Abnormal Pressure Natriuresis -...

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Brief Review

Abnormal Pressure NatriuresisA Cause or a Consequence of Hypertension?

John E. Hall, H. Leland Mizelle, Drew A. Hildebrandt, and Michael W. Brands

In all forms of chronic hypertension, the renal-pressure natriuresis mechanism is abnormalbecause sodium excretion is the same as in normotension despite the increased blood pressure.However, the importance of this resetting of pressure natriuresis as a cause of hypertension iscontroversial. Theoretically, a resetting of pressure natriuresis could necessitate increasedblood pressure to maintain sodium balance or it could occur secondarily to hypertension.Recent studies indicate that, in several models of experimental hypertension (includingangiotensin II, aldosterone, adrenocorticotrophic hormone, and norepinephrine hypertension),a primary shift of renal-pressure natriuresis necessitates increased arterial pressure tomaintain sodium and water balance. In genetic animal models of hypertension, there alsoappears to be a resetting of pressure natriuresis before the development of hypertension.Likewise, essential hypertensive patients exhibit abnormal pressure natriuresis, although theprecise cause of this defect is not clear. It is likely that multiple renal defects contribute toresetting of pressure natriuresis in essential hypertensive patients. With long-standing hyper-tension, pathological changes that occur secondary to hypertension must also be considered. Byanalyzing the characteristics of pressure natriuresis in hypertensive patients and by comparingthese curves to those observed in various forms of experimental hypertension of known origin,it is possible to gain insight into the etiology of this disease. (Hypertension 1990;15:547-559)

I n many patients with hypertension, there are noobvious renal defects. Most of the commonindexes used to evaluate renal function, such as

glomerular filtration rate (GFR) or renal plasmaflow, are often within the normal range, which leadsmany investigators to believe that hypertension candevelop in the absence of kidney abnormalities. Yet,there is one aspect of kidney function, the relationbetween renal sodium and water excretion and arte-rial pressure, that is abnormal in all types of experi-mental and clinical hypertension. Normally, anincrease in arterial pressure would elevate sodiumexcretion, a phenomenon often referred to as pres-sure natriuresis.1-3 The fact that hypertensivepatients are in sodium balance and have normalsodium excretion (equal to intake) despite increasedblood pressure indicates that pressure natriuresis isreset. The mechanisms responsible for this resettingand its role in hypertension have been the subject ofconsiderable controversy. The goal of this paper is to

From the Department of Physiology and Biophysics, Universityof Mississippi Medical Center, Jackson, Mississippi.

Supported by grants HL-23502, HL-39399, and HL-11678 fromthe National Institutes of Health. D.A.H. and M.W.B. weresupported by National Research Service awards F32 HL-07931and F32 HL-08171.

Address for correspondence: John E. Hall, PhD, Department ofPhysiology and Biophysics, University of Mississippi Medical Cen-ter, 2500 North State Street, Jackson, MS 39216-4505.

briefly review the function of pressure natriuresis innormal regulation of arterial pressure and body fluidvolumes, the evidence that abnormalities of pressurenatriuresis play a causal role in hypertension, andsome potential mechanisms by which pressure natri-uresis may be reset in hypertension.

Renal-Body Fluid Feedback Controlof Arterial Pressure

The renal-pressure natriuresis mechanism has beenpostulated to be a primary component of a feedbacksystem for long-term regulation of arterial pressureand body fluid volumes.14 Under most conditions,this mechanism acts to stabilize arterial pressure aswell as body fluid volumes. For example, distur-bances that elevate arterial pressure without impair-ing renal excretory capability also tend to increasesodium and water excretion through pressure natri-uresis and diuresis, thereby reducing extracellularfluid volume and returning blood pressure towardnormal (Figure 1). Hypertension caused by increasesin cardiac output or total peripheral resistance can-not be sustained if pressure natriuresis is unalteredbecause sodium excretion would remain abovesodium intake until arterial pressure returned com-pletely to the original set point. Similarly, reductionsin blood pressure tend to lower sodium excretion andincrease extracellular fluid volume until blood pres-sure returns to normal. An important aspect of this

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548 Hypertension Vol 15, No 6, Part 1, June 1990

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FIGURE 1. Graphs showing predicted effects of a hyperten-sive stimulus, caused either by increased cardiac output orincreased total peripheral resistance, without a shift of therenal-pressure natriuresis curve. Blood pressure is initiallyelevated but cannot be sustained at that level because sodiumexcretion exceeds intake, thereby reducing extracellular fluidvolume until blood pressure eventually returns to normal whereintake and output of sodium are balanced.

feedback system is that there are many neuro-humoral systems that act to amplify its effectiveness.For example, increases in blood pressure not onlytend to raise renal excretion directly through hydrau-lic effects on the kidney but also inhibit formation ofangiotensin II (Ang II) and aldosterone, which fur-ther elevates renal excretion and decreases extracel-lular fluid volume, promoting a more rapid recoveryof blood pressure.5

Although pressure natriuresis normally acts tostabilize. blood pressure, abnormalities of renalhemodynamics or tubular reabsorption can alter theset point at which arterial pressure and sodiumexcretion are controlled. For example, excessive for-mation of antinatriuretic hormones or diseases thatreduce renal excretory capability could shift thepressure natriuresis curve to higher pressures andtend to cause sodium retentio'n and increased extra-cellular fluid volume if intake remained constant.Accumulation of fluid would continue until bloodpressure increased sufficiently to restore renal excre-

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FIGURE 2. Line graph showing relations between arterialpressure and sodium excretion in control dogs and in dogsinfused with converting enzyme inhibitor SQ-14,225 (capto-pril) or angiotensin II (All) (5 ng/kg/min). Data wereobtained by measuring arterial pressure at different levels ofsodium intake under steady-state conditions. Reprinted withpermission.6

tion to normal through pressure natriuresis. In thesteady state, renal excretion would be maintainedequal to intake but at the expense of hypertension.

