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BackgroundThe purpose of this study was to test whether carvedilol has an antioxidant effect in humans in vivo.
Methods and ResultsWe administered 3.125 mg of carvedilol twice daily to normal subjects for 1 week. ROS generation
by polymorphonuclear leukocytes and mononuclear cells fell from 3146183.43 and 3036116 mV to 1856157 and
189663 mV (P,0.025), respectively. m-Tyrosine fell from 4.2460.99 to 4.0360.97 ng/mL (P50.01), and o-tyrosine
fell from 4.5961.10 to 4.2460.99 ng/mL (P50.004) in the absence of a change in phenylalanine concentrations.
ConclusionsWe conclude that carvedilol significantly inhibits ROS generation by leukocytes and oxidative conversion
of phenylalanine to m- and o-tyrosine. (Circulation. 2000;101:122-124.)
Key Words: carvedilol n oxygen n leukocytes n amino acids
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Received June 22, 1999; revision received October 20, 1999; accepted November 2, 1999.
From the Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo and Kaleida Health, Buffalo, NY.
Correspondence to Paresh Dandona, MD, Director, Diabetes Endocrinology Center of Western New York, Division of Endocrinology, Diabetes, and
Metabolism, State University of New York at Buffalo and Kaleida Health, 3 Gates Circle, Buffalo, NY 14209. E-mail pdandona@kaleidahealth.org
2000 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
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Dandona et al Carvedilol Inhibits ROS Generation 123
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Figure 1. ROS generation by PMNLs before and after 7-day Figure 2. ROS generation by MNC (in millivolts).
treatment with carvedilol. ROS generationinduced chemilumi-
nescence was measured in millivolts, assayed in 200 000 MNCs
in HBSS, and stimulated with FMLP. Plasma phenylalanine concentration did not change after
carvedilol. Plasma m-tyrosine concentration fell from
Assay of o-Tyrosine, m-Tyrosine, 4.2460.99 to 4.0360.97 ng/mL (P50.01). The ratio of
and Phenylalanine m-tyrosine to phenylalanine changed from 0.3560.07 to
o-Tyrosine, m-tyrosine, and phenylalanine were measured by high 0.3360.07 mmol/mol phenylalanine (P50.005).
performance liquid chromatography using the technique described Plasma o-tyrosine concentration fell from 4.5961.10 to
by Ishimitsu et al.9 4.2460.90 ng/mL (P50.004). The ratio of o-tyrosine to
Statistical Analysis
Comparisons of the ROS generation values at baseline and on day 8 TABLE 1. Plasma m-Tyrosine and o-Tyrosine Concentrations
were carried out by Wilcoxon rank sum test, because the distribution of (ng/mL) and Phenylalanine Concentrations (mg/mL) Before and
the values was not normally distributed. The values of o-tyrosine and After 7 Days of Treatment With 6.25 mg Carvedilol
m-tyrosine before and after carvedilol were compared by paired t test.
m-Tyrosine o-Tyrosine Phenylalanine
TABLE 2. Plasma m-Tyrosine/Phenylalanine and rate of hospital admissions.1 Although the reduction in sudden
o-Tyrosine/Phenylalanine Ratios Before and After 7 Days of death in such patients may be a function of the antiarrhythmic
Treatment With 6.25 mg Carvedilol (mmol/mol Phenylalanine) effects of carvedilol, the reduction of deterioration of congestive
m-Tyrosine/ o-Tyrosine/ heart failure may be due to its antioxidant effects, possibly
Phenylalanine Phenylalanine through the protection of the myocardium from ROS damage.
The mechanism underlying this inhibitory effect of carve-
Subject Baseline Day 8 Baseline Day 8
dilol on ROS generation is not clear from our data. Carvedilol
1 0.33 0.32 0.34 0.35 has been shown to possess antioxidant properties in various
2 0.35 0.31 0.33 0.31 animal models.9,10 The experimental data have been focused
3 0.33 0.32 0.47 .042 on carvedilol as a chemical antioxidant. There is only 1 report
4 0.45 0.43 0.48 0.43 based on a human study, which demonstrates that the ex vivo
5 0.31 0.29 0.28 0.26
oxidizability of LDL prepared from sera of patients treated
with carvedilol is significantly diminished.11 Our assay sys-
6 0.38 0.36 0.40 0.36
tem determines actual ROS generation by leukocytes, thus
7 0.41 0.42 0.44 0.41
focusing on the biological antioxidant property of carvedilol.
8 0.21 0.21 0.27 0.26 It is possible that carvedilol exerts its antioxidant effect by
Mean 0.35 0.33 0.37 0.35 both chemical and biological mechanisms.
SD 0.07 0.07 0.08 0.07 In conclusion, we have demonstrated that carvedilol inhibits
(P50.005) (P50.002) ROS generation by PMNLs and MNCs significantly, even after a
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Circulation. 2000;101:122-124
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doi: 10.1161/01.CIR.101.2.122
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2000 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/101/2/122
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