Studies of the mechanism of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema: The effect of an ACE inhibitor on cutaneous responses to bradykinin, codeine, and histamine

Studies of the mechanism of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema: The effect of an ACE inhibitor on cutaneous responses to bradykinin, codeine, and histamine Michael

W. Anderson,

MD,* and Richard

D. deShazo,

MD****

Orlando,

Flu.

To understand better the mechanism of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema, we studied the effects of ACE-inhibitor treatment on wheal-and-flare responses to histamine, codeine, and bradykinin in 10 normal subjects. No change in the size of wheal-and-flare reactions to histamine occurred, but the size of wheal reactions to codeine and bradykinin increased in all study subjects after ingesting the ACE inhibitor, captopril. Five of 10 study subjects developed flushing reactions after ACE-inhibitor treatment. We conclude that inhibition of bradykinin metabolism by ACE inhibitors is the probable cause of ACE inhibitor-related angioedema and that substance P is not the predominant mediator in this process. (J ALLERGY CLIN IMMUNOL 1990;85:856-8.)

ACE inhibitors are effective for the treatment for hypertension and congestive heart failure.‘.’ Recently, angioedema and urticaria have been reported as adverse reactions to these agents. Such adverse reactions frequently occur shortly after the first dose and appear to be dose related. ‘34,’ Moreover, since these reactions occur with chemically unrelated ACE inhibitors, a nonimmunologic mechanism has been suggested.‘. 9 ACE inhibitors not only block the conversion of angiotensin I to angiotensin II but also decrease the metabolism of bradykinin.” Because bradykinin is a potent vasodilator, it has been hypothesized that these reactions might result from decreased metabolism of endogenous tissue bradykinin.‘, 9 ACE inhibitors also block the metabolism of substance P, a potent neuropeptide in the C fibers of the skin.” Our study was designed to determine if bradykinin, substance P, or both are related to these adverse reactions. Furthermore, we asked if these mediators act directly on blood vessels of the skin or indirectly through mast cells or the sensory C fibers of the skin. To address From the *Allergy-Immunology Sections, Departments of Medicine and Pediatrics, Tulane University School of Medicine, New Orleans, La., and the **University of South Alabama School of Medicine, Mobile, Ala. Received for publication June 9, 1989. Revised Nov. 17, 1989. Accepted for publication Dec. 1, 1989. Reprint requests: Michael W. Anderson, MD, 85 W. Miller, Suite 405, Orlando, FL 32806. l/1/18675

666

M

ACE: Angiotensm-converting enzyme

these questions, we evaluated dermal responses to histamine, codeine, and bradykinin in a group of normal control subjects before and after treatment with an ACE inhibitor. Our data suggest that bradykinin plays the major role in these adverse reactions to ACE inhibitors by acting directly on the blood vessels of the skin. METHODS Subjects Ten healthy subjects,aged24 to 45 years, with no history of heart disease, asthma, hypertension, or drug allergy, formed the study group. None were taking medication, and none had ever taken ACE inhibitors. All subjectsgave written informed consent to the study, which was approvedby the Institutional Review Board at Tulane University Medical School. Skin tests Three dilutions of histamine (2.75, 1.1, and 0.55 mg/mI; Center Laboratory, Port Washington, N.Y.), codeine phosphate(0.2,0.04, and 0.008 mg/mI; a nonspecific mastcell degranulator), and bradykinin (40.0, 8.0, and 1.6 kg/ml, i.e., 30, 6.5, and 1.3 mmol/L solutions, respectively; Sigma Chemical Co., St. Louis, MO., lot 117F58001) were prepared in normal saline and sterilized by

VOLUME NUMBER

ACE inhibitor-associated

85 5

TABLEI

Medietor

Histamine wheal

angiarderna

_.-..--

Dilution

Mean

k SEM size (cma) of wheal (n = 10)

No.

