Section Review: Cardiovascular & Renal: Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiovascular diseases

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) comprise at least seven families of isozymes coded by related but distinct genes, grouped on the basis of their structural and enzymatic characteristics. Five of these families are known to be present in the cardiovascular system. A number of potent inhibitors have been synthesised with relative selectivity for some PDEs. However, there is no selective inhibitor of PDE1 (calmodulin-activated), and only one compound has been reported which selectively inhibits PDE2 (stimulated by cGMP). Available information is limited to pharmacological and therapeutic properties of drugs selectively inhibiting two PDEs specific for cAMP (PDE3, inhibited by milrinone-like cardiotonics, and PDE4, inhibited by rolipram) and a cGMP-PDE (PDE5, inhibited by zaprinast). Differential expression of PDEs and differential subcellular localisation provide the possibility of selectively targeting cardiovascular and platelet functions with selective PDE inhibitors. The resulting effects include short- and long-term modulation of cardiac and vascular inotropy, cardiac rhythm and exoitability, thrombosis, inflammatory responses to injury and, probably, proliferation of vascular smooth muscle cells. PDE3 inhibitors have been investigated in heart failure. Despite leading to marked haemodynamic improvement, chronic treatment with PDE3 inhibitors does not increase (and may even decrease) survival, due to arrhythmias (probably induced by excessive cAMP accumulation). PDE4 inhibitors are being actively investigated in inflammatory diseases. Their actions in endothelial cells may also lead to antithrombotic effects. PDE5 inhibitors might compensate the pathological impairment of nitric oxide-induced cGMP levels seen in atherosclerosis and after endothelial injury. Preclinical studies suggest that they may reduce myointimal proliferation after angioplasty. Identification of isozymes expressed in each tissue and determination of their possible pathological alterations will probably be possible in the near future. This will afford clarification of the role of PDEs in the cardiovascular system and the potential therapeutic uses of PDE inhibitors.