© 2000 American Heart Association, Inc.
Editorials |
TP or Not TP: Primary Mediators in a Close Runoff?
From the Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia.
Correspondence to Dr G.A. FitzGerald, Center for Experimental Therapeutics, 153 Johnson Pavillion, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. E-mail garret{at}@spirit.gcrc.upenn.edu
Key Words: Editorials • thromboxane • atherosclerosis • isoprostane • oxidant stress
Aspirin has emerged as a remarkably safe, inexpensive, and effective drug for the secondary prevention of the complications of atherosclerotic disease. It acts by inhibiting the enzyme prostaglandin (PG) G/H synthase, actually a bifunctional protein that sequentially catalyzes the conversion of arachidonic acid to the highly reactive endoperoxide intermediates PGG2 and PGH2 via its cyclooxygenase (COX) and peroxidase functions. This enzyme, colloquially termed COX, has been crystallized1 and the mechanism of action of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) elucidated.2 3 4 The catalytic site is buried deep within the core of the enzyme and is accessed by the substrate via a hydrophobic tunnel. Aspirin irreversibly acetylates a serine residue at position 529 in the human enzyme,5 close to but not at the catalytic site, though still blocking access to it by the arachidonic acid substrate. NSAIDs, by contrast, act reversibly as competitive inhibitors at the catalytic site. Indeed, transient occupancy of that site after dosing with an NSAID may mask the serine from the effects of a subsequent dose of aspirin.6
The beneficial effects of aspirin in
cardiovascular disease have been attributed to its
inhibitory effects on COX in platelets. In these cells,
thromboxane (Tx) synthase further catalyzes the conversion
of PGH2 to
TxA2,7 which exerts proaggregatory,
vasoconstrictor, and proliferative effects via a membrane-bound, G
protein–coupled receptor, the TP.8 Two isoforms (
and
ß) of the TP have been cloned,8 9 both of which are
transcribed in human platelets, although only TP appears to be
translated.10 Transcripts of both isoforms are present
in vascular cells.11 Although the isoforms differ in their
rates of agonist-induced desensitization12 and propensity
to couple with G proteins,13 little is known of their
disparate roles in vivo. The importance of TxA2
in platelet activation is thought to derive principally from its
role as an amplifying signal for other stronger, primary agonists, such
as thrombin and ADP.14 However, the clinical efficacy of
aspirin complements that of ticlopidine,15 a drug that
selectively inhibits platelet aggregation induced by ADP but not TP
agonists ex vivo. Clopidogrel, a close relative of ticlopidine, appears
to act by a similar mechanism.15 In a large-scale clinical
trial, clopidogrel emerged as slightly more efficacious than aspirin in
the secondary prevention of myocardial infarction and
stroke.16
The irreversible acetylation of Ser529 by aspirin in the
COX of anucleate platelets explains the cumulative inhibition of
the capacity of platelets to generate TxA2,
commonly measured as serum concentrations of its hydrolysis product
TxB2. Thus, daily administration of 75 mg of
aspirin takes 3 to 4 days to inhibit completely serum
TxB2 ex vivo.17 Interestingly, like
low-dose aspirin, 75 mg of clopidogrel also takes several days to
inhibit platelet function ex vivo, perhaps owing to the gradual
accumulation of a metabolite that binds to a subclass of purinergic
receptors, although this has yet to be established in vivo. As in the
case of aspirin, loading doses of clopidogrel have been investigated
and are likely to be employed in acute settings of vascular occlusion.
Studies designed to assess the potentially additive effects of aspirin
with clopidogrel have been initiated. Finally,
dipyridamole has been reformulated to correct prior
problems with variable and transient bioavailability. This new
preparation has been shown to be as effective as low-dose aspirin in
the secondary prevention of stroke, and the benefit from a combination
of the 2 is roughly additive.18 This has led to the US
Federal Drug Administration approval of an
aspirin-dipyridamole combination for this indication.
Although oral inhibitors of the platelet
glycoprotein IIb/ßIII have been disappointing, 3
antiplatelet drugs—low-dose aspirin, clopidogrel, and
dipyridamole—have been proven effective in the
secondary prevention of cerebrovascular and/or
cardiovascular disease. Their mechanisms of action
suggest that their benefits might be additive, although this remains to
be established in a clinical trial. This has "raised the bar" for
the development of potentially novel therapies in this arena.
