General Cardiology Cardiology 1992:80:312-323

a Endocrinology Section, Department of Internal Medicine, University of Ferrara; b Department of Nephrology and c Nuclear Medicine Service, S. Anna Hospital, Ferrara, Italy

Keywords Natriuretic peptides, atrial Blood pressure Heart rate Chronic renal failure Essential hypertension Circadian rhythms

Loss of the Nocturnal Increase in Plasma Concentration of Atrial Natriuretic Peptide in Hypertensive Chronic Renal Failure

Abstract Diurnal change of plasma atrial natriuretic peptide (ANP) concentration was investigated in 12 patients with hyperten­ sion due to chronic renal failure (CRF) and in 12 patients with essential hypertension (EH) of comparable degree. Blood pres­ sure (BP) monitoring was performed at 15-min intervals, while peripheral blood samples were obtained at 4-hour inter­ vals starting from 8.00 h. The mean 24-hour plasma levels ( ± SEM) of ANP were 24.3 ± 1.8 pmol/1 in EH and 23.4 ± 1.2 pmol/1 in CRF. In EH. plasma ANP concentration was highest at 4.00 h (33.5 ± 0.8 pmol/1) and lowest at 16.00 h (15.5 ± 0.6 pmol/1). In CRF, no significant circadian change was present (22.2 ± 3.1 and 20.4 ± 3.6 pmol/1, respectively), and the nocturnal fall in BP was lost. Our data demonstrate that in CRF the loss and possible reversal of the nocturnal decline in BP is associated with the disappearance of any sig­ nificant circadian variation in the circulating concentrations of ANP. These findings suggest a role for ANP in the altera­ tion of BP variability of CRF, possibly mediated by auto­ nomic dysfunction, and are further evidence for the existence of a relation between the circadian rhythms of ANP and BP.

This study was supported by grants from the Italian National Research Council (CNR. Rome. Italy: Prevention and Control of Disease Factors. Subproject Stress; No. 9 1.00214.PF41) and from the Italian Ministry of Univer­ sity and Scientific and Technological Research (code 90/60/06/045).

Received: May 28. 1991 Accepted after revision: December 11, 1991

Introduction The controlling mechanism for the circa­ dian variation in arterial blood pressure (BP), though not yet known, is likely to be neuro-

Francesco Portaluppi, MD Endocrinology Section Institute oflnternal Medicine University of Ferrara, Via Savonarola 9 1-44100 Ferrara (Italy)

© 1992 S. Karger AG. Basel 0008-6312/92/ 0806-0312$2.75/0

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Francesco Portaluppia Loris M ontanaria Luciana Vergnania Giovanni Tarronib Cavallini0 Paolo Gillib Bruno Bagnic Ettore C. degli Ubertia

Table 1. Relevant clinical data and mean 24-hour cardiovascular parameters of 12 patients with CRF

Sex

Male Male Male Male Male Male Female Female Female Female Female Female

Age years

Clinical diagnosis

Creatinine clearance

47 39 43 61 27 59 49 59 51 56 40 56

CGN CGN CGN CGN CGN CGN CPN CGN CPN CPN CPN CGN

35 28 34 25 18 33 19 17 21 16 39 31

BP, mm Hg systolic

diastolic

148 148 147 140 168 132 146 145 148 140 151 145

88 85 90 88 100 96 87 92 92 92 96 87

HR beats/min 85 76 92 84 89 66 84 102 91 80 92 92

Creatinine clearance was normalized to body surface area (ml/min). CGN = Chronic glomerulonephritis; CPN = chronic pyelonephritis.

turnal drop in BP can be lost or reversed [59], but there have been no reports on the cir­ cadian change in plasma ANP levels in this condition. Therefore, we investigated the cir­ cadian rhythm of ANP and its temporal rela­ tionships with the patterns of BP and heart rate (HR) in a group of hypertensive patients with CRF matched for sex, age and mean 24hour BP with a control group of patients affected by uncomplicated essential hyperten­ sion (EH).