Neurohumoral Modulation of Pressure NatriuresisAny neurohumoral system capable of causing long-

term changes in renal excretory function could influ-ence blood pressure regulation by altering pressurenatriuresis. A reduction in renal excretory capabilitywould tend to shift the curve to high pressures,whereas a chronic increase in renal excretory capabil-ity would be associated with a shift of pressure natri-uresis toward lower blood pressures. Under steady-state conditions, no change in sodium excretion wouldbe observed because changes in blood pressure wouldcompensate for primary changes in renal excretoryfunction. In most instances, the various neurohumoralsystems act in concert with the basic pressure natri-uresis mechanism to prevent chronic changes in bloodpressure, but there are certain pathophysiologicalconditions associated with abnormal activity of theseneurohumoral systems that may alter the set point atwhich blood pressure is regulated.

Renin-Angiotensin SystemOne of the most powerful modulators of pressure

natriuresis, and consequently of long-term bloodpressure control, is the renin-angiotensin system(RAS). Figure 2 shows an analysis of the steady-stateinterrelations between Ang II, arterial pressure, andsodium excretion during chronic changes in sodiumintake in three groups of dogs with different levels ofactivity of the RAS.6 In these experiments, sodiumintake was raised progressively in steps from 5 toapproximately 500 meq/day and maintained at eachlevel until balance between intake and output ofsodium was achieved. In normal dogs with an intactRAS, sodium balance was maintained with only



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Hall et al Pressure Natriuresis in Hypertension 549

minor changes in blood pressure (5-10 mm Hg) overthe entire range of sodium intake, indicating a veryeffective pressure natriuresis mechanism. In fact, thesteepness of the chronic curve relating arterial pres-sure to sodium excretion is due in large part tochanges in Ang II formation in response to changesin sodium intake or arterial pressure. When Ang IIwas infused at a low rate (5 ng/kg/min) throughoutthe experiment so that circulating levels could notdecrease, very large increases in blood pressure(40-50 mm Hg) were needed to maintain sodiumbalance when intake was raised. This observationindicates that the inability to suppress Ang II forma-tion greatly reduces the effectiveness of pressurenatriuresis. In a third group of dogs, Ang II forma-tion was blocked throughout the experiment with theconverting enzyme inhibitor captopril (SQ-14,225).After blockade of Ang II formation, renal excretorycapability was markedly increased because sodiumbalance was maintained at lower than normal bloodpressures.

Thus, appropriate changes in activity of the RASplay a key role in allowing the normal individual toadapt to a wide range of sodium intakes withminimal changes in blood pressure. However,abnormalities of the RAS, such as the inability todecrease Ang II formation appropriately inresponse to high sodium intake, can also causepronounced effects on pressure natriuresis andtherefore long-term blood pressure regulation.

Atrial Natriuretic Factor

Another hormone that may play a role in modu-lating pressure natriuresis is atrial natriuretic factor(ANF). Numerous studies have demonstrated thatANF has powerful acute effects on sodium excretion(See References 7 and 8 for reviews) and that thishormone shifts the acute pressure natriuresis curveto lower blood pressures.9'10 Recently, ANF has beendemonstrated to have powerful chronic effects onrenal excretory function. To assess the long-termdirect actions of ANF on the kidney while controllingfor various neurohumoral changes that might over-ride its natriuretic effects, Mizelle et al11 used a splitbladder technique and infused ANF into one renalartery for several days while infusing vehicle into thecontralateral kidney; thus, measurements of separaterenal function could be made in ANF- and vehicle-infused kidneys. This is a powerful method for study-ing the long-term direct effects of ANF on renalfunction because both the infused and contralateralkidneys are exposed to the same blood pressure andneural influences and the same circulating hormonesand other constituents of the blood except for ANF.Therefore, any differences in renal function can beattributed to differences in ANF concentrations. Inthese experiments, ANF infusion at low physiologicalrates caused pronounced increases in renal excretionthat persisted as long as ANF was infused. Sodiumexcretion in the contralateral kidney decreased byalmost an identical amount so that the total sodium

balance was maintained relatively constant. Thesefindings indicate that ANF, at physiological concen-trations, is capable of increasing renal excretoryfunction chronically and provides the basis for apossible role of ANF in long-term regulation of bodyfluid volumes and blood pressure.

To further examine the importance of intrarenalversus systemic actions of ANF in long-term regula-tion of blood pressure, Hildebrandt et al12 recentlycompared the chronic blood pressure effects of ANFinfused at very low rates directly into the kidney withthe effects produced by intravenous infusions at thesame rates. The results from these studies demon-strated that intrarenal infusions of ANF at rates toolow to have any major systemic actions caused pro-nounced decreases in blood pressure over a period ofseveral days. These findings demonstrate that physi-ological increases in intrarenal levels of ANF canreduce blood pressure chronically while increasingrenal excretory capability, indicating a shift of renal-pressure natriuresis. However, the importance of thiseffect in different physiological and pathophysiolog-ical conditions has not been fully elucidated.

The precise mechanisms by which ANF alterslong-term pressure natriuresis are not well under-stood. Part of the natriuretic effect of ANF may bemediated through interactions with the RAS.9 Forexample, ANF reduces renin secretion and mayantagonize the renal tubular and vascular actions ofAng II.13-15 Further studies are needed, however, toquantify the importance of interactions betweenANF and the RAS and the exact mechanisms bywhich ANF influences chronic pressure natriuresisand blood pressure regulation.