The advent of pharmacological inhibitors of the TP19 20 21 inauspiciously coincided with the initial trials establishing the efficacy of aspirin in cardiovascular disease.22 23 24 This confounded their development in 2 ways. First, as the effects of aspirin were attributed to inhibition of TxA2, TP antagonists had little additional benefit to offer. Perhaps preservation of the ability of the vasculature to generate other PGs such as prostacyclin (PGI2) was a plus, but this was a strictly theoretical concept. Against that, it was difficult for TP antagonists to compete against aspirin at 20 cents a tablet. Two clinical trials of TP antagonists were performed, both addressing the possibility that they might modify restenosis after angioplasty.
In the CARPORT (Coronary Artery Restenosis Prevention on Repeated Thromboxane A2 antagonism) study, the antagonist GR32191, given before percutaneous transluminal coronary angioplasty (PTCA) and for 6 months thereafter, did not differ significantly from the effects of intravenous aspirin given immediately before PTCA on luminal diameter as assessed by angiography performed 6 months after the intervention.25 However, the limitations of this uncontrolled experience and of relying on an angiographic end point at a single time were highlighted by the M-HEART (Multi-Hospital Eastern Atlantic Restenosis Trial) II study.26 In that study, all patients received aspirin before PTCA due to its role, by then established, in the prevention of periprocedural myocardial infarction27 but were randomized to continuing treatment with the TP antagonist sulotroban, aspirin, or placebo. In this case, the angiographic estimate of vascular occlusion at 6 months was a secondary end point and did not differ between the groups. By contrast, continued treatment with either aspirin or sulotroban significantly reduced the later myocardial infarction rate in the 6 months after PTCA when compared with the placebo group. These observations left many unanswered questions. First, aside from there being no measure of the degree of synthesis inhibition achieved by aspirin or of TP blockade by either antagonist, the divergence of the time-integrated clinical and "snapshot" angiographic end points in the M-HEART II study illustrated the limited information available from CARPORT. Second, the hypothesis that TP blockade might be superior to aspirin was configured on the preservation of PGI2 formation during TP blockade. PGI2 has significant antiproliferative effects. Both virally delivered PGI synthase and a PGI2 analogue, beraprost, have been shown to reduce significantly the proliferative response to experimental angioplasty.28 29 However, the procedure-related increase in PGI2 biosynthesis, like that in TxA2, is short-lived and suppressed by aspirin in patients undergoing PTCA,30 31 and the patients assigned to sulotroban were receiving aspirin at that time.
Cayette and colleagues32 now report observations that
suggest that reconsideration of the role of TP antagonism is timely.
Using a newly synthesized TP antagonist, S18886, which is
devoid of partial agonist activity, they report that atherogenesis can
be retarded in the apoE-knockout (KO) mouse. Oddly, aspirin has no
effect. One possibility is that inhibition of other COX products by
aspirin, such as PGI2, might have obscured a
benefit from inhibiting TxA2. We now know that
deletion of the PGI2 receptor—the IP—results in
an increased response to thrombotic stimuli in vivo,8 but
the role of this mediator in atherogenesis is unknown. We also now know
that there are 2 forms of COX.4 The second isoform is a
distinct gene product and is readily regulated in its expression by
growth factors, tumor promoters, and cytokines. The tertiary
structures of the 2 enzymes are remarkably similar4 ;
however, the hydrophobic channel of COX-2 is more accommodating. Both
COX isozymes form small amounts of 11(S)- and
15(S)-hydroxyeicosatetraenoic
acids (HETEs). It is unknown whether they contribute to COX actions in
vivo, although some HETEs have been shown to be weak TP agonists in
vitro. 15(S)-HETE can also be formed as a primary
product by the 15-lipoxygenase enzyme. Deletion of
this enzyme reverses atherogenesis in the apoE-KO
mouse.33 Interestingly, unlike the case with COX-1,
inhibition of COX-2–dependent PG synthesis by aspirin, but not by
NSAIDs, ex vivo or in vitro is accompanied by increased generation of
both 11- and 15-HETEs, but now in the R stereoconfiguration.
