THE HORMONAL CONTROL OF BODY SODIUM · change of GFR does not appear to disrupt sodium homeostasis (Surtshin, Rolf and White, 1951). There-fore, tubular reabsorption must also change,

POSTGRAD. MED. J. (1964), 40, 479

THE HORMONAL CONTROL OF BODY SODIUMJ. D. H. SLATER, M.A., M.B., M.R.C.P.

First Assistant, The Medical Unit, Middlesex Hospital, W.I.

OUR body cells are bathed in a fluid whosesalt content resembles that of the primordialsea where we presumably had our originsseveral billion years ago. Since this seaprobably contained about one-third as muchsalt as sea-water to-day (Strauss, 1957) its saltcontent approached that of our extracellirlarfluid. Among invertebrates there are widevariation in the osmotic concentration ofbody fluids, but the "milieu int6rieur" of manand all classes of vertebrates is remarkablyconstant, both osmotically and volumetrically.Claude Bernard's (1878) oft-quoted idea thatthis stability was "la condition de la vie libre,ind6pendante" still appears axiomatic. Whennot associated with changes of the volume ofbody fluid compartments, quite large fluctua-tions of serum osmolarity are tolerable butwhen, as is more usual, changes in the volumeof the body fluid compartments take place,then, the "freedom and independence ofexistence" is clearly curtailed.

Since salt balance can be preservedindefinitely on a diet as low in sodium as thedietician's ingenuity can fashion it, there mustbe potent renal mechanisms for the conserva-tion of salt; without these mechanisms ouraquatic ancestors presumably could neverhave migrated from salt to fresh water.The volume of the extracellular fluid

depends on its salt content since sodium, whichis actively extruded from cells, largely deter-mines its osmolanrty. The total amount ofsodium in the body is therefore very delicatelycontrolled, and, allowing 3 to 4 days for equi-libration, sodium output exactly equals sodiumintake. In normal people extrarenail sodiumlosses are negligible if sweating is avoided,so that salt balance can only be achievedby variations of sodium output throughthe kidney. Looked at in another way,our very survival depends on the abilityof the kidney to reabsorb the 173 'litresof water and 24,000 milliequivalents of sodiumfiltered by the glomeruli each day. On anaverage salt intake about 99.5 per cent of theglomerular filtrate must be reabsorbed to

maintain a steady state. Large changes ofintake induce only very small changes insodium reabsorption; a change of only 0.75 percent in the amount of sodium realbsorbed willmaintain a steady state despite doubling orhalving an average salt intake. Therefore, themechanism(s) by which the kidney is able todetect and respond to changes in salt intakemust be very sensitive indeed.

Mechanism of Salt ExcretionMuch data is now available which strongly suggests

that the volume of the extracellular fluid (ECF), orrather that portion of it which is physiologicallyeffective, is one of the main factors which determinesthe rate of renal sodium excretion, at least innormal individuals (Epstein, 1956, Strauss, 1957,Smith, 1957). How is the kidney able to regulate it?The kidney can only alter the rate of sodium

excretion by two mechanisms-by changes in therate of glomerular filtration (GFR) or by changesin the rate of tubular reabsorption. GFR is deter-mined by ha:modynamic factors such as the renalblood flow and the relative resistance to flow offeredby the afferent and efferent arterioles of theglomerular tuft and by the colloid osmotic pressureof the plasma proteins. The factors governing therate of sodium reabsorption by the tubules will betentatively assessed in this account because it islikely that hormonal, or at least humoral, factorsare important.For years there has been an earnest controversy

concerning the relative importance of glomerularfiltration and tubular reabsorption in mediatingfunctional adjustments of sodium excretion. Wesson(1957) and O'Connor (1962) have been articulateprotagonists of the idea that functional alterationsof sodium excretion are -largely determinedhiemodynamically by indetectably small changes infiltration rate. If, but only if, we assume that therate of tubular sodium reabsorption is constant andunrelated to the sodium load, then a 1 per cent changein GFR for a given plasma sodium concentrationcould halve or double the rate of sodium excretion.By present methods of estimation, such a smallchange of G3FR lies within the limits of experimentalerror, so that the hypothesis becomes rather sterilebecause it cannot be tested experimentally. It iscertainly true, however, that all the rapid changesin the rate of sodium excretion seen with manceuvressuch as motionless standing, salt infusions andacute sequestration of blood or hremorrhage arealso associated with parallel changes of the rate ofglomerular filtration. Qualitatively, even slightacute changes of GFR can lead to large changes of

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POSTGRADUATE MEDICAL JOURNAL

sodium excretion in the dog (Selkurt, 1951; Mueller,Surtshin, Rolf and White, 1951), but quantitativelythe relationship between the two is quite unknown(Wesson, 1957). It cannot be assumed, as is oftenthe case, that there is a sort of immutable, instant-aneous "glomerulo-tubular balance" so that a fixedproportion of the filtered load is always reabsorbed.For example, there may well be a lag after anacute reduction of GFR before the rate of tubularreabsorption is also reduced. This, therefore, makesit impossible to decide from acute experimentswhether a given fall of GFR, detectable or not, canaccount for an observed fall of the rate of sodiumexcretion. When, however, GFR and sodium excre-tion move in opposite directions or when there isa large and unequivocal change of GFR withouta corresponding change of sodium excretion, thentubular reabsorption must be changing. This is wellillustrated by the experiments of Black, Platt andStanbury (1951). After some days of sodium depriva-tion in normal people, a rapid infusion of hyipertonicsaline increased GFR unequivocally, but the rateof urinary sodium excretion still remained low.Many acute experiments concerning renal salt

handling have been performed in the dog, whichappears to use changes of GFR to regulate sodiumexcretion to a greater extent than humans (Chalmers,Lewis and Pawan, 1952). This should temper undueenthusiasm for extrapolation from dog to man.Finally, when trying to interpret relatively short-termexperiments, we should realise that a permanentchange of GFR does not appear to disrupt sodiumhomeostasis (Surtshin, Rolf and White, 1951). There-fore, tubular reabsorption must also change, althoughadjustments to altered sodium intake probably occurmore slowly.