In addition to the RAS and ANF, other neuro-humoral systems may also influence blood pressureby altering renal-pressure natriuresis. For example,DiBona16 recently reviewed evidence that the renalnerves may influence renal excretory capability andblood pressure regulation in several models of exper-imental hypertension. Other hormone systems, suchas the kallikrein-kinin system, the renal prostaglan-dins, and other natriuretic factors besides ANF, havealso been postulated to be important in regulatingrenal excretory function and arterial pressure.17"21

Unfortunately, there are few data concerning thequantitative importance of these systems in long-term regulation of pressure natriuresis, and it is notalways prudent to extrapolate from the results ofacute experiments.

Abnormal Renal-Pressure Natriuresisin Hypertension

As discussed above, renal-pressure natriuresis isabnormal in all forms of chronic hypertensionbecause average sodium excretion is approximatelythe same as in normotension, assuming that sodiumintake is normal. Figure 3 illustrates the approximatesteady-state relations between blood pressure andsodium excretion in several types of hypertension. Ineach example, the pressure natriuresis curve is



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FIGURE 3. Schematic drawing show-ing steady-state relations between arte-rial pressure and sodium excretion andsodium intake in various forms ofhypertension. K ,̂ glomerular capillaryfiltration coefficient; SHR, spontane-ously hypertensive rats; Goldblatt, one-kidney, one clip Goldblatt hypertensiverats.

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shifted so that sodium balance occurs at elevatedblood pressures. Obviously, a shift of this curve tohigher pressures must occur in all forms of chronichypertension, otherwise sodium excretion wouldremain above intake until it caused severe volumedepletion and circulatory collapse. However, notethat the characteristics of pressure natriuresis differin various forms of hypertension. As discussed below,the differing slopes and intercepts of the pressurenatriuresis curves in various forms of hypertensionmay provide clues about the etiology of hypertension.

Although it is clear that there are abnormalities ofpressure natriuresis in hypertension, the importanceof these abnormalities as a cause of hypertension hasbeen debated. According to the renal-body fluidfeedback concept,1 a primary reduction of renalexcretory capability, caused by decreased GFR orincreased tubular reabsorption, initiates a compen-satory increase in blood pressure that serves tomaintain fluid balance. Reductions in renal excretorycapability can be due to various intrinsic functionalor pathological changes in the kidney or to neuro-humoral factors that influence renal excretion. In thesteady state, normal sodium excretion would bemaintained and the initial change in GFR or tubularreabsorption would be masked by the elevated bloodpressure.

An opposing view of abnormal pressure natriuresisin hypertension is that it occurs secondarily toincreased arterial pressure.22-24 This concept pre-dicts that hypertension is initiated by abnormalitiesof the heart or peripheral vasculature that tend toelevate cardiac output or total peripheral vascularresistance and that the kidneys secondarily adapt toincreased blood pressure to maintain sodium bal-ance. Obviously, if the kidneys could completely reset

their pressure natriuresis mechanism and maintainnormal sodium excretion independently of changes inblood pressure initiated by nonrenal abnormalities,renal-pressure natriuresis would not play a significantrole in long-term blood pressure regulation. There-fore, one of the most important and controversialissues concerning the role of the kidneys in thepathogenesis of hypertension is whether arterialpressure has a long-term effect on sodium and waterexcretion, or alternatively, whether the kidneys canregulate sodium excretion independently of bloodpressure. Unfortunately, this has been a difficultquestion to answer experimentally because attemptsto produce long-term changes in renal perfusionpressure (e.g., renal artery stenosis) are usuallyaccompanied by compensatory changes in systemicarterial pressure or neurohumoral changes that alsoinfluence renal excretion. However, recent studieshave addressed this problem by examining the role ofpressure natriuresis in various models of experimen-tal hypertension in which the direct effects ofincreased blood pressure were separated from otherfactors that influence renal excretion.

Hypertension Caused by Antinatriuretic HormonesExcessive secretion of mineralocorticoids or other

antinatriuretic hormones such as Ang II typicallycauses transient sodium retention and gradual eleva-tion of blood pressure.1819-25-26 Sodium retention lastsfor only a few days and is followed by an "escape" inwhich sodium excretion returns to normal. The mech-anisms responsible for this escape have been thesubject of considerable research, and various conceptshave been proposed to explain this phenomenon.18"19

According to the renal-body fluid feedback concept,mineralocorticoids or Ang II reduce renal excretory



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capability and initiate a sequence of events that ele-vate arterial pressure. Increased blood pressure thenrestores sodium excretion to normal through pressurenatriuresis. However, because mineralocorticoids andAng II almost invariably raise total peripheral vascularresistance, the high blood pressure has also beenpostulated to be caused by direct or indirect effects ofthese agents to constrict the peripheral vascula-ture.27-30 For example, mineralocorticoids have beenpostulated to activate the sympathetic nervous systemor to stimulate the release of a ouabain-like circulatinginhibitor of sodium-potassium adenosine triphospha-tase secondary to volume expansion,31'32 changes thatare believed to cause peripheral vasoconstriction andhypertension. The escape from sodium retention hasalso been postulated to be independent of increasedarterial pressure and to be mediated by increasedformation of various natriuretic factors, such as aouabain-like natriuretic hormone, ANF, kinins, pros-taglandins, or reduced renal sympathetic nerveactivity.17-21

