitiveness. J. Immunol., 8:163-182, 1923. Coffey, R. G., and Middleton, E. Jr.: Leukocyte adenosine triphosphatase (ATPase) activity in asthma: Effect of corticosteroid therapy (abst.). J. Allerg. Clin. Immunol., 53:98, 1974. Coffey, R. G., Hadden, J. W., Hadden, E. M., and Middleton, E., Jr.: Stimulation of ATPase by norepinephrine: An alpha adrenergic receptor mechanism (abst.). Fed. Proc., 30:497, 1971. Cooke, R. A.: Infective asthma: Indication of its allergic nature. Am. J. Med. Sci., 183:309-317,1932. Cookson, D. U., and Reed, C. E.: A comparison of the effects of isoproterenol in the normal and asthmatic subject. Am. Rev. Resp. Dis., 88:636-643, 1963. Eppinger, H., and Hess, L.: Vagotonia. A clinical study in vegetative neurology. New York, Nervous and Mental Disease Publishing. Company, 1915, pp. 47-48. Fink, J. N., and Schueter, D. P.: Passive transfer of methacholine sensitivity (abst.). J. Allerg., 43:167-168, 1969. Fireman, P., Palm, C. R., Friday, G. A., and Drash, A. L.: Metabolic responses to epinephrine in asthmatic, eczematous, and normal subjects (abst.). J. Allerg., 45:117, 1970. Fishel, C. W., and Zwemer, R. J.: Aggregation of platelets from B. Pertussis-infected mice and atopically sensitive human individuals (abst.). Fed. Proc., 29:640, 1970. Gillespie, E., Valentine, M. D., and Lichtenstein, L. M.: Cyclic AMP metabolism in asthma: Studies with leukocytes and lymphocytes. J. Aller g. Clin. Immunol., 53:27-33, 1974. Grieco, M. H., Pierson, R. W., and Pi-sunyer, F. X.: Comparison of the circulatory and metabolic effects of isoproterenol, epinephrine, and metroxamine in normal and asthmatic subjects. Am. J. Med., 44:863-872, 1968. Harwell, W. B., Patterson, J. T., Lieberman, P., and Beachey, E.: Platelet aggregation in atopic and normal patients. J. Allerg. Clin. Immunol., 51:274-284, 1973. Hemels, H. G. W. M.: The effect of propranolol on the acetyl choline-induced sweat gland response in atopic and non-atopic subjects. Brit. J. Derm., 83:312-314, 1970. Inoue, S.: Effects of epinephrine on asthmatic children. J. Allerg., 40:337-348, 1967. Itkin, I. H.: Bronchial hypersensitivity to mecholyl and histamine in asthma subjects. J. AI!erg., 40:245-256, 1967. Kirkpatrick, C. H., and Keller, C.: Impaired responsiveness to epinephrine in asthma. Am. Rev., Resp. Dis., 96:692-699, 1967. Kumar, L., Newcomb, R. W., and Molk, L.: Effect of live measles vaccine on bronchial sensitivity of asthmatic children to metacholine (abst.). J. Allerg., 45:104, 1970. Lands, A. M., Arnold, A., McAuliff, J. P., Luduena, F. P., and Brown, T. G., Jr.: Differentiation of receptor systems activated by sympathomimetic amines. Nature (London), 214:597-598, 1967. Leeks, H. I., Wood, D. W., and Donsky, G.: The metabolic, circulatory, and bronchomotor responses of asthmatic children to epinephrine infusion. J. Allerg., 44:261-271, 1969. Lee, T. P., Storms, W., Busse, W., and Reed, C. E.: A study of atopic epidermis: Adenyl cyclase system and mitosis (abst.). J. AI!erg. Clin. lmmunol., 53:99, 1974. Lockey, S. D., Jr., Glennon, J. A., and Reed, C. E.: Comparison of some metabolic responses in normal and asthmatic subjects to epinephrine and glucagon. J. Allerg., 40:349-354, 1967. Logsdon, P. J., Middleton, E., Jr., and Coffey, R. G.: Stimulation of leukocyte adenyl cyclase by hydrocortisone and isoproterenol in asthmatic and nonasthmatic subjects. J. AI!erg. Clin. Immunol., 50:45-56, 1972.
