Correspondence

Sympathomimetic Agents and Airway Hyperreactivity

N Engl J Med 1993; 328:665-666March 4, 1993

Article

To the Editor:

The reports by Cheung et al.1 and O'Connor et al.2. (Oct. 22 issue) that the repeated administration of (±)-salmeterol1 or (±)-terbutaline2 results in diminished protection against bronchoconstrictor stimuli, despite sustained bronchodilator activity, are consistent with an earlier description of this phenomenon in patients exposed to (±)-albuterol3. In each instance this paradox has been interpreted as a manifestation of tolerance (i.e., adrenoceptor tachyphylaxis), disregarding the possibility that acute suppression of airway hyperreactivity by adrenoceptor activation4 may be nullified by the progressive induction of hyperreactivity during sustained exposure to these racemic mixtures5.

It has long been recognized that the repeated administration of (±)-isoproterenol, (±)-albuterol, and (±)-terbutaline increases the susceptibility of guinea pigs to lethal doses of inhaled spasmogens6. This phenomenon is a direct consequence of the heightened sensitivity of the airways to injected or inhaled spasmogens4,5. The loss of protection cannot be attributed to tolerance, since the inhalation of (±)-isoproterenol or the injection of (±)-albuterol immediately before challenge wholly abrogated responses to antigen that would otherwise have been lethal3.

In their study of the effect of one week of treatment with (±)-terbutaline, O'Connor et al.2 contrasted the slight loss of protective effect when methacholine was the bronchoconstrictor stimulus with the marked loss of protection when adenosine was the bronchoconstrictor stimulus. In making their conclusions, these authors assume that sensitivity to the bronchoconstrictor effects of methacholine and of mast-cell products (i.e., histamine, prostanoids, and peptidoleukotrienes) is not influenced by regular exposure to sympathomimetic agents. In the guinea pig, such an assumption is demonstrably invalid6. Hence, selective increased responsiveness to different airway spasmogens may reasonably be included as an alternative explanation for these findings. It would have been preferable to exclude this possibility by direct experimental observation.

K. Hoshiko, B.Sc.
I.D. Chapman, Ph.D.
J. Morley, Ph.D., F.R.C.Path.
Sandoz Pharma, CH-4002 Basel, Switzerland

6 References

1. 1

   Cheung D, Timmers MC, Zwinderman AH, Bel EH, Dijkman JH, Sterk PJ. Long-term effects of a long-acting β₂-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med 1992;327:1198-1203
   Full Text | Web of Science | Medline

2. 2

   O'Connor BJ, Aikman SL, Barnes PJ. Tolerance to the nonbronchodilator effects of inhaled β₂-agonists in asthma. N Engl J Med 1992;327:1204-1208
   Full Text | Web of Science | Medline

3. 3

   Jenne JW, Ahrens RC. Pharmacokinetics of β-adrenergic compounds. In: Jenne JW, Murphy S, eds. Drug therapy for asthma: research and clinical practice. Lung biology in health and disease. Vol. 31. New York: Marcel Dekker, 1987:213-58.
   

4. 4

   Morley J, Chapman ID, Foster A, Hoshiko K, Mazzoni L. Effects of (+) and racemic salbutamol on airway responses in the guinea-pig. Br J Pharmacol 1991;104:Suppl:295P-295P abstract.
   

5. 5

   Morley J, Hoshiko K, Chapman ID, Mazzoni L. The selective nature of airway hyperreactivity. J Physiol 1992;446:117P-117P
   Web of Science

