Endogenous Regulation of the Pulmonary Response to Isoproterenol

Endogenous Regulation of the Pulmonary Response to Isoproterenol* Harry Bass..\I.D., F.C.C.P. o 0

Pulmonary function was evaluated before and after isoproterenol administration in eight asthmatic patients who had been taking daily suppressive doses of glucocorticosteroids prior to study. Results were compared when the patients were not on glucoccrticosteroid therapy, after glucocorticosteroid therapy, and after ACTH stimulation. Before isoproterenol administration, values were significantly closer to normal after ACTH than on no therapy or glucocorticosteroid therapy. Isoproterenol response was of great magnitude when no therapy was given and minimal after glucocorticosteroids or ACTH. Following isoproterenol, values were significantly closer to normal following ACTH compared to glucocorticosteroid therapy, and values on no therapy were intermediate not separating significantly from glucocorticosteroid therapy or ACTH stimulation. ACTH stimulates an increase in adrenal adenyl cyclase, cyclic AMP, and phenylethanolamine-N-methyl transferase with a resultant increase in the conversion of norepinephrine to epinephrine, a potent beta stimulator. The inability of these suppressed patients to release ACTH following discontinuation of glucocorttcosteroids led to diminished epinephrine production, diminished endogenous beta stimulation, and maximal response to isoproterenol.

Bronchial asthma is characterized by episodes of shortness of breath with wheezing and symptom-free intervals which occur spontaneously or as the result of therapy. The basic defect is an alteration in the host leading to increased respon-

siveness of airways to many stimuli manifested hy spasm of smooth muscle and increased mucus production.' Daily variation occurs ill the rcsponsiveness of the airways and the number of agents provoking a response, and could he due to environmental factors, internal control mechanisms, or hoth. 2 .3 The observation that isoproterenol would reverse abnormalities of pulmonary function in patients with bronchial asthma and coexisting hypoadrenalism and that it caused little or no change in patients with bronchial asthma while they wen' on glucocorticosteroid therapy led to this study, performed to

°From the Pulmonary Division. Department of \!edieine, Pete-r Bent Brigham Hospital and Harvard \Iedical School, Boston. Supported hy grants from the John A. Hartford Foundation, USPHS :\0..'5-S0 I-HH·O.'54HU-OH, and General Clinical Research Center Program of the Division of Research Resource. IH :\0..'5-\10 I-HH-000.31-1l. 00 Director, Pulmonarv Division and Senior Associate in \1£'<1icine, Pete-r Bent B'righam Hospital; Assistant Professor of \It'dieine, Harvard \I{'(lical School.

x

Reprint requests: Dr. Bass, Peter Bent Brigham Hospital, 721 ll untinuton A.rC/me, Boston 02159

Table I-Mean Values ± Standard Deviation (SD) lor LUnll Volumes anti Mixing Efficiellcy 0/ Eillht Patients 'c>ith Bronchial Asthma

Oil

No Therapy. Glueocorticosteroid (St,.roi,l) Therapy, and alter ACTH Stimulation (ACTH). V"lues

lor Vital Capacity (VC). Functional Residual Capacity (FRC). Residual Volume (RV). Total Lunll Capacity (TLC).

Residual Volume/Total Lunll Capacit~· (RV/TLC), Ex piratorv Reserve Volume (ERV). Inspiratory Ca/Jacity (lC). atul Mixillll Efficieucv (ME) Are Expre""ed as Percent 0/ the Predicted Normal Standard, Tlu-rapv I,,'fol'<' Isoprou-n-nol Indo

\T FH(' H\' T/,(' H\' '1'1,(' EH\'

«'

:\11-:

:\onl' 71 t 1\1 IO!l ::': 21 I-I!I ± i :~ !lH ::': I!I lii:~

±

:~7

4S ± -II SO ± HI ii2 -t IX

.-

:'t,'roid

± ± ± ± ± ± SO ±

72 III 147 !l7 IW ,')2

12 ~O

4S I!l 2·1 2:~

II ·Iii + II

TIH'rapy af'tr-r boprol<'I'<'IIl,1

.\( 'Til

\'0/1('

± ±

+

S4 120 1(\0 112 1:~Ii (\7 Sli 71i

14 IS ± ·Iii

± ± ±

:~ii

±

:~!I

±

I~

~!l

12

14

!l:~

117 Iii,') 112 I :~S 7S 10,,) .')7

II

± 2!1 ± :m

± IH ± 22 ± (il ± 2!1

± 2ii

:'tt'roid

sn

11·1

::': II ± 2H

IW + :~7 -,

10,;

