title: Suppression of adrenal βarrestin1-dependent aldosterone production by ARBs: head-to-head comparison.
abstract: The known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion is mediated by either Gq/11 proteins or βarrestin1 (βarr1), both of which can couple to its type 1 receptors (AT₁Rs), present in adrenocortical zona glomerulosa (AZG) cell membranes. In the present study, we examined the relative potencies of all the currently used in the clinic AT₁R antagonist drugs (angiotensin receptor blockers, ARBs, or sartans) at preventing activation of these two signaling mediators (G proteins and βarrs) at the AngII-bound AT1R and, consequently, at suppression of aldosterone in vitro. All ARBs were found to be potent inhibitors of G protein activation at the AT₁R. However, candesartan and valsartan were the most potent at blocking AngII-induced βarr activation at this receptor, among the tetrazolo-biphenyl-methyl derivatives, translating into excellent efficacies at aldosterone suppression in H295R cells. Conversely, irbesartan and losartan were largely G protein-selective inhibitors at the AT₁R, with very low potency towards βarr inhibition. As a result, they were very weak suppressors of βarr1-dependent aldosterone production in H295R cells. These findings provide important pharmacological insights into the drug class of ARBs and medicinal chemistry insights for future drug development in the field of AngII antagonism.
authors: Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA.
authors: Samalia
authors: S
authors: Dabul
authors: Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA.
authors: Ashley
authors: A
authors: Bathgate-Siryk
authors: Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA.
authors: Thairy Reyes
authors: TR
authors: Valero
authors: Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA.
authors: Malika
authors: M
authors: Jafferjee
authors: Translational Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors: Emmanuel
authors: E
authors: Sturchler
authors: Translational Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors: Patricia
authors: P
authors: McDonald
authors: Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA.
authors: Walter J
authors: WJ
authors: Koch
authors: Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA.
authors: Anastasios
authors: A
authors: Lymperopoulos
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D015384:Zona Glomerulosa; D000071557:beta-Arrestins; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D057911:Angiotensin Receptor Antagonists; D019390:Arrestins; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D010750:Phosphoproteins; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000071557:beta-Arrestins; D000098682:Steroidogenic Acute Regulatory Protein; D000804:Angiotensin II; D000450:Aldosterone; D000068756:Valsartan; D019204:GTP-Binding Proteins; D014633:Valine; C081643:candesartan
references: Nat Chem Biol. 2012 Jul;8(7):622-30
references: 22634635
references: J Am Coll Cardiol. 2011 Jan 18;57(3):356-65
references: 21232674
references: J Biomol Screen. 2009 Jan;14(1):49-58
references: 19171920
references: Nat Clin Pract Nephrol. 2007 Sep;3(9):486-92
references: 17717561
references: J Am Coll Cardiol. 2014 Dec 30;64(25):2805-6
references: 25541135
references: Pharmacol Rev. 2010 Jun;62(2):305-30
references: 20427692
references: Biochem Pharmacol. 2000 Apr 15;59(8):927-35
references: 10692557
references: Mol Cell Endocrinol. 2004 Dec 30;228(1-2):23-38
references: 15541570
references: Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):9988-93
references: 18621717
references: N Engl J Med. 2001 Dec 6;345(23):1689-97
references: 11759649
references: Nephrology (Carlton). 2006 Oct;11(5):462-6
references: 17014562
references: Trends Pharmacol Sci. 2007 Aug;28(8):416-22
references: 17644195
references: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10782-7
references: 12949261
references: Science. 1996 Jan 19;271(5247):363-6
references: 8553074
references: JAMA. 2011 Jan 12;305(2):175-82
references: 21224459
references: Pharmacol Rev. 2013 Apr;65(2):809-48
references: 23487168
references: Br J Pharmacol. 1999 Feb;126(4):1057-65
references: 10193788
references: Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5825-30
references: 19289825
references: J Biomol Screen. 2007 Apr;12(3):312-9
references: 17307886
references: Hypertension. 2002 Jul;40(1):28-33
references: 12105134
references: Curr Chem Genom Transl Med. 2013 Apr 03;7:1-8
references: 24396729
references: Hypertension. 2014 Feb;63(2):404-12
references: 24218435
references: Am J Hypertens. 2012 Jul;25(7):818-26
references: 22552267