Increased tubular reabsorption of sodium is bynow well-established in patients accumulating cedemafluid. The GFR is clearly below normal in cardiacfailure, (Merrill, 1946) even when due allowance ismade for age (Wesson, 1957), but there is now alarge body of data (Davis, 1960) which stronglysuggests that the rate of tubular sodium reabsorptionis increased. In the hypoproteinaemic states (thenephrotic syndrome and cirrhosis of the liver) theGFR is not significantly different from normal(Wesson, 1957) and there are numerous well-documented accounts of supranormal rates, as mightbe anticipated when the colloid osmotic pressure ofthe plasma is reduced. Since the urine of thesepatients is often practically devoid of sodium, toconclude that increased tubular reabsorption ofsodium is largely responsible for the cedema, becomesinescapable.Once one accepts that the rate of tubular re-

absorption of sodium is the major variable in thecontrol of renal sodium output in man, then theproblem becomes that of detecting the factors whichdetermine it.

The Role of the Adrenal Cortex in MediatingChanges of Sodium ExcretionThe adrenal glands are necessary to maintain

life, an action parallel to the "mineralocorti-coid" activity of the steroid hormones whichpromote the reabsorption of sodium and thesecretion of potassium by the renal tubules.However, the adrenocortical hormones onlyincrease the rate of tubular sodium reabsorp-

tion by such a small increment that sodiumdeficiency in adrenocortical failure can beovercome by a modest increase of salt intake.Nevertheless, without the mineralocorticoidaction of steroid hormones, our capacity tocurtail sodium losses in the face of a reducedintake is seriously impaired. Lipsett and Pear-son (1958) showed that even when adrenal-ectomised patients are maintained on relativelyhigh quantities of cortisone (50-75 mg. daily),by the fifth day on a low salt diet (when anormal person would have reached equilibrium)the rate of urinary sodium excretion was stillsome three to four times imore than the intake.Nevertheless, the rate of sodium excretion didfall by about half, in associ,ation with a sharpreduction of GFR.The adrenal cortex normally only secretes

sufficient amounts of three known steriods(cortisol, aldosterone and corticosterone) whichare important physiologically. Under normalconditions and in physiological quantities theyprobably exert their mineralocorticoid effectsmainly on the distal tubule (Vander, Malvin,Wilde, Lapides, Sullivan and McMurray, 1958)where they promote sodium reabsorption, bothin association with chloride and, more character-istically, by increasing the rate of exchange ofsodium with potassium and hydrogen ions.Whether adrenocortical steroid hormones caninfluence sodium reabsorption by the proximaltubule is still unknown but, by implication(v. infra), they appear to do so.Of the steroids involved, it can be roughly

calculated from the known potency ratios inanimals (O'Connor, 1962) and the estimatedrate of secretion from turnover studies afterthe injection of radioactive tracers in man, thatabout 70 per cent of the "mineralocorticoid"activity leaving the gland under normal condi-tions is due to aldosterone, about 20 per centto cortisol and about 10 per cent to corticost-erone. Aldosterone is, then, the predominantmineralocorticoid despite the fact that the rateof cortisol secretion, which accounts for over90 per cent of the "glucocorticoid" activityleaving the adrenal, is 100 times greatergravimetrically. By "mineralocorticoid activity"is meant either the overall effect of prolongingthe life of an adrenalectomised animal or themore specific effect of reducing the rate ofurinary sodium excretion. Actually, sincecortisol (and its synthetic analogues) but notaldosterone or desoxycorticostercne increasesthe glomerular filtration rate in adrenalecto-mised dogs (Garrod, Davies and Cahill, 1955;Slater, Mestitz, Walker and Nabarro, 1961

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SLATER: The Hormonal Control of Body Sodium

some of the "mineralocorticoid" renal tubulareffects of glucocorticoids are partially annulled.Thus adrenocortical steroid hormones, parti-cularly aldosterone, do have biological attri-butes which could be evoked to explain manyof the changes of the rate of sodium excretionwhich are seen physiologically and pathologic-ally.

Aldosterone and Sodium HomeostasisAldosterone was first isolated in 1953 by

Tait, Simpson and Grundy by a brilliant andpainstaking combination of chemical analy-sis and biological assay for mineralocorticoidactivity of the "amorphous" fraction of adrenalgland extracts. This fraction was known to bethe most potent in maintaining life afteradrenalectomy. Once discovered, aidosteronesoon came to be regarded as a major factorin regulating renal sodium excretion via changesin the rate of tubular reabsorption, not onlyin cedematous conditions, but also in physiolo-gical situations such as sodium depletion andrepletion, the erect and supine posture, andhemorrhage. Really good evidence regardingthe role of aldosterone in these situations hasbeen slow in coming despite many thousands ofsomewhat confusing publications. Evidence isneeded that changes in the rate of sodiumexcretion are indeed associated with changesin the amount of biologically-effective aldoster-one available to the renal tubular cells. Theclosest approach to this would be to measurethe concentration of aldosterone in the circulat-ing plasma and to assume that the ratiobetween free and protein-bound forms of thehormone found i,n the plasma also holds true atthe cell surface. But aldosterone circulates insuch minute quantities (of the order of tens ofmille-micrograms or nanograms per 100 ml.)that a direct measurement of the plasma con-centration is barely possible, even today.Another approach would be to try and obtainan index of the 24-hour average pliasma level bymeasuring the rate of excretion of biologicallyactive hormone in the urine. However, only aminute proportion of secreted aldosterone isexcreted unchanged in the urine (about 0.2 percent). Therefore, use has invariably been madeof the fact that about 5 per cent of secretedaldosterone can be released from a conjugate byacid hydrolysis of the urine. This is nowthought to be an 18-glucoronide (formerly Tait's3-oxo-conjugate). The aldosterone so liberatedcan then be measured either biologically or, withgreater precision, chemically. Quite apart fromthe inherent inaccuracies of measurement, the

