Submitted February 23, 2006
Accepted July 25, 2006
Nitric oxide deficiency promotes vascular side-effects
of cyclooxygenase inhibitors in vivo
Peter B Anning, Barbara Coles, Jonathan Morton, Haibin Wang, Jashim Uddin, Jason D Morrow, Sudhansu K Dey, Lawrence J Marnett, and Valerie B O'Donnell*
Department of Medical Biochemistry and Immunology, University of Wales College of Medicine, Cardiff
Pediatrics, Cell & Developmental Biology and Pharmacology, Vanderbilt University, Tennessee,
Departments of Biochemistry and Chemistry, Vanderbilt University, Tennessee
Pediatrics, Cell & Developmental Biology and Pharmacology, Vanderbilt University, Tennessee
* Corresponding author; email: o-donnellvb{at}cardiff.ac.uk.
The cardiovascular safety of COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) has recently been called into question. The factors that predispose to adverse events by NSAIDs are unknown. Since patients with arthritis have decreased nitric oxide (NO) bioavailability, the in vivo effects of NSAIDs on murine vascular tone and platelet activity in the presence/absence of NO were examined. Here we show that acute hypertensive and pro-thrombotic activities of the COX-2 selective inhibitor celecoxib are revealed only after in vivo inhibition of NO generation. The non-selective NSAID indomethacin was hypertensive but anti-thrombotic when NO was absent. In vitro myography of aortic rings confirmed that vasoconstriction required inhibition of both NOS and COX-2, and was abolished by supplementation with exogenous NO. These data indicate that NO suppresses vascular side-effects of NSAIDs, suggesting that risk will be greatest in patients with impaired vascular function associated with decreased NO bioavailability.
