title: Optimum AT1 receptor-neprilysin inhibition has superior cardioprotective effects compared with AT1 receptor blockade alone in hypertensive rats.
abstract: Neprilysin inhibitors prevent the breakdown of bradykinin and natriuretic peptides, promoting vasodilation and natriuresis. However, they also increase angiotensin II and endothelin-1. Here we studied the effects of a low and a high dose of the neprilysin inhibitor thiorphan on top of AT1 receptor blockade with irbesartan versus vehicle in TGR(mREN2)27 rats with high renin hypertension. Mean arterial blood pressure was unaffected by vehicle or thiorphan alone. Irbesartan lowered blood pressure, but after 7 days pressure started to increase again. Low- but not high-dose thiorphan prevented this rise. Only during exposure to low-dose thiorphan plus irbesartan did heart weight/body weight ratio, cardiac atrial natriuretic peptide expression, and myocyte size decrease significantly. Circulating endothelin-1 was not affected by low-dose thiorphan with or without irbesartan, but increased after treatment with high-dose thiorphan plus irbesartan. This endothelin-1 rise was accompanied by an increase in renal sodium-hydrogen exchanger 3 protein abundance, and an upregulation of constrictor vascular endothelin type B receptors. Consequently, the endothelin type B receptor antagonist BQ788 no longer enhanced endothelin-1-induced vasoconstriction (indicative of endothelin type B receptor-mediated vasodilation), but prevented it. Thus, optimal neprilysin inhibitor dosing reveals additional cardioprotective effects on top of AT1 receptor blockade in renin-dependent hypertension.
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Lodi C W
authors.initials: LC
authors.lastname: Roksnoer
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: van Veghel
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: de Vries
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Usha M
authors.initials: UM
authors.lastname: Bhaggoe
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Edith C H
authors.initials: EC
authors.lastname: Friesema
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Frank P J
authors.initials: FP
authors.lastname: Leijten
authors.affiliation: Attoquant Diagnostics, Medical University of Vienna, Vienna, Austria.
authors.forename: Marko
authors.initials: M
authors.lastname: Poglitsch
authors.affiliation: 1] Attoquant Diagnostics, Medical University of Vienna, Vienna, Austria [2] Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Domenig
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marian C
authors.initials: MC
authors.lastname: Clahsen-van Groningen
authors.affiliation: Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ewout J
authors.initials: EJ
authors.lastname: Hoorn
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Jan Danser
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Batenburg
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001835:Body Weight; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology; D019332:Endothelin-1 / Q000097:blood; D000077405:Irbesartan; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology; D009929:Organ Size; D010880:Piperidines / Q000494:pharmacology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D044023:Receptor, Endothelin B / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D015244:Thiorphan / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010880:Piperidines; D011480:Protease Inhibitors; D044140:Receptor, Angiotensin, Type 1; D044023:Receptor, Endothelin B; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D013777:Tetrazoles; C472610:atrial natriuretic peptide, rat; C086539:BQ 788; D009320:Atrial Natriuretic Factor; D015244:Thiorphan; D015260:Neprilysin; D000077405:Irbesartan
references.citation: Hypertension. 2010 Feb;55(2):516-22
references.pmid: 20026759
references.citation: J Hypertens. 2010 Oct;28(10 ):2145-55
references.pmid: 20625318
references.citation: Br J Pharmacol. 2004 May;142(1):125-35
references.pmid: 15066907
references.citation: Circulation. 1999 Jun 22;99(24):3132-8
references.pmid: 10377076
references.citation: Lancet. 2000 Aug 19;356(9230):615-20