The acetyl residue is thought to force realignment of the 
end of
the arachidonic acid carbon chain, which is usually
oriented in an L-shaped configuration in the hydrophobic
channel.34 Mutation to their COX-1 equivalents of 3
residues predicted to be critical to the spatial and flexibility
differences in the COX-2 channel abolishes this feature in the mouse
enzyme.35 Both COX isoforms are present, with
remarkably similar distributions, in human atherosclerotic
plaque.36 Although this may also be true in the
atherosclerotic mouse, it is unknown whether 15(R)-HETE has
any biological effects in aspirin-treated animals. Thus for now, the
role of TP activation by HETEs in explaining the discrepancy between
the effects of aspirin and the TP antagonist in the study
of Cayette and colleagues32 remains quite
speculative. Perhaps the explanation is more mundane. The relationship
between inhibition of the capacity of platelets to generate
TxA2—estimated by serum
TxB2—and inhibition of Tx-dependent platelet
activation is remarkably nonlinear. Just 5% residual capacity is
sufficient fully to sustain function.37 In the present
study, the aspirin regimen suppressed serum TxB2
by only 70% to 75%, and TP-dependent platelet activation is
likely to have been unimpaired. Clearly, platelets may be a source
of growth factors relevant to atherogenesis, but activation of TPs in
other cells may also be relevant. In tissues other than the
platelet, we have no information as to the relationship between
biosynthetic capacity and function.
Cayette and colleagues32 raise the possibility that the
discrepant results between aspirin and S 18886 might also be explained
if isoprostanes (iPs), free radical–catalyzed products of
arachidonic acid, played an important role in TP
activation. Indeed, at least 2 iPs—iPF2-III
(also known as
8-iso-PGF238 ) and
iPE2-III—exert potent effects on platelet
function and vascular tone, and these actions are prevented by TP
antagonists and absent in TP-deficient
mice.39 Generation of iPs is increased in both
humans with atherosclerosis40 and in
apoE-KO mice, and iP suppression with vitamin E retards atherogenesis
in this model.41 Perhaps the use of TP
antagonists should be reconsidered in other syndromes in
which oxidant stress and COX activation coincide, such as
occlusion/reperfusion and inflammation. We are at a very early stage in
elucidating the biological actions of iPs and related compounds, some
of which may act as incidental ligands at other PG
receptors.42
Where do the observations of Cayette and colleagues32 lead us? It would certainly be interesting to confirm the effects of the compound in murine models more reminiscent of the human disease.43 It would also be reassuring to confirm that similar effects are observed with structurally distinct antagonists and TP deletion. It remains a formal possibility that the observed effects relate to properties of S 18886 that are unrelated to TP antagonism. Such studies will also increase our sense of the magnitude of the effect we might anticipate with TP antagonism. This seems consistent, but somewhat modest, in the apoE-KO mouse. Should such studies reinforce our confidence, modern imaging modalities such as electron beam CT of the coronary44 or ultrasonography of the carotid arteries45 afford noninvasive approaches to assess the impact of TP antagonism on plaque progression in humans. Reagents are now available for the study of TP expression in human disease,46 and model systems have implicated TP activation in settings previously not considered when these drugs were under development.47 Finally, TP antagonists may even be worth considering as alternative platelet inhibitors to aspirin in certain circumstances. For example, because platelets express COX-1 only, selective inhibitors of COX-2 do not afford cardioprotection. However, in the absence of any actual clinical data, the empiric combination of these drugs with low-dose aspirin has some theoretical limitations. Even low-dose aspirin causes gastrointestinal side effects,48 which may erode the postulated benefit of selective COX-2 inhibition on the gastrointestinal tract. By contrast, TP antagonism has been shown to protect against NSAID-induced enteropathy in the rat.49 Similarly, selective COX-2 inhibitors, NSAIDs, and even low doses of conventionally formulated aspirin depress PGI2 biosynthesis in healthy individuals.50 51 Combination of TP antagonists with COX-2 inhibitors would afford at least similar cardioprotection to that of aspirin25 while sparing PGI2 formation from further suppression.
In summary, the provocative studies of Cayette et al32 draw attention to a class of compounds that were previously abandoned for reasons that were rational at the time. Now that we know more about the breadth of potential TP ligands and are increasingly informed of the biology of PGs as a result of the availability of receptor-deficient mice, it would seem worthwhile to reconsider the contemporary utility of this interesting class of compounds.