rate of excretion of acid-released aldosteronewill only reflect the plasma level if (1) therenal clearance rate of the hormone is constantand (2) the proportion of the total secretedaldosterone metabolised along this particularmetabolic pathway also remains constant. Forexample, a 5 per cent reduction of the 95 percent of aldosterone present in the form of othermetabolites could double the amount ofaldosterone which can be released 'by acidhydrolysis.The more recent application of radioisotopic

procedures for the indirect measurement of thesecretion rate of aldosterone (Laumas, Taitand Tait, 1961; Peterson 1959) has been agreat stimulus, but to infer that a change ofsecretion rate implies a corresponding changeof plasma level makes the assumption that therate of metabolic disposal is constant. Actually,if the rates of both secretion and metabolicdlearance are known, it is possible to arriveat an indirect measure of the plasma level ofaldosterone.With these remarks, it will be seen how the

whole question of the relationship between thelikely changes in plasma aldosterone concentra-tion which could influence renal tubular activity,and the changes in sodium excretion, is be-devilled by almost insurmountable problems ofmeasurement. It is, perhaps, all the moresurprising, that there is a considerable amountof good evidence which points to an inverserelationship between the rate of aldosteroneexcretion and the rate of sodium excretionboth in cedematous states and in the physiolo-gical response of the kidney to changes ofextracellular fluid volume (Leutscher andJohnson, 1954; Davis, Goodkind, Pechet andBahu, 1956; Duncan, Liddle and Bartter, 1956).But even if the rate of excretion of the acid-released metabolite does reflect the plasma level,to observe such a relationship does notnecessarily imply that the one causes the other.Even though adrenalectomised patients, main-tained on adequate steroid replacement therapy,cannot achieve sodium balance on a low sodiumdiet, this should not in any sense imply thatthe adrenal glands also mediate changes ofsodium excretion under normal circumstances.It may mean only that some adrenocorticalsteroid activity is necessary, and that thechanges of aldosterone level observed are notwithin the range of responsiveness of the renaltubules. Indeed, the idea that they are not soinvolved, but merely provide a sort of obli-gatory biochemlcal backcloth against whichother factors actually mediate physiological

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changes has been espoused under the term the"permissive" action of the steroids (Ingle, 1952).It is certainly difficult to demonstrate renaltubular effects when aldosterone is given tonormal dogs although it is easy to do so afteradrenalectomy (Barger, Berlin and Tulenko,1958).One approach to the problem is to follow the

relationship between the rate of renal sodiumexcretion and some index of the plasma levelof aldosterone as a function of time during thecourse of the renal response to sodium depriva-tion. This was done by Crabbe, Ross and Thorn(1958) who measured the rate of urinaryexcretion of acid-released aldosterone. Theywere unable to obtain a significant relation-ship between the urinary sodium output andthe urine output of this particular aldosteronemetabolite. In view of the foregoing remarksthis is not surprising, although they were able(Thorn, Ross, Crabbe and Van't Hoff, 1957)to show an inverse relationship between urinesodium excretion and acid-released aldoster-one excretion in random urines collected fromnormal people.

Another, theoretically more profit-able lineis to observe the effects of an antagonist ofaldosterone at the tubular level. One such,a 17-spirolactosteroid now marketed as spiro-nolactone, was synthesised by Kagawa, Cellaand Van Arman (1957) who were able toshow in rats that the compound, whose chemicalstructure was designed to resemble that ofaldosterone and so inhibit its action com-petitively, was biologically inert unless theadrenal glands were present. In dog and manthe pharmacological properties of spiro-nolactone in doses which are too low to haveany physiological or toxic effect are, convinc-ingly, only those of a mineralocorticoidantagonist at the renal tubular level (Liddle,1958; Slater, 1960). Ross and Winternitz (1961)have shown that, in a single subject takiingspironolactone, sodium deprivation modifies therenal response so that after five days on a ricediet containing only 3 mEq of sodium, equilibra-tion with intake had still not been reached;furthermore, the rate of fall of urinary sodiumexcretion (half-time 1.45 days) was significantlyslower than the rate of fall observed in normalsubjects (mean half-time 0.54 days SD 0.12days). However, Mills (1963) in a similar experi-ment was unable to find evidence that thediurnal fluctuations of urine sodium outputare even partly aldosterone-dependent.The role of aldosterone in mediating changes

of sodium excretion in short-term experiments

is even more dubious. Quite apart fromhaemodynamic factors, it is a puzzling andchallenging fact that there is a delay of upto one hour before the renal tubular effectsof injected steroid are apparent, even whenthe steroid is brought into intimate contactwith the effector organ. This was clearly shownby Barger, Berlin and Tulenko (1957), andconfirmed by Ganong and Mulrow (1958), whoinjected d-aldosterone directly into one renalartery; the characteristic effect on sodium andpotassium excretion was seen simultaneouslyin both kidneys some 30-60 minutes later. Thiswould appear to exclude aldosterone frommediating at least the early changes of sodiumexcretion in such manceuvres as motionlessstanding, hemorrhage and acute salt loading.Furthermore, Addisonian or adrenalectomisedpatients maintained on an adequate andconstant amount of replacement steroid canmanipulate their rate of sodium excretion inan apparently normal fashion, following bothquick changes of posture and sequestration ofblood in the legs (Rosenbaum, Papper andAshley, 1955; Epstein, 1956). We may reason-ably conclude, therefore, that hwemodynamicfactors are dominant in experiments wherechanges of sodium excretion are seen withinminutes or possibly hours, but that there issome evidence to suggest that alterations ofaldosterone levels are a major variable indetermining long-term adjustments to alteredsodium intake. The evidence is incomplete,indirect and hardly justifies any idea thataldosterone controls renal sodium excretion inthe way that the antidiuretic hormone controlsurine flow.