To resolve these issues and to directly test theimportance of pressure natriuresis in regulatingsodium balance in hypertension, we compared thechronic blood pressure and renal effects of aldoste-rone or Ang II infusion in dogs in which renalperfusion pressure was either permitted to increaseor servo-controlled at the normal level.25-26 In normaldogs, aldosterone or Ang II infusion caused relativelymild hypertension, with sodium excretion decreasingtransiently and then returning toward control on thesecond day of infusion, and after 7 days cumulativesodium balance was only slightly elevated. In con-trast, when renal perfusion pressure was servo-controlled during aldosterone (Figure 4) or Ang IIinfusion (Figure 5), sodium excretion remained con-siderably below intake throughout the experiment.Therefore, cumulative sodium balance continued toincrease, which caused pronounced edema in severaldogs. The systemic arterial hypertension was alsomuch more severe when renal artery pressure wasprevented from increasing, and some dogs developedsevere ascites or pulmonary edema within a few days.When the servo-controller was stopped and renalperfusion pressure was allowed to increase to hyper-tensive levels while Ang II or aldosterone infusionswere continued, there was a prompt escape fromsodium retention and cumulative sodium balance,and arterial pressure returned to about the samelevels measured in normal dogs during aldosteroneor Ang II infusion.

The results from these studies indicate that pres-sure natriuresis plays an essential role in maintainingsodium balance in mineralocorticoid and Ang IIhypertension. When this mechanism was preventedfrom operating, severe fluid retention occurred,which would eventually lead to complete circulatorycollapse. Although these observations emphasize theimportance of pressure natriuresis, they do not ruleout the possibility that other factors may also beimportant in maintaining sodium balance in response

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to Ang II or mineralocorticoid excess. It is possiblethat various natriuretic hormones, especially ANF,could play a role in minimizing the rise in bloodpressure needed to maintain sodium balance.

The intrarenal mechanisms by which increased arte-rial pressure allows escape from the antinatriureticeffects of aldosterone or Ang II appear to be related tosmall increases in GFR and renal plasma flow anddecreases in fractional sodium reabsorption2526 (seeReferences 18 and 19 for further review). With pro-longed hypertension, lasting for months or years,pathological changes in the glomerular capillaries maycause reductions in GFR that necessitate furtherelevations in arterial pressure and inhibition of tubu-lar reabsorption to maintain sodium balance. How-ever, the observation that GFR and renal plasma floware elevated as mineralocorticoid hypertension devel-ops, even though renal excretory capability is reduced,illustrates an important point: evaluation of renalexcretory capability cannot be based on steady-statemeasurements of renal hemodynamics, tubular reab-sorption, or even sodium excretion as each of thesevariables is influenced by various compensatory mech-anisms that are set into motion as hypertension devel-ops. In the case of mineralocorticoid hypertension,increased GFR and renal plasma flow, along with areduction in proximal fractional reabsorption, appear



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FIGURE 5. Line graphs showing effects of angiotensin IIinfusion in a dog in which renal perfusion pressure wasservo-controlled at the normal level After 4 days, severehypertension arid sodium and water retention resulted inpulmonary edema. Reprinted with permission.26

to be important compensations for a primary increasein distal tubular sodium reabsorption. In the steadystate, distal tubular delivery of sodium is increased tooffset increased distal reabsorption, and a decrease inrenal excretory capability is apparent only when thearterial pressure that is needed to maintain sodiumexcretion equal to intake is considered.

Hypertension Caused by "Vasoconstrictors"

An abnormality of renal-pressure natriuresis hasalso been found in several forms of hypertension thatare usually considered to be caused by peripheralvasoconstriction. For example, both norepinephrineand vasopressin are among the most potent peripheralvasoconstrictors of the body. In fact, vasopressin ismore powerful as a vasoconstrictor than Ang II.33 Yet,with chronic infusions of vasopressin or norepineph-rine, only small increases in blood pressure areobserved as long as kidney function is not im-paired.33"36 The fact that these powerful vasoconstric-tors do not usually cause pronounced chronic hyper-tension, even though they elicit large acute increasesin vascular resistance and blood pressure, is difficult toexplain if one considers changes in peripheral vascularresistance to be a primary cause of hypertension.However, the failure of vasopressin or norepinephrine

to cause severe sustained hypertension is explainableif one considers their modest antinatriuretic actions.

Although vasopressin is a potent antidiuretic hor-mone, it does not have a major antinatriuretic action.Therefore, increases in arterial pressure that resultfrom peripheral vasoconstriction tend to cause natri-uresis, which offsets the fluid retention initiated byvasopressin.33-35'36 When vasopressin was infusedchronically in normal dogs at a rate that producedmaximal antidiuresis, there was initially a modestincrease in blood pressure associated with transientincreases in urine osmolality and decreased urinevolume. However, after 3-4 days urine volume andosmolality returned toward normal and arterial pres-sure began to decrease, averaging only a few milli-meters of mercury above control after 1-2 weeks ofinfusion.35 This decline of blood pressure was asso-ciated with increased sodium excretion and a nega-tive sodium balance. In contrast, when pressurenatriuresis was prevented by servo-controlling renalarterial pressure, vasopressin infusion caused pro-nounced and sustained decreases in urine volume,increased urine osmolality, a slight retention ofsodium, and severe hypertension.35

Thus, the pressure natriuresis and diuresis mech-anisms play an essential role in offsetting the antidi-uretic effect of vasopressin, thereby minimizing vol-ume expansion and hypertension even thoughvasopressin is one of the most powerful vasoconstric-tors known. The modest transient hypertension thatoccurs when renal function is normal depends pri-marily on increased volume rather than the periph-eral vasoconstriction. Cowley et al37 found that, whentotal body weight was held constant by decreasingfluid intake during vasopressin infusion in dogs, therewas no significant increase in blood pressure. However,when fluid retention is severe because of impairedpressure natriuresis, vasopressin may cause largeincreases in blood pressure. In our experiments,35 whenrenal artery pressure was servo-controlled duringchronic vasopressin infusion, continuous retention offluid occurred and blood pressure increased markedly.Thus, the chronic hypertensive effects of vasopressin,although modest in animals with normal renal function,may be more severe when renal function is impaired.

