Renin Inhibition Improves Pressure Natriuresis in Essential Hypertension

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-aldosterone 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 angiotensin II (AngII) at noon when patients had been supine for 1 h. rameters, and body weight. The mean values for these parameters 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). The irR was virtually identical UNaV on the two PN study days. The same determined using the renin IRMA Pasteur kit, with a coefficient of applied for kaliuresis, which displayed stable values on the variation of 15.9% (interassay) and 6.6% (intra-assay), both at 31 pg/ml. Blood samples for the measurement of AngII were collected consecutive study days, after a cumulative potassium retention Ϯ into prechilled Vacutainer tubes containing an inhibitor cocktail con- of 42 11 mmol had been observed during the preceding sisting of ethylenediaminetetraacetic acid, the angiotensin-converting treatment days. Body weight stabilized at 83.1 Ϯ 2.9 kg. enzyme inhibitor cilazaprilat, and the renin-inhibitor Ro 42-5892 to The effect of remikiren on renal hemodynamics was as- prevent the formation of AngII during further analysis. After imme- sessed as changes in RVR could play a role in shifts of PN. diate separation, plasma was stored at Ϫ20°C until analysis. AngII GFR did not change (90 Ϯ 4to88Ϯ 3 ml/min), whereas ERPF was determined using the Nichols Institute Diagnostics AngII RIA increased from 395 Ϯ 25 to 426 Ϯ 23 ml/min. As a result, with a coefficient of variation of 5.1% (interassay, mean value 31 filtration fraction fell from 23.1 Ϯ 0.6 to 20.7 Ϯ 0.6% and pg/ml) and 4% (intra-assay, mean value 42 pg/ml). During analysis, RVR fell from 24.0 Ϯ 1.7 to 20.3 Ϯ 1.3 10Ϫ2mmHg.ml.minϪ1. plasma was first separated from plasma proteins by ethanol extraction. The group means of BP and UNaV at the different time The extracted plasma AngII was measured in a sensitive and specific points during the 48-h assessment of PN are depicted in Figure competitive protein-binding RIA with a detection limit of 3.6 pg/ml. 1. It shows a normal diurnal rhythm for BP with a clear fall GFR and effective renal plasma flow (ERPF) were measured by during the night. During remikiren treatment, BP is lower and constant infusion of 125I-iothalamate and 131I-hippuran, respectively. The day-to-day coefficient of variation of this method is 2.2% and the diurnal pattern is preserved. UNaV displays the normal 5.0%, respectively (13). GFR and ERPF are corrected for standard diurnal pattern with higher values during the day and lower body surface area (1.73m2). Two consecutive 2-h clearances were values during the night. This pattern was unchanged during measured. Filtration fraction is calculated as GFR/ERPF and ex- remikiren treatment. pressed as a percentage. Renal vascular resistance (RVR) is calculated The relationship between BP at a given period and the as the ratio of mean arterial BP and ERPF. corresponding UNaV is depicted for the individual patients in J Am Soc Nephrol 11: 1813–1818, 2000 Renin Inhibition Improves PN in Essential Hypertension 1815

Table 1. Mean values for BP, UNaV, hormonal parameters, and body weight during the two consecutive observation days during baseline and during remikiren treatmenta

Baseline Remikiren

Day 1 (0–24 h) Day 2 (24–48 h) Day 3 (0–24 h) Day 4 (24–48 h)

MAP (mmHg)b 109.5 Ϯ 1.9 107 Ϯ 1.9 101.9 Ϯ 1.7d 100.8 Ϯ 1.7d UNaV (mmol/24 h) 37.2 Ϯ 2.8 42.0 Ϯ 2.8 39.3 Ϯ 3.7 45.2 Ϯ 5.3 Ϯ Ϯ Ϯ Ϯ UkV (mmol/24 h) 89.1 2.8 91.6 2.8 90.2 3.4 90.8 3.8 UCrV (mmol/24 h) 17.2 Ϯ 0.7 17.4 Ϯ 0.9 17.1 Ϯ 0.8 17.1 Ϯ 0.7 UVol (ml/24 h) 1657 Ϯ 83 1780 Ϯ 80 1677 Ϯ 130 1791 Ϯ 161 PRA (nmol/h)c 2.34 Ϯ 0.48 2.23 Ϯ 0.44 0.79 Ϯ 0.11d 0.82 Ϯ 0.13d irR (ng/L)c 46.6 Ϯ 8.8 44.8 Ϯ 8.0 66.7 Ϯ 11.5d 65.7 Ϯ 124d PAC (pmol/L)c 768 Ϯ 98 689 Ϯ 66 634 Ϯ 89 660 Ϯ 84 Body weight (kg) 84.0 Ϯ 3.2 84.0 Ϯ 3.2 83.2 Ϯ 2.9d 83.1 Ϯ 2.9d

a UNaV, urinary excretion of sodium, potassium, and creatinine; MAP, mean arterial pressure; UkV, urinary excretion of potassium; UCrV, urinary excretion of creatinine; UVol, diuresis; PRA, plasma renin activity; irR, immunoreactive renin; PAC, plasma aldosterone concentration. b Mean of all measured values during 24 h. c Measured at noon. d P Ͻ 0.05 study day versus baseline (two-way ANOVA).