Aldosterone and Oedema FormationWhatever the final conclusion regarding the

role of aldosterone in mediating changes ofsalt excretion physiologically, a reasonable casecan be made, with certain assumiptions (v. infra),for its being a major factor in the pro-duction of cedema, at least that of liver andrenal disease. From a large literature, threemain pieces of evidence appear to predominate.Davis, Howell and Southworth (1953) haveshown that the excessive fluid retention whichcan be induced in dogs by constricting thethoracic inferior vena cava-an excellentstimulus to aldosterone production-could onlybe mimicked after adrenalectomy if desoxy-corticosterone acetate (DOCA) was given in20 to 50 times the amount needed for fullreplacement in otherwise untouched adrena-lectomised dogs.

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Similarly, Giroud and his colleagues (1961)have demonstrated that aminonucleosidenephrosis in rats is adrenal-dependent. Toreproduce the fluid retention seen in animalswith intact adrenal glands, ten times the amountof aldosterone necessary for replacement innormal animals was required.

Finalliy, in man, the effect of the 17-spiro-nolactosteroids when given to patients withcirrhosis of the liver or the nephrotic syndromecan be so dramatic that alil the visible cedema-fluid disappears. Usually, however, the effect isrelatively small. Since, from the doses used,competition with aldosterone for receptor siteson the renal tubule is far from being on amolecule-for-molecule basis, the fact thatspironolactone is usually a weak diurectic mayonly mean that the effect of aldosterone on therenal tubule is only partially inhibited in thequantities used. It is, perhaps, considerablymore significant that an cedematous patientcan be rendered "dry" by spironolactone alone.In cardiac failure the effect of aldosteroneantagonism is small (Bartter, Gann andThomas, 1960) unless cardiac cirrhosis of theliver has supervened (Slater, 1960) but then,haemodynamic factors predominating, hyper-aldosteronism is usually not a conspicuousfeature of cardiac failure in contrast to theintense hypersecretion of aldosterone in patientswith the nephrotic syndrome or cirrhosis of theliver.

But, if inappropriate overproduction ofaldosterone is really important in cedemaformation, prolonged administration of aldo-sterone or other mineralocorticoid steroidhormones such as desoxycorticosterone mightbe expected to lead to sodium retention andultimately the appearance of cedema. This doesnot happen (August, Nelson and Thorn, 1958).By some mechanism which may be hemodyn-amic or may involve a process of tubularantagonism, an "escape" from the effect ofmineralocorticoids on ion transport occurs. Thetiming of this "escape" will vary with the saltintake and the dose of steroid used, but innormal people and in animals it always occurs.It may have its pathological counterpart inthe syndrome of primary aldosteronism whencedema is strikingly absent and hypokalemiaprominent. This contrasts with the fluid reten-tion and normal serum potassium levels seenin the secondary hyperaldosteronism of cirrh-osis and nephrosis.

It is therefore clear that, for fluid retention totake place, there must be some other importantfactor operating apart from an increased

circulating level of aldosterone. Whatever itsnature, whether humoral or circulatory, itwould appear likely that its main effect is toincrease the rate of proximal tubullar sodiumreabsorption. If this is greatly enhanced itcan be reasonably argued that insufficientsodium is delivered either to the site of free-water formation or to the site of exchangebetween potassium and sodium further downthe nephron. Impaired free-water excretion isa characteristic feature of cedematous states(Ralli, Leslie, Stueck and Laken, 1951) andsodium depletion (McCance and Widdowson,1937). It is unlikely to be due to excess anti-diuretic hormone (Lamdin, Kleeman, Rubiniand Epstein, 1956; Schedl and Bartter, 1960).In contrast to normal people, the infusion ofmannitol into patients with cirrhosis of theliver or cardiac failure increases the free-waterclearance (Bell, Schedl and Bartter, 1964;Schedl and Bartter, 1960). Similarly, potassiumdepletion is conspicuous by its absence in thesecondary hyperraldosteronism of untreatedpatients with cirrhosis and nephrosis. Sincetubular potassium secretion largely occurs inexchange for sodium (Berliner, Kennedy andHilton, 1950), a reduced delivery of sodiumto the distal tubule will reduce the urinaryloss of potassium that would presumablyotherwise occur in response to high levels ofcirculating aldosterone.From the fact that 85 per cent of filtered

sodium is reabsorbed proximally, it is clearthat an influence which even slightly changedthe rate of this erstwhile "obligatory" sodiumreabsorption would have a profound influenceon the rate of renal sodium excretion. Sincethe fluid retention of cirrhosis of the liverappears to be largely aldosterone-dependent,and since proximal tubular sodium reabsorp-tion is enhanced in this condition, it can beargued that aldosterone must be acting onthe proximal tubule.

Non-Adrenal Factors Influencing TubularSodium Reabsorption

Others have sought to discover evidence fornon-adrenal factors ,affecting tubular reabsorp-tion. The posture and thigh-cuffing experimentsof Rosenbaum, Papper, and Ashley (1955) inadrenalectomised patients were continued forseveral hours; the rate of urine sodium excre-tion remained low despite a clearly rising rateof glomerular filtration. Since the quantity ofsteroid replacement was constant, the authorsfelt compelled to postulate the existence ofsome other non-adrenal factor which promotes




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tubular sodium reabsorption. But this inter-pretation cannot be accepted until we knowwhether the circulatory level of biologically-active steroid was, in fact, constant. Changesof posture are known to change the rate ofliver blood flow which may well be a criticalfactor in determining the steroid plasma level.

Ingenious cross-circulation experiments withcorrection for fluid displacements have beenperformed by de Wardener, Mills, Claphamand Hayter (1961) in an attempt to avoid thevexed question of whether saline infusionsincrease renal sodium excretion haemodyna-mically or by changes of tubular reabsorption.In 3 experiments, when supramaximal quan-tities of anti-diuretic hormone (with a mineral-ocorticoid to suppress aldosterone production)were given to both dogs, the saline-infusedanimal nevertheless excreted much more sodiumthan the other despite apparently equivalentchanges of filtered sodium load. It was thereforeconcluded that changes in the concentration ofan ephemeral hormone, other than aldosterone,was responsible.

