Effects of urate-lowering agents on arrhythmia vulnerability in post-infarcted rat hearts

Tsung Ming Lee, Shinn Zong Lin, Nen Chung Chang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Hyperuricemia has been shown to be associated with ventricular arrhythmias. However, the mechanisms remained unknown. We assessed whether different urate-lowering agents can attenuate arrhythmias through lowering urate itself or inhibiting xanthenes oxidize (XO) activity in infarcted rats. Male Wistar rats after ligating coronary artery were randomized to either allopurinol, or febuxostat, chemically unrelated inhibitors of XO, benzbromarone or vehicle for 4 weeks. Post-infarction was associated with increased oxidant stress, as measured by myocardial superoxide, isoprostane, XO activity and dihydroethidine fluorescence staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham-operated rats. Sympathetic hyperinnervation was blunted after administering both XO inhibitors, assessed by immunofluorescent analysis, Western blotting and real-time quantitative RT-PCR. Besides, the XO inhibitors-attenuated nerve growth factor levels were reversed in the presence of peroxynitrite generator. Arrhythmic scores in the XO inhibitors-treated infarcted rats were significantly lower than that in vehicle. For similar levels of urate lowering, the uricosuric agent benzbromarone had no beneficial effects on oxidative stress, sympathetic hyperinnervation or arrhythmia vulnerability. Chronic use of XO inhibitors, but not uricosuric agent, down-regulated sympathetic innervation probably through a superoxide-dependent pathway and plays a role in the beneficial effect on arrhythmogenic response.

Original languageEnglish
JournalJournal of Pharmacological Sciences
DOIs
Publication statusAccepted/In press - Jan 5 2016

Fingerprint

Xanthenes
Uric Acid
Cardiac Arrhythmias
Uricosuric Agents
Benzbromarone
Superoxides
Isoprostanes
Hyperuricemia
Allopurinol
Peroxynitrous Acid
Nerve Growth Factor
Oxidants
Infarction
Wistar Rats
Real-Time Polymerase Chain Reaction
Coronary Vessels
Norepinephrine
Oxidative Stress
Fluorescence
Western Blotting

Keywords

  • Antioxidants
  • Arrhythmia
  • Cardiac remodeling
  • Heart failure

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Effects of urate-lowering agents on arrhythmia vulnerability in post-infarcted rat hearts. / Lee, Tsung Ming; Lin, Shinn Zong; Chang, Nen Chung.

In: Journal of Pharmacological Sciences, 05.01.2016.

Research output: Contribution to journalArticle

@article{a684831e484344d895b0b4b5d5b57866,
title = "Effects of urate-lowering agents on arrhythmia vulnerability in post-infarcted rat hearts",
abstract = "Hyperuricemia has been shown to be associated with ventricular arrhythmias. However, the mechanisms remained unknown. We assessed whether different urate-lowering agents can attenuate arrhythmias through lowering urate itself or inhibiting xanthenes oxidize (XO) activity in infarcted rats. Male Wistar rats after ligating coronary artery were randomized to either allopurinol, or febuxostat, chemically unrelated inhibitors of XO, benzbromarone or vehicle for 4 weeks. Post-infarction was associated with increased oxidant stress, as measured by myocardial superoxide, isoprostane, XO activity and dihydroethidine fluorescence staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham-operated rats. Sympathetic hyperinnervation was blunted after administering both XO inhibitors, assessed by immunofluorescent analysis, Western blotting and real-time quantitative RT-PCR. Besides, the XO inhibitors-attenuated nerve growth factor levels were reversed in the presence of peroxynitrite generator. Arrhythmic scores in the XO inhibitors-treated infarcted rats were significantly lower than that in vehicle. For similar levels of urate lowering, the uricosuric agent benzbromarone had no beneficial effects on oxidative stress, sympathetic hyperinnervation or arrhythmia vulnerability. Chronic use of XO inhibitors, but not uricosuric agent, down-regulated sympathetic innervation probably through a superoxide-dependent pathway and plays a role in the beneficial effect on arrhythmogenic response.",
keywords = "Antioxidants, Arrhythmia, Cardiac remodeling, Heart failure",
author = "Lee, {Tsung Ming} and Lin, {Shinn Zong} and Chang, {Nen Chung}",
year = "2016",
month = "1",
day = "5",
doi = "10.1016/j.jphs.2016.03.009",
language = "English",
journal = "Journal of Pharmacological Sciences",
issn = "1347-8648",
publisher = "Japanese Pharmacological Society",

