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Circulation, Vol 86, 56-63, Copyright © 1992 by American Heart Association
DA Brezinski, RW Nesto and CN Serhan
BACKGROUND. Percutaneous transluminal coronary angioplasty (PTCA) is a
widely used and important method of reperfusing coronary arteries. However,
it is also associated with serious complications such as acute reocclusion
and accelerated restenosis. The factors as well as the mechanisms involved
in PTCA-associated complications remain to be fully elucidated. Because
peptidoleukotrienes and lipoxins are potent vasoactive compounds, the
formation of which is not inhibited by aspirin (ASA) treatment in vitro, it
is possible that these eicosanoids are involved in PTCA-associated untoward
events. To test this, we determined the intracoronary levels of
peptidoleukotrienes and lipoxin A4 (LXA4) as well as thromboxane (TX) and
5S,12S- dihydroxyeicosatetraenoic acid (5S,12S-DiHETE; a product of double
dioxygenation) after plaque rupture and evaluated the impact of ASA
therapy. METHODS AND RESULTS. PTCA was performed on 12 patients with
coronary artery disease, six undergoing ASA therapy and six without ASA
therapy, for at least 2 weeks before PTCA. By means of a technique that
permitted sampling of intracoronary blood at the plaque site in situ,
samples were taken immediately before and 10 seconds after initiation of
plaque rupture. Lipoxygenase (LO)-derived products, including LXA4 and
5S,12S-DiHETE, and a marker of cyclooxygenase activity, i.e., TXB2, were
quantitated after extraction and chromatography using deuterium- labeled
internal standards and electron capture negative ion chemical ionization
mass spectrometry. Peptidoleukotrienes (LTC4 and LTD4) were quantitated
after reverse-phase high-performance liquid chromatography coupled with
radioimmunoassay. Intracoronary blood taken before PTCA showed no
detectable levels of these eicosanoids (the minimum limits of detection
were within the picomole range). In contrast, each of these LO products was
detected after PTCA. Patients undergoing ASA treatment showed elevated
levels of each LO product examined compared with those not receiving ASA.
Eicosanoid levels were (mean +/- SEM): LTC4, 7.10 +/- 1.22 ng/ml (ASA)
versus 0.48 +/- 0.10 ng/ml; LTD4, 4.92 +/- 0.56 ng/ml (ASA) versus 1.17 +/-
0.48 ng/ml; LXA4, 24.98 +/- 4.11 ng/ml (ASA) versus 15.83 +/- 2.43 ng/ml;
5S,12S-DiHETE, 19.47 +/- 3.98 ng/ml (ASA) versus 11.98 +/- 1.83 ng/ml;
TXB2, complete blockage (ASA) versus 31.04 +/- 7.38 ng/ml (p less than 0.05
for LTC4 and LTD4). To distinguish between dilatation of whole blood versus
dilatation of whole blood and atheroma for contribution of eicosanoids, we
also monitored their formation in Gore-tex grafts. Upon balloon inflation,
TXB2 was generated, but LO products were not detected. In contrast,
injection of platelet- and leukocyte-directed agonists within the graft led
to both peptidoleukotriene and lipoxin formation. CONCLUSIONS. The results
indicate that PTCA triggers the intraluminal release of peptidoleukotrienes
and LXA4 and that ASA therapy enhances their appearance in intracoronary
blood. In addition, they provide direct evidence for LO products (LTC4,
LTD4, and LXA4) in a local milieu in vivo. Moreover, the presence of the
double dioxygenation product 5S,12S- DiHETE (a potential marker of 5- and
12-LO interactions) suggests that transcellular metabolic events can
contribute to eicosanoid formation in vivo.
ARTICLES
Angioplasty triggers intracoronary leukotrienes and lipoxin A4. Impact of aspirin therapy
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
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