The Control of Aldosterone SecretionWhatever the final conclusion about the pre-

cise role of aldosterone in the preservation ofsalt balance, its import cannot be denied,particularly in cedema formation. We have seenhow renal sodium excretion appears to belargely a function of the extracellular fluidvolume and that under most circumstancesthe rate of renal sodium excretion variesinversely with the rate of excretion of the acid-released urinary conjugate of aldosterone.Assuming this reflects the plasma level andassuming that the plasma level is largely afunction of the rate of secretion, it wouldappear reasonable to predict that changes ofextracellular fluid volume would be a majorfactor influencing the rate of aldosteronesecretion.Changes of extracellular fluid volumeThe excellent series of experiments by

Bartter and his colleagues in man (Bartter,Mills, Biglieri and Ddlea, 1959) clearly showedthat an expansion of the extracellular fluid(ECF), whether associated with an increase,no change, or a decrease in the volume ofintracellular fluid, reduced the rate of urinaryexcretion of the acid-released aldosteronemetabolite and increased renal sodium excre-tion. Conversely a contraction of ECF volume,whether associated with a decrease or anincrease in the volume of the intracellularfluid, increased the rate of aldosterone excre-

tion and reduced renal sodium excretion.Finally, it was shown, by infusing salt-pooralbumin, that expansion of the intravascularfluid alone would still produce a fall in therate of aldosterone excretion. Since there was anet decrease in the total ECF volume, this is amost convincing demonstration that it is intra-vascular and not interstitial cell volume thatmatters. If we assume that the excretion ofaldosterone, as the acid-released conjugate,mirrors its secretion, then changes of bloodvolume are at least one factor likely to havea profound influence on the latter. But howis the adrenal able to sense these changes?Changes of electrolyte composition of theextracellular fluidConcomitant alterations of the plasma con-

centration of sodium or potassium wereexplored particularly by the Australian workers(Blair-West, Coghlan, Denton, Goding, Munro,Peterson and Wintour, 1963; Coghlan, Denton,Goding and Wright, 1960). They transplantthe one remaining adrenal gland of a sheepinto its neck so that local changes incomposition of the blood supplying the gliandcan be made without disturbing the rest ofthe animal. The rate of steroid secretion canthen be measured directly, and in selectedanimals the transplant retains apparentlynormal responsiveness for years; it may evengrow medullary tissue. Local infusions ofglucose to lower the plasma sodium concentra-tion by clinically large amounts are associatedwith only a small increase in the rate ofaldosterone secretion. A relatively large in-crease in the potassium concentration, however,is a sharp stimulus to the secretion of aldo-sterone, especially when accompanied by adecrease of sodium concentration.

It is now clear that local changes of plasmapotassium concentration can also be animportant stimulus to aldosterone secretion inthe dog (Urquhart, Davis and Higgins, 1962)but, in man, very large changes of potassiumbalance only change the rate of aldosteroneexcretion to a relatively small extent whenappropriate compensation is made for the factthat potassium loss causes sodium retentionand vice versa. Profound hyponatrxmia follow-ing water loading in man is associated with alow rate of aldosterone excretion, even whensufficient potassium is given to reduce sharplythe plasma sodium-to-potassium ratio (Bartter,Liddle, Duncan, Barber and Delea, 1956),which again emphasises the physiologicalinsignificance of changes of plasma sodiumand potassium concentration in man.




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Arterial receptor areasIf, then, it is the volume of the blood rather

than its composition which is the majorvariable in regulating aldosterone secretion,what function of it provides the afferentstimulus? Under- or over-filling of the venousside is probably not important because a re-duced amount of blood in the central veins(as in constriction of the thoracic inferior venacava) and also distension of the central veins(as in oardiac failure) are both associated withhyperaldosteronism. With each, however, thereis a tendency for inadequate filling of the sys-temic arterial tree which, it has been suggested,is a major influence on the rate of renal sodiumexcretion (Epstein, Post and McDowell, 1953).Therefore, localised receptor areas have beenlooked for in the arterial system. Already itappears that constriction of at least two majorarteries, the carotid and the renal (v.infra), will stimulate aldosterone production.Constriction of the carotid arteries was dis-covered by Bartter, Mills and Gann (1960) to bea strong stimulus to the secretion of aldosteronein normal dogs stressed by surgery. This wasconfirmed by Carpenter, Davis and Ayers (1961a and b) but, in their hands, the stimulus wasa very weak one. Both this effect and theintense aldosterone-stimulating effect of acuteconstriction of the inferior vena cava in normaldogs stressed by surgery was found by Bartterand his colleagues to be prevented by priorremoval of all visible nerves from the thyro-carotid arterial junction, but not by denervationof the carotid sinus. The significance of theseexciting results was questioned when Carpen-ter and his colleagues showed that hyperaldo-steronism persisted in dogs with chronicconstriction of the thoracic inferior vena cavadespite extensive stripping of all visible nervoustissue from the central arterial tree. Moreover,hypophysectomy greatly weakens the aldo-sterone-stimulating effect of acute, but notchronic, constriction of the inferior vena cava,and Biglieri and Ganong (1961) showed thatafter hypophysectomy, carotid artery compres-sion failed to increase aldosterone secretion,although it would do so in normal animals. Itcould be argued that some ACIH is necessary"synergistically" and it certainly seems unlikelythat all the acute effects descriibed by Bartter,Mills and Gann (1960) can be explained on thebasis of changes of ACTH production, but sincethese are extremely difficult experiments with ahigh biological and chemical variability,adequate interpretation must await further data.Certainly the more recent discovery that

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FIG. 1.-The effect of constriction of both renalarteries on the production of aldosterone, corti-costerone and cortisol in 5 dogs hypophysectom-ised 6 to 14 days previously, plotted as adifference from the mean of the control data(Slater, Barbour, Henderson, Casper and Bartter,1964). Each point is the secretion rate over a 20to 30 minute period. Blood collections were started35, 70 and 95 minutes after constriction wasapplied. The constriction was then released and2 final samples collected 60 to 75 minutes later.

