(Circulation. 2000;101:2833.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Cardiovascular Responses to the Isoprostanes iPF2
-III and iPE2-III Are Mediated via the Thromboxane A2 Receptor In Vivo
From Duke University and Durham Veterans Affairs Medical Centers (L.P.A., D.T., T.M.C.), Durham, NC; the Center for Experimental Therapeutics, University of Pennsylvania (B.R., A.L.L., G.A.F.), Philadelphia, Pa; and the Department of Medicine, University of North Carolina (J.-E.F., B.H.K.), Chapel Hill, NC.
Correspondence to Garret A. FitzGerald, MD, University of Pennsylvania Medical Center, Center for Experimental Therapeutics, 832 BRB II/III, Philadelphia, PA 19104. E-mail garret{at}spirit.gcrc.upenn.edu
Background—Isoprostanes (iPs) are
free radical–catalyzed products of arachidonic
acid that reflect lipid peroxidation in vivo. Several iPs exert
biological effects in vitro and may contribute to the functional
consequences of oxidant stress. For example, iPF2
-III
(8-iso PGF2) and iPE2-III
modulate platelet function and vascular tone. Although these
effects are blocked by antagonists of the receptor (TP) for
the cyclooxygenase product
thromboxane A2, it has been speculated that the
iPs may activate a receptor related to, but distinct from, the
TP.
Methods and Results—Transgenic mice (TPOEs) were generated in
which the TP-ß isoform was under the control of the preproendothelin
promoter. They overexpressed TP-ß in the vasculature but not in
platelets and exhibited an exaggerated pressor response to infused
iPF2-III compared with wild-type mice. This was blocked
by TP antagonism. The platelet response to the iP was unaltered in
TPOEs compared with wild-type mice. By contrast, both the pressor
response to iPF2-III and its effects on platelet
function were abolished in mice lacking the TP gene. This was also true
of the effects of infused iPE2-III on mean
arterial pressure and platelet aggregation.
Conclusions—Both iPF2-III and iPE2-III
exert their effects on platelet function and vascular tone in vivo
by acting as incidental ligands at membrane TPs rather than via a
distinct iP receptor. Activation of TPs by iPs may be of importance in
syndromes in which cyclooxygenase activation and
oxidant stress coincide, such as in
atherosclerosis and reperfusion after tissue
ischemia.
Key Words: isoprostane • receptors • thromboxane
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