Similar results have also been observed with othervasoconstrictors, such as norepinephrine, and withadrenocorticotrophic hormone, which potentiatesthe hypertension produced by vasoconstrictors suchas norepinephrine.34-38-40 Each of these forms ofhypertension begins with an increase, rather than adecrease, in sodium excretion. The finding thatsodium excretion increases transiently could be inter-preted as evidence that the hypertensive action ofthese hormones is unrelated to any impairment ofrenal excretory capability. However, it appears thatthe transient natriuresis occurs secondarily toincreased blood pressure caused by peripheral vaso-constriction or increased cardiac output and thatnorepinephrine and adrenocorticotrophic hormoneboth have a slight antinatriuretic effect on the kidney



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FIGURE 6. Graphs showing probable long-term relationbetween arterial pressure and sodium excretion and sodiumintake before and during infusion of a powerful peripheralvasoconstrictor that has a relatively weak effect on renal-pressure natriuresis. The normal curve (solid line) is comparedwith the vasoconstrictor curve (dashed line). Initially, thevasoconstrictor would cause natriuresis, because arterial pres-sure is elevated (to point B) above the set point for balancebetween intake and output of sodium (point C).

that is responsible for the mild hypertension that thesehormones produce chronically.34-39 If pressure natri-uresis is prevented by servo-controlling renal arterypressure, both of these hormones can cause severehypertension that parallels sodium retention.34-39

Figure 6 shows the probable relation betweenblood pressure and sodium excretion after infusion ofa powerful peripheral vasoconstrictor that has arelatively weak antinatriuretic effect on the kidney(e.g., norepinephrine). The antinatriuretic effect ofthe vasoconstrictor would shift the renal-pressurenatriuresis mechanism to higher blood pressures,thereby necessitating a small increase in blood pres-sure to maintain sodium balance. However, if theantinatriuretic action of the vasoconstrictor is weak,compared with its peripheral vascular actions, bloodpressure would be elevated above the renal set pointfor regulation of sodium balance (to point B ratherthan point C where intake and output are balanced)and would cause a transient natriuresis. Only a

transient natriuresis would be expected becauseextracellular fluid volume would decrease and arte-rial pressure would eventually stabilize at a level(point C) at which sodium intake and output arebalanced. This explanation fits with our finding thatthe natriuretic effects of vasoconstrictors such asnorepinephrine and vasopressin are abolished whenrenal perfusion pressure is prevented from increas-ing. In fact, there is a slight sodium retention whenrenal perfusion pressure is servo-controlled in thesemodels of hypertension.38

Thus, there is strong experimental support for thebasic premise of the renal-body fluid feedback con-cept, that increases in blood pressure have a majorlong-term effect on sodium excretion. In all forms ofexperimental hypertension studied thus far, there is ashift of the pressure natriuresis mechanism to ahigher blood pressure, which initiates and sustainsthe hypertension. In some cases, the renal actions ofthese hypertensive stimuli may be obscured by othereffects, such as peripheral vasoconstriction orchanges in vascular capacity, that increase bloodpressure above the renal set point at which sodiumbalance is maintained. In these circumstances,sodium excretion may actually increase as hyperten-sion develops. However, the maintenance of elevatedblood pressure chronically depends on the changes inrenal function that contribute to the shift of renal-pressure natriuresis.

Can Abnormal Pressure Natriuresis MechanismOccur Secondarily to Chronic Increases

in Blood Pressure?In the experimental models of hypertension dis-

cussed above, primary changes in renal-pressurenatriuresis resulted in adaptations of blood pressure(i.e., hypertension occurred as a compensatoryresponse to maintain sodium and water balance).These experiments also illustrate another importantpoint: if pressure natriuresis is impaired and imbal-ances between fluid intake and output are main-tained, severe edema and complete circulatory col-lapse occur within a few days. Rapid adaptations ofblood pressure to primary alterations in renal func-tion are essential for survival in these forms ofhypertension.

Although high blood pressure may satisfy theimmediate need to maintain sodium balance, it mayalso lead to additional changes in renal excretoryfunction that can exacerbate the hypertensive pro-cess over long periods of time. A good example is thehypertension that develops after placing a Goldblattclip on one renal artery while leaving the contralat-eral kidney intact (two-kidney, one clip Goldblatthypertension). Initially, the hypertension is caused byimpaired function of the clipped kidney, while thecontralateral intact kidney undergoes natriuresis,which partly ameliorates the hypertension.41 Fullcompensation for impaired function of the clippedkidney is not achieved by the contralateral kidneybecause its excretory function is also partly attenu-



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ated by various functional changes, such as increasedcirculating Ang II.142 Therefore, increased bloodpressure is necessary to maintain sodium excretionand intake in balance.