Figure 1. The graphs in both panels indicate mean arterial pressure (MAP, mmHg, mean Ϯ SEM). The bars in both panels denote urinary sodium excretion (UNaV, umol/min, mean Ϯ SEM). For both parameters, measurements were performed during 2 ϫ 24 h, both during baseline (left) and during remikiren (right) treatment.

Figure 2, during baseline and remikiren treatment. The corre- from a highly significant correlation in all studied patients and sponding values of the linear regression parameters are given a steeper slope of the regression line in all patients but one. The in Table 2. During the baseline assessment, a significant cor- slopes of the individual patients during remikiren treatment relation between UNaV and BP values was observed in only ranged from 0.63 to 2.4, indicating that a rise in natriuresis three of eight patients, all three with a relatively low baseline ranging from 0.63 to 2.4 umol/min was observed per mmHg PRA. During remikiren treatment, higher BP values were more rise in BP. No correlation was present between the excretions closely associated with higher natriuresis values, as is apparent of creatinine or potassium and BP during either baseline or 1816 Journal of the American Society of Nephrology J Am Soc Nephrol 11: 1813–1818, 2000

evidence for involvement of the RAAS in the relationship between BP and sodium status in humans (17). Evidence for a role of the RAAS in the PN curve in secondary forms of hypertension was provided by Kimura et al. (18), who demonstrated normalization of the PN curve after causal treatment of primary hyperaldosteronism (removal of the adenoma) and renovascular hypertension (angioplasty), respectively. However, the other component of the PN feedback loop, the pressure dependency of sodium excretion in humans, has gained little attention. In isolated kidneys and in whole-animal preparations, the responsiveness of sodium excretion to short- term fluctuations in BP is well established. It was pointed out that the cumulated effects of short-term coupling of sodium excretion to fluctuations in BP would be an essential part of the PN feedback loop (3). Our study is the first to analyze the pressure dependency of sodium excretion in humans from the spontaneous short-term fluctuations in BP in individual essential hypertensive patients. The value of such an individual assessment has been empha- sized, referring to the heterogeneous nature of essential hypertension (4). We opted for the analysis of spontaneous fluctuations for two main reasons. First, we wanted to analyze the role of the PN response in the normal daily maintenance of BP and sodium homeostasis in hypertensive men. Second, this approach circumvents the need for deliberate induction of changes in BP as measures that can reproducibly and safely elicit changes in BP in men, such as infusion of vasopressor or -depressor agents, usually exert direct, pharmacologic effects on sodium excretion as well. For our approach, it is crucial that Figure 2. This graph shows the linear regression analysis between sodium balance be strictly controlled, to preclude that sodium UNaV (Y-axis, umol/min) and MAP (mmHg) in all individual pa- excretion is confounded by fluctuations in overall sodium tients, both during baseline (E, dashed line) and during remikiren (F, intake (19). Our patients, therefore, were hospitalized, and not solid line). From 8:00 a.m. to 12:00 p.m., each data point refers to a only overall sodium intake but also the timing of food intake 2-h period, whereas from 12:00 p.m. to 8:00 a.m., each data point over the 48-h observation period was fixed and similar during refers to a 4-h period. The patient numbers correspond with the the baseline study period and the remikiren study period. parameters of regression analysis and plasma renin activity as denoted Patients were ambulant during those days, with fixed times for in Table 2. activity and rest. Accordingly, the pattern of sodium excretion over the 48-h period can be expected to be affected not only by BP but also by the modifying effects of activity, posture, and remikiren, indicating that the observed change in the relation- food intake. This approach was chosen because it mimics the ship between BP and sodium excretion is specific for sodium conditions in normal life as closely as possible. excretion. Under these conditions, a normal diurnal pattern of sodium excretion and BP was observed, consistent with the condition Discussion of uncomplicated hypertension without significant renal target Blockade of the RAAS by the renin-inhibitor remikiren organ damage in our patients (16-20). During baseline, no reinforced the relationship between spontaneous fluctuations in significant relationship was found between sodium excretion BP and UNaV in ambulant essential hypertensive individuals and BP in five of eight patients. Thus, under normal conditions, in balance on a fixed sodium diet. an effect of spontaneous fluctuations in BP on fluctuations in The relationship between BP and renal sodium excretion has sodium excretion cannot be demonstrated in the majority of the been hypothesized to be crucial to the homeostasis of BP and patients. It should be noted that our study did not include circulating volume. In humans, this relationship has been stud- normal controls; therefore, it cannot be ascertained from our ied mainly as the response of BP to changes in sodium status, data whether the absence of such a relationship is specific for i.e., sodium sensitivity of BP. Sodium sensitivity of BP was the condition of essential hypertension, as such a conclusion shown to be modified by many factors, such as race (14), renal would require a comparison with healthy control subjects. function impairment (15), and diurnal patterns of posture and Remarkably, during specific RAAS blockade, the relation- activity (16). It is interesting that RAAS blockade increases ship between spontaneous fluctuations in BP and sodium ex- sodium sensitivity of BP in essential hypertension, providing cretion was reinforced, as is apparent from a significant cor- J Am Soc Nephrol 11: 1813–1818, 2000 Renin Inhibition Improves PN in Essential Hypertension 1817