Before ceptotril

. ----

After captotril

Mean change in size

g Value

1

1.14 r 0.19

0.98 r 0.06

0.16 2 0.18

SO.39

0.78 + 0.09 0.57 ? 0.10

0.88 t 0.10 0.61 t 0.08

0.10 + 0.07 0.04 t 0.06

-50.20 -+X,.36

Histamine

1

flare

2 3

9.79 -1- 2.59 4.64 k 1.70 0.94 k 0.29

10.63 t 3.21 5.35 i 2.32

0.84 '-c 0.30 0.71 t 0.72

-a,51 SO.35

1.98 2 0.59

1.04 t 0.65

.a. 15

1

1.87 2 0.20 1.43 k 0.16 0.91 +- 0.14

2.26 It 0.18 1.99 t 0.19 1.37 +- 0.12

0.39 t 0.22 0.56 -t 0.21 0.46 t 0.09

so. 11

2 3

22.89 t 3.24 16.32 r 2.42 6.83 t 1.56

5.95 2 2.65 4.92 t 2.48 3.21 e 1.89

Codeine

1

16.94 ? 1.87

flare

2 3

11.40 ~fi 1.58 3.62 k 1.59

Bradykinin

1 2 3

1.78 + 0.28 1.01 2 0.12

2.73 t 0.22

wheal

0.80 r 0.22

1.41 '-+ 0.15

filterization. Each subject received intradermal injections of 0.05 ml of each dilution of these three agentson the volar aspect of one arm. After 15 minutes, the wheal-and-flare areaswere outlined on the skin with a ballpoint pen. Each area was then covered with transparent tape, and the ink imprint on the tape was transferredto graph paper.The area of wheal-and-flare reaction was quantified by counting the number of boxes on the graph paper enclosed by the ink imprint. Data were recorded in this manner for all wheal and flare reactions. After the initial skin tests were recorded, each study subject ingested a single 25 mg captopril tablet (Capoten; E. R. Squibb and Sons, Inc., Princeton, N.J.). One hour later, all nine intraclermal tests were repeatedat a similar location on the opposite arm, and the measurementswere recorded similarly. Wheal reactions and flare reactions of each dilution of his&amineand codeine were analyzed separately. Wheal reactions alone were analyzed for bradykinin, which did not induce flare reactions at the doses used. Results of pre- and postcaptopril treatmentvalues were analyzed with the Student’spaired t test. Sitting blood pressure and radial pulse were taken initially and at 15 minutes after application of skin tests. RESULTS (Table I) Skin respowe before and after captopril There were no significant changes in the size of the histamine wheal or flare reactions in the 10 study subjects after captopril administration. In contrast, wheal sizes increased for two of the three dilutions of codeine (0.04 and 0.008 mg/ml) at p < 0.003 and p < 0.001, respectively. All subjects had increases in wheal sizes after captopril for the first codeine dilution as well. These increases did not reach statistical sig-

I--

or flare

2 3

Codeine wheal

857

1.97 -?r0.35

a.03 ~0.001 SO.05 SO.08

i(l. 12

0.95 '- 0.27 ~0.006 0.96 t 0.33 SO.02 0.61 it 0.16 SO.005 ___.--_.-

nificance (p > 0.05). The dermal Bare reaction for the first dilution of codeine (0.2 mg/mli increased significantly (p < 0.05) after captopril administration. However, the size of flare reactions to codeine were not significantly (p > 0.05) affected by ACEinhibitor treatment at the other two doses. The size of wheal reactions to bradykinin increased significantly in all subjects after captopril administration for all three dilutions of bradykinin (p < 0.006, p < 0.02, and p < 0.005, respectively). No Aare reactions to bradykinin were noted before or after ACE inhibitor in any study subject. Vascular

changes

after captoprH

treatment

No study subject reported either an unusual response to skin testing before ingestion of captopril, or angioedema, or urticaria. However, five of the 10 study subjects experienced symptomatic and visible cutaneous facial flushing after taking the captopril and receiving skin tests. These flushing reactions occurred 2 to 3 minutes after the last bradykinin injection and lasted for approximately 5 minutes. The reactions were associated with a decrease in diastolic pressure of at least 10 mm Hg in three of the five subjects. No changes in the systolic blood pressure or pulse occurred in these subjects. The flushing reaction could not be reproduced in one of the five study subjects who flushed during the original experiments when that subject ingested captopril, and all the skin tests were repeated except bradykinin. Four the study subjects subsequently had the entire study repeated with the substitution (unknown to the

858

Anderson

and deShazo

study subjects) of a placebo for the captopril. No significant changes in any wheal-and-flare reactions were observed for this group before and after placebo ingestion. DISCUSSION

