CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES AND VASCULAR SMOOTH-MUSCLE

At least 30 different phosphodiesterase (PDE) enzymes have now been id entified in mammalian tissues and cells, many of which are products of separate genes. These different isoenzyme forms can be subdivided int o seven families based on their genetic and functional characteristics . Relatively specific inhibitors are available for at least five of th ese PDE families. A functional classification based on substrate speci ficity, regulatory properties, and sensitivity to inhibition by isozym e- and tissue-selective inhibitors can be used in describing the PDEs of vascular smooth muscle. Inhibition of these PDEs, especially with i nhibitors of the PDE3 isoform, promotes vascular relaxation, particula rly if the preparation of smooth muscle has been preconracted. For the most part, the drugs appear to act directly on smooth muscle; their e ffects are usually observed in endothelium-denuded preparations. In ad dition to their cardiotonic properties, many PDE3 inhibitors possess a ntiplatelet and thrombolytic activities, thereby suggesting the potent ial benefit of these drugs in treating diseases of the cardiovascular system. Isozyme- and cell-specific drugs have been shown to alter the synthetic state (i.e. proliferative phenotype) of smooth muscle cultur es toward the appearance of the contractile phenotype. This suggests t he possible use of selective PDE inhibitors to minimize the problem of restenosis seen after angioplasty. The development of novel methods t o deliver more potent and selective PDE inhibitors to individual cell types and subcellular locales will lead to new therapeutic uses for th is class of drugs in diseases of the cardiovascular system.