Patients and Methods We studied 12 hypertensive patients admitted to our department of nephrology with a diagnosis of CRF due to parenchymal kidney disease. None of them required a treatment by hemodialysis. We excluded patients with parkinsonism, diabetes mellitus, alcohol­ ism and all reversible disorders which may temporarily worsen renal function, including heart failure. We also excluded patients with echocardiographic evidence of left ventricular hypertrophy. The relevant clinical data of this group of patients are reported in table l. Each CRF patient was matched with a subject affected by

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hormonal, so that it seems important to look for the rhythmicity of the humoral factors that have been proven to affect the cardiovas­ cular and renal systems. Atrial natriuretic peptide (ANP) is among them. Normal [l] and essential hypertensive [2] subjects stud­ ied in our hospital showed significant circa­ dian variations in plasma concentrations of ANP opposite to the simultaneous changes observed in BP values. These findings suggest the existence of a relation between the circadian variability of BP and the daily changes in the plasma levels of ANP. If this is true, a modification of the 24-hour pattern of BP occurring in many diverse conditions should be accompanied by consistent alterations in the circadian rhythm of ANP. In fact, previous findings from our laboratory demonstrate that the rhythm of ANP is lost in patients with congestive heart failure [3], a condition known to be associated with a blunted nocturnal fall in BP [4], Hypertension due to chronic renal failure (CRF) is another condition in which the noc­

Table 2. Relevant clinical data and mean 24-hour cardiovascular parameters of 12 patients with uncompli­

cated EH Sex

Male Male Male Male Male Male Female Female Female Female Female Female

Age years

Clinical diagnosis

Creatinine clearance

48 36 45 64 28 58 44 60 56 48 43 59

EH EH EH EH EH EH EH EH EH EH EH EH

130 117 137 106 145 127 98 139 98 122 83 104

BP, mm Hg systolic

diastolic

140 146 141 148 165 137 142 147 147 143 154 142

89 86 93 86 102 99 86 96 97 97 101 92

HR beats/min 76 90 87 61 72 85 92 89 69 71 64 80

Creatinine clearance was normalized to body surface area (ml/min).

314

monitor was done by using a data interface unit (model 90209 Spacelabs. Redmond. Washington) installed on an IBM PS/2 personal computer. A mean (± SD) of 109 ± 7 BP readings were taken in each patient, with an error percentage of 8 ± 6% and with 91 ± 8 read­ ings per patient fulfilling the editing criteria. In order to separate day from night values. 08.00 and 20.00 h were taken as discriminant. Twenty-four-hour urine collections for volume, so­ dium. potassium and creatinine were also obtained. Blood samples ( 10 ml) were drawn into precooled plastic tubes containing I mg/ml ethylenediamine tetraacetic acid disodium salt and aprotinin (Trasylol. Bayer. Milan. Italy: 500 KlU/ml). They were promptly centrifuged at 3,000 g for 15 min at 0 °C. and then the plasma was frozen at -8 0 °C until the assay was per­ formed. All samples were processed in duplicate in the same assay. ANP was measured by RIA combined with an extraction step, using reagents supplied by Immuno Technology Service Production BV (Wijchen. The Netherlands). The intra- and interassay coefficients of variation are 8.6 and 11.6%, respectively, and the sen­ sitivity is 2.1 prnol/1. All 24-hour data are expressed as means ± SEM. unless otherwise indicated. Preliminary analysis of data confirmed the acceptability of the assumptions of normal distribution and homogeneous variances.

Portaluppi/Monlanari/Vergnank T arroni/Cavallini/Gilli/Bagni/ degli Uberli

ANP in Rena) Failure

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uncomplicated EH (with no echocardiographic evi­ dence of left ventricular hypertrophy) of the same sex. similar age (difference from matching CRF patient always < 5 years of age) and similar mean 24-hour BP (difference always < 5 mm Hg for both systolic and diastolic 24-hour levels). On the other hand, all EH patients had normal renal scintigrams, pvelograms and renal function tests. The relevant clinical data of this second group are reported in table 2. After informed consent was obtained, the subjects were restricted to the hospital room and kept on a stan­ dard daily diet of 100 mmol sodium and 80 mmol potassium for the duration of the study. The sleep span in darkness lasted from 22.00 to 06.30 h and was never interrupted during withdrawal of blood. Meals were given at precise times as follows: breakfast at 08.15 h, lunch at 12.15 h. small snack at 16.15 h and dinner at 20.15 h. Starting from the evening of the 6th day. each subject remained recumbent until the study was com­ pleted. On the 7th day of hospitalization, an intravenous cannula was inserted at 6.30 h and kept open with a slow infusion of 0.9% saline (total amount of infusion: 250 ml). Beginning at 8.00 h. venous samples were drawn every 4 h for 24 h. On the same day. BP and HR were measured every 15 min by an ambulatory moni­ tor (model 90207 Spacelabs. Redmond. Washington. USA). The analysis of data provided by the automatic

Table 3. BP and HR in the two groups studied

Mean 24 h

Day (8-19.59 h)

