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EXPERIMENTAL STUDY

Production of 8-epi prostaglandin F₂ in human platelets during administration of organic nitrates

^* Department of Therapeutics and Pharmacology, Queen’s University Belfast, Belfast, Ireland

Manuscript received January 28, 2002; revised manuscript received April 24, 2002, accepted May 7, 2002.

^* Reprint requests and correspondence: Dr. Lawrence McGrath, Department of Therapeutics and Pharmacology, Whitla Medical Building, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Ireland.
l.mcgrath{at}qub.ac.uk

OBJECTIVES: The objective of this study was, using isolated platelets as a surrogate for vascular cells, to examine the effect of nonintermittent organic nitrate administration on 8-epi prostaglandin F₂ (8-epi PGF₂) content and the effect of concurrent oral ascorbate administration.

BACKGROUND: The long-term efficacy of organic nitrates is hampered by hemodynamic tolerance, which develops during continuous administration. This has been associated with altered production of superoxide and nitric oxide, as well as oxidative stress. This effect may be ameliorated by the co-administration of antioxidants.

METHODS: Ten healthy male subjects received nitroglycerin (NTG) transdermally at a dosage of 0.4 mg/h for 3 days with ascorbate or lactose (1.2 g/day). After two weeks washout, the treatment was repeated with reversed ascorbate/lactose. Platelets were prepared by centrifugation and esterified 8-epi PGF₂ measured at the start and finish of each treatment by immunoassay.

RESULTS: Nitroglycerin, in the absence of supplemental ascorbate, was associated with a significant increase in platelet-esterified 8-epi PGF₂, from 32.9 (95% confidence interval [CI] 11.8 to 54.0) to 51.0 (95% CI 16.3 to 85.7) pg/mg protein (p < 0.05). Co-administration of ascorbate with NTG resulted in a significant decrease in 8-epi PGF₂ production, from 38.8 (95% CI 24.9 to 52.7) to 19.0 (95% CI 13.5 to 24.5) pg/mg protein (p < 0.05).

CONCLUSIONS: Continuous NTG administration results in an increase in platelet-esterified 8-epi PGF₂, a free radical and cyclooxygenase-dependent compound. This is reversed by co-administration of the free radical scavenger ascorbate. Whether this increase is merely a marker for increased oxidative stress or a mediator of oxidative injury contributing to the hemodynamic changes observed in nonintermittent organic nitrate treatment has yet to be resolved.

Abbreviations and Acronyms   AT1   angiotensin II type 1 receptor   CI   confidence interval   EDTA   ethylenediamine tetraacetic acid   8-epi PGF2   8-epi prostaglandin F2   NADPH   nicotinamide adenine dinucleotide phosphate reduced form   NO   nitric oxide   NOS   nitric oxide synthase   NTG   nitroglycerin   O2·–   superoxide anion

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