Classification of Phosphodiesterases and the Therapeutic Effects of their Inhibitors (Review)

Phosphodiesterase (PDE) is an enzyme that catalyses the hydrolysis of phosphodiester bonds. The enzyme is also takes responsibility for the hydrolysis of cyclic 3',5'adenosine monophosphate (cAMP) and 3',5'cyclic guanosine monophosphate (cGMP). The PDE enzymes in mammals are classified into 11 families, namely PDE1-PDE11. The classification is on the basis of amino acid sequences, substrate specificities, regulatory properties, pharmacological properties, tissue distribution. Various PDE of the same family are related with regards to functionality but differs in their specificities for substrates. Some are hydrolases with selective preferences for cAMP (PDE4, 7 and 8), while the selective preference for some others is for cGMP (PDE5, 6 and 9). Some have the ability to hydrolyse both cAMP and cGMP (PDE1, 2, 3, 10 and 11). cAMP, and cGMP both has important roles in the regulation of inotropic mechanisms in the human myocardium. However, cAMP greatly affects other tissues, and different phosphodiesterase isoenzymes are found in many other tissues. Drugs with inhibitory effects on phosphodiesterase (thus reducing the breakdown of cAMP) have a therapeutic action on the heart, lung, and vasculature as well as on platelet function and inflammatory mechanisms. Inhibitors like these are commonly used as "biochemical tools" to study of role which cyclic nucleotides plays in the cell, but they also may be useful to investigate the structural and functional activities of PDE. As therapeutic agents, they can also be utilized in controlling the pathophysiological changes of responses generated by the cyclic nucleotides in the central nervous system (CNS), cardio-vascular, lung, digestive tract and respectively. PDE enzymes are often targets for inhibition by pharmacological processes due to their unique tissue distribution, structural and functional properties and the inflammatory process. The effect of many of these drugs is evident in more than one isoenzyme, and many tissues possess more than one isoenzyme. As a result, phosphodiesterase inhibitors (PDEI) can have a multiplicity of effects. For example, theophylline has effects on the lung, as well as cardiac and vascular effects; amrinone affects cardiac, vascular and platelet functions. The PDE inhibition, change the intracellular response to extra cellular signals by affecting the processes by the the cyclic nucleotides.