references.pmid: 10968433
references.citation: Hypertension. 1995 Dec;26(6 Pt 2):1160-6
references.pmid: 7498988
references.citation: Lancet. 2000 Aug 19;356(9230):608-9
references.pmid: 10968427
references.citation: PLoS One. 2012;7(11):e44481
references.pmid: 23144773
references.citation: Hypertension. 2003 Mar;41(3):383-9
references.pmid: 12623931
references.citation: Am J Physiol Renal Physiol. 2013 Oct 15;305(8):F1177-88
references.pmid: 23986520
references.citation: J Cardiovasc Pharmacol. 1991 Feb;17(2):296-304
references.pmid: 1709235
references.citation: Am J Physiol. 1988 Sep;255(3 Pt 2):F474-8
references.pmid: 2901230
references.citation: Am J Physiol. 1988 Dec;255(6 Pt 2):F1220-4
references.pmid: 2849318
references.citation: Circulation. 2015 Jan 6;131(1):54-61
references.pmid: 25403646
references.citation: J Am Coll Cardiol. 2000 Aug;36(2):479-86
references.pmid: 10933361
references.citation: Nature. 1990 Apr 5;344(6266):541-4
references.pmid: 2181319
references.citation: Clin Exp Pharmacol Physiol. 2004 Sep;31(9):650-5
references.pmid: 15479174
references.citation: Kidney Int. 1992 Jan;41(1):24-36
references.pmid: 1593860
references.citation: Cardiovasc Res. 1999 Nov;44(2):407-15
references.pmid: 10690317
references.citation: J Hypertens. 2014 Jun;32(6):1255-63
references.pmid: 24637873
references.citation: Circ Res. 1977 Jul;41(1):19-26
references.pmid: 862138
references.citation: Am J Hypertens. 1996 Aug;9(8):795-802
references.pmid: 8862226
references.citation: J Hypertens. 2008 Feb;26(2):322-33
references.pmid: 18192847
references.citation: Front Pharmacol. 2012 May 30;3:93
references.pmid: 22661949
references.citation: Lancet. 2010 Apr 10;375(9722):1255-66
references.pmid: 20236700
references.citation: Cardiovasc Res. 2004 Mar 1;61(4):771-9
references.pmid: 14985074
references.citation: Physiol Rev. 2007 Jul;87(3):825-72
references.pmid: 17615390
references.citation: Circ Res. 2011 Sep 2;109(6):609-10
references.pmid: 21885833
references.citation: N Engl J Med. 2014 Sep 11;371(11):993-1004
references.pmid: 25176015
references.citation: Am J Physiol Renal Physiol. 2014 Jun 15;306(12):F1489-98
references.pmid: 24717731
references.citation: Am J Physiol. 1999 Apr;276(4 Pt 2):H1197-206
references.pmid: 10199843
references.citation: Hypertension. 1997 Jun;29(6):1240-51
references.pmid: 9180624
references.citation: Hypertension. 1994 Jul;24(1):37-48
references.pmid: 8021006
references.citation: Am J Physiol Renal Physiol. 2001 Jan;280(1):F34-42
references.pmid: 11133512
references.citation: Am J Hypertens. 2004 Feb;17(2):103-11
references.pmid: 14751650
references.citation: J Pharmacol Sci. 2010;113(3):276-80
references.pmid: 20595785
references.citation: Am J Hypertens. 2008 Jul;21(7):733-41
references.pmid: 18464748
references.citation: J Am Soc Nephrol. 2011 Sep;22(9):1707-19
references.pmid: 21852580
references.citation: Circulation. 1998 Jun 16;97(23 ):2323-30
references.pmid: 9639376
references.citation: Am J Physiol Renal Physiol. 2008 Oct;295(4):F1063-70
references.pmid: 18667482
references.citation: J Renin Angiotensin Aldosterone Syst. 2012 Sep;13(3):409-12
references.pmid: 22930101
references.citation: Hypertension. 2004 Nov;44(5):746-50
references.pmid: 15452027
references.citation: Circulation. 2005 Mar 1;111(8):1006-11
references.pmid: 15710752
references.citation: Cardiovasc Res. 2010 Jun 1;86(3):401-9
references.pmid: 20071356
references.citation: J Clin Invest. 2005 Oct;115(10):2894-903
references.pmid: 16167081
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 19;109(25):10095-100
references.pmid: 22665796
references.citation: Nephrol Dial Transplant. 2015 Jan;30(1):115-23
references.pmid: 25107336
references.citation: Hypertension. 2014 May;63(5):942-50
references.pmid: 24470465
references.citation: Circ Heart Fail. 2013 May;6(3):594-605
references.pmid: 23694773
references.citation: Br J Pharmacol. 2014 Jun;171(11):2726-38
references.pmid: 24467585
references.citation: Clin Sci (Lond). 2007 Jun;112(7):393-401
references.pmid: 17125466
references.citation: Cell Metab. 2011 Apr 6;13(4):469-75
references.pmid: 21459331