References
1. Picot D, Loll PJ, Garavito M. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature. 1994;367:243–249.[Medline] [Order article via Infotrieve]
2. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets, I: acetylation of a particulate fraction protein. J Clin Invest. 1975;56:624–632.
3.
Patrono C. Aspirin as an antiplatelet drug.
N Engl J Med. 1994;330:1287–1294.
4.
Smith WL, Garavito RM, DeWitt DL.
Prostaglandin endoperoxide H synthases
(cyclooxygenases)-1 and -2. J Biol
Chem. 1996;271:33157–33160.
5. Funk CD, Funk LB, Kennedy M, Pong A, FitzGerald GA. Human platelet/erythroleukemia cell PGG/H synthase: cDNA cloning, expression, mutagenesis and gene chromosomal assignment. FASEB J. 1991;5:2304–2312.[Abstract]
6. Loll PJ, Picot D, Garavito RM. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol. 1995;2:637–643.[Medline] [Order article via Infotrieve]
7.
Hamberg M, Svensson J, Samueilsson B.
Thromboxanes: a new group of biologically active compounds
derived from prostaglandin endoperoxides.
Proc Natl Acad Sci U S A. 1975;72:2994–2998.
8. Hirata M, Hayashi Y, Ushikubi F, et al. Cloning and expression of cDNA for human thromboxane A2 receptor. Nature.. 1991;349:617–620.[Medline] [Order article via Infotrieve]
9.
Raychowdhury MK, Yukawa M, Collins LJ, McGrail SH,
Kent KC, Ware JA. Alternative splicing produces a divergent cytoplasmic
tail in the human endothelial thromboxane
A2 receptor. J Biol Chem. 1994;269:19256–19261.
10.
Habib A, FitzGerald GA, Maclouf J.
Phosphorylation of the thromboxane
receptor, the predominant isoform expressed in human platelets.
J Biol Chem. 1999;274:2645–2654.
11.
Miggin SM, Kinsella BT. Expression and tissue
distribution of the mRNAs encoding the human thromboxane
A2 receptor (TP) and ß isoforms.
Biochim Biophys Acta. 1998;1425:543–559.[Medline]
[Order article via Infotrieve]
12.
Parent JL, Labrecque P, Orsini MJ, Benovic JL.
Internalization of the TxA2 receptor and ß
isoforms: role of the differentially spliced COOH terminus in
agonist-promoted receptor internalization. J Biol Chem. 1999;274:8941–8948.
13.
Vezza R, Habib A, FitzGerald GA. Differential coupling
of the thromboxane receptor isoforms with Gh. J
Biol Chem. 1999;274:12774–12779.
14. FitzGerald GA. Mechanisms of platelet activation: TxA2 as an amplifying signal for other agonists. Am J Cardiol. 1991;68:11B–15B.[Medline] [Order article via Infotrieve]
15.
Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel.
Circulation. 1999;100:1667–1672.
16. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329–1339.[Medline] [Order article via Infotrieve]
17. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982;69:1366–1372.
18. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study, II: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1–13.[Medline] [Order article via Infotrieve]
19. Gresele P, Arnout J, Janssens W, Deckmyn H, Lemmens J, Vermylen J. BM 13.177, a selective blocker of platelet and vessel wall thromboxane receptors, is active in man. Lancet. 1984;1:991–994.[Medline] [Order article via Infotrieve]
20.
Darius H, Smith JB, Lefer AM. Beneficial effects of a
new potent and specific thromboxane receptor
antagonist (SQ-29, 548) in vitro and in
vivo. J Pharmacol Exp Ther. 1985;235:274–281.
21. Humphrey PPA, Hallet P, Hornby EJ, Wallis CJ, Collington EW, Lumley P. Pathophysiological actions of thromboxane A2 and their pharmacological antagonism by thromboxane receptor blockade with GR32191. Circulation. 1990;81(suppl I):I-42–I-52.