Table 2. Linear regression parameters (slope of the regression line, regression coefficient r, and P value) for BP and urinary sodium excretion for individual patients during baseline and remikiren, and individual values for PRA (PRA trough values measured at noon are given). Patients are arranged according to PRA during baselinea

PRA Slope r P

Baseline Remikiren Baseline Remikiren Baseline Remikiren Baseline Remikiren

1 5.03 0.94 Ϫ0.12 0.9 0.81 0.74 0.007 0.01 2 3.14 1.14 0.61 1.51 0.18 0.68 0.66 0.0001 3 2.72 1.1 0.12 1.41 0.66 0.90 0.18 0.001 4 2.22 0.58 0.13 0.92 0.48 0.55 0.81 0.008 5 1.89 1.06 1.13 1.89 0.002 0.58 0.48 0.0001 6 1.5 0.7 0.90 1.68 0.007 0.84 0.002 0.0003 7 1.15 0.5 0.95 0.63 0.0003 0.74 0.0003 0.0002 8 0.6 0.42 1.44 2.4 0.18 0.54 0.18 0.02

a PRA, plasma renin activity. relation between sodium excretion and BP in all patients, with due to blockade of RAAS activity and consequently reduced a steeper slope of the regression equation in seven of eight AngII effects. The latter is likely to be relevant not only by patients. These findings strongly suggest that RAAS blockade allowing renal vasodilation but also by allowing a decrease in improves the PN response and support the hypothesis that in tubular sodium reabsorption in response to higher renal perfu- hypertension, RAAS activity may play a role in blunting PN. sion pressure (22). Experimental data support a specific effect Such a role for the RAAS is further supported by our finding of the RAAS in the relationship between renal sodium excre- that a correlation between BP and sodium excretion during tion and fluctuations in BP (4). It is interesting and in line with baseline was more readily apparent in patients with a lower our data that blockade of the AngII (subtype 2) receptor was baseline PRA level. This is in line with the assumption by found to improve the PN response in rats even independent Staessen et al. (16) that the presence of a nocturnal correlation from renal hemodynamics (23). Recent strong supporting data between BP and sodium excretion between different individu- for such a differential mechanism of the AngII blockade- als, as opposed to the absence of such a relationship during induced shift in PN was obtained in hypertensive double- daytime, is explained by the lower endogenous renin activity transgenic rats that contain both the human renin and angio- during the night. tensinogen genes. In these rats, the ACE inhibitor cilazapril

It should be noted that the relationship between BP and and the AT1 blocker losartan, both in submaximal doses, sodium excretion during remikiren treatment was found at an exerted additive effects on the PN curve. Whereas cilazapril overall BP level that was lower than that during the untreated improved sodium and water excretion mainly by increasing condition. Thus, during RAAS blockade, the kidney is able to renal blood flow and glomerular filtration, losartan decreased excrete sodium at a lower overall BP level and displays a more tubular sodium reabsorption without marked effects on renal clearcut natriuresis in response to short-term elevations in BP. hemodynamics (24). Whether either of these mechanisms pre- Several mechanisms could account for the more clear-cut dominates during renin inhibition cannot be learned from our association between natriuresis and BP during renin inhibition. data and demands further study. The renal vasodilation observed during RAAS blockade might We conclude that in essential hypertensive patients, the result in a greater transmission of changes in renal perfusion relationship between natriuresis and BP is improved during pressure to the postglomerular renal microcirculation, i.e., peri- renin inhibition, supporting a role for the RAAS in the PN tubular and the medullary circulation, with concomitant trans- mechanism. In addition, our data suggest that resetting of the mission of BP changes to renal interstitial pressure. The latter PN mechanism by remikiren may contribute to its BP-lowering has been shown to play an important role in mediating the action. The stronger association between BP fluctuations and tubular responses to elevated renal perfusion pressure (21). natriuresis during remikiren might well account for the kid- It should be noted that our study did not include a control neys’ ability to excrete sodium and maintain sodium balance group with another renal vasodilator or a time control group. without expansion of extracellular volume at a lower overall Thus, we cannot conclusively dissociate between the possible BP level. roles of renal vasodilation and the role of reduced AngII activity as such. Moreover, we cannot exclude that the phar- Acknowledgments macologic intervention synchronized BP and the diurnal ex- We acknowledge the support of Prof. P. van Brummelen, Dr. W. cretion pattern of sodium by an unidentified mechanism other Fischli, and G. Verweij (Hoffman-La Roche AG). Remikiren was than enhancement of the BP dependency of natriuresis. How- kindly supplied by Hoffmann-La Roche AG, Basel, Switzerland. ever, combining our data with those from the literature sug- Furthermore, we acknowledge A. van Zanten for the skillful assess- gests that the alterations in the PN curve in our study likely are ment of the hormonal parameters. 1818 Journal of the American Society of Nephrology J Am Soc Nephrol 11: 1813–1818, 2000

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