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COX‐2 inhibitors selectively block prostacyclin synthesis in endotoxin exposed vascular smooth muscle cells
Author(s) -
Schildknecht Stefan,
Bachschmid Markus,
Baumann Achim,
Ullrich Volker
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0609fje
Subject(s) - prostacyclin , septic shock , vascular smooth muscle , vasodilation , shock (circulatory) , endothelium , medicine , endocrinology , lipopolysaccharide , platelet , chemistry , pharmacology , smooth muscle , sepsis
High levels of prostacyclin (PGI 2 ; measured as 6‐keto‐PGF 1α ) have been reported in patients under septic shock. Because this was at variance with our previous findings of nitration and inhibition of PGI 2 synthase by endotoxin (LPS) in the endothelium, we examined the role of vascular smooth muscle as an alternative source of PGI 2 . Bovine aortic smooth muscle cells (SMC) in passage 1 contained high levels of PGI 2 synthase but no activity and no detectable levels of COX‐1 or COX‐2. LPS exposure for 3 h caused COX‐2 mRNA and protein levels to rise during 8 h together with a large increase in PGI 2 synthase activity. In contrast, cytokines lead to only a moderate increase of both PGI 2 and PGE 2 . Specific COX‐2 inhibitors completely blocked PGI 2 formation but PGE 2 synthesis only partially. Unexpectedly, • NO formation remained low over 6–8 h, which may be a reason for the lack of nitration and inhibition of prostacyclin synthase in LPS exposed SMC. Our results can explain the clinical observation of severe hypotension in progressive stages of septic shock as a mechanism to compensate endothelial dysfunction. According to our data, the use of COX‐2‐specific inhibitors may not be advisable in septic patients. In contrast, administration of COX‐1‐specific blockers could prevent platelet aggregation during progressed stages of endotoxic shock.