Phosphodiesterase inhibitors: new opportunities for the treatment of asthma.

Abstract

Theophylline has been a mainstay in the treat- ment of asthma for over 50 years.Its thera- peutic value stems from a combination of anti- inflammatory and bronchodilator activities in addition to its ability to increase diaphragmatic contractility.14Although the pharmacological effects of theophylline have been studied extensively both in the laboratory and in the clinic, the molecular mechanisms res- ponsible for its activity in asthma remain ill defined.In fact, several cellular activities probably contribute to its action, including cyclic nucleotide phosphodiesterase inhibi- tion,' 5 adenosine receptor antagonism,6 stimulation of catecholamine release,7 and a poorly understood ability to increase the num- ber and activity of suppressor T lymphocytes.8Of theophylline's many activities, phos- phodiesterase inhibition may be the most important.Hypothetically, at least two therapeutically beneficial effects could result from inhibition of phosphodiesterase activity and the consequent rise in intracellular aden- osine 3',5'-monophosphate (cAMP) or guan- Cyclic AMP osine 3',5'-monophosphate (cGMP) concen- trations in key cells concerned in the pathophysiology of asthma (figure).Firstly, both cAMP and cGMP mediate airway smooth muscle relaxation,9 10 so a rise in either of these second messengers in airway smooth muscle should result in bronchodilatation.Secondly, the ability of PDE inhibitors to increase the cAMP content of inflammatory cells leads to an inhibition of cell activation.5 1112 In principle, then, PDE inhibitors should possess antiinflammatory activity.Although it is useful in the treatment of asthma, the value of theophylline is limited by a narrow therapeutic index and a wide range of gastrointestinal, central nervous system, and cardiovascular side effects.`4These sideeffects are generally ascribed to its lack of selectivity.Of particular importance in this respect is theophylline's ability to antagonise adenosine receptors and inhibit phosphodiesterase activity in inappropriate tissues (for example, gastrointestinal, central nervous sys- tem, cardiovascular).213 The development of drugs that couple the efficacy of theophylline CyclicGMP| Hormone Receptor