In the early stages of hypertension, removal of theclipped kidney restores blood pressure to normal,whereas removal of the contralateral kidney exacer-bates the hypertension.43 However, with prolongedhypertension pathological changes in the vasculatureof the contralateral kidney begin to appear and addto the impairment of renal function.44 At this stage,removal of the clipped kidney or unclipping onlypartially restores blood pressure.44'45 However,removal of the contralateral "normal" kidney andunclipping together usually normalizes blood pres-sure.46 This observation indicates that chronic expo-sure to high blood pressure in the untouched kidneymay cause structural changes that alter its pressurenatriuresis mechanism and contribute to progressionof hypertension. Thus, the two-kidney, one clip Gold-blatt model of hypertension, although initiated byincreased preglomerular resistance in part of the renaltissue, is characterized by functional or pathologicalchanges in the remaining normal renal tissue thatcontribute to the maintenance of hypertension. Asimilar situation could occur when there are patchyareas of renal ischemia due to a variety of causes,including renal infarcts, nonhomogeneous constrictionof the renal vasculature, or nonhomogeneousnephrosclerosis.1-47 In fact, any abnormality of renalfunction that causes underperfusion in one area of thekidney is likely to cause impairment of the remainingnephrons via the renin released from underperfusednephrons.1'47

Conceivably, any initial disturbance of renal func-tion that leads to compensatory increases in intrare-nal pressures due to increased systemic arterial pres-sure or preglomerular vasodilation could causepathological changes that would eventually result inglomerular membrane or arteriolar damage,48 there-by gradually shifting pressure natriuresis to higherand higher blood pressures. In this way, renal-pressure natriuresis could gradually adapt to chronicincreases in blood pressure. This adaptation, how-ever, would not act as a physiological mechanism tomaintain sodium balance; instead, these changescould be a pathological cause of further increases inblood pressure that would in turn be important inmaintaining sodium balance.

Abnormal Pressure Natriuresis inEssential Hypertension

In most patients with hypertension, no specific renaldysfunction can be identified in the early stages of thedisease, and there is little evidence for increased levelsof antinatriuretic hormones such as Ang II or aldo-sterone. Thus, the hypertension of these patients isusually referred to as "idiopathic" or "essential."However, it is clear that renal excretory function is notnormal in these patients because the renal-pressurenatriuresis mechanism is reset so that normal sodium

excretion is maintained only at elevated blood pres-sures. Omvik et al23 demonstrated that when arterialpressure was acutely reduced by nitroprusside infu-sion in patients with essential hypertension, sodiumexcretion decreased below normal indicating thatpressure natriuresis was reset in these patients. Simi-lar abnormalities of renal-pressure natriuresis havebeen found in all animal models of genetic hyperten-sion studied thus far.2-41'49"53

The observation of abnormal pressure natriuresisin essential hypertension is not direct evidence thatsuch an abnormality plays a causal role in elevatingblood pressure. However, in genetic models of spon-taneous hypertension that have many similarities tohuman essential hypertension, there is evidence thatabnormalities of pressure natriuresis occur beforethe development of hypertension and are not merelysecondary to increased blood pressure. For example,in prehypertensive Dahl salt-sensitive (DS) rats theslope of the relation between urine flow and renalperfusion pressure measured in acute experiments isconsiderably less than that seen in Dahl salt-resistant(DR) rats53 (Figure 7). The fact that this occursbefore the rats develop hypertension suggests thatabnormal pressure natriuresis in the DS rat is notcaused by renal damage secondary to hypertensionbut represents an intrinsic difference between thekidneys of DS and DR rats. The mechanisms thatunderlie the shift of pressure natriuresis in DS ratsare not entirely clear but may be related in part toabnormalities of renal hemodynamics. Roman53

demonstrated that a shift of GFR autoregulation tohigher pressures occurred in prehypertensive DS ratsfed a low sodium diet. Recently, Tobian et al54 alsodemonstrated that there is a glomerular defect inprehypertensive DS rats that limits their capacity toincrease GFR in response to amino acid infusion.Cross transplantation studies between DS and DRrats indicate that the hypertension of these ratsfollows abnormal kidney function.55-56

In Okamoto spontaneously hypertensive rats (SHR),abnormalities of renal function also appear to play arole in causing hypertension. Transplantation of kid-neys from SHR to Wistar-Kyoto (WKY) rats pro-duces hypertension in the previously normotensiverecipient.57-59 Moreover, this alteration in renal func-tion is not merely the result of damage secondary tohypertension because transplantation of kidneysfrom SHR even before they develop hypertensioneventually causes hypertension in the WKY ratrecipient.57 Acute studies in SHR suggest that mul-tiple abnormalities of renal function may occur atdifferent stages of hypertension. Renal blood flowautoregulation has been reported to be shifted tohigher blood pressures in young 10-week-old SHRcompared with WKY control rats.60 When differ-ences in neural and endocrine influences in thekidneys are minimized by renal denervation and bymaintaining plasma levels of vasopressin, aldoste-rone, cortisol, and norepinephrine constant by intra-venous infusion, the slope of the renal-pressure



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URINE FLOWul/mln

120

80

40

SO CHUMEXCRETION

uEq/mtn

20

15

ID-

100 12S 150 175 200

RENAL ARTERIAL PRESSUREinm HQ

FIGURE 7. Line graphs showing effect of changes in renalperfusion pressure on urine flow and sodium excretion in Dahlsalt-resistant rats, in hypertensive Dahl salt-sensitive rats, andin prehypertensive Dahl salt-sensitive rats fed a low salt diet.Adapted from Reference 53.

natriuresis curve of SHR is reduced compared withthat of WKY rats.52 This finding suggests that theremay be intrinsic changes in renal function that con-tribute to resetting of pressure natriuresis in SHR.However, chronic studies in intact SHR suggest thatincreased renal nerve activity and immunologicalabnormalities may also contribute in part to a paral-lel shift of pressure natriuresis.61-62

In the Milan strain of SHR, cross transplantationstudies between normotensive and hypertensive ratsalso indicate that the hypertension follows thekidney.63-64 Several lines of evidence recentlyreviewed by Bianchi et al65 suggest that hypertensionin Milan rats may be initiated by a primary increasein renal tubular reabsorption. However, the exactintrarenal mechanisms responsible for abnormalpressure natriuresis in each of these models ofgenetic hypertension have not been fully elucidated.