}

TY - JOUR

T1 - Effects of urate-lowering agents on arrhythmia vulnerability in post-infarcted rat hearts

AU - Lee, Tsung Ming

AU - Lin, Shinn Zong

AU - Chang, Nen Chung

PY - 2016/1/5

Y1 - 2016/1/5

N2 - Hyperuricemia has been shown to be associated with ventricular arrhythmias. However, the mechanisms remained unknown. We assessed whether different urate-lowering agents can attenuate arrhythmias through lowering urate itself or inhibiting xanthenes oxidize (XO) activity in infarcted rats. Male Wistar rats after ligating coronary artery were randomized to either allopurinol, or febuxostat, chemically unrelated inhibitors of XO, benzbromarone or vehicle for 4 weeks. Post-infarction was associated with increased oxidant stress, as measured by myocardial superoxide, isoprostane, XO activity and dihydroethidine fluorescence staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham-operated rats. Sympathetic hyperinnervation was blunted after administering both XO inhibitors, assessed by immunofluorescent analysis, Western blotting and real-time quantitative RT-PCR. Besides, the XO inhibitors-attenuated nerve growth factor levels were reversed in the presence of peroxynitrite generator. Arrhythmic scores in the XO inhibitors-treated infarcted rats were significantly lower than that in vehicle. For similar levels of urate lowering, the uricosuric agent benzbromarone had no beneficial effects on oxidative stress, sympathetic hyperinnervation or arrhythmia vulnerability. Chronic use of XO inhibitors, but not uricosuric agent, down-regulated sympathetic innervation probably through a superoxide-dependent pathway and plays a role in the beneficial effect on arrhythmogenic response.

AB - Hyperuricemia has been shown to be associated with ventricular arrhythmias. However, the mechanisms remained unknown. We assessed whether different urate-lowering agents can attenuate arrhythmias through lowering urate itself or inhibiting xanthenes oxidize (XO) activity in infarcted rats. Male Wistar rats after ligating coronary artery were randomized to either allopurinol, or febuxostat, chemically unrelated inhibitors of XO, benzbromarone or vehicle for 4 weeks. Post-infarction was associated with increased oxidant stress, as measured by myocardial superoxide, isoprostane, XO activity and dihydroethidine fluorescence staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham-operated rats. Sympathetic hyperinnervation was blunted after administering both XO inhibitors, assessed by immunofluorescent analysis, Western blotting and real-time quantitative RT-PCR. Besides, the XO inhibitors-attenuated nerve growth factor levels were reversed in the presence of peroxynitrite generator. Arrhythmic scores in the XO inhibitors-treated infarcted rats were significantly lower than that in vehicle. For similar levels of urate lowering, the uricosuric agent benzbromarone had no beneficial effects on oxidative stress, sympathetic hyperinnervation or arrhythmia vulnerability. Chronic use of XO inhibitors, but not uricosuric agent, down-regulated sympathetic innervation probably through a superoxide-dependent pathway and plays a role in the beneficial effect on arrhythmogenic response.

KW - Antioxidants

KW - Arrhythmia

KW - Cardiac remodeling

KW - Heart failure

UR - http://www.scopus.com/inward/record.url?scp=84964584548&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964584548&partnerID=8YFLogxK

U2 - 10.1016/j.jphs.2016.03.009

DO - 10.1016/j.jphs.2016.03.009

M3 - Article

C2 - 27129614

AN - SCOPUS:84964584548

JO - Journal of Pharmacological Sciences

JF - Journal of Pharmacological Sciences

SN - 1347-8648

ER -