Nitric oxide deficiency promotes vascular side effects of cyclooxygenase inhibitors.
The cardiovascular safety of COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) has recently been called into question. The factors that predispose to adverse events by NSAIDs are unknown. Because 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 or absence of NO were examined. Here, we show that acute hypertensive and prothrombotic activities of the COX-2-selective inhibitor celecoxib are revealed only after in vivo inhibition of NO generation. The nonselective NSAID indomethacin was hypertensive but antithrombotic 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.
Anning
Peter B
PB
Department of Medical Biochemistry and Immunology, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom.
Coles
Barbara
B
Morton
Jonathan
J
Wang
Haibin
H
Uddin
Jashim
J
Morrow
Jason D
JD
Dey
Sudhansu K
SK
Marnett
Lawrence J
LJ
O'Donnell
Valerie B
VB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D001168:Arthritis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001682:Biological Availability; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000172:deficiency*; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000172:deficiency* / Q000493:pharmacokinetics / Q000494:pharmacology; D011720:Pyrazoles / Q000009:adverse effects* / Q000494:pharmacology; D013449:Sulfonamides / Q000009:adverse effects* / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D009569:Nitric Oxide; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D007213:Indomethacin