22. Lewis HD, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE 3d. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of a Veterans Administration cooperative study. N Engl J Med. 1983;309:396–403.[Abstract]
23. ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349–360.[Medline] [Order article via Infotrieve]
24. Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky G, Kostuk WJ, Melendez LJ, Myers MG. Aspirin, sulfinpyrazone, or both in unstable angina. N Engl J Med. 1985;313:1369–1375.[Abstract]
25.
Serruys PW, Rutsch W, Heyndrickx GR, Danchin N, Mast
EG, Wijns W, Rensing BJ, Vos J, Stribbe J. Prevention of
restenosis after percutaneous transluminal
coronary angioplasty with thromboxane
A2 receptor blockade: a randomized, double-blind,
placebo-controlled trial. Circulation. 1991;84:1568–1580.
26.
Savage MP, Goldberg S, Bove AA, Deutsch E, Vetrovec G,
Macdonald RG, Bass T, Margolis JR, Whitworth HB, Taussig A. Effect of
thromboxane A2 blockade on clinical
outcome and restenosis after successful coronary
angioplasty: Multi-Hospital Eastern Atlantic Restenosis Trial
(M-Heart II). Circulation. 1995;92:3194–3200.
27. Schwartz L, Bourassa MG, Lesperance J, Aldridge HE, Kazim F, Salvatori VA, Henderson M, Bonan R, David PR. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med. 1988;318:1714–1719.[Abstract]
28.
Todaka T, Yokoyama C, Yanamoto H, Hashimoto N, Nagata
I, Tsukahara T, Hara S, Hatae T, Morishita R, Aoki M, Ogihara T, Kaneda
Y, Tanabe T. Gene transfer of human prostacyclin synthase prevents
neointimal formation after carotid balloon injury in rats.
Stroke. 1999;30:419–426.
29. Isogaya M, Yamada N, Koike H, Ueno Y, Kumagai H, Ochi Y, Okazaki S, Nishio S. Inhibition of restenosis by beraprost sodium (a prostaglandin I2 analogue) in the atherosclerotic rabbit artery after angioplasty. J Cardiovasc Pharmacol. 1995;25:947–952.[Medline] [Order article via Infotrieve]
30.
Roy L, Knapp H, Robertson RM, FitzGerald GA.
Endogenous biosynthesis of prostacyclin during cardiac
catheterization and angiography in man.
Circulation. 1985;71:434–449.
31.
Braden G, Knapp HR, FitzGerald GA. Suppression of
eicosanoid formation during coronary angioplasty by fish oil
and aspirin. Circulation. 1991;84:679–685.
32.
Cayatte AJ, Du Y, Oliver-Krasinki J, et al. The
thromboxane receptor antagonist S18886 but not aspirin inhibits
atherogenesis in apo E–deficient mice: evidence that eicosanoids other
than thromboxane contribute to atherosclerosis. Arterioscler
Thromb Vasc Biol. 2000;20:1724–1728.
33. Cyrus, T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton MRF, Funk CD. J Clin Invest. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest. 1999;103:1597–1604.[Medline] [Order article via Infotrieve]
34.
Schneider C, Brash AR. Stereospecificity of hydrogen
abstraction in the conversion of arachidonic acid to
15R-HETE by aspirin-treated cyclooxygenase-2.
J Biol Chem. 2000;275:4743–4746.
35.
Rowlinson SW, Crews BC, Goodwin DC, Schneider C, Gierse
JK, Marnett LJ. Spatial requirements for 15-(R)-hydroxy-5z,
8z, 11z, 13E-eicosatetraenoic acid synthesis within the
cyclooxygenase active site of murine COX-2.
J Biol Chem. 2000;275:6586–6591.
36.
Schonbeck U, Sukhova GK, Graber P, Coulter S, Libby P.
Augmented expression of cyclooxygenase-2 in human
atherosclerotic lesions. Am J Pathol. 1999;155:1281–1291.
37.
Reilly IAG, FitzGerald GA. Inhibition of
thromboxane formation in vivo and ex
vivo: implications for therapy with platelet
inhibitory drugs. Blood. 1987;69:180–186.
38.
Lawson JA, Rokach J, FitzGerald GA. Isoprostanes:
formation, analysis and use as indices of lipid peroxidation
in vivo [Mini-review]. J Biol Chem. 1999;274:24441–24444.
39.