6. 6

   Conolly ME, Davies DS, Dollery CT, George CF. Resistance to β-adrenoceptor stimulants (a possible explanation for the rise in asthma deaths). Br J Pharmacol 1971;43:389-402
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with Hoshiko et al. that the loss of protection by β₂-adrenoceptor agonists against bronchoconstrictor stimuli in vivo might be explained by progressive worsening of airway hyperresponsiveness during regular exposure to these drugs. In our study, however, we explicitly tested this hypothesis by measuring methacholine responsiveness, without pretreatment with salmeterol, 48 and 96 hours after the last dose of salmeterol in the washout period. We did not find any change in hyperresponsiveness, nor did Roberts et al.1 or Beach et al.,2 whose studies were also designed to detect potential worsening of airway hyperresponsiveness after the cessation of regular salmeterol therapy. Consequently, our observation of a loss of protection by salmeterol after four and eight weeks of regular treatment in patients with asthma cannot be explained by a concomitant increase in airway hyperresponsiveness. The phenomenon is more likely to be caused by tolerance or tachyphylaxis at the β₂-adrenoceptor level3.

D. Cheung, M.D.
P.J. Sterk, M.D., Ph.D.
University Hospital Leiden, 2300 RC Leiden, the Netherlands

3 References

1. 1

   Roberts JA, Bradding P, Holgate ST, Howarth PH. Effects of a six week course of salmeterol on bronchial reactivity. Thorax 1992;47:230P-230P abstract.
   Web of Science

2. 2

   Beach JR, Young CL, Harkawat R, Neill P, Walters EH, Hendrick DJ. Measurement of airway responsiveness during regular treatment with salmeterol and salbutamol. Eur Respir J 1991;4:Suppl:199s-199s abstract.
   

3. 3

   Nijkamp FP, Engels F, Henricks PAJ, Van Oosterhout AJM. Mechanisms of β-adrenergic receptor regulation in lungs and its implications for physiological responses. Physiol Rev 1992;72:323-367
   Web of Science | Medline

Author/Editor Response

Diminished responsiveness to β-agonists has been observed with most β-agonist-mediated responses after prolonged administration and is caused by β-receptor tolerance due to uncoupling and down-regulation of β-receptors. The fact that the bronchodilator response to β-agonists fails to show tolerance is the surprising observation. The reduced airway responsiveness to inhaled AMP reported in our study after prolonged treatment with inhaled terbutaline is unlikely to be explained by an increase in airway responsiveness as a result of exposure to racemic terbutaline, since this would not account for the difference observed between the responses to AMP and to methacholine, which should be similar if Hoshiko and colleagues are correct. It should be emphasized that the observations they have reported in anesthetized guinea pigs may not be relevant to human subjects, since they have used very large doses of infused β-agonists. Guinea pig airways may have nonspecific responses to the inactive enantiomers of adrenergic drugs, since both (±)- and (+)-propranolol cause bronchoconstriction in guinea pigs,1 whereas (±)- but not (+)-propranolol causes bronchoconstriction in patients with asthma2.

We agree with Hoshiko et al. that a possible explanation for the discrepancy between the loss of protection against AMP and methacholine may be that there is a difference in responsiveness between a cholinergic agonist and other spasmogens, such as histamine and sulfidopeptide leukotrienes released from airway mast cells. Some evidence against this possibility is provided by the observation that after the regular inhalation of terbutaline there is a reduction in protection against inhaled histamine that is of a similar order to the reduction we observed with methacholine3. To explore this rather unlikely possibility would have involved several additional prolonged studies in the same patients, and such studies are rather more difficult to conduct than those in anesthetized guinea pigs.

Brian J. O'Connor, M.R.C.P.I.
Peter J. Barnes, M.A., D.M., D.Sc., F.R.C.P.
National Heart and Lung Institute, London SW3 6LY, United Kingdom

3 References

1. 1

   Ney UM. Propranolol-induced airway hyperreactivity in guinea-pigs. Br J Pharmacol 1983;79:1003-1009
   Web of Science | Medline

2. 2

   Ind PW, Barnes PJ, Durham SR, Kay AB. Propranolol-induced bronchoconstriction in asthma: β-receptor blockade and mediator release. Am Rev Respir Dis 1984;129:A10-A10 abstract.
   

3. 3

   Vathenen AS, Knox AJ, Higgins BG, Britton JR, Tattersfield AE. Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1988;1:554-558
   CrossRef | Web of Science | Medline