The possibility that these observations in animalsmay be relevant to the pathogenesis of human essen-tial hypertension is supported by the findings of

Curtis et al,66 who reported that transplantation ofkidneys from normotensive donors to patients withessential hypertension and renal failure led to com-plete normalization of blood pressure. If the highblood pressure in these patients was caused by somefactor extrinsic to the kidneys, hypertension shouldhave eventually reappeared after transplantation.However, blood pressure remained normal in allpatients for an average follow-up period of 4.5 years.Parfrey67 also reported that, in children born toparents who were both hypertensive, the pressurenatriuresis curve was shifted when compared withthat of children with normotensive parents, evenbefore the onset of hypertension. These observationsprovide further support for the view that abnormalpressure natriuresis in essential hypertensive patientsmay be a cause and not merely a consequence ofincreased blood pressure. However, as discussedabove, once the hypertensive process begins patho-logical changes can occur in the kidneys that can addto the shift of the pressure natriuresis curve andfurther elevate blood pressure.

Possible Mechanisms of Shift in Pressure Natriuresisin Essential Hypertension

A single renal defect responsible for shifting pres-sure natriuresis and elevating blood pressure inhuman essential hypertension has not been found. Itseems likely that essential hypertension is a hetero-geneous disease beginning with different abnormali-ties of renal hemodynamics or tubular reabsorptionin different patients. Unfortunately, measurementsof various indexes of kidney function after hyperten-sion is established or even during the slow insidiousdevelopment of hypertension may not provide a greatdeal of insight into the pathophysiological processesthat initiate hypertension because these measure-ments represent a summation of compensatorymechanisms and abnormalities involved in causinghypertension. For example, renal vascular resistanceis almost invariably increased in patients with essen-tial hypertension.41-6869 Yet, high renal vascular resis-tance could be an autoregulatory response toincreased blood pressure in some cases or it couldplay a causal role in others if it is increased suffi-ciently to lower renal blood flow and GFR.

In some instances, reduced renal excretory capa-bility may be associated with a compensatoryincrease in renal blood flow and GFR, as occurswhen there is a primary increase in tubular reabsorp-tion (i.e., early stages of mineralocorticoid hyperten-sion). In an attempt to document abnormalities ofrenal hemodynamics in essential hypertension, vari-ous workers have reported increased, decreased, orno change in renal blood flow at various stages ofhypertension.68'69

Such variability is expected with different insults tothe kidney and when factors known to influence renalblood flow and GFR, such as sodium and proteinintake, are uncontrolled. Also, episodic measure-ments made during resting conditions may not accu-



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rately reflect the average values for renal hemody-namics existing throughout the day during periods ofstress and activity as well as inactivity. For patientswith hypertension who have greater responses tovasoconstrictors, reductions in renal blood flow andGFR may not be present during resting conditionsbut could occur during periods of activity and couldplay a role in the pathogenesis of hypertension.Perhaps even more important, it is usually not pos-sible to sequentially analyze the changes in renalfunction that occur during the onset of hypertensionin humans or to conduct detailed and invasive exper-iments that allow separation of those abnormalitiesthat could cause hypertension from those that merelyoccur as part of an overall compensatory response.Therefore, rather than listing the various alterationsin kidney function that have been reported, it may bemore useful to briefly consider the types of renalabnormalities that have been shown experimentallyto cause hypertension and the characteristic changesin pressure natriuresis in these models comparedwith those found in essential hypertension.

Effects of Increased Preglomendar Resistance

The observation that many patients with essentialhypertension demonstrate a parallel shift of the renal-pressure natriuresis curve, similar to that found inexperimental models of hypertension caused byincreased preglomerular resistance (e.g., Goldblatthypertension), is consistent with the possibility thathypertension in these patients may be caused byincreased preglomerular resistance. Widespread con-striction of preglomerular vessels, due to extrinsicneurohumoral influences or intrinsic abnormalitiessuch as resetting of the macula densa feedback mech-anism, would be predicted to cause essentially thesame renal and circulatory changes as observed in theone-kidney, one clip Goldblatt model of hypertension.After compensatory increases in blood pressure, onemight expect to find nearly normal renal blood flow,GFR, and plasma renin activity that are in factobserved in many essential hypertensive patients.

Effects of Reduced Glomendar CapillaryFiltration Coefficient

Another abnormality of renal function that couldlead to hypertension by altering pressure natriuresisis a reduction in the glomerular capillary filtrationcoefficient (K{). The chronic hypertensive effect of adecrease in Kt would, of course, depend on thesensitivity of GFR to changes in Kt. In some ratstrains in which filtration pressure equilibrium exists,GFR is relatively insensitive to changes in Kt and ishighly dependent on renal plasma flow.70 However,in many rat strains and in other species, such as thedog, as well as humans, filtration pressure equilibriumprobably does not occur in most circumstances.71

Therefore, reducing Kt would be expected to initiallylower GFR and sodium excretion while increasingrenin secretion via the macula densa mechanism.However, as arterial pressure increased, GFR and

renin release could be restored toward normal so thatthe only persistent abnormality of renal functionwould be reduced filtration fraction, increased glo-merular hydrostatic pressure, and perhaps smallincreases in renal blood flow. Increases in renal bloodflow and restoration of GFR could occur in partthrough a macula densa feedback72 as well as throughincreases in blood pressure. Unfortunately, a compen-satory increase in glomerular hydrostatic pressure,needed to offset a decrease in Kt, could lead toadditional renal dysfunction over a period of years bycausing glomerulosclerosis,48 thereby reducing Kf evenfurther and requiring additional increases in arterialpressure and glomerular hydrostatic pressure to main-tain GFR constant. Obviously, such a sequence couldinitiate a vicious cycle leading to progressive renaldamage and eventually kidney failure.48 The clinicalcounterpart to this sequence may be found in hyper-tension caused by glomerulonephritis or possiblyessential hypertension with more subtle dysfunction ofthe glomerular capillary membrane. In contrast tohypertension caused by increased preglomerular resis-tance, hypertension due to reduced K{ is associatedwith a decreased slope of the pressure natriuresiscurve (Figure 2). The significance of this reducedslope is that it causes arterial pressure to be very saltsensitive; increases in sodium intake exacerbate thehypertension, whereas low sodium intake amelioratesthe high blood pressure.1