Audoly LP, Rocca B, Fabre J-E, Koller BH, Thomas D,
Loeb A, Coffman TM, FitzGerald GA. Cardiovascular
responses to the isoprostanes, iPF2-III and
iPE-III are mediated via the
thromboxane A2 receptor in
vivo. Circulation. In press.
40.
Reilly M, Praticò D, Delanty N, DiMinno G,
Tremoli E, Rader D, Kapoor S, Rokach J, Lawson J, FitzGerald GA.
Increased formation of distinct F2 isoprostanes
in hypercholesterolemia.
Circulation. 1998;98:2822–2828.
41. Praticò D, Tangirala RK, Rader DJ, Rokach J, FitzGerald GA. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nat Med. 1998;4:1189–1192.[Medline] [Order article via Infotrieve]
42.
Kunapuli P, Lawson JA, Rokach JA, Meinkoth JL,
FitzGerald GA. Prostaglandin F2
(PGF2) and the isoprostane,
8-,12-iso-isoprostane F2-III,
induce cardiomyocyte hypertrophy: differential
activation of downstream signaling pathways. J Biol
Chem. 1998;273:22442–22452.
43. Rader D, FitzGerald GA. State of the art: arthrosclerosis in a limited edition [News and Views]. Nat Med. 1998;4:899–900.[Medline] [Order article via Infotrieve]
44. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827–832.[Abstract]
45.
Sharrett AR, Patsch W, Sorlie PD, Heiss G, Bond MG,
Davis CE. Associations of lipoprotein cholesterols,
apolipoproteins A-I and B, and triglycerides with carotid
atherosclerosis and coronary heart disease: the
Atherosclerosis Risk in Communities (ARIC) study.
Arterioscler Thromb. 1994;14:1098–1104.
46.
Habib A, Vezza R, Creminon C, Maclouf J, FitzGerald GA.
Rapid, agonist-dependent phosphorylation of human
thromboxane receptors: minimal involvement of protein
kinase C. J Biol Chem. 1997;272:7191–7200.
47. Rocca B, Loeb A, Strauss JA, Vezza R, Li H-W, FitzGerald GA. Directed vascular expression of the thromboxane A2 receptor results in intrauterine growth retardation. Nat Med.. 2000;6:219–221.[Medline] [Order article via Infotrieve]
48. Patrono C, Coller B, Dalen JE, FitzGerald GA, Fuster V, Gent M, Hirsh J, Roth G. Sixth ACCP Consensus Conference on Antithrombotic Therapy Platelet-Active Drugs: the relationships among dose, effectiveness, and side effects. Chest.
49.
Ogletree ML, O’Keefe EH, Durham SK, Rubin B, Aberg G.
Gastroprotective effects of thromboxane receptor
antagonists. J Pharmacol Exp Ther. 1992;263:374–380.
50.
McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S,
Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by
cyclooxygenase (COX)-2: the human pharmacology of a
selective inhibitor of COX-2. Proc Natl Acad Sci
U S A. 1999;96:272–277.
51. FitzGerald GA, Oates JA, Hawiger J, et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest.. 1983;71:676–688.
This article has been cited by other articles:
 |
|
 |
|
  J.-L. Cracowski and O. Ormezzano Isoprostanes, emerging biomarkers and potential mediators in cardiovascular diseases Eur. Heart J., October 1, 2004; 25(19): 1675 - 1678. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bolla, D. You, L. Loufrani, B. I. Levy, S. Levy-Toledano, A. Habib, and D. Henrion Cyclooxygenase Involvement in Thromboxane-Dependent Contraction in Rat Mesenteric Resistance Arteries Hypertension, June 1, 2004; 43(6): 1264 - 1269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Halushka and P. V. Halushka Why Are Some Individuals Resistant to the Cardioprotective Effects of Aspirin?: Could It Be Thromboxane A2? Circulation, April 9, 2002; 105(14): 1620 - 1622. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Praticò, C. Tillmann, Z.-B. Zhang, H. Li, and G. A. FitzGerald Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice PNAS, March 1, 2001; (2001) 61607398. [Abstract] [Full Text]
|
|
|
|
|
|
D. Pratico, C. Tillmann, Z.-B. Zhang, H. Li, and G. A. FitzGerald Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice PNAS, March 13, 2001; 98(6): 3358 - 3363. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||