Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Sympathetic activation and endothelial dysfunction as therapeutic targets in obesity-related hypertension Brent Egan a and Guido Grassi b,c See original paper on page 393 T he interest in obesity, hypertension and the meta- bolic syndrome has escalated together with the burgeoning obesity epidemic over the past 30 years. Obesity, especially in association with abdominal fat pat- tern, is linked not only with elevated blood pressure but also with abnormalities of insulin action, glucose and lipid metabolism, proinflammatory factors and oxidative stress, the fibrinolytic system, the autonomic nervous system and endothelial dysfunction as well as other structural and functional vascular abnormalities [1,2]. As a result, interest in therapies that simultaneously address multiple abnor- malities has also erupted. In this regard, renin–angiotensin system blockade has generated considerable interest as a single pharmacological intervention, which favourably alters multiple components of the cardiometabolic syn- drome [3–5]. The study by Dorresteijn et al. [6] examines the effects of various classes of antihypertensive agents on several risk factors and risk markers in obese hypertensive patients . The investigators employ a rigorously designed, four-way, double-blind, crossover study in obese adults with blood pressures of at least 130 mmHg systolic and/or at least 85 mmHg diastolic on no antihypertensive treatment. The authors show that blockade of the renin–angiotensin system with aliskiren 300 mg daily is more effective than either moxonodine 0.4 mg daily or hydrocholorothiazide 25 mg daily for lowering blood pressure over an 8-week treatment period. Moreover, only aliskiren improved flow- mediated dilation, a clinical marker of endothelial function, relative to the placebo control. Although only hydro- chlorothiazide reduced the urinary markers of oxidative stress, none of the therapies altered serum markers of adipocyte function or oxidative stress. Moreover, none of the three treatments reduced pulse-wave velocity, an index of vascular stiffness, although aliskiren and hydrochloro- thiazide equally improved estimates of central blood pressure and the augmentation index. The findings in the current report will be compared with a sample of previous studies on the effects of various blockers of the renin –angiotensin system on blood pressure and other variables that cluster with high-risk obesity. PREVIOUS STUDIES WITH RENIN^ ANGIOTENSIN SYSTEM BLOCKADE IN OBESITY-ASSOCIATED HYPERTENSION In the Treatment in Obese Patients with Hypertension (TROPHY) study, 232 obese patients were randomized to lisinopril (10, 20, 40 mg/day), hydrochlorothiazide (12.5, 25, 50 mg/day) or placebo [7]. Doses were escalated during the trial as needed to control elevated blood pressure values. After 12 weeks, lisinopril lowered SBP/DBP by 9.2/8.3 mmHg, hydrochlorothiazide by 10.0/7.7 mmHg and placebo by 4.5/3.3 mmHg. Similar to the current report, TROPHY investigators included 24-h ambulatory blood pressure monitoring. Lisinopril reduced 24-h SBP/DBP by 10.5/7.2 mmHg and hydrochlorothaizide by 12.4/ 6.7 mmHg. TROPHY, while lacking the crossover design of the current report, addressed one of its limitations, which is a comparison of single doses of the various compounds. Although lisinopril controlled office DBP better than the thiazide diuretic, no significant differences were observed between the two therapies in the magnitude of the blood pressure-lowering effects in the office environment or over a 24-h period. Of note, nearly half of obese hypertensive patients in the TROPHY trial required the highest doses of hydrochlorothiazide, that is, 50 mg/day, which exceeds the more typically prescribed upper limit of 25 mg daily that was the focus of the current report. Moxonidine did not significantly lower elevated blood pressure values among obese hypertensive patients in the present report [6]. However, other evidence indicates that the sympathetic nervous system plays an important role in obesity-related hypertension in dogs and in humans [8,9]. The potential reasons for apparent discrepancies between the blood pressure-lowering effects of different ‘sympatho- lytic’ therapies go beyond the scope of this commentary. Journal of Hypertension 2013, 31:259–260 a Department of Medicine and Geriatrics, University of South Carolina, Charleston, South Carolina, USA, b Clinica Medica, Universita` Milano-Bicocca and c Istituto di Ricerca a Carattere Scientifico IRCCS Multimedica, Sesto san Giovanni, Milan, Italy Correspondence to Brent Egan, MD, Medical University of South Carolina, 135 Rutledge Avenue, 1230 RT, Charleston, SC 29425, USA. Tel: +1 843 792 1715; e-mail: eganbm@musc.edu J Hypertens 31:259–260 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0b013e32835d0dcf Journal of Hypertension www.jhypertension.com 259 Editorial Comment