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Platelet nitric oxide and superoxide release during the development of nitrate tolerance: effect of supplemental ascorbate.

Abstract：

BACKGROUND:The therapeutic benefits that accompany the continuous administration of organic nitrates are attenuated by the development of tolerance to the compounds. Altered superoxide production and NO bioavailability have been implicated in contributing to the development of tolerance, an effect that may be ameliorated by the administration of antioxidants. METHODS AND RESULTS:We studied the effect of 3 days of continuous transdermal administration of nitroglycerin (NTG) (10 mg/24 hours) on platelet free radical (NO and superoxide anion [O2*-] activity) with and without coadministration of supplemental ascorbate (2.4 g/24 hours). NAD(P)H oxidase activity, nitric oxide synthase (NOS) activity, and cyclic guanosine monophosphate (cGMP) content were also assessed. Radial artery pressure pulse waveforms were used to track the hemodynamic actions of NTG. Three days of NTG/placebo was associated with a significant increase in platelet NO and O2*- production from 1.0+/-1.17 to 2.52+/-0.88 pmol/10(8) platelets and 13.2+/-4.8 to 72.5+/-34.4 pmol/10(8) platelets, respectively (P<0.01 for both). These changes were accompanied by increased platelet NADH oxidase activity from 47.9+/-11.0 to 65.3+/-13.6 pmol O2*- min/mg protein and cGMP content from 0.60+/-0.10 to 0.89+/-0.16 pmol/10(9) platelets (P<0.05 for both). Administration of NTG/ascorbate attenuated both NO and O2*- release in platelets. CONCLUSIONS:Three days of continuous transdermal administration of NTG was accompanied by increased platelet NO and O2*- production and NADH oxidase activity that was suppressed by coadministration of oral ascorbate. Although a significant degree of tolerance would be expected during continuous nitrate administration, a residual hemodynamic action could be identified by arterial pulse contour analysis.

journal_name

Circulation

journal_title

Circulation

authors

McVeigh GE,Hamilton P,Wilson M,Hanratty CG,Leahey WJ,Devine AB,Morgan DG,Dixon LJ,McGrath LT

doi

10.1161/01.cir.0000021600.84149.78

subject

Has Abstract

pub_date

2002-07-09 00:00:00

pages

208-13

issue

eissn

0009-7322

issn

1524-4539

journal_volume

106

pub_type

临床试验,杂志文章,随机对照试验

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Platelet nitric oxide and superoxide release during the development of nitrate tolerance: effect of supplemental ascorbate.