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31. Logsdon, P. J., Carnright, D. U., Middleton, E., Jr., and Coffey, R. G.: The effect of phentolamine on adenylate cyclase and on isoproterenol stimulation in leukocytes from asthmatic and non-asthmatic subjects. J. Allerg. Clin. Immunol., 52:148-157, 1973. 32. Maselli, R., Meltzer, E. 0., and Ellis, E. F.: Pharmacologic effects of epinephrine in asthmatic children (abst.). J. Allerg., 45:117, 1970. 33. Masuda, T., Naito, A., Kinoshita, M., Harada, S., Sasagawa, S., Araki, H., and Makino, S.: Acetylcholine inhalation test in atopic dermatitis. J. Allerg., 40:193-201, 1967. 34. Maternowski, C.]., and Mathews, K. P.: The prevalence of ragweed pollinosis in foreign and native students at a midwestern university and its implications concerning methods for determining the inheritance of atopy. J. Allerg., 33:130-140, 1962. 35. McDonald, J. R., Tan, E. M., Stevenson, D. D., and Vaughan, J. H.: Platelet aggregation in asthmatic and normal subjects (abst.). J. Allerg. Clin. Immunol., 53:105-6, 1974. 36. Mcintosh, K., Ellis, E. F., Hoffman, L. S., Lybass, R. G., Eller, J J., and Fulginiti, V. A.: The association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children. J. Pediat., 82:578-590, 1973. 37. Middleton, E., Jr., and Finke, S. R.: Metabolic response to epinephrine in bronchial asthma. J. Allerg., 42:288-99, 1968. 38. Minor, T. E., Dick, E. C., DeMeo, A. N., Ouellette, J. ]., Cohen, M., and Reed, C. E.: Viruses as precipitants of asthmatic attacks in children. ].A.M.A., 227:292-298, 1974. 39. Nelson, H. S.: The effect of ephedrine on the response to epinephrine in normal men. J. Allerg. Clin. lmmunol., 51:191-198, 1973. 40. Nelson, H. S., Branch, L. B., Black, J. W., Pfeutze, B., Spaulding, H. S., Summers, R., and Wood, D.: S ubsensitivity to epinephrine following the administration of epinephrine and ephedrine to normal individuals. J. Allerg. Clin. Immunol., in press. 41. Ohman, J. L., Jr., Lawrence, M., and Lowell, F. C.: Effect of propranolol on the eosinopenic responses of cortisol, isoproterenol, and aminophylline. J. Allerg. Clin. Immunol., 50:151-56, 1972. 42. Ouellette, J. ]., and Reed, C. E.: Increased response of asthmatic subjects to methacholine after influenza vaccine. J. Allerg., 36:558-563, 1965. 43. Parker, C. D., Bilbo, R. E., and Reed, C. E.: Methacholine aerosol as test for bronchial asthma. Arch. Int. Med., 115:452-458, 1965. 44. Parker, C. W., and Smith, J. W.: Alterations in cyclic adenosine monophosphate metabolism in human bronchial asthma. J. Clin. Invest., 52:48-59, 1973. 45. Patel, K. R., and Kerr, J. W.: The airways response to phenylephrine after blockade of alpha and beta receptors in extrinsic bronchial asthma. Clin. Allerg., 3:439-48, 1973. 46. Reed, C. E.: Beta adrenergic blockade, bronchial asthma and atopy. J. Allerg., 42:238242, 1968. 47. Reed, C. E., Cohen, M., and Enta, T.: Reduced effect of epinephrine on circulating eosinophils in asthma and after beta-adrenergic blockade or Bordetella Pertussis vaccine. J. Allerg., 46:90-102, 1970. 48. Schwartz, H. J., and White, L. W.: Urinary and plasma cyclic AMP responses to epinephrine in asthmatic and normal subjects (abst.). J. Allerg. Clin. Immunol., 51 :88-89, 1973. 49. Simonsson, B. G., Svedmyr, N., Skoogh, B. E., Andersson, R., and Bergh, N. P.: In vivo and in vitro studies on alpha-receptors in human airways. Potentiation with bacterial endotoxin. Scand. J. Resp. Dis., 53:227-236, 1972. 50. Solinger, A., Bernstein, I. L., and Glueck, H. L.: The effect of epinephrine on platelet aggregation in normal and atopic subjects. J. Allerg., 51:29-34, 1973. 51. Sutherland, E. W., and Rail, T. W.: The relation of adenosine 3'5'-phosphate and phosphorylase to the actions of catecholamines and other hormones. Pharmacal. Rev., 12:265-299, 1960. 52. Szentivanyi, A.: The beta adrenergic theory of the atopic abnormality in bronchial asthma. J. Allerg., 42:203-232, 1968. 53. Townley, R. G., Ryo, U. Y., and Kang, B.: Bronchial sensitivity to methacholine in asthmatic subjects free of symptoms for one to twenty-one years (abst.). J. Allerg., 47:91-2, 1971. 54. Warndorff, J. A.: The response of the sweat gland to acetylcholine in atopic subjects. Brit. J. Derm., 83:306-11, 1970. 55. Zaid, G., and Beall, G. N.: Bronchial response to beta-adrenergic blockade. N. Eng. J. Med.,275:580-584, 1966. 56. Zaid, G., Beall, G. N., and Heimlich, E. M.: Bronchial response to exercise following betaadrenergic blockade. J. Allerg., 42: I 77-181, 1968. Fitzsimons Army Medical Center Denver, Colorado 80240
