Benefits from angiotensin-converting enzyme inhibitor ‘beyond blood pressure lowering’: beyond blood pressure or beyond the brachial artery? Kozo Hirata, Charalambos Vlachopoulos, Audrey Adji and Michael F. O’Rourke Objective The substantial benefits of ramipril over conventional therapy in high-risk patients are not always associated with clinically significant differences in brachial arterial pressure, and largely remain unexplained. We undertook this acute study to establish the magnitude of and reason for different acute effects of ramipril and atenolol on arterial pressure. Methods We enrolled 30 patients, who took 10 mg ramipril, 100 mg atenolol, and placebo at intervals of > — 7 days, in a randomized, double-blind, placebo-controlled trial. After baseline, measurements were taken at 30 – 60 min intervals for 5 h, and comprised cuff brachial pressure, radial artery tonometry with generation of central aortic pressure, and pulse wave velocity for aorta, upper limb and lower limb arteries. Results Both ramipril and atenolol reduced arterial pressure, and the diastolic pressure fall was similar in the aorta and brachial artery, but the systolic pressure fall for ramipril was greater than for atenolol (by 5.2 mmHg, P < 0.0001) in the aorta compared with the brachial artery. The aortic systolic pressure difference with ramipril in comparison with atenolol was accompanied by an absolute difference of 10.7% (P < 0.0001) in the augmentation index, denoting a reduction in peripheral wave reflection by ramipril. The aortic pulse wave velocity fell to a similar degree with ramipril in comparison with atenolol, but fell to a greater degree (1.35 and 0.44 m/s, respectively, P < 0.0001 for both) in muscular arteries of the lower and upper limbs. Conclusion A greater (average, 5.2 mmHg) decrease in aortic systolic pressure caused by ramipril may explain the greater benefit of ramipril over atenolol. The difference is attributable to decreased stiffness of peripheral arteries and a reduction in wave reflection. J Hypertens 23:551–556 Q 2005 Lippincott Williams & Wilkins. Journal of Hypertension 2005, 23:551–556 Keywords: aortic systolic pressure, arterial stiffness, wave reflection, arterial tonometry, angiotensin-converting enzyme inhibitors St Vincent’s Hospital and Clinic, University of New South Wales, Sydney, Australia. Conflict of interest: Michael F. O’Rourke is a founding director of AtCor Medical, manufacturer of pulse wave analysis systems. Correspondence and requests for reprints to Prof. Michael F. O’Rourke, St Vincent’s Clinic, 438 Victoria Street, Darlinghurst NSW 2010, Australia. Tel: +61 2 8382 6874; fax: +61 2 8382 6875; e-mail: M.ORourke@unsw.edu.au Received 23 April 2004 Revised 27 August 2004 Accepted 14 October 2004 See editorial commentary page 485 Introduction The important Heart Outcomes Prevention Evaluation (HOPE) [1] and the Losartan Intervention For Endpoint Reduction [2] studies showed benefits from an angioten- sin-converting enzyme inhibitor (ACEI) and an angio- tensin receptor blocker, respectively, which could not be explained from conventional measures of brachial artery systolic and diastolic pressure reduction. These studies were generally interpreted [3] as showing benefits of suppressing angiotensin at tissue level, and so ‘beyond blood pressure lowering’. Some commentators [4,5] ques- tioned this interpretation on the basis that conventional brachial cuff measures of systolic pressure can under- estimate systolic pressure reduction in central (carotid, coronary, renal) arteries and in the left ventricle. Such a differential effect has been established for an ACEI in rats over a period of months [6,7] and in acute studies of nitrates in humans [8–11]. The human studies have usually been undertaken at cardiac catheterization [8– 10] or at cardiac surgery [11], and their relevance to long- term studies have been questioned in the past. However, studies with a vasodilating beta-blocker [12], an ACEI [13], an ACEI/ diuretic combination [14] and isosorbide mononitrate [15] have shown that acute effects of such drugs, and of conventional beta-blockers, are maintained or enhanced [16] in long-term therapy, and so are relevant to trials such as the HOPE and Losartan Intervention For Endpoint Reduction studies. In order to throw more light on this contentious issue, we accordingly undertook an acute study over 5 h, where the arterial properties and pressure could be measured cen- trally and peripherally after administration of an ACEI, a beta-blocker and a placebo. We sought to confirm a differential effect on brachial and central pressure, and to explain the underlying mechanism. Methods Subjects The study was performed on a group of 30 (25 men and five women) subjects (mean age, 67  10 years) with one or more coronary risk factors (hypertension, diabetes Original article 551 0263-6352 ß 2005 Lippincott Williams & Wilkins