Reid I A
Department of Physiology, University of California, San Francisco, CA 94143-0444, USA.
Curr Pharm Des. 1999 Sep;5(9):725-35.
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.
在大多数细胞中，环磷酸腺苷（cAMP）的稳态水平最终取决于腺苷酸环化酶合成cAMP的速率以及环核苷酸磷酸二酯酶（PDEs）水解cAMP的速率。PDEs有多种形式，根据其底物特异性、调节方式和动力学特性可分为七个家族。现在已有许多PDE家族的选择性抑制剂。例如米力农和曲喹辛（PDE3）；咯利普兰和Ro 20-1724（PDE4）；以及扎普司特、西地那非和双嘧达莫（PDE5）。这些抑制剂已被证明是研究PDEs在细胞功能中作用的有价值工具。大多数PDE家族的代表存在于肾脏中，最近在本实验室和其他实验室的研究提供了证据，表明其中一些参与肾素分泌的调节。特别是，给予选择性PDE抑制剂对肾素分泌有显著影响。例如，PDE3抑制剂米力农和曲喹辛可增加清醒兔的基础肾素水平，并增强肾素对β-肾上腺素能刺激的分泌反应。米力农也可增加人类受试者的肾素分泌。PDE4抑制剂咯利普兰和Ro 20-1724均可增加兔的肾素分泌，并增强肾素对β-肾上腺素能刺激的反应。其他实验室的研究表明其他PDE家族也参与肾素分泌的控制。本综述的目的是介绍有关PDEs的当前概念，并讨论它们在肾脏控制肾素分泌中的作用。
