title: Stimulation of placental prorenin secretion by selective inhibition of cyclic nucleotide phosphodiesterases.
abstract: Prorenin secretion by human villous placenta is known to be stimulated by activation of adenylate cyclase and enhanced cyclic AMP (cAMP) generation. Placental tissue contains predominantly type III (cGMP-inhibited) and type IV (cAMP-specific) phosphodiesterases (PDEs), which inactivate cAMP. To evaluate the role of PDE subtypes in the regulation of prorenin secretion by human placenta, explants were cultured in the presence of isobutylmethylxanthine (IBMX), a non-selective PDE inhibitor, and selective inhibitors for various PDE subtypes. Inhibition of PDE subtypes with cilostamide (type III), Ro 20-1724 (type IV) and zardaverine (types III and IV) increased prorenin release. Inhibition of type I (Ca(2+)/calmodulin-dependent) PDE by 8-MeoM-IBMX and of type V (cGMP-specific) PDE by zaprinast or dipyridamole did not affect prorenin secretion. The stimulation of prorenin secretion by PDE inhibitors was attenuated by cAMP-dependent protein kinase inhibition. The selective PDE inhibitors caused a parallel increase in media cAMP and prorenin and also increased tissue prorenin levels. These studies demonstrate that cAMP degradation by type III and IV PDE isoenzymes is a major regulatory mechanism for placental prorenin secretion. It is suggested that enhancers of adenylate cyclase activity are constitutively present in placenta and influence prorenin synthesis and release.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Downing
authors.forename: A M
authors.initials: AM
authors.lastname: Poisner
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D006063:Chorionic Gonadotropin / Q000032:analysis; D003470:Culture Media / Q000737:chemistry; D046508:Culture Techniques; D000242:Cyclic AMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000032:analysis*; D006801:Humans; D010920:Placenta / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D012083:Renin / Q000032:analysis*
chemical_list: D006063:Chorionic Gonadotropin; D003470:Culture Media; D004792:Enzyme Precursors; D011724:Pyridazines; D015363:Quinolones; C021294:cilostamide; D000242:Cyclic AMP; D011494:Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D012083:Renin; D015056:1-Methyl-3-isobutylxanthine; C066436:zardaverine