"-

Iii

II:~

±

:~:~

Iili ::': :~4 \11 ::': IS iiO ::': 22

\('TII \11 "- II

100 127 I(Hi 10,;

m

± 2" -t :~o -t I;, +

21'

+ ·to

10;, + 22 SO + :~7 -,

15

ENDOGENOUS REGULATION OF PULMONARY RESPONSE TO ISOPROTERENOL

Table 2-Mean JIalue» ::t: Standard Deviation lor Flow Rates and Steady State Diffusing Capacity 01 Eight Patients with Bronchial Asthma on No Therapy, Glucocorticosteroid Therapy (Steroid), and alter ACTH Stimulation (ACTH). Jlalues lor Maximal Jloluntary Jlentilation (MJlR), Forced Expiratory Jlolume".,., .
Therapy lx-for« Isoproterenol

A

Indpx :\IVV F E V0 75 PFR :\1:\IFR FEV1 DLcoII DLcolll

:-itproid

~')JlP

·Hi

·10 3!l 28 -t6 128 62

± ± ± ± ± ± ±

18

H

60 56 -t!l 23

± II

± ± ± ± H ± 161 ± 93 ±

as ± 16

It)

15 23

35 15 -to 103 67

J()

-t3

23

± ± ± ± ±

16 7 13 2!l 2!l

evaluate the effect of glucocorticosteroids on the pulmonary response to isoproterenol. METHODS

Eight patients with bronchial asthma (five men and three women) who had taken daily suppressive doses of glucocorticosteroids for three years or longer wen' studied. Four of tllt'se patients had chronic bronchitis in addition to bronchial asthma. The patients wert' admitted to the Peter Bent Brigham Hospital's Clinic-al Hesearch Center for study. Medications were discontinued the morning following admission and dexamethasone started for its mineralocorticoid effect. Daily

Table 3-Significant Difference» in Pulmonary Function before Isoproterenol in Patients with Bronchial Asthma When Rpsults on No Therapy Arp Comparpd to Results alter ACTH Stimulation and When Results on Glucocor· ticosteroid Therapy Arp Compared to Results alter ACTH Stimulation. JI"lups Expressed as Percent 01 Predicted Normal Standard. .\CTII

~o

Index

Vital capar-it v Total lung r-npru-itv (TIP) Itpsidual volunu- /TLC Expirn torv rosr-rvr- volume FE\'o.7.,; .ec X -to Peak flow rate

vs Thr-rupy

:\1 pall SD*

71 !lfi 15:J -t8 -to 3!l

± ± ± ± ± ±

± I!l 19 37 H

In 15

Stproid

Stimulnt ion :\1pan SD

8-t 112 136 67 ,')6 -t9

± ± ± ± ± ±

± l-t 13 35 39 20 19

p< p
:\CTH vs Stimulation

Indpx

Therupv

Vital ,'apa"ity Total lung cnpnr-it v Maximul volunt nrv

72 ± 12 !l7 ± l!l

8-t ± I-t p «l.OI 112 ± 13 p
:~5

± 11 ± Ifi 3,,) ± 16

60 ± l-t p <0.05 56 ± 20 p -co.m -t9 ± l!l p <0.0;)

15 ± 7 -t5 ± II

23 ± !l p < (l.O,') 76 ± 39 p <0.02

vont ilat ion

FEV on .ec X -to I'pak flow rut« \Iaximal mid-cxpirntorv flow ratr\I ixinz p/fi,·ipn,'.\·

H

Xon«

:-itproid

77 ± 18

71 ± 10 o':> ± 2-t 57 ± 31 3-t ± 23 H ± 20 117 ± 31 ,')fi ± It

:\CTH

*SD=:-itandard dovin t ion.

