Inducible nitric oxide synthase activity is increased in patients with rheumatoid arthritis and contributes to endothelial dysfunction.
BACKGROUND
Recent in vitro studies suggest that inducible nitric oxide synthase (iNOS) activity mediates endothelial dysfunction. Rheumatoid arthritis (RA) is a chronic inflammatory condition and is associated with endothelial dysfunction and increased risk of cardiovascular disease. The aim of the study was to establish the contribution of iNOS to endothelial function.


METHODS
Forearm blood flow (FBF) was measured during intra-arterial infusions of acetylcholine (ACh), sodium nitroprusside (SNP), N(G)-monomethyl-l-arginine (l-NMMA) and aminoguanidine (AG) in 12 RA patients and 13 healthy control subjects. Levels of C-reactive protein (CRP) and myeloperoxidase (MPO) were assessed. FBF data are presented as mean percentage changes in the ratio (infused/control arm) of FBF + or - SEM.


RESULTS
FBF response to ACh was reduced in patients with RA compared to controls (179 + or - 29 v. 384 + or - 72%, respectively; P=0.01), but SNP response was not (P=0.5). FBF response to AG differed between patients and controls (-15 + or - 2% v. 13 + or - 4%, respectively; P<0.001), whereas the response to l-NMMA did not (P=0.4). In a multiple regression model log CRP, AG response and LDL were found to be independent predictors of endothelial function (R(2)=0.617, P<0.001).


CONCLUSIONS
RA patients have endothelial dysfunction and increased iNOS activity in comparison to controls. Furthermore, CRP and iNOS activity were independently associated with endothelial function. Our data demonstrates that inflammation is a key mediator in a process of endothelial dysfunction possibly via activation of iNOS and increased production of MPO.
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Box 110, Cambridge, UK. km391@cam.ac.uk
Kaisa M
KM
Mäki-Petäjä
Joseph
J
Cheriyan
Anthony D
AD
Booth
Frances C
FC
Hall
John
J
Brown
Sharon M L
SM
Wallace
Mike J
MJ
Ashby
Carmel M
CM
McEniery
Ian B
IB
Wilkinson
D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000503:physiopathology*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008297:Male; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012039:Regional Blood Flow / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D018836:Inflammation Mediators; D019323:omega-N-Methylarginine; D052247:Nitric Oxide Synthase Type II