Inducible nitric oxide synthase activity is increased in patients with rheumatoid arthritis and contributes to endothelial dysfunction ☆ Kaisa M. Mäki-Petäjä a, ⁎ ,1 , Joseph Cheriyan a,1 , Anthony D. Booth a , Frances C. Hall b , John Brown c , Sharon M.L. Wallace a , Mike J. Ashby a , Carmel M. McEniery a , Ian B. Wilkinson a a Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Box 110, Cambridge, UK b Dept of Clinical Medicine, University of Cambridge, Addenbrooke's Hospital, Box 157, Cambridge, UK c Trinity College, University of Cambridge, UK Received 23 October 2007; received in revised form 16 January 2008; accepted 11 February 2008 Available online 20 June 2008 Abstract 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 ± SEM. Results: FBF response to ACh was reduced in patients with RA compared to controls (179 ± 29 v. 384 ± 72%, respectively; P = 0.01), but SNP response was not (P = 0.5). FBF response to AG differed between patients and controls (- 15 ± 2% v. 13 ± 4%, respectively; P b 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 b 0.001). Conclusion: 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. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Endothelial dysfunction; Inflammation; Nitric oxide synthase; Rheumatoid arthritis; Forearm blood flow International Journal of Cardiology 129 (2008) 399 – 405 www.elsevier.com/locate/ijcard ☆ Funding source: Miss Mäki-Petäjä is currently a GlaxoSmithKline funded PhD student. Drs. Wilkinson and McEniery and Miss Wallace are supported by grants from The British Heart Foundation and Dr. Hall is supported by The British Medical Association's Doris Hillier Prize. This work was carried out in The British Heart Foundation sponsored vascular research laboratory at Addenbrooke's Hospital, Cambridge, U.K. ⁎ Corresponding author. Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, BOX 110, Cambridge CB2 0QQ, UK. Tel.: +44 1223 586852; fax: +44 1223 216893. E-mail address: km391@cam.ac.uk (K.M. Mäki-Petäjä). 1 KMP and JC have contributed equally towards the manuscript. 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.02.011