Bronchoprotection by salmeterol: cell stabilization or functional antagonism? Comparative effects on histamine- and AMP-induced bronchoconstriction.

Salmeterol provides bronchoprotection against a number of constrictor stimuli for more than 12 h after a single dose. This effect could be due either to functional antagonism at the level of airway smooth muscle or to cell-stabilizing effects of the compound. In this study, we attempted to clarify this mechanism by comparing the effects of salmeterol (50 micrograms), salbutamol (200 micrograms) and placebo on the airway responsiveness to histamine (to assess functional antagonism), and to adenosine 5'-monophosphate (AMP) (to assess additional cell-stabilizing effects), 14 h after drug treatment. Thirteen patients with mild allergic asthma were studied in a double-blind, randomized protocol on 6 days, at least 48 h apart. Forced expiratory volume in one second (FEV1) was measured before and 15 min after inhalation of the study medication. Then, 14 h later (8 a.m. the following morning), a bronchoprovocation test with histamine or AMP was performed. We found that 14 h after inhalation, salmeterol still had a significant effect on FEV1 in comparison to placebo and salbutamol. The provocative dose producing a 20% fall in FEV1 (PD20histamine) was significantly increased after salmeterol, whilst the increase in PD20AMP did not reach significance. The shift in PD20 (in doubling dose steps) induced by salmeterol pretreatment was not different between histamine and AMP. We conclude that the prolonged protective effect of salmeterol occurs via an extended bronchodilating and functional antagonistic action and not via a cell-stabilizing effect.

[1]  E. Walters,et al.  Changes in methacholine induced bronchoconstriction with the long acting beta 2 agonist salmeterol in mild to moderate asthmatic patients. , 1993, Thorax.

[2]  J E Cotes,et al.  Lung volumes and forced ventilatory flows , 1993, European Respiratory Journal.

[3]  J. Kemp,et al.  A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. , 1992, The New England journal of medicine.

[4]  A. Zwinderman,et al.  Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. , 1992, The New England journal of medicine.

[5]  J. Palmer,et al.  A twelve month comparison of salmeterol with salbutamol in asthmatic patients. European Study Group. , 1992, The European respiratory journal.

[6]  R. Pauwels,et al.  The effect of inhaled salmeterol on methacholine responsiveness in subjects with asthma up to 12 hours. , 1992, The Journal of allergy and clinical immunology.

[7]  A. Cartier,et al.  Durée de l'effet bronchoprotecteur du salmétérol dans l'asthme induit par l'hyperventilation d'air froid sec , 1992 .

[8]  P. Barnes,et al.  Tolerance to the nonbronchodilator effects of inhaled beta 2-agonists in asthma. , 1992, The New England journal of medicine.

[9]  M. Johnson,et al.  Salmeterol: a potent and long‐acting inhibitor of inflammatory mediator release from human lung , 1991, British journal of pharmacology.

[10]  A. Tattersfield,et al.  A single-dose comparison of inhaled albuterol and two formulations of salmeterol on airway reactivity in asthmatic subjects. , 1991, The American review of respiratory disease.

[11]  S. Holgate,et al.  The effect of inhaled ipratropium bromide alone and in combination with oral terfenadine on bronchoconstriction provoked by adenosine 5'-monophosphate and histamine in asthma. , 1991, The Journal of allergy and clinical immunology.

[12]  S. Holgate,et al.  Protection against allergen-induced asthma by salmeterol , 1990, The Lancet.

[13]  J. Hedner,et al.  Inhaled salmeterol and salbutamol in asthmatic patients. An evaluation of asthma symptoms and the possible development of tachyphylaxis. , 1990, The American review of respiratory disease.

[14]  P. T. Larsson,et al.  Altered adrenoceptor responsiveness during adrenaline infusion but not during mental stress: differences between receptor subtypes and tissues. , 1989, British journal of clinical pharmacology.

[15]  S. Holgate,et al.  The contribution of histamine to immediate bronchoconstriction provoked by inhaled allergen and adenosine 5' monophosphate in atopic asthma. , 1987, The American review of respiratory disease.

[16]  S. Holgate,et al.  Adenosine-induced bronchoconstriction in asthma: role of mast cell-mediator release. , 1985, The Journal of allergy and clinical immunology.