Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Gly460Trp a-adducin gene polymorphism and endothelial function in untreated hypertensive patients Francesco Perticone a , Angela Sciacqua a , Cristina Barlassina b , Lucia Del Vecchio b , Maria Chiara Signorello a , Chiara Dal Fiume b , Francesco Andreozzi a , Giorgio Sesti a and Daniele Cusi b Objectives Endothelium-dependent vasodilatation is impaired in essential hypertension. Besides traditional and emerging cardiovascular risk factors, genetic factors may also promote deleterious alterations of endothelial physiology. The aim of the present study was to investigate the relationship between the 460Trp allele of ADD1 and endothelium-dependent vasodilation in 110 never-treated hypertensive patients. Methods Forearm blood flow (FBF) was measured during intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) at increasing doses. Analysis of endothelium-dependent and endothelium-independent vasodilation was tested according to ADD1 genotype. Results The FBF values at the three incremental doses of ACh were 5.22 W 0.24 (R76%), 8.64 W 0.45 (R193%) and 14.74 W 0.71 (R395%) ml/100 ml of tissue per min for Gly460Gly and 4.63 W 0.20 (R51%), 6.84 W 0.36 (R123%) and 11.22 W 3.8 (R269%) ml/100 ml of tissue per min for 460Trp. Thus, ACh-stimulated FBF was significantly reduced in hypertensive subjects carrying the 460Trp allele of ADD1 (P < 0.001). SNP-stimulated FBF was not affected by ADD1. Conclusions The main finding in this study was that in essential hypertensives the 460Trp allele of ADD1 is strongly associated with an impaired endothelium- dependent vasodilation, a powerful predictor of cardiovascular risk. J Hypertens 25:2234–2239 Q 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins. Journal of Hypertension 2007, 25:2234–2239 Keywords: endothelium, genes, hypertension a Chair of Internal Medicine and Cardiovascular Diseases Unit, ‘G. Salvatore’ Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro and b Department of Sciences and Biomedical Technologies, University of Milano and Policlinico Multimedica, Sesto San Giovanni (Milano), Italy Correspondence to Francesco Perticone, MD, Department of Experimental and Clinical Medicine, Policlinico Mater Domini – Viale Europa, Campus Germaneto, Catanzaro, Italy Tel: +39 0961 3647149; fax: +39 0961 3647192; e-mail: perticone@unicz.it Received 18 January 2007 Revised 7 April 2007 Accepted 21 June 2007 Introduction Traditional and emerging cardiovascular risk factors are associated with endothelial dysfunction [1–3]. Other yet- unknown causes, including genetic factors, may promote deleterious alterations of endothelial physiology in hypertensive [2] as well as in healthy subjects [3]. Adducin is present into the cells as an a – b or a – g hetero- dimer (a  b, a  g) or hetero-tetramer (2a  2b, 2a  2g). Its subunits, which are similar but not identical, map on different chromosomes. The 460Trp allele of the Gly460Trp polymorphism of a-adducin (ADD1) was documented in both positive and negative associ- ations with a form of salt-sensitive hypertension [4–6]. The same polymorphism interacts with the angiotensin- converting enzyme (ACE) I/D polymorphism on the slope of the pressure–natriuresis function in hyperten- sive subjects [7] as well as on incidence of hypertension [8], intima–media thickness (IMT) [9] and degree of renal dysfunction [10] in a sample of the general popu- lation. Besides its effect on Na pump activity [11–13] adducin is able to modulate cell-signal transduction through changes in the actin cytoskeleton, providing a link between its hypertension-associated allele and end- organ damage [12]. The present study was designed to test whether the 460Trp allele of ADD1 affects endothelial function, in a group of recently discovered, never-treated, essential hypertensive patients. Methods Study population The study included a total of 110 middle-aged out- patients recruited at Catanzaro University Hospital (72 men and 38 women, mean age 45 years) with a well-documented history of chronic primary hyperten- sion (time from first report of high blood pressure: 4–7 months). All patients were Caucasian and their families had been living in Calabria for at least two generations. Physical examination and review of medical history were performed before beginning the study. Each patient underwent standard electrocardiography, rou- tine blood biochemistry and chest radiography. Causes of secondary hypertension were excluded in all patients by appropriate clinical and biochemical examination. 2234 Original article 0263-6352 ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins