title: Angiotensin II-aldosterone interaction in human coronary microarteries involves GPR30, EGFR, and endothelial NO synthase.
abstract: OBJECTIVE
  The aim of this study was to investigate the aldosterone-angiotensin (Ang) II interaction in human coronary microarteries (HCMAs).
  
  
  RESULTS
  HCMAs, obtained from 75 heart-beating organ donors, were mounted in myographs and exposed to Ang II, either directly or following a 30-min pre-incubation with aldosterone, 17β-oestradiol, hydrocortisone, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, the extracellular regulated kinase 1/2 (ERK1/2) inhibitor PD98059, the GPR30 antagonist G15, or the epidermal growth factor receptor (EGFR) antagonist AG1478. Ang II constricted HCMAs in a concentration-dependent manner. All steroids, at nanomolar levels, potentiated Ang II and G15 prevented this effect. The potentiation disappeared or was reversed into Ang II antagonism at micromolar steroid levels. NO synthase (NOS) inhibition prevented the latter antagonism in the case of 17β-oestradiol, whereas both aldosterone and 17β-oestradiol at micro- (but not nano-) molar levels induced endothelial NOS phosphorylation in human umbilical vein endothelial cells. AG1478, but not SB203580 or PD98059, abolished the Ang II-induced contraction in the presence of aldosterone or 17β-oestradiol, and none of these drugs affected Ang II alone.
  
  
  CONCLUSIONS
  Steroids including aldosterone affect Ang II-induced vasoconstriction in a biphasic manner. Potentiation occurs at nanomolar steroid levels and depends on GPR30 and EGFR transactivation. At micromolar steroid levels, this potentiation either disappears (aldosterone and hydrocortisone) or is reversed into an inhibition (17β-oestradiol), and this is due to the endothelial NOS activation that occurs at such concentrations.
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine,  Erasmus MC, Dr Molewaterplein 50, room EE1418b, 3015 GE Rotterdam,  The Netherlands.
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Batenburg
authors.forename: Pieter M
authors.initials: PM
authors.lastname: Jansen
authors.forename: Antoon J
authors.initials: AJ
authors.lastname: van den Bogaerdt
authors.forename: Alexander H
authors.initials: AH
authors.lastname: J Danser
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology*; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D001160:Arterioles / Q000187:drug effects* / Q000201:enzymology; D002478:Cells, Cultured; D002648:Child; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D009213:Myography; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020239:Receptor Cross-Talk; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C109584:GPER1 protein, human; D006727:Hormone Antagonists; D047428:Protein Kinase Inhibitors; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D000450:Aldosterone; D004958:Estradiol; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006854:Hydrocortisone