Night (20-7.59 h)

Change (night-day)

CRF Systolic BP, mm Hg Diastolic BP. mm Hg HR, beats/min ANP. pmol/l

146.6 ±8.3 91.1 ±4.3 86.1 ±9.2 23.4 ±1.2

143.8 ±2.6** 87.1 ±1.9** 90.0 ±2.7 21.9 ±0.8

149.5 ±2.7** 95.1 ± 1.2** 82.2±2.7 21.1 ±0.7**

5.7 ±2.3** 8.0 ±1.9** -7.8 ± 1.2 -0.9 ±0.2**

EH Systolic BP. mm Hg Diastolic BP, mm Hg HR, beats/min ANP. pmol/l

146.4 ±7.2 93.9± 5.9 77.5 ±10.9 24.3 ±1.8

153.8 ±2.1 101.1 ± 1.7 81.9 ±3.2 21.4 ± 0.9

139.1 ±2.3 86.8 ±2.1 73.0 ±3.2 27.1 ± 1.1

- 14.7 ± 1.2 -13.3 ± 1.5 -8.9 ±0.8 5.9 ±0.6

** p < 0.001 compared with the corresponding value in EH.

Results Figures 1 and 2 show the 24-hour levels of BP. HR and ANP in CRF and EH patients. Table 3 summarizes the BP and HR data obtained in the two groups studied. The mean 24-hour plasma levels of ANP were 24.3 ± 1.8 pmol/l in EH and 23.4 ± 1.2 prnol/1 in CRF. in both groups significantly higher (p < 0.001) than those obtained in our laboratory' (13.3 ± 1.5 pmol/l) from a group of 10 nor­ mal subjects of comparable age previously studied [I]. In EH patients, the peak plasma ANP of 33.5 ± 0.8 pmol/l occurred at 04.00 h. Except

for time 00.00 h, the peak value was signifi­ cantly different from all other means (p < 0.01). At 16.00 h, ANP fell to its lowest value of 15.5 ± 0.6 pmol/l, different from all other means (p < 0.01) except for time 20.00. The highest BP and HR values occurred in the early afternoon, simultaneously with the low­ est plasma concentrations of ANP. In CRF patients, the mean plasma ANP levels at 04.00 h and 16.00 h were 22.2 ± 3 .1 and 20.4 ± 3.6 pmol/l, respectively, the dif­ ference being not significant. The comparison of mean ANP levels between times of assess­ ment revealed no significant difference throughout the 24 h. In these patients, the nocturnal fall in BP was also lost. The correlation coefficients between ANP. BP and HR are reported in table 4. along with the results of the significance tests. In the EH group, the plasma concentrations of ANP showed a significant, though not close, in­ verse correlation with the correspondent lev­ els of systolic BP. Instead, no significant cor­ relation was found between ANP and BP in the CRF patients.

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Hence, analysis of variance was used for comparison of mean hormone levels between limes of assessment. Duncan’s multiple range test was used to determine the location of significant differences in mean values. Calculation of the correlation coefficients between ANP. BP and HR was also performed by using the BP and HR values measured at each time of assessment of ANP levels. The correlation coefficients were tested for significance by standard procedures. In all tests, p < 0.05 was considered significant.

DIASTOLIC BP (mm Hg)

ESSENTIAL HYPERTENSION

ANP (pmol/L)

TIME (Clock Hour)

Fig. 1. Diurnal changes in hourly systolic and diastolic BP. HR and ANP in patients with EH. Data points are means ± SD. Hor­ izontal lines indicate total group mean values for the 24-hour peri­ od. * p < 0.01, as compared with values at 4.00 h.

TIME (Clock Hour)

ANP (pmol/L)

DIASTOLIC BP (mm Hg)

RENAL FAILURE

Fig. 2. Diurnal changes in hourly systolic and diastolic BP, HR and ANP in patients with CRF. Data points are means ± SD. Horizontal lines indicate total group mean values for the 24-hour period.

Portaluppi/Monlanari/Vcrgnani/ Tarroni/Cavallini/Gilli/Bagni/ degli Uberti

ANP in Renal Failure

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3I6

TIME (Clock Hour)

CRF r

Systolic BP Diastolic BP HR

EH p

-0.412 NS -0.192 NS -0.126 NS

r

p

-0.609

Loss of nocturnal increase in plasma concentration of atrial natriuretic peptide in hypertensive chronic renal failure.

Diurnal change of plasma atrial natriuretic peptide (ANP) concentration was investigated in 12 patients with hypertension due to chronic renal failure...
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