Production of 8-epi prostaglandin F(2alpha) in human platelets during administration of organic nitrates.
OBJECTIVE
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 F(2alpha) (8-epi PGF(2alpha)) 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 PGF(2alpha) 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 PGF(2alpha), 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 PGF(2alpha) 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 PGF(2alpha), 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.
Department of Therapeutics and Pharmacology, Queen's University Belfast, Belfast, Northern Ireland. l.mcgrath@qub.ac.uk
Lawrence T
LT
McGrath
Lana
L
Dixon
David R
DR
Morgan
Gary E
GE
McVeigh
D000328:Adult; D001205:Ascorbic Acid / Q000097:blood / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000097:blood*; D016166:Free Radical Scavengers / Q000097:blood / Q000494:pharmacology; D005609:Free Radicals / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D005996:Nitroglycerin / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D016166:Free Radical Scavengers; D005609:Free Radicals; D014665:Vasodilator Agents; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D005996:Nitroglycerin; D001205:Ascorbic Acid