Action of Mediators on Airway Smooth Muscle: Functional Antagonism as a Mechanism for Bronchodilator Drugs

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Abstract
The beta-adrenoceptor agonists have become the cornerstone of bronchodilator therapy. These agents are "functional" or "physiologic" antagonists that actively relax airway smooth muscle through a cyclic-AMP (cAMP)-mediated decrease in myoplasmic Ca2+ content. Hence, unlike specific receptor antagonists, the sympathomimetics should reverse bronchoconstriction regardless of the mediator(s) involved. Indeed, one of the primary beneficial attributes of beta-adrenoceptor agonists is their inhibitory activity against a wide range of bronchoconstrictors. As successful as the sympathomimetic bronchodilators have been, they are not without liabilities. These liabilities include: 1) cardiovascular and skeletal muscle side effects, 2) an inherent subsensitivity of the patient population to beta-adrenoceptor agonists, 3) the development of tolerance, and 4) loss of efficacy during severe asthmatic episodes. These limitations are not specific for individual agents but are shared by all beta-adrenoceptor agonists. A significant improvement in the pharmacotherapy of asthma would be obtained by identifying novel bronchodilators devoid of one or more of the aforementioned liabilities. The development of isozyme-selective phosphodiesterase (PDE) inhibitors is one promising approach toward this goal. Interest in PDE inhibition as a therapeutic target has been renewed by the realization that PDEs exist in multiple isoforms and that the distribution of these isoforms varies significantly among tissues. This information, coupled with the recent synthesis of PDE inhibitors selective for several of the isozymes, raises the possibility of breeding organ-selectivity into this class of compounds. Results from preliminary experiments with isozyme-selective PDE inhibitors have helped to identify appropriate drug targets in airway smooth muscle. These early studies suggest that the synthesis of novel isozyme-selective PDE inhibitors not only may provide tools with which to understand the biologic function of various PDE isozymes, but may also lead to the development of improved therapeutic agents.