J Am Soc Nephrol 11: 1813–1818, 2000 Renin Inhibition Improves Pressure Natriuresis in Essential Hypertension PIETER VAN PAASSEN,* DICK DE ZEEUW,*† PAUL E. DE JONG,* and GERJAN NAVIS*† *Department of Medicine, Division of Nephrology, and †Department of Clinical Pharmacology, University Hospital Groningen and Groningen University Institute for Drug Exploration (GUIDE), The Netherlands. Abstract. Pressure natriuresis (PN), i.e., a rise in renal sodium remikiren treatment, mean arterial pressure was 101.9 Ϯ 1.7 excretion in response to a higher BP, is involved in long-term and 100.8 Ϯ 1.7 mmHg (P Ͻ 0.05, versus baseline). Urinary BP regulation. PN is blunted in essential hypertension, but the sodium excretion was 39.3 Ϯ 3.7 and 45.2 Ϯ 5.3 mmol/24 h mechanism is unknown. This study assessed the role of the (not significant versus baseline), and plasma renin activity was renin-angiotensin-aldosterone system (RAAS) in PN in eight 0.79 Ϯ 0.11 and 0.82 Ϯ 0.13 nmol/L per h (P Ͻ 0.05 versus essential hypertensive men from the individual correlations baseline). During remikiren treatment, BP correlated positively between spontaneous fluctuations in BP and time correspond- with sodium excretion in all patients but in only three of eight ing changes in sodium excretion (collected at 2- and 4-h patients without treatment. The slope of the regression equa- intervals for 48 h), during strict sodium balance, without treat- tion was steeper during remikiren treatment in seven of eight ment, and during renin inhibition (remikiren, 600 mg oral patients. Thus, the relationship between BP and natriuresis was compound). Without treatment, daily values for mean arterial more readily apparent during RAAS blockade, suggesting that pressure were 109.5 Ϯ 1.9 and 107 Ϯ 1.9 mmHg, for urinary RAAS activity blunts PN in hypertensive patients. Improved sodium excretion were 37.2 Ϯ 2.8 and 42.0 Ϯ 2.8 mmol/24 h, PN may contribute to the hypotensive effect of RAAS block- and for plasma renin activity were 2.34 Ϯ 0.48 and 2.23 Ϯ 0.44 ade and to maintenance of sodium balance at a lower BP level nmol/L per h, respectively, for two consecutive days. During without volume expansion. Pressure natriuresis (PN) is the increase in renal sodium ex- humans were performed by testing the response of BP to a cretion in response to a rise in arterial pressure (1). This change in sodium status (12). No data, however, are available mechanism is part of a feedback loop that seems to play an on the effect of a change in BP on sodium excretion in essential important role in long-term BP control (2). The pressure- hypertensive individuals. We therefore investigated whether induced rise in renal sodium excretion with subsequent reduc- spontaneous fluctuations in BP are associated with correspond- tion in extracellular volume restores BP to its previous level. ing changes in sodium excretion in patients in balance on a Animal studies demonstrated that short-term fluctuations in BP fixed sodium intake. To test the hypothesis that RAAS activity elicit corresponding changes in renal sodium excretion thought is involved in the impairment of PN in essential hypertension, to constitute the key factor in the PN feedback loop (3). we also investigated whether blockade of the RAAS by the PN is present in isolated kidneys and thus reflects an intrin- specific renin-inhibitor remikiren could improve the pressure– sic renal property. However, in vivo, the PN curve is modified natriuresis relationship. by neurohumoral factors such as the renin-angiotensin-aldoste- rone system (RAAS) (4), the sympathetic nervous system (5), and atrial natriuretic factor (6). In hypertension, the PN rela- Materials and Methods tionship is abnormal and shifted to the right (7,8). Several Patients and Protocol humoral and intrarenal hemodynamic mechanisms have been Eight essential hypertensive Caucasian men were studied. Their median age was 51 yr (range, 45 to 57 yr), and they weighed 84 kg suggested to contribute to the abnormal PN curve in hyperten- (range, 74 to 102 kg). All subjects had mild to moderate essential sion (9–11). Whereas PN has been the subject of much inves- hypertension without clinically relevant end-organ damage. Sitting tigation, few data on the role of BP in promoting natriuresis are diastolic BP at study entry was 100 mmHg (range, 95 to 104). available in human hypertension. Nearly all studies on PN in Creatinine clearance was 111 ml/min (range, 98 to 125). Excluded were patients with secondary hypertension, patients who weighed more than 120% of their ideal body weight (Metropolitan Life Insur- Received November 8, 1999. Accepted February 18, 2000. ance Table), and patients with a history of alcohol or other drug abuse. Correspondence to Dr. Gerjan Navis, Department of Medicine, Hanzeplein 1, All subjects gave their informed consent, and the study was approved 9713 GZ Groningen, The Netherlands. Phone: ϩ31-503612621; Fax ϩ31- by the local ethics committee. All antihypertensive medication had 503619310; E-mail: [email protected] been withdrawn at least 3 wk before entry in the study. 