title: Angiotensin-II subtype 2 receptor agonist (CGP-42112) inhibits catecholamine biosynthesis in cultured porcine adrenal medullary chromaffin cells.
abstract: Angiotensin II subtype 2 receptor (AT(2)-R) is abundantly expressed in adrenal medullary chromaffin cells. However, the physiological roles of AT(2)-R in chromaffin cells remain to be clarified. Therefore, we investigated the effects of CGP42112 (AT(2)-R agonist) on catecholamine biosynthesis in cultured porcine adrenal medullary cells. We initially confirmed AT(2)-R was predominantly expressed in porcine adrenal medullary cells by [(125)I]-Ang II binding studies. CGP42112 (>==1 nM) significantly inhibited cGMP production from the basal value. Tyrosine hydroxylase (TH) is a rate-limiting enzyme in the biosynthesis of catecholamine, and its activity is regulated by both TH-enzyme activity and TH-synthesis. CGP42112 (>==1 nM) significantly inhibited TH-enzyme activity from the basal value. These inhibitory effects of CGP42112 on TH-enzyme activity and-cGMP production were abolished by PD123319 (AT(2)-R antagonist) while CV-11974 (AT(1)-R antagonist) was ineffective. We also tested whether decrease of cGMP is involved in the inhibitory effect of CGP42112 on TH-enzyme activity. Pretreatment of 8-Br-cGMP (membrane-permeable cGMP analogue) prevented the inhibitory effect of CGP 42112 on TH-enzyme activity. Similar to that of TH-enzyme activity, CGP42112 (>==1 nM) significantly reduced TH-mRNA and TH-protein level from the basal value, and these inhibitory effects were abolished by PD123319 but not CV-11974. These findings demonstrate that CGP 42112 reduces both TH-enzyme activity and TH-synthesis and that these inhibitory effects could be mediated by decrease of cGMP production.
authors.affiliation: Department of Clinical Pathology, University of Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Takekoshi
authors.forename: K
authors.initials: K
authors.lastname: Ishii
authors.forename: K
authors.initials: K
authors.lastname: Isobe
authors.forename: T
authors.initials: T
authors.lastname: Nanmoku
authors.forename: Y
authors.initials: Y
authors.lastname: Kawakami
authors.forename: T
authors.initials: T
authors.lastname: Nakai
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001713:Biphenyl Compounds; D002395:Catecholamines / Q000096:biosynthesis*; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000819:agonists* / Q000378:metabolism; D013552:Swine; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002395:Catecholamines; D007093:Imidazoles; D009842:Oligopeptides; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C060894:CGP 42112A; C073402:PD 123319; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D014446:Tyrosine 3-Monooxygenase; D006152:Cyclic GMP; C081643:candesartan