Enalapril and Losartan Reduce Sympathetic Hyperactivity in Patients with Chronic Renal Failure INGE H.H.T. KLEIN,* GERRY LIGTENBERG,* P. LIAM OEY † , HEIN A. KOOMANS,* and PETER J. BLANKESTIJN* *Department of Nephrology and Hypertension and † Department of Clinical Neurophysiology, University Medical Center Utrecht, The Netherlands. Abstract. The aim of this study was to compare the effects on BP and sympathetic activity of chronic treatment with an angiotensin (Ang)-converting enzyme (ACE) inhibitor and an AngII receptor blocker in hypertensive patients with chronic renal failure (CRF). In ten stable hypertensive CRF patients (creatinine clearance, 46  17 ml/min per 1.73 m 2 ), muscle sympathetic nerve activity (MSNA), plasma renin activity (PRA), baroreceptor sensitivity, and 24-h ambulatory BP were measured in the absence of antihypertensive drugs (except diuretics) after 6 wk of enalapril (10 mg orally) and after 6 wk of losartan (100 mg orally). The order of the three phases was randomized. Normovolemia was controlled with diuretics and confirmed with extracellular fluid volume measurements throughout the study. Both enalapril and losartan reduced MSNA (from 33  10 to 27  13 and 27  13 bursts/min, respectively; P  0.05) and average 24-h BP (from 141  8/93  8 to 124  9/79  8 and 127  8/81  9 mmHg; P  0.01). PRA was not different during the treatments. The change in BP and the change in MSNA during the treatments were correlated (r = 0.70 and r = 0.63, respectively; both P  0.05). Barore- ceptor sensitivity was not affected by the treatments. This is the first study to compare the effects of ACE inhibition and AngII blockade on MSNA. In hypertensive CRF patients, enalapril and losartan equally reduced BP and MSNA. Differences in modes of action of the two drugs did not result in differences in effects on MSNA, supporting the view that AngII-mediated mechanisms contribute importantly in the pathogenesis of sym- pathetic hyperactivity in these patients. Sympathetic hyperactivity in chronic renal failure (CRF) is caused by mechanisms arising in the failing kidneys (1). The renin system is often activated in hypertensive patients with CRF. There is clear evidence that high circulating angiotensin II (AngII) levels can stimulate central sympathetic outflow by a direct effect on the vasomotor center in the brain stem, which in humans can be quantified as increased muscle sympathetic nerve activity (MSNA) (2). We showed that MSNA is in- creased in patients with CRF and that this hyperactivity was reduced by chronic angiotensin-converting enzyme (ACE) in- hibition (3). These findings support the idea that AngII is involved in the pathogenesis of the sympathetic hyperactivity. However, ACE inhibition did not completely normalize the MSNA in these patients. There is increasing evidence that sympathetic hyperactivity contributes to the cardiovascular risk profile, not only by its effect on BP, but also independent of this effect (4). The hypothesis in the present study was that AngII receptor blockade in an equally effective antihypertensive regimen more effectively reduces the sympathetic hyperactivity than ACE inhibition. AngII receptor blockers are well accepted as antihypertensive agents in patients with CRF (5–7). Their BP lowering effect is comparable to that of ACE inhibitors (7,8). However, although both classes of drugs primarily interfere with the renin-angiotensin system, their modes of action show distinct and possibly relevant differences. Specific for ACE inhibitors is that they also inhibit the metabolism of kinins, resulting in increased levels of bradykinin (8,9), which may contribute to their BP lowering effect. Inhibition of AngII formation is unavoidably incomplete, because high concentra- tions of AngI lead to AngII formation through nonACE path- ways (10). AngII receptor blockers do not inhibit kinin degra- dation, but they are presumed to more completely block the renin cascade (8). The BP lowering effect of AngII receptor blockade depends more on the blockade of the AngII pathway, and thus perhaps on inhibition of sympathetic activity. We therefore compared in hypertensive patients with CRF the effects of chronic equally antihypertensive treatment with ena- lapril and losartan on MSNA in a randomized crossover study. Materials and Methods Subjects We included 13 hypertensive CRF patients. In ten patients (mean age, 45  10 yr; 7 men; body mass index, 26  2 kg/m 2 ; creatinine clearance: between 20 and 70 ml/min, mean value, 46  17 ml/min per 1.73 m 2 , stable during the 3 mo before the study), we were successful in obtaining MSNA measurements in all three study ses- sions. Clinical characteristics of the excluded patients were not dif- Received July 25, 2002. Accepted October 16, 2002. Correspondence to Peter J. Blankestijn, Department of Nephrology and Hy- pertension, room F03.226, University Medical Center, PO Box 85500, 3508 GA Utrecht, The Netherlands. Phone: 31-30-2507336; Fax: 31-30-2543492; E-mail: p.j.blankestijn@azu.nl 1046-6673/1402-0425 Journal of the American Society of Nephrology Copyright © 2003 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000045049.72965.B7 J Am Soc Nephrol 14: 425–430, 2003