(By permission of SURGERY, GYNECOLOGY &OBSTETRICS).

constriction of the renal arteries (Fig. 1) andhence the renin-angiotensin system (v. infra)will stimulate the adrenal cortex in hypo-physectomised dogs has temporarily eclipsedfurther work on other areas of the arterialtree.On the efferent side, the regulation of aldo-

sterone secretion has been shown to behormonally, or at least humorally, mediatedboth in the sheep (Denton, Goding and Wright,1959) and dog (Yankopoulos, Davis, Klimanand Peterson, 1959). This situation is also com-

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CORTI SOL CORTICOSTERONE ALDOSTERONE

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10 -

FIG. 2.-The rate of adrenocorticosteroid productionbefore and 18 hours after hypophysectomy in 6conscious dogs deprived of dietary sodium.Secretion rates have been calculated withallowance for the uptake of aldosterone byerythrocytes (Slater and others, 1964). Dataplotted on a log-scale to emphasise proportionalchanges.

(By permission of THE JOURNAL OF CLINICALINVESTIGATION).

plex but has been partially clarified by therecent discovery of the direct steroid-stimulatingeffects of angiotensin. Before considering this,two other potentially relevant hormonalmechanisms should be mentioned.The role of the pituitaryBy analogy with the ACTH-cortisol system

the role of the pituitary gland has beenextensively studied. Large doses of ACTH willcertainly increase aldosterone excretion but theeffect is short-lived in man even when sodiumretention is prevented. Furthermore, suppressionof the pituitary with cortisone does not reducethe rate of aldosterone excretion (Liddle,Duncan and Bartter, 1956). The pattern ofadrenocortical stimulation with decreasingdoses of ACTH in dogs shows quite clearlythere is no dose of ACTH which stimulatesaldosterone production without also stimulatingthe production of cortisol (Slater, Barbour,Henderson and Casper, 1963). A patient with-out his adrenal glands dies of sodium deficiencyif deprived of salt, whereas a patient withouthis pituitary gland conserves salt normally(MacLean, Lipsett, Li, West and Pearson, 1957)and dies eventually of cortisol deficiency with-out gross electrolyte imbalance. After hypo-physectomy the zona glomerulosa of theadrenal gland, where aldosterone is produced,does not atrophy, whereas the zona fasciculata,where cortisol is produced, does. Even from theevidence available in 1940, Swann was able topostulate the existence of a separate non-pituitary mechanism for the control ofmineralocorticoid activity of the adrenal

glands. Nevertheless, more recent workconcerning the acute effects of hypophysectomyin dogs appeared to implicate the pituitary(Davis, Bahn, Yankopoulos, Kliman andPeterson, 1959; Slater, 1963). Most of this workwas done in heavily anwsthetised dogs acutelystressed by surgery. To avoid this the effect ofhypophysectomy by estimating the adrenocorti-costeroid secretion rates has been assessedbefore and some 18 hours after surgery, whenthe animal was calm and conscious (Fig. 2). Aswas expected, aldosterone secretion does notchange despite sharp falls in the rate of cortisoland corticosterone secretion.Role of the pineal

Since, therefore, the pituitary can be excludedas a major factor, Farrel produced thephylogenetically fascinating idea that the func-tion of the pineal gland was concerned withthe control of aldosterone secretion (Farrell,1958). He found that extracts of beef dience-phalon stimulated the secretion of aldosteronein decerebrate dogs and that a large part ofthis activity could be accounted for by thatpresent in the pineal gland (Farrell, 1959). Butpinealectomy does not reduce aldosteronesecretion and the usual increase in aldosteronesecretion following salt-deprivation is seen inpinealectomised dogs (Farrell, 1960). Unfortun-ately, experimentail confirmation of the adreno-glomerulotrophic effects of pineal extracts andcompounds therefrom is still awaited so thatat the present time it is virtually impossibleto assess the importance of the pinesal-hypothal-amic system. Nevertheless, it seems highly likelythat the central nervous system is somehowinvolved, possibly in mediating fine adjustmentsof aldosterone production, but it is clear fromthe work of Davis and his colleagues thathyperaldosteronism in dogs can persist and beproduced despite chronic extensive hypo-thalamic lesions or even decapitation.The role of the kidneysThe finding of Deane and Masson (1957)

that, in the rat, renal extracts produce adrenalhyperplasia, the discovery by Biron, Kiow,Nowacynski, Brouillet and Genest (1961) thatthe adrenaI glands are stimulated by angiotensinII in man and Bartter's description of hyper-plasia of the juxtaglomerular complex in apatient with hyper-aldosteronism due to bilateraladrenal hyperplasia (1962), all suggested thatthe kidneys may be important in the control ofaldosterone via the renin-angiotensin system.Three separate groups in the United Statesstudied this simultaneously and independently

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HYPOPHYSECTOMIZED, NEPHRECTOMIZED DOGS

RENAL EXTRACT FROM HYPOX. DOS RENAL EXTRACT FROM NORMAL DOSDEPRIVED OF SALT TREATED WITH DOCA S EXTRA SALT

7/27/SI S/S/S IW//////X E~///////M

CORTISOL | CORTISOLI

mjUg/min

l l500

250 A- ~ ~

MEAN S. P.m Ho 5? S 35J 35IJ12 123120 51 511 30 J3 2 54 S1

ALDOSTERONE ALDOSTERONE

20-

0 20 40 100 120 0 20 40 120 140MIN. MIN.