CHEST, VOL. 61, NO, 1, JANUARY 1972

l-t 20 19 9

l-t 55 26

n

6-t 35 -t!l 11!1 fi5

± ± ± ± ± ±

I!l 26 17 17 -t3 I :~

:\CTll

82 7-t 71 -tfi 59 180

n

± ± ± ± ± ± ±

22 20 3!l 25 18 9-t 26

24-hour urine samples were collected for determination of creatinine and 17-hydroxycorticosteroids (17-0HCS) on 12 consecutive days.' During the initial five days of study medications other than daily dexamethasone and isoproterenol, given during pulmonary studies, were avoided. A 48hour ACTH stimulation test was initiated the morning of day six. On day eight dexamethasone was stopped and on day nine patients were given glucocorticosteroids at twice their preadmission dose. Pulmonary function tests were perfonned in the same order and at the same tim" of day on 12 consecutive days. Measurements included total lung capacity and its suhdivisions by spirometry and helium dilution. Speed of equilihration with helium was measured and expressed as mixing efficiency." From maximal effort expiratory flow curves, separate calculations were performed for peak flow rate, maximal mid-expiratory flow rate, forced expiratory volume.; ;" "P" X 40, and forced expiratory volume"",. SPC (FEV I) .fI.7 Maximal voluntary ventilation was measured on a nine liter spirometer during 12 seconds of hyperventilation.' Steady state diffusing capacity was measured and calculated using the end-tidal sample method (D L" " 1I ) 9 and correcting for dead space (D L" " IlI ) .10 Studies were performed while the patient was seated, compared to normal standards, and expressed as percent of predicted normal standard."-tO For isoproterenol administration, patients were instructed to breathe out completely to residual volume and then to breathe in slowly and completely to total lung capacity. Aerosol was released at the beginning of inspiration and patients were advised to hold their breath for a few seconds at total lung capacity to achieve better drug absorption." Pulmonary studies were repeated after a IS-minute waiting period to achieve maximal drug effect.'" RESl'LTS

Indices of pulmonary function were analyzed before isoproterenol, after isoproterenol and for response to isoproterenol. Measurements obtained after five days of no glucocorticostcroid therapy when 17-OHCS were lowest (2.7 mg/24 hr ± SO 1.4) were compared to measurements on day ten after patients had received twice the preadmission dose of glucocorticosteroids and 17-0HCS were higher (7..5 mg/24 hr ± 4.4) and to measurements on day eight after the 48 ACTH stimulation when

16

HARRY BASS

Table 4-Mpall

JIalues ::!: Slamlartl Dt>viatioll before l soproterenot (bt>lort» ComparNI to after I soproterenol (altt>r) lor Jlital Ca/Jacity (JlC). Total LUllg Capacity (TLC). l nepiratorv' Capacity (lC). Ex piratory Reseroe JIolurue (ERJI). Maximal Jloluntary Jlt>t,tilation (MJlJI). Forced Ex piratorv Jlolumt>".,:. s rc: X 40 (FEJI",.). Peak Flow Rare (PFR). anti Mt,ximal Mitl-t>xpiratory Flow Rate (MMFR) wht>t, Eight Patients with Bronchial Allthma W"t>rt> on No TI't>rapy. Receiving Glucocorttcosteroid Therapy. ami alter ACTH Slimuilltion Are Exprpsst>d As Predicted Normal Stamlartl. :\ 0

Thr-rupv

.\<"1'11 Stilllulation

S"'l"oid Th"l"a p~' --"

Bdof"('

n'

TLC J('

EH\"

:'IIVV FE\"o 75 PFH

:'II:\IFR

71 !lli SO -lS

.\fll'l"

± W ± IH ± W ± -l·1

·Hi ± IS -lO ± IIi :JH ± II) 2S ± 2:l

H:l ± 112 ± 105 ± 7S ± 77±

l-l IIi

2H 61 IS n+ IH 6-l ± 26 31) ± 17

p<

Bl'fol"('

Aftr-r

p < o.nn p «Ull p
72 ± 12

Sli ± l-l

p<

Ikfol"('

p
S-l ± l-l

ns

71 ± 10 {iii ± 2-l 57 ± 31

!I-l

± II

p< p < O.Oii UK

ns H ± II 35 ± re 35 ± 16

.\fl'·1"

Sli ± 12

ns

p
ns

IOii ± 22

HO ± l-l

S2 ± 22

-lH ± IB ± !l

71 ± 3H -l6 ± 2,1

2:~

p
p <0.02

ns

p
ns = not significant.

17-0HCS were highest (24.5 mg/24 hrs ± 10.8) (Tables I and 2). Measurements obtained on day ten after glucocorticosteroid therapy were compared to measurements obtained on day eight after ACTH stimulation. The paired t analysis was used for all comparisons. Before isoproterenol, most pulmonary indices were significantly closer to normal after ACTH stimulation. Residual volume, functional residual capacity, and diffusing capacity did not vary in relation to 17-0HCS (Table 3). A response to isoproterenol of large magnitude occurred on no therapy and a minimal response after glucocorticosteroid therapy or ACTH stimulation (Table 4). After isoproterenol, values on no therapy were similar to values after ACTH stimulation: however, values on glucocorticosteroid therapy remained significantly more abnormal than those values after ACTH stimulation (Table 5).

