Cardiometabolic and Inflammatory Benefits of Sympathetic Down-Regulation with Zamicastat in Aged Spontaneously Hypertensive Rats.
Journal
ACS pharmacology & translational science
ISSN: 2575-9108
Titre abrégé: ACS Pharmacol Transl Sci
Pays: United States
ID NLM: 101721411
Informations de publication
Date de publication:
11 Oct 2019
11 Oct 2019
Historique:
received:
13
06
2019
entrez:
8
4
2020
pubmed:
8
4
2020
medline:
8
4
2020
Statut:
epublish
Résumé
The hyperactivity of the sympathetic nervous system (SNS) plays a major role in the development and progression of several cardiovascular diseases. One strategy to mitigate the SNS overdrive is by restricting the biosynthesis of norepinephrine via the inhibition of dopamine β-hydroxylase (DBH). Zamicastat is a new DBH inhibitor that decreases norepinephrine and increases dopamine levels in peripherally sympathetic-innervated tissues. The cardiometabolic and inflammatory effects of sympathetic down-regulation were evaluated in 50 week old male spontaneously hypertensive rats (SHRs) receiving zamicastat (30 mg/kg/day) for 9 weeks. After 8 weeks of treatment, the blood pressure (BP) and heart rate (HR) were assessed by tail cuff plethysmography. At the end of the study, 24 h urine, plasma, heart, and kidney were collected for biochemical and morphometric analyses. Zamicastat-induced sympathetic down-regulation decreased the high BP in SHRs, with no observed effect on HR. The heart-to-body weight ratio was lower in SHRs treated with zamicastat, whereas the body weight and kidney-to-body weight ratio were similar between both SHR cohorts. Zamicastat-treated SHRs showed reduced 24 h urine output, but the urinary amount of protein excreted and creatinine clearance rate remained unchanged. Zamicastat treatment significantly decreased plasma triglycerides, free fatty acids, and aspartate aminotransferase levels. Aged SHRs showed higher plasma levels of inflammatory markers as compared with age-matched normotensive Wistar-Kyoto rats. The inflammatory benefits attained with DBH inhibition were expressed by a decrease in CRP, MCP-1, IL-5, IL-17α, GRO/KC, MIP-1α, and RANTES plasma levels as compared with untreated SHRs. In conclusion, DBH inhibition decreased norepinephrine levels, reduced end-organ damage, and improved cardiometabolic and inflammatory biomarkers in aged male SHRs.
Identifiants
pubmed: 32259069
doi: 10.1021/acsptsci.9b00039
pmc: PMC7089015
doi:
Types de publication
Journal Article
Langues
eng
Pagination
353-360Informations de copyright
Copyright © 2019 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
Références
Circ Res. 2016 Apr 15;118(8):1327-36
pubmed: 27081113
Curr Hypertens Rep. 2002 Jun;4(3):237-44
pubmed: 12003707
Hypertension. 1996 Apr;27(4):955-61
pubmed: 8613274
Biochim Biophys Acta. 2010 Dec;1802(12):1259-67
pubmed: 20153824
Circ Res. 2012 Oct 12;111(9):1190-7
pubmed: 22904093
Jpn J Pharmacol. 1993 Nov;63(3):295-303
pubmed: 7906318
J Cardiovasc Pharmacol. 2000;35(7 Suppl 4):S1-7
pubmed: 11346214
J Am Coll Cardiol. 2018 May 15;71(19):e127-e248
pubmed: 29146535
Hypertension. 1982 Nov-Dec;4(6):764-72
pubmed: 6292083
Naunyn Schmiedebergs Arch Pharmacol. 1986 Jul;333(3):219-23
pubmed: 3762736
Am J Physiol Regul Integr Comp Physiol. 2001 Oct;281(4):R1071-8
pubmed: 11557612
Med Chem. 2007 Jan;3(1):61-5
pubmed: 17266625
Eur J Heart Fail. 2008 Dec;10(12):1186-91
pubmed: 18851926
Hypertens Res. 2015 Jan;38(1):30-8
pubmed: 25298210
Am J Physiol Heart Circ Physiol. 2012 Dec 1;303(11):H1353-65
pubmed: 23001837
Hypertension. 2003 Oct;42(4):613-8
pubmed: 12975385
Br J Pharmacol. 1987 Jan;90(1):91-8
pubmed: 3814924
Arzneimittelforschung. 1975 Jan;25(1):55-9
pubmed: 1173769
AACN Adv Crit Care. 2008 Oct-Dec;19(4):364-85; quiz 386-7
pubmed: 18981739
Eur J Pharmacol. 2019 Jan 5;842:125-132
pubmed: 30401628
Circulation. 2008 Jun 24;117(25):e510-26
pubmed: 18574054
Diabetes. 2006 Dec;55(12):3594-603
pubmed: 17130509
Am J Hypertens. 1998 Jan;11(1 Pt 1):59-65
pubmed: 9504451
Diabetologia. 2000 May;43(5):533-49
pubmed: 10855527
J Med Chem. 1986 Jun;29(6):887-9
pubmed: 3712378
J Hypertens. 2013 Jul;31(7):1281-357
pubmed: 23817082
Br J Pharmacol. 1992 Nov;107(3):710-4
pubmed: 1472968
Hypertension. 1999 Oct;34(4 Pt 2):724-8
pubmed: 10523349
J Med Chem. 1987 Mar;30(3):486-94
pubmed: 3820219
FASEB J. 2013 Aug;27(8):2927-38
pubmed: 23616567
Biochim Biophys Acta. 2010 Apr;1802(4):416-31
pubmed: 20060897
Hypertension. 1991 Jul;18(1):1-8
pubmed: 1677640
Compr Physiol. 2014 Jul;4(3):1177-200
pubmed: 24944034
Mech Ageing Dev. 2011 Jun-Jul;132(6-7):298-304
pubmed: 21699911
Circulation. 2019 Mar 5;139(10):e56-e528
pubmed: 30700139
Physiol Rev. 2010 Apr;90(2):513-57
pubmed: 20393193
J Am Soc Hypertens. 2016 Mar;10(3):207-16
pubmed: 26803288
Eur Heart J. 2012 May;33(9):1058-66
pubmed: 22507981
J Hypertens. 2005 Feb;23(2):417-26
pubmed: 15662231
Orphanet J Rare Dis. 2006 Mar 30;1:7
pubmed: 16722595
Circ Res. 2015 Mar 13;116(6):1022-33
pubmed: 25767287
Life Sci (1962). 1964 Jul;3:763-7
pubmed: 14203977
Am J Hypertens. 2010 Oct;23(10):1052-60
pubmed: 20651696
Circ Res. 2015 Aug 28;117(6):547-57
pubmed: 26156232
Med J Aust. 2016 Jul 18;205(2):85-9
pubmed: 27456450
J Pharmacol Exp Ther. 1987 May;241(2):554-9
pubmed: 3572812
Curr Pharm Des. 1998 Dec;4(6):469-79
pubmed: 10197057
J Clin Pharmacol. 1993 Mar;33(3):286-91
pubmed: 8096525
Exp Physiol. 2010 May;95(5):581-6
pubmed: 20008032