ACE has multiple substrates,including angiotensin I, kinins to include bradykinin, and sensory neuropeptides to include substanceP.lo*I’ Bradykinin increasesvascular permeability and induces wheal formation when it is injected into the skin and has been postulated to cause the angioedema noted in some patients who receive ACE-inhibitor treatment.‘. 9 In that regard, serum levels of bradykinin are elevated in experimental animals after ingestion of ACE inhibitors . ‘O Two previous studies reported that the ACEinhibitor, enalapril, increaseddermal responsesto bradykinin.‘, I2Our study demonstratesthat therapy with a chemically unrelated ACE-inhibitor, captopril, also increaseswheal reactions to intradermal injections of bradykinin. Furthermore, in our study, wheal reactions induced by the nonspecific mast cell degranulator, codeine, also increased in size with ACE inhibition. ACE inhibitors block the metabolism of bradykinin and the sensory neuropeptide substanceP, as well as angiotensin I.” SubstanceP is presentin human skin, and the intradermal injection of substanceP causes wheal-and-flare reactions. Therefore, it is possible that increased dermal levels of either bradykinin or substanceP could contribute to the syndrome of angioedemanoted with ACE-inhibitor therapy. Our data support the notion that bradykinin is the predominant mediator of these reactions, although these data do not completely exclude a role for substanceP. If ACE inhibition increasedlevels of substanceP such that it contributed to angioedema, codeine- and histaminerelated flare reactions should have consistently increased in size with ACE-inhibitor treatment, since such hare reactions have been demonstrated to be causedby a neural axon reflex mediatedby substance P.13This was not the case. Thus, because codeine causesmast cell degranulation and becausemast cell degranulation leads to generation of tissue bradykinin,14 inhibition of bradykinin metabolism by ACE inhibition most likely led to the increasein the wheal size in the experiments with codeine noted. The fact that 50% of the study subjectsexperienced a cutaneous flushing reaction after bradykinin injec-

J. ALLERGY

CLIN. IMMUNOL. MAY 1990

tion and ACE-inhibitor treatment suggeststhat bradykinin metabolism was inhibited enough that systemic absorption occurred. Furthermore, some individuals appeared to be more sensitive than other individuals to a given dose of bradykinin under the experimental circumstances used. This observation suggests that angioedema associated with ACEinhibitor treatment is an exaggeration of a common responseto this class of drugs and may reflect a difference in the kinetics of bradykinin metabolism in the subjects at risk for these reactions. It is possible that careful interpretation of skin test results with bradykinin in the presenceof ACE inhibition may predict thoseindividuals at greatestrisk for angioedemawhile they are receiving ACE-inhibitor therapy. The possibility that ACE-inhibitor therapy may increase the severity of anaphylaxis by inhibiting the metabolism of bradykinin requires evaluation. REFERENCES 1. Wood SM, Mann RD, Rawlins MD. Angioedema and urticaria associated with angiotensin-converting enzyme inhibitors. Br Med J 1987;294:91-2. 2. Wilkin JK, Hammon JJ, Kirkendall WM. The captoprilinduced eruption. Arch Dermatol 1980;116:902-5. 3. Coulter DM, Edwards IR. Cough associated with captopril and enalapril. Br Med J 1987;294: 1521. 4. Sesoko S, Kaneko Y. Cough associated with the use of captopril. Arch Intern Med 1985;145:1524. 5. Semple PF, Herd GW. Cough and wheeze caused by inhibitors of angiotensin converting enzyme. N Engl J Med 1986;314:61. 6. Webb D, Benjamin N, Collier J, Robinson B. Enalaprilinduced cough. lancet 1986;2: 1116. I Town GI, Hallwright CP, Maling T, et al. Angiotensinconverting enzyme inhibitors and cough. N Z Med J 1987;100:161. 8. Femer RE, Simpson JM, Rawlins MD. Effects of intradermal bradykinin after inhibition of angiotensin-converting enzyme. Br Med J 1987;294:1119-20. 9. Newball HH, Keiser HR. Relative effects of bradykinin and histamine on the respiratory system of man. J Appl Physiol 1973;35:552-6. 10. Regoli D, Barabi J. Pharmacology of hradykinin and related kinins. Pharmacol Rev 1980;32:1-46. 11. Casceiri M, Bull H, Mumford R, et al. Carboxyterminal tripeptidyl hydrolysis of substance P by purified rabbit lung angiotensin-converting enzyme and the potentiation of substance P activity in vivo by captopril and MIC 422. Mol Pharmacol 1983;25:287-93. 12. Fuller RW, Warren JB, McCasken M, et al. Effect of enalapril on the skin response to bradykinin in man. Br J Clin Pharmacol 1987;23:88-90. 13. Foreman JC. Neuropeptides and the pathogenesis of allergy. Allergy 1987;42:1-11. 14. Wasserman SI. Mediators of immediate hypersensitivity. J ALLERGYCLIN IMMUNOL 1983;72:101-15.