FIG. 3.-Adrenocortical response in dogs withoutpituitary or kidneys, to saline extracts of kidneysfrom (a) a hypophysectomised dog deprived ofsalt and (b) a normal dog loaded with salt.

in recently hypophysectomised dogs (Davis,Carpenter, Ayers, Holman and Bahn 1961;Ganong and Mulrow, 1962; Slater, Barbour,Henderson, Casper and Bartter, 1963, 1964).Each group found that nephrectomy uniformlyreduced, if it did not abolish, the adrenocorticalresponse to acute haemorrhage, although thegland was still easily stimulated by ACTH.They each also showed that saline extracts ofthe kidney would stimulate the adrenal cortex.That this effect is not due to renal sequestrationof ACTH but, rather, is related to the saltbalance of the animal whose kidney is used,is indicated in Fig. 3. The effect of nephrectomyis, however, not so clear-cut. Performed as anacute experiment in recently traumatised,sodium-depleted, and hypophysectomisedanimals under heavy anesthesia, nephrectomysharply reduced the rate of aldosterone secre-tion to basal levels. There was, however, arelatively slight fall in aldosterone secretionseen in conscious or lightly anasthetisedhypophysectomised animals where one remain-ing kidney was removed with minimal trauma

some 18 hours after major surgery (Slater,1963). Similarly, Blair-West and his colleagues(1963) found that the rate of aldosteronesecretion often remained well above basal insodium-depleted sheep despite hypophysectomyand bilateral nephrectomy. More data on thisimportant question is needed, but it is alreadyclear that the kidneys do not produce a trophicsubstance affecting aldosterone secretion similarin importance, for example, to ACTH in thecontrol of cortisol secretion. Nevertheless, therecent finding of extractable renin in the bloodvessels (Gould, Skeggs and Kahn, 1964) may,if the amounts are sufficient, prove to be theexplanation.

The Renin-Angiotensin SystemAs long ago as 1898 Tigerstedt and Bergman

discovered that extracts of the kidney wouldraise the blood pressure. Following Gold-blatt's demonstration in 1934 (Goldblatt, Lynch,Hanzal, and Summerville) that renal ischaemiaproduces hypertension, interest in themechanism of this hypertensive effect of renal




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Liver

ANGIOTENSIN I

1 2 3 4 5 6 7 8 t 9 10Asp- Arg - Val - Tyr - Val - His - Pro - Phe - His - Leu

ANGIOTENSIN 11

RENIN

\ JUXTAGAPP.

ANGIOTENSIN I

(INERT )circslatingconverting er

ANGIOTENSIN II

(ACTIVE )

;LOMERULARARATUS

nzyme

FIG. 4.-The renin-angiotensin system.

extracts was stimulated, chiefly with regard tothe cause of hypertension. From the pioneerwork of Page, Pickering, Braun-Menendez andtheir collaborators (Page and Bumpus, 1961),it has now become clear that renal tissuecontains a proteolytic enzyme, renin, whichsplits specifically a leucyl-leucine bond ina circulating cx-globulin of hepatic origin(renin sulbstrate or angiotensinogen) to producea largely inert decapeptide, angiotensin I.A circu'lating enzyme then splits off twoaminoacids to produce angiotensin II, anoctapeptide which is the most potent pressorsubstance known. Angiotensin is destroyed ina short time by potent enzymic systems,collectively known as "angiotensinase", whichare present in all tissues and circulatingblood. It is now almost certain that the reninliberated from the kidney originates in thegranular cells of the juxtaglomerular apparatus(Cook land Pickering, 1958; Bing and Kazi-mierczak, 1962; Hartroft, Sutherland andHartroft, 1964) and possibly even in thegranules themselves (Skelton, Chandra andBernardis, 1964). First described by Ruyter(1925), these cells were studied by Goor-maghtigh (1945) as an example of the endocrinefunction of the renal arterioles. The granularor afibrillar cells are found in the media ofthe afferent arteriole, near the glomerular tuft.They alwlays lie in contact with a group ofspecialised cells, the macula densa, in the

ADRENAL EFFECTS OF ANGIOTENSIN IN A DOGWITH NO PITUITARY OR KIDNEYS

ANGIOTENSIN Ir ANGIOTENSIN 31

20 |0.025 pg/min | | 0.5pg/min |

ADRENAL PLASMA 2.0FLOW IDiIIrrml/min innBLOOD PRESSURE

mmHg 500 IL--LL 2/1000 l

CORTISOL|l ll l

500 IImrig/min A I

0

CORTICOSTERONE 5001 I l ll

mpg/mino

ALDOSTERONE mpA1 .E..nI

-31 6 30 IOO RD 200 2i0 270minutes

FIG. 5.-Pattern of adrenocortical response to angio-tensin II in a hypophysectomised, nephrectomiseddog.

(By permission of THE JOURNAL OF CLINICALINVESTIGATION).

distal convoluted tubule of the same nephron.Teleologically this arrangement is dangerouslyseductive-what better anatomical basis forsensing the filling of the arterial tree? Fig. 4shows the overall picture of the system todaythough, if this is anything like the broadlyanalagous kinin-forming system, it will soonrequire considerable modification.The importance of angiotensin in the control

of sodium metabolism has become evident inthe past few years. Indeed, it appears possiblethat the real physiological role of angio-tensin is on renal salt excretion rather than onthe control of blood pressure.

Angiotensin (or rather the synthetic asparticp-amide) is a confusingly versatile molecule.Apart from being a senior member of thegrowing band of polypeptides which affectsmooth muscle (so that it may influence sodiumexcretion hemodynamically) it stimulates theproduction of adrenocortical steroids, liberatescatecholamines from the adrenal medulla(Feldberg and Lewis, 1963) and inhibits distaltubular reabsorption of sodium (Vander, 1963).To make the all-important separation of phar-macological from likely physiological effects isextremely difficult since we know so little aboutthe circulating concentration of angiotensin. Inany case, the local concentration at the site of




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renin liberation in the juxtaglomerular com-plex may be quite different, and yet it is justhere that angiotensin is in a strong position toinfluence the rate of both glomerular filtrationand distal tubular sodium reabsorption. Thereare at least two obvious ways already knownby -which the renin-angiotensin system caninfluence renal sodium excretion. It can operatedirectly on the kidney or indirectly via thestimulation of production of aldosterone. Thereal question is whether angiotensin does, in,fact, and if so, under what circumstances.