Effects of Increased Tubular Reabsorption

Some essential hypertensive patients show pressurenatriuresis characteristics that cannot be explainedentirely by preglomerular constriction or decreased Kt.For example, renal-pressure natriuresis may have adecreased slope in some individuals indicating thatthey are salt-sensitive, whereas hypertension causedprimarily by preglomerular constriction is usually notsalt-sensitive.1 Also, many patients with essentialhypertension have decreased plasma renin activity.Both abnormalities, the low plasma renin activity andthe salt-sensitivity of blood pressure, could beexplained by increased tubular reabsorption or by acombination of changes leading to increased fractionalreabsorption and renal vasoconstriction.

In general, those forms of experimental hyperten-sion that are initiated by increased tubular reabsorp-tion (e.g., mineralocorticoid hypertension) are salt-sensitive.1'58 In these types of hypertension, thepressure natriuresis curve has a reduced slope ratherthan a parallel shift as occurs with increased preglo-merular resistance. Another feature of hypertensioncaused by primary increases in tubular reabsorption indistal parts of the nephron beyond the macula densa isthat it is often associated with secondary suppressionof plasma renin activity and a tendency toward extra-cellular volume expansion (e.g., mineralocorticoidhypertension). However, when increased tubularreabsorption is coupled with peripheral vasoconstric-tion (e.g., Ang II hypertension), the degree of volumeexpansion depends on the relative severity of renal



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and peripheral vasoconstriction. With severe periph-eral vasoconstriction and decreased vascular capaci-tance, much less volume is needed to raise bloodpressure sufficiently to offset the increase in tubularreabsorption and to maintain fluid balance. If vascularcapacitance is markedly reduced, a much smallervolume is needed to raise blood pressure, and extra-cellular fluid volume may actually be reduced despitean increase in tubular reabsorption.

Effects of Reduced Nephron NumberAnother factor that could increase salt-sensitivity

of blood pressure and decrease plasma renin activityin essential hypertensive patients is a gradual loss ofnephrons due to aging or to periodic mild insults tothe kidney occurring over a long period of time.Reduction in kidney mass, in the absence of otherabnormalities, usually does not cause hyperten-sion.1'58 Experimental studies have demonstratedthat surgical removal of large portions of the kidney,to the point that uremia occurs, rarely causes severehypertension as long as sodium intake is normal.73'74

When entire nephrons are lost without ischemiaoccurring in the remaining nephrons, overall glomer-ular filtration and tubular reabsorption capability aresimultaneously reduced so that balance between fil-tration and reabsorption can be maintained withoutmajor adaptive changes in arterial pressure. How-ever, kidneys with reduced numbers of nephrons arevery susceptible to additional insults that impairrenal excretory function. Thus, hypertension associ-ated with mineralocorticoid excess is much moresevere after renal mass is reduced.58 Also, the abilityto increase sodium excretion in response to theadditional challenge of high sodium intake requires agreater arterial pressure after decreasing kidneymass73'74 (i.e., blood pressure becomes very salt-sensitive).

Loss of nephrons could also lead to decreasedplasma renin activity. Although total renal blood flowand GFR would tend to be reduced with nephronloss, functional and morphological compensations inthe remaining nephrons would tend to cause vasodi-lation and increased single nephron GFR as well asincreased distal delivery of sodium chloride. Anincrease in single nephron GFR and distal tubularsodium chloride delivery in the surviving nephronswould be expected to inhibit renin synthesis andsecretion via a macula densa mechanism.75-76 Insupport of this possibility, there is usually a gradualdecline in the number of functioning glomeruli afterthe fourth decade of life.77 Also, the observation thaturine concentrating ability decreases with age, eventhough levels of antidiuretic hormone are normal orelevated,78 supports the possibility of a gradualdecrease in medullary tonicity with age that in turncould be the result of high solute delivery orincreased medullary blood flow in the remainingnephrons.

Although it is clear that essential hypertensivepatients have abnormal pressure natriuresis, the pre-

cise causes of this defect are unclear. It is probablyunwise to ascribe a single cause for all essentialhypertensive patients. It may be more useful to ana-lyze the renal and circulatory abnormalities of theseindividuals and then compare them to various knowncauses of experimental hypertension. In this way, itmay be possible to determine whether the hyperten-sion is initiated by increased preglomerular resistance,increased tubular reabsorption, decreased numbers offunctioning nephrons, reduced glomerular capillaryfiltration coefficient, or some combination of theseabnormalities. With long-standing hypertension,pathological changes that occur secondary to hyper-tension must also be considered. By analyzing thecharacteristics of pressure natriuresis in hypertensivepatients and by comparing these curves to thoseobserved in various forms of experimental hyperten-sion of known origin, it is often possible to gain insightinto the etiology of this disease.

Acknowledgment

We thank Mrs. Ivadelle Osberg Heidke for excel-lent secretarial assistance.

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KEY WORDS • blood pressure • sodium excretion • angiotensin• renin • atrial natriuretic factor • essential hypertension •kidney



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J E Hall, H L Mizelle, D A Hildebrandt and M W BrandsAbnormal pressure natriuresis. A cause or a consequence of hypertension?

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