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(Circulation. 2002;106:208.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Platelet Nitric Oxide and Superoxide Release During the Development of Nitrate Tolerance

Effect of Supplemental Ascorbate

Gary E. McVeigh, MD, PhD; Paul Hamilton, BSc; Martin Wilson, BSc; Colm G. Hanratty, MD; William J. Leahey, BSc; Adrian B. Devine, BSc; David G. Morgan, MRCP; Lana J. Dixon, MRCP; Lawrence T. McGrath, PhD

From the Department of Therapeutics and Pharmacology, The Queen’s University of Belfast, North Ireland, UK.

Correspondence to Dr G. Mc Veigh, Department of Therapeutics and Pharmacology, The Whitla Medical Building, The Queen’s University of Belfast, 97 Lisburn Rd, Belfast BT9 7BL, Ireland. E-mail g.mcveigh{at}qub.ac.uk

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/10⁸ platelets and 13.2±4.8 to 72.5±34.4 pmol/10⁸ 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/10⁹ 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.

Key Words: nitroglycerin • platelets • nitric oxide

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