J. Endocrinol. Invest. 13: 559-566, 1990

Nocturnal oscillations in plasma renin activity during sleep inhypertensive patients: the influence of perindopril

G. Brandenberger*, J.L. Imbs**, J.P. Libert*, J. Ehrhart*, C. Simon*, J.Ph. Santoni***, andM. Follenius** Laboratoire de Physiologie et de Psychologie Environnementales UMR 32, CNRS/INRS, 67087 StrasbourgCedex, ** Service d'Hypertension Arterielle et des Maladies Vasculaires du CHR de Strasbourg, 67000Strasbourg, *** Institut de Recherches Internationales Servier 22, 92201 Neuilly sur Seine, France.

ABSTRACT. In previous studies, we established astrong concordance between nocturnal oscilla­tions in plasma renin activity (PRA) and REM­NREM sleep cycles. To determine whether thisrelation persists in the case of moderate essentialhypertension and if it is influenced by antihyper­tensive therapies affecting renin release, six nor­mal subjects and six hypertensive patients werestudied. The normal subjects underwent one con­trol night. The hypertensive patients were studiedduring a first night when a ptacebo was given.Four of them underwent a second night followinga single dose of an angiotensin-converting enzyme(ACE) inhibitor, perindopril; and a third night, 45days later, with the antihypertensive treatment. Inaddition, two of the patients underwent two night­studies, after a single and repeated doses of abeta-blocker, atenolol, to see whether preventingrenin release modified the sleep structure. Therelationship between the nocturnal PRA oscilla­tions and the sleep stage patterns persisted in

INTRODUCTIONSleep is organized in cycles of different stages,grossly divided into Rapid Eye Movement (REM)sleep and Non-REM (NREM) sleep, each charac­terized by specific electrophysiological, autonomicand motor changes. Extending the results ot Mullen(1), we have reported similar cycles averaging 100min both for REM-NREM sleep alternation and fornocturnal levels in plasma renin activity (PRA) (2,3). Both phenomena are strongly linked. NREM

Key-words: Renin activity, sleep, ultradian rhythm, hypertension, beta­blocker, angiotensin-converting-enzyme inhibitor.

Correspondence: Dr. G. Brandenberger, Laboratoire de Physiologie et dePsychologie Environnementales, 21 rue Becquerel, 67087 StrasbourgCedex, France.

Received October 6, 1989; accepted April 19, 1990.

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hypertensive patients receiving placebo. In patientswho had low PRA levels, the increases associatedwith NREM sleep were small. However, the meanrelative amplitude of the oscillations, expressedas a percentage of the nocturnal mean, was about600/0, which was similar to that in normotensivesubjects. Active renin and PRA oscillations wereclosely coupled. ACE activity profiles displayeddamped fluctuations and no systematic relation­ship with sleep stages. Perindopril, in single orrepeated doses led to striking increases in PRAand amplified the nocturnal oscillations withoutdisturbing their relationship to specific sleepstages. Atenolol almost supressed PRA fluctua­tions, while regular REM-NREM sleep cycles per­sisted. These results indicate that the relation be­tween PRA oscillations and sleep stage alternationpersists in moderate essential hypertension, andis preserved during perindopril therapy which in­creases the oscillation amplitude.

sleep phases invariably coincide with increasingPRA levels, and REM sleep phases always occurwhen PRA levels are decreasing. Spontaneous andprovoked awakenings blunt the rise in PRA normallyassociated with NREM sleep. So, PRA curves ex­actly reflect the patterns of sleep stage distribution:when sleep cycles are regular, PRA levels displaya strong ultradian rhythm. For irregular sleep cycles,PRA curves reflect all disturbances in the sleepstructure (4).The renin-angiotensin system plays an importantrole in the control of arterial blood pressure, so, inrecent years great attention has been paid to itsinhibition, with different drugs, in an attempt to nor­malize blood pressure (5-9).This study was designed to determine whether thepreviously described relation between nocturnal

G. Brandenberger, J.L. Imbs, J.P. Libert, et al.

PRA levels and the sleep stage patterns persists inmoderate essential hypertension before and afterthe administration of a newACEinhibitor, perindopril,well-known to increase renin release by removingfeedbackfrom angiotensin II.The nocturnalprofiles,obtained from blood collected at 10-min intervals,were compared to the concomitant sleep stagepatterns in untreated patients, after the first andafter repeated doses of the antihypertensive drug.In addition, as it has been shown that disturbingsleep modifies renin release from the kidneys (4),a beta-blocker, atenolol was given to see whether,conversely, any alteration in renin release modifiesthe sleep structure.

MATERIALS AND METHODS

SubjectsStudies were performed in 6 male patients withmoderate essential hypertension and in six normalsubjects matched for age (43.2 ± 3.8 yr vs 41.6 ±3.5 yr) and weight (82.7 ± 5.1 kg vs 81.1 ± 4.8 kg).The control subjects were normal volunteers, ingood health, with a mean systolic pressure of 119± 9 mmHg and a mean diastolic pressure of 78 ±4 mmHg. The hypertensive patients had a docu­mented evidence of hypertension for about 8 yearsprior to the study. At the end of a 4-week placeboperiod, their mean blood pressure was 152 ± 4mmHgfor systolic and 99 ± 1.5 mmHg for diastolic(± SE). Cases of heart or lung disease, as well asneurological, renal, endocrine or metabolic dis­orders, and secondary forms of hypertension wereexcluded. They all gave their informed consent.The experiments were approved by the StrasbourgHospital Ethics Committee.

ProcedureDuring the investigation, the control subjects andthe hypertensive patients were on their usual Nadiet. Na excretion in the 24-h urine samples col­lected the day before the experiment was between150 and 212 meq/24h. The normal subjects under­went one control night. In the hypertensive patients,all drugs including hypotensive agents were with­drawn for 30 days, during which they received aplacebo. They were studied during one night (NI)between the 18th and the 21 st day of placebo.Mean blood pressure in the morning was 152 ± 4mmHg for systolic and 99 ± 2 mmHg for diastolic.Four of the patients were studied during a secondnight (N2) after the first administration of 4 mg

560

perindopril. Since oral perindopril doses act within4h (1 0), the drug was given exceptionally at 2200h. Mean blood pressure in the morning was 139 ±4 mmHgfor systolic and 88 ± 2 mmHg for diastolic.The patients underwent a third night (N3) betweenthe 43rd and 47th days of the antihypertensivetreatment. The patients received daily 4 mg perin­dopril taken, as usual, in the morning. Blood pres-sure was then 137 ± 3 mmHg for systolic and 81± 4 mmHg for diastolic. In addition, two of thepatients were treated with a beta-blocker atenolol(ICI-Pharma, Cergy, France) at doses of 50 mgonce a day.They underwenttwo night-studies aftera single dose (50 mg at 22:00 h) and repeated 50mg morning doses, 45 days later. Blood pressurewas then normalized (140 and 138 mmHg for sys­tolic and 95 and 90 mmHg for diastolic).The studies were performed in a sound-proof, air­conditioned sleep chamber. Thesubjects were kept inathermoneutral environment(20 C).A standardmeal(900 kcal; carbohydrate: 45%; fat: 34%; protein: 21 %)was served at 19:15 h. Before the subjects enteredthe sleep chamber, electrodes were attached forthe following uninterrupted electrophysiological re­cordings: two electro-encephalograms (EEG leadsF3-A2 and C3-A2); two electro-oculograms (rightand left from the outer canthus with reference tothe left mastoid); one electromyogram of the men­talis and one electrocardiogram. Sleepstages werescored for each 30 s period of the night accordingto established criteria (11 ). Subjects went to bed at22:30 h. The light was switched off at 23:00 handpatients were awakenedat 08:00h.Throughout theexperiment, the patientswere observed with closedcircuit television.

Blood sampling and plasma measurementsAn intravenous catheter was inserted, under localanesthesia, into an antecubital vein at 21 :00 handkept patent with heparinized saline solution (500I.U. heparin · rnl' of 0.9 g NaCI . 100 ml'). Bloodwas collected continuously from 23:00to 08:00 h inan adjoining room. Samples were collected every10 min in plastic tubes containing either EDTA (1mg . mt' blood) for plasma renin activity, or heparin(50 J.lg . rnl' blood)for active renin and ACE activitymeasurements. They were immediatelycentrifugedat 4 C and the plasma stored at -25 C. A maximumof 200 ml blood was removed during each night.Plasma renin activity was measured by radio-im­munoassay of the angiotensin-I generated afterplas-

ma incubation (12); the intra-assay coefficient ofvariation (CV) for duplicate samples was 4.0% forlevels comprised between 10-20 ngAI . mr' . rr ' :6.0% for levels between 2-10 ngAI . ml' . rr ' :10.0% for levels between 1-2 ngAI . rnr' . h"; forlevels less than 1 ngAI . rnl" . h-1, it was 30%.Activerenin level was measured with a radioimmunometricmethod using commercially available kits (Diag­nostics Pasteur, Lyon, France). This method usestwo monoclonal antirenin antibodies; the intra-assaycoefficient of variation for duplicate samples was10%. ACE activity was measured with the fluorimet ­ric method of Unger et al. (13); the intra-assay CVfor duplicate samples was 6%.The detection limit forPRA was 0.18 ngAI . rnl' . h', and for act ive rening,10 ng . 1-'.

Data analysisThe data were subjected to spectral analysis todetermine the periods of the nocturnal oscillations.First, the data were smoothed using a three-pointmoving average. Then, a difference filter, definedas Xd1= Xl - X(t -1) was used to remove low-frequen­cy components. The Fourier transformation of theautocorrelation function, and a Blackman and Tukeywindow were used to determine the spectral densityfunction (14). The bandwidth of the spectral windowwas 0.01 cycle ' rnirr' . and the frequency spacingwas 0.0019 cycle . rnlrr ' . Frequencies with thehighest spectral densities were identified. Their sig­nificance was tested by comparing their variancewith the residual variance with the residual variancein the remaining frequency bands of the spectrum.All values are expressed as means ± SE. Individual

PRA oscillations in hypertensive patients

PRA curves , illustrated in Figures 1-4, weresmoothed using the moving averages method overa 3-point span.

The relationship between PRA oscillations and sleepstagesThe nocturnal curves were analysed using the pulseanalysis program ULTRA at a threshold of 3 timesthe coefficients of variat ion (15). The relationsh ipbetween the dominant sleep stage (NREM and REMsleep) and the ascending and descending portionsof PRA oscillations was analysed peak by peak.The association of the sleep stages and the differentportions of PRA oscillations were tested by X2.

RESULTS

Nocturnal PRA profilesHypertensive patients receiving placebo. Figure 1illustrates the nocturnal PRA profiles with the cor­responding sleep stage patterns in 2 hypertensivepatients who had regular REM-NREM sleep cyclesand in 2 typical control subjects. The previouslydescribed relationship between the dominant sleepstages and the nocturnal PRA fluctuations persistedin the control subjects and in the hypertensive pa­tients . In the control subjects, NREM sleep wasinvariably linked to increasing PRA levels, and REMsleep always coincided with decreasing PRA levels.In the hypertensive patients, 22 REM phases wererecorded, 18 occurred when PRA levels were de­creasing or at nadir; 4 of them occurred when PRAlevels were unchanged. NREM sleep phases were

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linked to increasing PRA levels (22 observations) orto unchanged PRA levels (4 observations). Thefrequency observed differed significantly accordingto the sleep stage (p < 0.001 ). So, for typical sleepstage patterns with the regular occurrence of REMsleep, PRA oscillated at about 100 min periodicity,with significant spectral density both in the controlsubjects and in the hypertens ive patients .Compared with the data on the control subjects, themean nocturnal levels and the mean absolute am­plitude of the oscillations did not differ significantly(mean levels: 2.2 ± 0.4 ngAI . mr' . rr ' in thecontrol subjects; 1.5 ± 0.1 ngAI . ml' . h' in thehypertensive patients). However, four of the 6 hy­pertens ive patients had low PRA levels (mean noc­turnallevel: 1.0 ngAI ' rnt' . h') and had also smalloscillations (mean absolute amplitude: 0.67 ngAI .rnr' . tr') , In all cases, the mean relative amplitude,expressed as a percentage of the nocturnal means,was about 60%. It was similar both in the normo­tensive subjects and in the hypertensive patients.

Hypertensive patients receiving perindopril. Eitherafter the first dose or after long term treatment,perindopril led to striking increases in PRA levels.The individual mean levels ranged between 2.0 and10.4 ngAI . rnl' . h' during night N2, after a firstdose of 4 mg perindopril at 22:00 h. They rangedbetween 2.8 and 9.1 ngAI . ml' . h-' during night N3after 45 days of a morning dose of 4 mg perindopril.

562

Figure 2 shows two individual examples of the sleepstage patterns and the nocturnal PRA profiles afterthe first and after repeated doses of perindopril.During both nights, the nocturnal PRA profiles hada general upward trend, but this trend was notsmooth and regular. The profiles were characterizedby brief leveling-off or large oscillations. Their ab­solute amplitudes ranged between 1.8 and 6.6 ngAI. rnr' . h' .The mean relative amplitude, expressedas a percentage of the nocturnal means , was un­changed (61%).Perindopril did not affect the relationships betweenthe nocturnal osc illations and the specific sleepstages: of the 34 REM sleep phases recorded duringthe eight nights studied (N2 and N3), all occurredwhen PRA levels were decreasing; of the 39 NREMsleep phases recorded, all but 3 coincided withincreasing PRA levels . The frequencies observeddiffered significantly according to the sleep stage(p< 0.001).

Hypertensive patients receiving atenolol. Atenololreduced mean PRA levels and almost suppressedthe nocturnal PRA oscillations. After the first dose,as after repeated doses, the mean nocturnal PRAlevels were low, ranging between 0.6 and 0.8 ngAI. rnr' . h' . Small fluctuations occurred throughoutthe night, but the increases in PRA associated withNREMsleep were generallybelowthe detection limitofthe analytical methodfor PRA. On the four nights,only 6

PRA oscillations in hypertensive patients

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. 1-1) . The nocturnal profiles of PRA and of activerenin exhibited parallel variations with synchronouspeaks and nadirs. Figure 4 illustrates concomitantPRA, active renin and ACE activity profiles for onepatient after a single 4 mg dose of perindopril at22:00 h. The coefficient of correlation between PRAand active renin levels in the blood samples col­lected every 10 min during the nights Nl , N2 andN3 ranged between 0.47 and 0.81 (54 samples foreach night; p< 0.001 ).

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increases associated with NREM sleep phases weredetected; 13 NREM sleep phases were recordedwith undetectable increases in PRA. Figure 3 illus­trates the sleep stage patterns and the nocturnalPRA profiles in one of the two patients who receivedatenolol. Regular REM-NREM sleep cycles wereobserved despite the absence of PRA oscillations.

Active reninThe individual mean levels of active renin paralleledthose of PRA in hypertensive patients receivingplacebo, as well as in patients receiving perindopril.Active renin levels were low in hypertensive patientsunder placebo , often below their limit of detection(individual mean levels: 16.1 - 35.8 ng . 1-1) . Aftera single 4 mg dose of perindopril and after 45 daysof treatment with perindopril, active renin levelswere higher (individual mean levels: 25.8 - 94.2 ng

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G. Brandenberger, J.L. tmbs, J.P. Libert, et al.

Plasma ACE activityThe individual mean levels in plasma ACE activityranged between 167 and 360 pmol . rnqprot'. mirr'. The nocturnal profiles displayed irregularand damped fluctuations, even in hypertensive pa­tients under perindopril, who had large PRA oscil­lations (Fig. 4). The ACE activity fluctuations boreno systematic relationships to the various sleepstages. Perindopril after the first dose caused de­creased ACE activity in the four patients studied.

DISCUSSIONIn previous studies on normotensive subjects wehave established a strong concordance betweenthe nocturnal PRA oscillations and the REM-NREMsleep cycles (2-4). The major findings of the presentexperiments are that this relation persists in mod­erate essential hypertension, and that it is not af­fected by an ACE inhibitor therapy which increasesrenin secretion.A number of studies have described the circadianpatterns of PRA levels in hypertensive patients,sometimes with long blood-sampling intervals (6,19), but few of those studies concerned the relationbetween PRA and sleep stages (19). The presentstudy demonstrates that in low renin hypertensivepatients, the nocturnal PRA profiles have small os­cillations. However, on average, the mean relativeamplitude expressed as a percentage of the noc­turnal mean of the oscillations was about 60%,which is similar both to that in the control subjectsand to that previously observed in younger volun­teers (4). Administration of an ACE inhibitor, perin­dopril, preserves these oscillations and strongly am­plifies their amplitude without disturbing their rela­tionships to sleep stages. Again, the mean relativeamplitude was unchanged. The PRA profiles providethen a new picture of the interactions between thisregulatory mechanism and the sleep-related mech­anism which generate the oscillations superimposedon the general upward trend. Measurements of ac­tive renin, whose variations paralleled those of PRA,confirmed the existence"'of a central control of reninsecretion and indicate that PRA measurements area good index of renin release.It has been previously shown that disturbances inthe sleep structure influence PRA levels (4): in par­ticular, spontaneous and provoked awakeningsblunt the rise normally associated with NREM sleep,which indicates that disturbing sleep modifies the

564

renin release from the juxtaglomerular cells. A ques­tion often raised is whether, conversely, the renin­angiotensin system is involved in the hemodynamicchanges favorizing the REM-NREM sleep alterna­tion. The results obtained after inhibition of the for­mation of the active hormone agiotensin II, andthose obtained in an additional experiment usingthe beta-blocker atenolol, enabled this hypothesisto be dismissed: the sleep structure was preserved,in particular, regular REM-NREM sleep cycles wereobserved in either cases. Atenolol barely crossesthe blood-brain barrier, so that a central action ofthe drug can probably be ruled out, although aneffect on the turnover of serotonin in the brain of therat has been described (20). Studies on animalshave indicated a major role for beta-1-adrenocep­tors in the control of renin release under variousconditions (21,22). In humans, acute beta-blockadewas seen to blunt the circadian periodicity of plasmarenin and aldosterone in normotensive and in hy­pertensive subjects with normal and high renin lev­els (23). However, establishing with more certaintythe involvement of beta-adrenoceptors in the ultra­dian PRA rhythm needs further experiments on nor-mal subjects, in whom PRA oscillations are generallylarger on control nights. Therefore, further investiga-tions in hypertensive patients did not seem to bejustified.It is well known that renin release is controlled byintra- and extrarenal mechanisms which interactwith mutual facilitation and sometimes mutual inhi­bition (24-27). Efforts have been made to identifythe principal factors concerned in this release. Theresults from this study and previous ones on normalman (1-3) provide evidence of an additional controlmechanism linked to the complex processes un­derlying the organization of sleep (28-32). The am­plitude of the pulsatile fraction is modulated bydifferent mechanisms: namely, the baroreceptorswhich lower the PRA oscillations in moderate es­sential hypertension and the osmoreceptors, sen­sitive to changes in Na load, which amplify theoscillations during a low Na diet (4). Feedback con­trol from angiotensin-II also modulates the renin­releasing action of central mechanisms, since wehave shown here that an ACE inhibitor stronglyamplifies the nocturnal oscillations. Independentlyfrom these mechanisms, the amplitude of the ultra­dian oscillations could be influenced by chronobi­ological mechanisms linked to circadian compo­nents. It has been suggested that the timer of the

REM-NREM sleep cycles interacts with the circa­dian clock. Further experiments should determinethe respective part of the intrinsic circadian rhyth­micity and of the sleep-related processes in pro­ducing the 24-hr PRA pattern.

ACKNOWLEDGMENTSThis work was supported by the Institut de Recherches Interna­tionales SERVIER (Neuilly sur Seine, France). The authors areindebted to B. Reinhardt, M. Simeoni and the sleep team forplasma renin activity measurements, experimental assistance,and sleep recordings. The skilfull technical assistance of E.Bruder is acknowledged. The authors also gratefully acknowl­edge Dr. E. Van Cauter for providing the ULTRA program.

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