Original ArticleThe Role of Cytokines and Inducible Nitric Oxide Synthase in Endotoxemia-Induced Endothelial DysfunctionDraisma, Annelies MD; Dorresteijn, Mirrin J MD; Bouw, Martijn P CCRN; van der Hoeven, Johannes G MD, PhD; Pickkers, Peter MD, PhDAuthor Information From the Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, The Netherlands. Received for publication April 9, 2009; accepted February 22, 2010. Funding sources: None. Conflict of interest: None declared. Reprints: Peter Pickkers, MD, PhD, Department of Intensive Care Medicine (551), Radboud University Nijmegen Medical Centre, PO box 9101, 6500 HB, Nijmegen, The Netherlands (e-mail: email@example.com). Journal of Cardiovascular Pharmacology: June 2010 - Volume 55 - Issue 6 - p 595-600 doi: 10.1097/FJC.0b013e3181da774b Buy Metrics Abstract Sepsis is characterized by a blunted vascular responses due to impairment of endothelial function. The aim of our study was to assess endothelial function and the role of cytokines and nitric oxide (NO). Endotoxin tolerance was induced in 14 healthy volunteers by intravenous injection of 2 ng·kg−1·d−1 lipopolysaccharide on 5 consecutive days. Forearm blood flow (FBF) was measured by strain-gauge plethysmography during dose-response curves of endothelium-dependent vasodilator acetylcholine and endothelium-independent vasodilator sodium nitroprusside before and 4 hours after LPS administration on days 1 and 5. In another study, 7 healthy volunteers were given selective inducible NO synthase inhibitor aminoguanidine intravenous continuously from 1 hour after a single LPS administration until 5 hours. FBF showed an attenuation of ACh-induced vasodilatory response with 67% (45%-72%) 4 hours after the first LPS administration (P = 0.01) with an unchanged dose-response curve to sodium nitroprusside. This attenuation to ACh infusion did not occur in the presence of aminoguanidine (P = 0.21) and also did not occur when tolerance was present on day 5 (P = 0.45). Our data demonstrate that endothelial dysfunction caused by endotoxemia does not occur when endotoxin tolerance develops, indicated by the absence of cytokine production and during administration of selective inducible NO synthase inhibitor aminoguanidine in vivo. © 2010 Lippincott Williams & Wilkins, Inc.