Biochemical regulation of airway smooth muscle tone: current knowledge and therapeutic implications

Abstract

Evidence collected during the last decade indicates that the molecular processes responsible for smooth muscle contraction are fundamentally different from those responsible for skeletal muscle contraction. Furthermore, because of the diverse functional roles of various smooth muscles, it would not be surprising if significant differences in regulatory processes also exist among different smooth muscles. Such diversity may already be exemplified by differences in cross-bridge kinetics and sources of activator Ca2+. Additional unique regulatory features of various smooth muscle types will undoubtedly be uncovered by further research. A convincing body of data suggests that activation of the adenylate cyclase/protein kinase cascade is responsible for the bronchodilation produced by beta-adrenoceptor agonists. Although the exact mechanism by which the activation of cAMP-dependent protein kinase induces relaxation is not clear, the phosphorylation of multiple substrates may be involved. Phosphorylation of these substrates can promote relaxation by decreasing the myoplasmic Ca2+ concentration, decreasing the Ca2+ sensitivity of the contractile apparatus, or both. Thus, because beta-adrenoceptor agonists act as physiologic antagonists of broncho-constriction, they should relax airway smooth muscle regardless of the mediator(s) responsible for the bronchospasm. Perhaps this is the major reason that the beta-adrenoceptor agonists have become the premier class of drugs used in the treatment of bronchial asthma. As useful as the sympathomimetic bronchodilators have been, they are not without liabilities. These liabilities include: cardiovascular and skeletal muscle side effects, an inherent subsensitivity of the asthmatic patient population to beta-adrenoceptor agonists, the development of tolerance and a loss of efficacy during severe asthmatic episodes. The fact that these drawbacks are probably shared by all sympathomimetic bronchodilators suggests that little therapeutic advantage will be gained by developing new beta-adrenoceptor agonists. The task of developing novel bronchodilators will be facilitated by an understanding at the molecular level of the diversity among smooth muscles and the processes that regulate smooth muscle tone. Hopefully, such knowledge will lead to a new generation of highly effective, tissue-selective bronchodilators with significant therapeutic advantages over those currently available.