Oxidant stress and aspirin-insensitive thromboxane biosynthesis in severe unstable angina.
BACKGROUND
Unstable angina is associated with enhanced lipid peroxidation and reduced antioxidant defenses. We have previously reported aspirin failure in the suppression of enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation in this setting. We tested the hypothesis that the in vivo formation of the F(2)-isoprostane 8-iso-prostaglandin (PG)F(2alpha), a bioactive product of arachidonic acid peroxidation, is enhanced in unstable angina and contributes to aspirin-insensitive TX biosynthesis.


RESULTS
Urine samples were obtained from patients with unstable angina (n=32), stable angina (n=32), or variant angina (n=4) and from 40 healthy subjects for the measurement of immunoreactive 8-iso-PGF(2alpha) and 11-dehydro-TXB(2). 8-Iso-PGF(2alpha) excretion was significantly higher in patients with unstable angina (339+/-122 pg/mg creatinine) than in matched patients with stable angina (236+/-83 pg/mg creatinine, P:=0.001) and control subjects (192+/-71 pg/mg creatinine, P:<0.0001). In patients with unstable angina, 8-iso-PGF(2alpha) was linearly correlated with 11-dehydro-TXB(2) excretion (rho=0.721, P:<0.0001) and inversely correlated with plasma vitamin E (rho=-0.710, P:=0. 004). Spontaneous myocardial ischemia in patients with variant angina or ischemia elicited by a stress test in patients with stable angina was not accompanied by any change in 8-iso-PGF(2alpha) excretion, thus excluding a role of ischemia per se in the induction of increased F(2)-isoprostane production.


CONCLUSIONS
These findings establish a putative biochemical link between increased oxidant stress and aspirin-insensitive TX biosynthesis in patients with unstable angina and provide a rationale for dose-finding studies of antioxidants in this setting.
Cipollone
F
F
Department of Medicine and Aging, University of Chieti "G. D'Annunzio" School of Medicine, Chieti, Italy.
Ciabattoni
G
G
Patrignani
P
P
Pasquale
M
M
Di Gregorio
D
D
Bucciarelli
T
T
Davì
G
G
Cuccurullo
F
F
Patrono
C
C
D000789:Angina, Unstable / Q000188:drug therapy* / Q000378:metabolism; D000975:Antioxidants / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D028441:F2-Isoprostanes; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D018384:Oxidative Stress; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011451:Prostaglandin-Endoperoxide Synthases; D013928:Thromboxane A2 / Q000096:biosynthesis* / Q000097:blood; D013997:Time Factors
D000975:Antioxidants; D028441:F2-Isoprostanes; D007527:Isoenzymes; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; C075750:8-epi-prostaglandin F2alpha; D013928:Thromboxane A2; D015237:Dinoprost; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin