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Renal Arterial Pressure Variability

A Role in Blood Pressure Control?

B. NAFZ AND P. B. PERSSON

Johannes-Müller-Institut für Physiologie, Humboldt Universität (Charité),10117 Berlin, Germany

ABSTRACT: It is becoming generally appreciated that blood pressure (BP) fluc-tuations can have major pathophysiological importance in hypertensives.Nonetheless, little is known regarding the influence of short-term changes inBP on kidney function, a crucial control element for long-term BP regulation.This overview summarizes first efforts to unravel the importance of BP dynam-ics on renal function. It seems that the kidney is not only an important controlelement in the BP regulation network; the renal vascular bed may also be verysusceptible to BP oscillations, which can occur, for example, from baroreflexmalfunction.

KEYWORDS: Arterial blood pressure; Hypertension; Nitric oxide; Renal bloodflow; Renin; Blood pressure oscillations

GENERAL IMPORTANCE OF BLOOD PRESSURE VARIATIONS

To maintain adequate blood flow to the organs, blood pressure (BP) and vascularresistance are controlled by a complex regulatory network, which establishes acrucial element for normal function of the cardiovascular system.1 The known inter-actions between the many, still not fully understood, components of this systemapparently improve overall cardiovascular performance. Most of these control ele-ments respond to very specific stimuli within a relatively narrow input range. Forinstance, renal excretory function and the renin-angiotensin system depend on per-fusion pressure as a control input. It seems, therefore, likely that excessive variationsin BP may perturb their regulation and thus compromise cardiovascular performanceunder these conditions. Hence, it is not surprising that the organism is equipped withpotent BP-buffering mechanisms, such as the arterial baroreceptor reflex, whichmaintain BP fluctuations within tight boundaries. The afferent branch of this reflexconsists of stretch receptors located in the carotid sinus region and the aortic arch,while the effector side of the reflex is mediated by the sympathetic and parasympa-thetic nervous system.2 Consequently, this reflex can serve to buffer BP fluctuationsthat are detected by the carotid sinus and aortic arch region, whereas remote changesin BP or blood flow, for example, within the vascular tree of the kidney, remainlargely unaffected. Such local changes in hemodynamics are known to induce the

Address for correspondence: P. B. Persson, Johannes-Müller-Institut für Physiologie, Hum-boldt Universität (Charité), Tucholskystrasse 2, D-10117 Berlin, Germany. Voice: +49-30-450-528162; fax: +49-30-450-528972.

[email protected]

408 ANNALS NEW YORK ACADEMY OF SCIENCES

release of vasoactive substances from the endothelium. One of them, nitric oxide(NO), has been suggested to act as a local buffer for BP fluctuations because fixingNO levels in conscious rats significantly enhances BP variability between 0.2 and0.6 Hz.3 Furthermore, genetically induced impairment of the endothelial NO systemelevates BP and also enhances short-term BP oscillations in mice.4

There have been a vast number of studies in recent years focusing on the descrip-tion of BP oscillations in order to quantify various aspects of cardiovascular control.Among these applications, the possibility of using spectral analysis of BP as a toolfor quantifying baroreflex sensitivity or sympathetic and vagal tone has attracted themost attention.5 In spite of the widespread investigations on the origin of BP vari-ability, astonishingly little is known about the importance of BP waves for cardio-vascular control. Remarkably, it has been recognized early that changes in thedynamic properties of BP commonly coincide with hypertension. This may beexplained by the fact that several BP buffers play also an important role in the regu-lation of mean BP. For instance, surgical or pharmacological interruption of thebaroreceptor reflex enhances short-term BP oscillations and can also elevate 24-h BPin conscious animals.1 It is well accepted that the average level of arterial BP estab-lishes a major determinant of future cardiovascular complications in hypertension.6

To a large degree, high BP seems to be responsible for cardiovascular disease, whichis the principal cause of death in industrialized nations.7 Interestingly, recent investi-gations show that the dynamic properties of BP are of significance for the develop-ment of hypertension-related end-organ damage in patients.6,8 In fact, changes in thedynamic properties of BP, which usually coincide with hypertension, seem to estab-lish an independent risk factor for cardiovascular complications. In light of theseresults, it seems of great importance to clarify to which extent BP variability modu-lates mechanisms, for example, renal sodium and water handling, which can play acrucial role in the development of hypertension.

BLOOD PRESSURE VARIABILITY TO THE KIDNEY

In particular, renal function may depend critically on oscillating perfusion pres-sure. The kidney is protected from slow variations in BP by at least two mechanismsguaranteeing blood flow and filtration rate autoregulation: the myogenic response ofvascular smooth muscles and the tubuloglomerular feedback mechanism. A conven-tional autoregulation diagram plots blood flow versus perfusion pressure. In acertain range, renal blood flow reveals little or no pressure-dependency.

It must be kept in mind, however, that this classical plot of the blood flow auto-regulation is derived from experiments that employed stepwise reductions in renalperfusion pressure. Thus, this description is only valid for very slow changes in BP.Due to time constants of the underlying mechanisms, the time course of an initialstimulus can gain major influence on the response of the system to that stimulus. Itseems therefore plausible that the influence of faster BP fluctuations on RBF cannotbe correctly described by the classical model of renal autoregulation. To clarify thecharacteristics of regulating systems at different stimulating frequencies, a spectralanalysis in the frequency domain has been shown to be a very helpful tool.9,10 Thisapproach can be of particular benefit for autoregulation studies of renal blood flow

409NAFZ & PERSSON: RENAL PERFUSION PRESSURE VARIABILITY

since, as mentioned above, the kidney has two potent autoregulatory mechanisms.As these two autoregulatory instruments operate in different frequency ranges, it ispossible to discern the individual autoregulatory potencies10,11 and, thus, to quantifythe individual effects of both autoregulatory mechanisms. Most importantly, thetransfer function provides information as to which oscillations can override bothmechanisms of autoregulation. A transfer function between renal arterial pressureand renal blood flow indicates to which extent and at what frequencies changes inpressure will alter blood flow to the kidney. Accordingly, the transfer function char-acterizes renal autoregulation in the frequency domain.10–15 The gain is calculatedby dividing the cross-spectral estimates by the corresponding autospectral values.The entire transfer function is then obtained by plotting each gain over the respectivefrequency. There are two frequency domains within which autoregulation takesplace: a fast mechanism at 0.1–0.2 Hz, recognized by the decrease of the gain belowthis frequency, and a slower one around 0.03 Hz, characterized by a peak of highgain.9 The faster mechanism probably corresponds to the myogenic response,whereas the slower one reflects the tubuloglomerular feedback. The latter conclu-sion has been substantiated by observations of similar fluctuations of tubular flowand chloride concentration.16 Furthermore, the oscillations are abolished by ureterligation17 or furosemide.18,19 Below 0.01 Hz, a plateau of low gain is attained. Thislevel reflects the autoregulatory efficiency. Thus, the two control elements of the kid-ney act as high-pass filters; that is, oscillations that occur above a certain frequencycannot be buffered. Consequently, these rapid blood pressure oscillations will leadto similar changes in renal blood flow, which can have important consequences formaintaining medullary osmolarity and renal NO synthesis. The latter two areassumed to be closely intertwined with long-term BP control: First, renal medullaryosmolarity is important in relation to pressure diuresis. According to the renal/body-fluid–pressure-control concept, fluid and electrolyte excretion is crucial for long-term BP regulation (see Refs. 1 and 20 for review). In line with this hypothesis, sev-eral investigators reported that an impaired capability of the kidney to form adequateamounts of urine induces hypertension.21 The renal medulla has a very high osmoticpressure, which is crucial for the fluid and electrolyte reabsorption that contributesto the formation of a concentrated urine. Increased medullary blood flow may washout the osmotic gradient within the renal medulla and thereby blunt the ability of thekidney to form a concentrated urine.22 Therefore, if BP oscillations induce changesin renal medullary hemodynamics, then longer-term BP may be affected via achange in renal fluid and sodium excretion.

A second pathway for connecting renal function to systemic BP may also beaffected by variations of BP and kidney blood flow: the renal NO system. NO for-mation has been seen as a crucial element in mediating pressure natriuresis,23 par-ticularly since the acute relationship between renal BP and sodium excretion isblunted by NO inhibition.24 The renal medulla is enriched in immunoreactive NOsynthase (NOS) protein and NOS enzymatic activity when compared with the renalcortex.25 Particularly high NOS activity is present in the inner medullary collectingducts, while less NOS activity is located in glomeruli and vasa recta. The latter sites,though, should be of more importance for pressure natriuresis. It is remarkable thatchanges in BP causing enhanced sodium excretion lead to likewise changes in renalmedullary NO activity.26 The importance of the renal medullary NO system for BP


control is underscored by experiments employing selective renal medullary NOS in-hibition. This maneuver diminishes sodium and water excretion and leads to hyper-tension.27 It seems likely that spontaneous BP oscillations, which are not effectivelybuffered by RBF autoregulation, augment intrarenal shear stress. This would takeplace at the level of the vascular wall. Shear stress, in turn, is known to enhance theliberation of NO along the renal vascular tree in vitro. Thus, again, one may expecta profound impact of BP oscillations on medullary blood flow, on renal excretoryfunction, and on longer-term BP regulation.25,28

Finally, the renin-angiotensin system interactions with BP are well known and areprobably of great importance in long-term BP control.29 BP regulation by renin takesplace via the direct vasoconstrictor effects of angiotensin II and via the influence onrenal fluid and sodium handling. A previous study employing BP oscillations to thekidney shed light on the importance of renal blood flow versus renal perfusion pres-sure for the release of renin.30 Renal perfusion pressure and renal blood flow weredissociated by impinging BP oscillations within the resonance frequency of renalautoregulation. In consequence, maximum blood flow occurred at minimal BP. Itwas found that BP is the dominant factor for renin release, with blood flow playingonly a minor role. Taking this study into account, it may seem as if BP oscillationsto the kidney may have an important effect on renin release, although oscillations inblood flow have no effect. This could be underscored by the particular relationshipbetween BP and renin release. The renin stimulus response curve describing thisrelationship is not linear, but is characterized by a threshold pressure below whichrenin release markedly increases. Above this threshold, only a meager effect of BPon renin release is found. BP oscillations slightly below the threshold pressure forrenin release should thus lead to greater renin release: The drops in BP markedlyenhance renin release, whereas the BP increments do not attenuate renin release tothe same extent.

EFFECT OF ENHANCING BP OSCILLATIONS TO THE KIDNEY

The following experiments were carried out to clarify whether enhanced BP vari-ability may affect renal functions. The working hypothesis was that normally occur-ring BP oscillations cannot be completely buffered by the mechanisms of kidneyblood flow autoregulation. Thus, the resulting blood flow variability may modifycertain functions of this organ.

As shown in FIGURE 1, BP oscillations (BPO) of 0.1 Hz elicit concurrent changesin renal cortical and medullary blood flow. Thus, the premise that BP oscillations atthis frequency can override renal blood flow autoregulation is warranted. This exper-iment was performed in the rat using the laser-Doppler technique; therefore, localrenal blood flow could only be estimated by the laser-Doppler flux signal (for detailsof the measurement, see Ref. 31).

The upcoming protocols were done in adult, chronically instrumented, pure-bredbeagles,32 which could move freely and undisturbed in their kennels during theexperiments. Data recording, control of renal BP, continuous urine sampling, andblood sampling were done via a swivel system from an adjacent room. Catheterswere advanced via the femoral arteries into the abdominal aorta, where they wereplaced distally and proximally to both renal arteries, respectively. An inflatable cuff


was positioned around the aorta, above the origin of the renal arteries and betweenthe tips of the catheters. Finally, a bladder catheter was implanted to allow continu-ous urine collection. The cuff and the distal catheter were connected to an electro-pneumatic pressure control system that was able to reduce and to oscillate renal BParound a preset level with high precision.

Three protocols were done. The first was a 24-h time control. In a second proto-col, acute Goldblatt hypertension was induced by reduction of mean renal BP to85 mmHg. The last protocol was designed to determine the influence of BP varia-tions on the onset of Goldblatt hypertension. To this end, renal BP was oscillatedsinusoidally over 24 h with a frequency of 0.1 Hz (amplitude ± 10 mmHg) aroundthe same mean pressure as in the second protocol, that is, 85 mmHg.

The 24-h mean value of BP was 110 ± 3 mmHg during control. The static reduc-tion of renal arterial BP to 85 mmHg increased systemic BP by almost 60 mmHg atthe end of the 24-h recording period (FIG. 2, p < 0.01). This BP increase wasmarkedly attenuated by superimposing 0.1-Hz oscillations. In this protocol, BPincreased by only half as much as seen during static BP reduction (FIG. 2, p < 0.01).

The static BP reduction decreased urine flow to roughly half of the control values(p < 0.01). Superimposing 0.1-Hz BP oscillations restored urine flow to near control

FIGURE 1. Induced BPO with a frequency of 0.1 Hz override the renal blood flowautoregulation and reach the renal medulla. RPP: renal perfusion pressure.


values. Changes in sodium and potassium excretion behaved similarly. Static renalBP reduction diminished sodium excretion to 20% of control (p < 0.01). When renalBP was oscillated at this reduced pressure, sodium excretion became twice as highas during static reduction of renal BP; however, control levels were not reached.

As shown in a recent publication,32 these data obtained in renovascular hyper-tensive dogs demonstrate a pronounced antihypertensive effect of BP oscillations tothe kidney. This may rely on changes in intrarenal microcirculation. BP oscillationsinduce changes in local blood flow, which presumably modulate physical forcesalong the nephron. Moreover, it is plausible that these BP oscillations interfere withthe local release of many vasoactive substances (e.g., prostaglandins and kinins),thereby changing local hemodynamics and kidney function.

Interestingly, 0.1-Hz oscillations in muscle sympathetic nerve activity and RR in-terval have been reported to be markedly attenuated during heart failure and bluntedduring severe heart failure in humans.33 Provided that the patterns of muscle sympa-thetic nerve activity and RR interval are mirrored by corresponding BP oscillations,one may speculate that BP oscillations facilitate excretion of fluid and electrolytes,thereby improving the prognosis of these patients.

The induced renal BP oscillations augment shear stress at the vascular wall.Endothelial shear stress stimulates NO release from arteries, thereby inducing vaso-dilatation and changes in intrarenal hemodynamics. Urinary NO3 excretion was usedas a marker for NO production. Unfortunately, the direct assessment of renal NO isstill not possible in freely moving animals. Thus, we aimed at obtaining greatestaccuracy by performing all experiments during the post-reabsorptive state when in-

FIGURE 2. Original recordings of RPP (A: P85; B: Osc) and systemic BP (C: P85;D: Osc). P85 elevated mean systemic BP to about 150 mmHg (E, black bar vs. white bar).This hypertensive effect was attenuated (E, gray bar) when mean RPP oscillated around thesame value of ≈85 mmHg (F). **p < 0.01


fluences of food composition on urinary NO3 are least. Furthermore, a very specificmass spectrometric analysis, instead of the Griess-Ilosvay reaction, was used. Thisavoids possible interference with most physiological NOx compounds. A stimulationin NO liberation was detectable only during the first 8 h of the experiments (FIG. 3).Thus, the prolonged antihypertensive effect of BP waves cannot be explained by adirect effect of the enhanced NO release.

Plasma renin activity in the oscillation protocol was about 30% less than that seenwith static pressure reduction. This may indicate an important role of the renin sys-tem in the observed antihypertensive effect. In light of the aforementioned stimulus-response curve of pressure-dependent renin release, the finding of an attenuatedrenin release in this protocol is surprising: a pronounced influence of renal BP onrenin release has been detected only below 90 mmHg.34 Thus, the minima of the BPoscillations lead to pressure-dependent stimulation in renin release, whereas maximain renal BP cannot reduce renin release to the same extent. Therefore, if one assumesthat possible hysteresis effects can be neglected, one would expect higher PRA dur-ing Osc than during P85. Evidently, the BP waves exerted a major influence on reninrelease in the freely moving dog. This suggests that the sustained antihypertensiveeffect of Osc on renovascular hypertension may at least in part be mediated bylowered PRA. In contrast to the prolonged effect on PRA, the stimulation of NOgeneration seems to be important only during the first 8 h of our experiments.

FIGURE 3. Osc doubled renal NO3 excretion during the first 8 h of the experiments(A), while the influence on acute changes of PRA was less pronounced (B). In face of the24-h reduction of RPP, NO3 excretion returned to normal (C), whereas Osc induced asignificant reduction in PRA versus P85 (D). *p < 0.05, **p < 0.01; C and D: mean valuesof last 8 h of the experiments.


CONCLUSIONS

By chronically oscillating renal BP around a reduced mean pressure, it was foundthat these BP waves enhance daily sodium and fluid excretion and attenuate the BPelevation during the onset of renal hypertension. Variations in BP at the frequencychosen for this study are largely unaffected by renal autoregulation and thus lead toconcomitant changes in renal blood flow. Since renal medullary blood flow plays akey role in controlling BP and water-electrolyte balance, it is not surprising thatthese oscillations in perfusion pressure evoke profound effects on renal excretoryfunction. The BP waves also blunted pressure-dependent renin release, which mayhave contributed significantly to the antihypertensive effect.

ACKNOWLEDGMENTS

These studies were supported by the German Research Foundation.

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