ChemInform Abstract: Role of Phosphodiesterase Isoenzymes in the Control of Renin Secretion: Effects of Selective Enzyme Inhibitors

Abstract

In most cells, the steady-state level of cAMP ultimately depends on the rate of cAMP synthesis by adenylyl cyclase and the rate of cAMP hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). PDEs exist in multiple forms that have been grouped into seven families based on their substrate specificity, mode of regulation and kinetic properties. Selective inhibitors of many PDE families are now available. Examples are milrinone and trequinsin (PDE3); rolipram and Ro 20-1724 (PDE4); and zaprinast, sildenafil and didyridamole (PDE5). These inhibitors have proven to be valuable tools to investigate the role of PDEs in cell function. Representatives of most PDE families are present in the kidneys, and recent studies in this and other laboratories have provided evidence that some of them participate in the regulation of renin secretion. In particular, administration of selective PDE inhibitors has marked effects on renin secretion. For example, the PDE3 inhibitors milrinone and trequinsin increase resting renin in conscious rabbits and enhance the renin secretory response to beta-adrenergic stimulation. Milrinone also increases renin secretion in human subjects. The PDE4 inhibitors rolipram and Ro 20-1724 both increase renin secretion in rabbits and also enhance the renin response to beta-adrenergic stimulation. Studies in other laboratories have implicated other PDE families in the control of renin secretion. The aim of this review is to present current concepts concerning the PDEs and to discuss their role in the control of renin secretion by the kidneys.