Mechanistic Insights Into the Therapeutic Use of High-Dose Allopurinol in Angina Pectoris

Narasimharajapura S. Rajendra; Sheila Ireland; Jacob George; Jill J. F. Belch; Chim C. Lang; Allan D. Struthers

doi:10.1016/j.jacc.2010.12.052

Mechanistic Insights Into the Therapeutic Use of High-Dose Allopurinol in Angina Pectoris

Narasimharajapura S. Rajendra, Sheila Ireland, Jacob George, Jill J. F. Belch, Chim C. Lang, Allan D. Struthers

Research output: Contribution to journal › Article › peer-review

116 Citations (Scopus)

Abstract

Objectives The aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD).

Background Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients.

Methods A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine.

Results Compared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 +/- 67% vs. 145 +/- 106%, p = 0.006) and flow-mediated dilation (4.2 +/- 1.8% vs. 5.4 +/- 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 +/- 7.0%, p < 0.001) but not with placebo.

Conclusions Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766) (J Am Coll Cardiol 2011;58:820-8) (C) 2011 by the American College of Cardiology Foundation

Original language	English
Pages (from-to)	820-828
Number of pages	9
Journal	Journal of the American College of Cardiology
Volume	58
Issue number	8
DOIs	https://doi.org/10.1016/j.jacc.2010.12.052
Publication status	Published - 16 Aug 2011

Keywords

allopurinol and endothelial dysfunction
coronary artery disease
vascular oxidative stress
xanthine oxidase
IMPROVES ENDOTHELIAL FUNCTION
ACUTE CORONARY SYNDROMES
LOW-DENSITY-LIPOPROTEIN
INDUCED HEART-FAILURE
OXIDATIVE STRESS
XANTHINE-OXIDASE
DEPENDENT VASODILATION
BRACHIAL-ARTERY
IN-VITRO
DYSFUNCTION

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Mechanistic Insights into the Therapeutic Use of High-Dose Allopurinol in Angina Pectoris
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@article{d9129a6cd75d4dd49419c8ea1460d4c8,

title = "Mechanistic Insights Into the Therapeutic Use of High-Dose Allopurinol in Angina Pectoris",

abstract = "Objectives The aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD).Background Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients.Methods A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine.Results Compared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 +/- 67% vs. 145 +/- 106%, p = 0.006) and flow-mediated dilation (4.2 +/- 1.8% vs. 5.4 +/- 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 +/- 7.0%, p < 0.001) but not with placebo.Conclusions Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766) (J Am Coll Cardiol 2011;58:820-8) (C) 2011 by the American College of Cardiology Foundation",

keywords = "allopurinol and endothelial dysfunction, coronary artery disease, vascular oxidative stress, xanthine oxidase, IMPROVES ENDOTHELIAL FUNCTION, ACUTE CORONARY SYNDROMES, LOW-DENSITY-LIPOPROTEIN, INDUCED HEART-FAILURE, OXIDATIVE STRESS, XANTHINE-OXIDASE, DEPENDENT VASODILATION, BRACHIAL-ARTERY, IN-VITRO, DYSFUNCTION",

author = "Rajendra, {Narasimharajapura S.} and Sheila Ireland and Jacob George and Belch, {Jill J. F.} and Lang, {Chim C.} and Struthers, {Allan D.}",

year = "2011",

month = aug,

day = "16",

doi = "10.1016/j.jacc.2010.12.052",

language = "English",

volume = "58",

pages = "820--828",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier",

number = "8",

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T1 - Mechanistic Insights Into the Therapeutic Use of High-Dose Allopurinol in Angina Pectoris

AU - Rajendra, Narasimharajapura S.

AU - Ireland, Sheila

AU - George, Jacob

AU - Belch, Jill J. F.

AU - Lang, Chim C.

AU - Struthers, Allan D.

PY - 2011/8/16

Y1 - 2011/8/16

N2 - Objectives The aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD).Background Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients.Methods A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine.Results Compared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 +/- 67% vs. 145 +/- 106%, p = 0.006) and flow-mediated dilation (4.2 +/- 1.8% vs. 5.4 +/- 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 +/- 7.0%, p < 0.001) but not with placebo.Conclusions Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766) (J Am Coll Cardiol 2011;58:820-8) (C) 2011 by the American College of Cardiology Foundation

AB - Objectives The aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD).Background Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients.Methods A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine.Results Compared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 +/- 67% vs. 145 +/- 106%, p = 0.006) and flow-mediated dilation (4.2 +/- 1.8% vs. 5.4 +/- 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 +/- 7.0%, p < 0.001) but not with placebo.Conclusions Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766) (J Am Coll Cardiol 2011;58:820-8) (C) 2011 by the American College of Cardiology Foundation

KW - allopurinol and endothelial dysfunction

KW - coronary artery disease

KW - vascular oxidative stress

KW - xanthine oxidase

KW - IMPROVES ENDOTHELIAL FUNCTION

KW - ACUTE CORONARY SYNDROMES

KW - LOW-DENSITY-LIPOPROTEIN

KW - INDUCED HEART-FAILURE

KW - OXIDATIVE STRESS

KW - XANTHINE-OXIDASE

KW - DEPENDENT VASODILATION

KW - BRACHIAL-ARTERY

KW - IN-VITRO

KW - DYSFUNCTION

U2 - 10.1016/j.jacc.2010.12.052

DO - 10.1016/j.jacc.2010.12.052

M3 - Article

C2 - 21835317

SN - 0735-1097

VL - 58

SP - 820

EP - 828

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 8

ER -

Mechanistic Insights Into the Therapeutic Use of High-Dose Allopurinol in Angina Pectoris

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