in residual volume and functional residual capacity and deterioration in mixing efficiency. In contrast, patients without coexisting airway disease had improvement in residual volume, functional residual capacity, and mixing efficiency following isoproterenol, Bidirectional changes following isoproterenol related to the presence or absence of airway disease, negated significance when change for the group was analyzed. Dead space ventilation is increased in bronchial asthma 15 and increases further after isoproterenol adrninistration." Increased dead space ventilation invalidates the assumption that gas tensions in endtidal air are similar to those in pulmonary capillary blood, making the 01.,,,11 an invalid estimate of diffusing capacity in patients with bronchial asthma, Correcting diffusing capacity for dead space ventilation (01.,,,111) gave an abnormally low value which did not vary in relation to 17-0HCS or change after isoproterenol suggesting that a dif-

DISCUSSIOX

Beta stimulation in the lungs following isoproterenol was manifested by an increase toward the normal standard for vital capacity, total lung capacity, inspiratory capacity, expiratory reserve volume, maximal voluntary ventilation, forced expiratory volume.r-; S{'C X 40, peak Row rate, and maximal mid-expiratory flow rate: however, residual volume, functional residual capacity, and mixing efficiency did not improve. Similar results have been reported previously.":':' The presence of chronic bronchitis in four patients and its absence in the other four patients accounted for the lack of significant change in residual volume, functional residual capacity, and mixing efficiency. When bronchospasm was relieved in patients with abnormal airways beyond the obstruction, these airways contributed a greater percentage to total ventilation with resultant increase

5--Mean JIalue« ± StamltlTtI Deviation lor Significant Di!Jt>rt>nces after l eoproterenol Administration. Difference» Present Only W"ht>n Result» on Gilleocorticosteroid Tht>rapy [steroid ) Art>Com part'll to Results after ACTH Stimulation (ACTH). Jlalut>s lor Vital Capacitv (JlC). Residua! Volumel Total Lung Ca/Jacity (RJI/ TLC). Inspiratory Capacity (lC). Pt>ak Flow Ratt> (PFR). Maximal Mitl-t>xpirator~' Flow Rate (MMFR). Mixin" E/Jicit>t,cy (ME). Stt>ally Statt> Di!Jusin" Capacily. Eml Titlal Samplt> (DL"oll) Arp ExpressNI as Percent 01 Predicted Normal Standard, Table

Index

St"mid

\T In'TLC J('

PFR :'11:\1 FH :'lIE

Dr.",,"

8li 1-l:J !ll 57 3-l 1)0 117

± l-l ± :J3 ± IS ± :JI

±

2:~

± 22 :~ I

±

.\('TII H-l 10ii 10ii 71 -lli 1'0 11'0

± II ± 2S ± 22

± :JB ± 2ii ± :J7 ± H-l

p L.,ss Than p -co.nt p<0.02 p <0.02 p<0.O,1 p <0.02 p <0.02 p<0.02

CHEST, VOL. 61, NO.1, JANUARY 1972

ENDOGENOUS REGULATION OF PULMONARY RESPONSE TO ISOPROTERENOL fusion defect in addition to a ventilation/perfusion defect may exist in patients with asthma. In asthmatic patients, FEV I remains in direct proportion to vital capacity until vital capacity is normal, following which FEV! increases toward normal." In this study, FEY! remained abnormally low and did not vary in relation to 17-0HCS or isoproterenol; however, mean vital capacity did not return to the predicted normal standard (Table 1). Expiratory flow rates other than the FEY I improved significantly following isoproterenol and were more sensitive gauges of isoproterenol response despite a decrease in vital capacity (Table 2). In the treatment of asthma, isoproterenol response may increase to a maximum and then with further clinical improvement the response dirninishes." That patients had their best pulmonary function before isoproterenol when stimulated with ACTH could be due to an increased production of epinephrine and increased endogenous beta stimulation resulting from stimulation by ACTH of increased adrenal adenyl cyclase, cyclic A~[P, and phenylethanolamine-N-methyl transferase, the enzyme necessary for the conversion of norepinephrine to epinephrine, a potent beta stimulator causing bronchodilatation in the lungs. Response to isoproterenol was best when 17OHCS was lowest. Inability to release ACTH in patients following discontinuation of glucocorticosteroid therapy could lead to decreased endogenous epinephrine, minimal endogenous beta stimulation, and maximal response to exogenous beta stimulation with isoproterenol. The regulation of endogenous epinephrine production by ACTH might explain why glucocorticosteroids are helpful in status asthrnaticus when used for their anti-inflammatory effect and why their longterm use in bronchial asthma is often not beneficial. REFEHE:-.iCES

American Thoracic Society: Statement on definition and classification of chronic bronchitis, asthma, and emphysema. Amer Hev Hesp Dis 8.'5:762, 1962

CHEST, VOL. 61, NO.1, JANUARY 1972

17

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