1046-6673/1110-1813 The patients were hospitalized during the study. They adhered to an Journal of the American Society of Nephrology equicaloric diet containing 50 mmol of sodium, 100 mmol of potas- Copyright © 2000 by the American Society of Nephrology sium, 60 g of proteins, and 2500 ml of fluids per day, provided at fixed 1814 Journal of the American Society of Nephrology J Am Soc Nephrol 11: 1813–1818, 2000 time points. Patients were allowed to walk around but were asked to Statistical Analyses adhere to comparable schedules of daily activities during all study Results are expressed as mean Ϯ SEM. Ranges are given when days. The 24-h urine was collected daily to determine urinary creat- appropriate. During the assessment of the pressure–natriuresis rela- inine, sodium, and potassium. BP was measured daily between 11:00 tionship, the 15-min BP values were averaged according to corre- a.m. and 12:00 p.m. while patients were in supine position. After a sponding real-time periods of urine collection. The impact of possible run-in period of7dtoensure stabilization of BP and sodium balance, collection errors by incomplete bladder emptying was avoided by the patients were studied for a 3-d baseline period without treatment, correcting urinary excretion of sodium or potassium for urinary cre- followed by7doftreatment with the renin inhibitor remikiren, 600 atinine excretion for each collection period. mg orally administered at noon. Renal hemodynamics were assessed The pressure–natriuresis relationship was assessed by performing a during baseline, at the first of the three baseline days, and on the fifth regression analysis between corresponding data on BP and natriuresis day of renin inhibition. for each individual patient separately. Statistical analysis was per- The pressure–natriuresis relationship was studied both during base- formed by using a paired, nonparametric ANOVA (Friedman) for line, on the last two pretreatment days, and on the sixth and seventh repeated measurements followed by Dunn’s correction for multiple days of remikiren treatment, after stabilization of urinary sodium comparisons and by using a paired Wilcoxon’s signed rank test. P excretion (UNaV) and body weight had been warranted. PN was values of less than 0.05 (two-sided) were considered to indicate assessed by performing 48-h continuous BP recordings, at 15-min statistical significance. intervals from 8:00 a.m. until 12:00 p.m. and every 30 min from 12:00 p.m. until 8:00 a.m.. Simultaneously, urine was collected every 2 h Results from 8:00 a.m. until 12:00 p.m. and every 4 h from 12:00 p.m. until All patients completed the protocol. During the run-in period 8:00 a.m. to determine the excretion of creatinine, sodium, and po- all patients reached steady state with respect to BP, urinary tassium in each portion. Blood was drawn to determine plasma renin excretion of sodium, potassium and creatinine, hormonal pa- activity (PRA), immunoreactive renin (irR), and immunoreactive an- giotensin II (AngII) at noon when patients had been supine for 1 h. rameters, and body weight. The mean values for these param- eters during the two baseline study days and the two remikiren study days are given in Table 1. These data show that dietary Methods compliance was excellent. The presence of steady state during the baseline study days as well as the remikiren study days is BP was recorded by an automatic noninvasive device (Dinamap®; Criticon Inc., Tampa, FL). Mean arterial pressure (MAP) was calcu- demonstrated by the similarity of data on the two consecutive lated as diastolic BP plus one third of the difference between systolic study days in both conditions. and diastolic pressure. For each 2-h period, the mean value was As is apparent from Table 1, remikiren induced a significant calculated. fall in BP. Remikiren led to effective 24-h blockade of the Urinary electrolytes and creatinine were measured by a standard renin angiotensin system, with a fall in PRA, a fall in AngII autoanalyzer technique (SMA-C, Technicon®, Tarrytown, NY). from 17 Ϯ 4to8Ϯ 2 ng/L at trough, and a corresponding Blood samples for measurement of PRA and irR were collected into feedback increase in irR. A variable natriuresis was observed at Vacutainer tubes containing ethylenediaminetetraacetic acid as an onset of remikiren treatment with an overall cumulative so- anticoagulant, at room temperature. After immediate separation, dium loss of 73 Ϯ 30 mmol (not significant). Important is that Ϫ plasma was stored at 30°C until analysis. PRA was assessed by the natriuresis stabilized in all patients before repeating the PN ® quantitation of generated AngI as measured by RIA (Rianen Ang I analysis during remikiren treatment, as is apparent from the RIA Kit; Cis Bio International, Gif-sur-Yvette, France).