Cyclic nucleotide phosphodiesterase isoenzymes and asthma--outstanding issues

Abstract

Cyclic nucleotide phosphodiesterase isoenzymes hydrolyse and thus inactivate the intracellular second messengers cyclic AMP and cyclic GMP. Inhibitors of these isoenzymes modulate tissue function by reducing the rate of breakdown of the cyclic nucleotides. Eukaryotic cells contain multiple forms of phosphodiesterase with differing regulatory characteristics and substrate specificities. At present, the majority of the identified isoenzymes can be grouped into five families (PDE I-PDE V). These isoenzymes have differing distributions and play differing relative roles in the hydrolysis of cyclic nucleotides between tissues. Thus, isoenzyme selective inhibitors may selectively modulate tissue function. Drugs which are therapeutically useful in asthma either bronchodilate or reduce the underlying inflammatory condition. Inhibitors of PDE III, PDE IV and PDE V relax airways smooth muscle. Inhibitors of PDE IV attenuate the activation of pro-inflammatory cells, an effect which in some assays is potentiated by additional PDE III inhibition. PDE V inhibition has not been shown to result in potentially useful anti-inflammatory activity. Despite various degrees of tissue selectivity, the possible side effect profile of isoenzyme selective phosphodiesterase inhibitors requires elucidation before these agents can be proposed as selective anti-asthma drugs. However, it is apparent that selective inhibitors of PDE III, PDE IV and PDE V may be useful bronchodilators, whilst PDE IV and PDE III/IV inhibitors also possess potentially useful anti-inflammatory activity. Such compounds require further evaluation in animals and man to clarify their full potential as therapeutic agents for the treatment of asthma.