The role of the renin-angiotensin system in thecontrol of aldosterone secretionThe first problem concerns the dose-response

relationship between angiotensin action andadrenocortical response. The critical criterionfor the designation of angiotensin, or any otherpotential candidate, as an aldosterone-stimulating hormone, is that it should affectthe secretion of aldosterone almost exclusively.However, in the hypophysectomised, nephrec-tomised dog (Carpenter, Davis and Ayers, 1961;Mulrow, Ganong, Cera and Kuljian, 1962;Slater, Barbour, Henderson, Casper and Bartter,1963) corticosterone secretion is stimulatedto a comparable degree whatever the doseof angiotensin given, whereas Davis findsthat constriction of the inferior vena cavabarely alters corticosterone secretion in theconscious, minimally stressed dog (Davis,Carpenter, Ayers and Bahn, 1960). Slater andcolleagues (1963) found, in addition, that when-ever aldosterone secretion is clearly stimulated,so also is that of cortisol (illustrated in Fig. 4).But the rate of corticosterone and cortisolsecretion reached is relatively modest com-pared with the effect of ACTH, which hasquite a different pattern of adrenocorticalstimulation (Slater and others, 1963; Mulrowand others, 1962). In the intact dog, therate of equilibration of the ACTH-cortisol (andcorticosterone) feed-back system may be suf-ficiently rapid to obscure changes of cortisoland corticosterone secretion in response toangiotensin. However, small amounts of angio-tension II infused locally into the transplantedadrenal gland in the neck of a sheep, (Blair-West and others, 1962) usually do not increasethe secretion of cortisol or corticosterone.Therefore, providing the responsiveness of theseadrenal transplants can be validated, eitherthere is a species difference or intravenousangiotensin injections promote cortisol secre-tion indirectly. With man, hypertensive quanti-ties of angiotensin II do stimulate the urinary

excretion of cortisol metabolites but thisappears trivial compared with the considerableincrease of excretion of aldosterone metabolites(Biron and others, 1961). In smaller, non-hypertensive, quantities an exclusive increaseof aldosterone excretion, as the acid-releasedmetabolite, is seen despite suppression of ACIHproduction with dexamethasone (Fig. 6). It istherefore possible that the pattern of adreno-cortical response to angiotensin is compatiblewith that caused by salt-deprivation and otherstimuli, though intense hyperaldosteronism isseen in many oedematous patients without anyapparent change of the rate of cortisol secre-tion, which implies the existence of some othervariable. This may be the pattern of responsive-ness of the adrenal zona glomerulosa. TheMelbourne group have shown that in the salt-depleted sheep small doses of ACIH givenlocally stimulate the secretion of much morealdosterone in relation to cortisol than in thesalt-repleted sheep (Blair-West, Coghlan,Denton, Goding, Wintour and Wright, 1963).There is now little doubt that in secondary

hyperaldosteronism, whether experimental orclinical, there is a considerable elevation ofcirculating renin-like activity (Brown and others,1964; Fasciolo and others, 1964; Davis, Higgins,and Urquhart, 1964) which is often beyondthe possible range of the likely error of themethod. It has been known for some time thatthe amount of renin which can be extractedfrom rat kidneys (Gross and Lichtlen, 1958)is both reduced by salt-loading and mineralo-corticoid administration and increased by saltdeprivation or adrenalectomy. The granularityof the juxtaglomerul-ar cells (Pitcock, Hartroftand Newmark, 1959; Tobian, 1960) variessimilarly. If the renin-store diminshes as therate of renin discharge diminshes (a somewhatsurprising feature which, on indirect evidence,nevertheless appears to be true), then it impliesthat the rate of renin discharge varies inverselywith the volume of the extracellular fluid andhence directly with the rate of aldosteronesecretion.

It is still uncertain whether the circulatingrenin concentration rather than the concentra-tion of renin substrate is the rate-limitingfactor for the production of angiotensin physio-logically, but, in dogs, sodium depletion, whichBrown and his colleagues find increases thecirculating renin concentration, does appearto elevate circulating angiotensin levels(Bartter, 1963; Scornik and Paladini, 1964).It must be said, however, that the whole ques-tion of the accurate and reliable assay of




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POSTGRADUATE MEDICAL JOURNAL August, 1964

ANGIOTENSIN INFUSION IN HEALTHY PEOPLE

0. 25 ,uqm. per minute

/962

FIG. 6.-Adrenal and metabolic effects of a 58-hourinfusion of small amounts of angiotensin II in7 healthy people, 2 of which (the lower 2 pointsunder "urine 17-OHCS") were given dexametha-sone.

renin and angiotensin in biological fluids onan analytical rather than preparative scale,is still overshadowed by methodological diffi-culties, although Boucher, Veyrat, le Cham-lain and Genest (1964) have considerablysimplified a very difficult method. That we arestill on the threshold of our understanding ofthe role of the renin-angiotensin system in thecontrol of aldosterone secretion is suggestedby some recent findings. Van Brunt, Biglieriand Ganong (1964) find in renin-immuniseddogs that the rate of aldosterone secretion isnormal and that it increases with salt-depriva-

200

60

160

mm Hg 140

120

00

so

so

60

ml/min 40

20

ml/min2

0

600

500gEqATh

400

300

200

00

0

600

400

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09 NoACUTE RENAL EFFECTS OF ANGIOTENSIN

INULIN CLEARANCE

URINE FLOW

_ URINE OSMOLARITY

0 20 40 60 60 0O 120 140 160 10MINUTES JULYvI

FIG. 7.-Acute renal effects of angiotensin II in apatient with Addison's disease.

tion although the animals are unresponsive tothe pressor action of injected renin. This mayonly mean that there is still enough circulatingangiotensin to mediate changes of aldosteronesecretion, but it also may imply that othermechanisms for aldosterone control are domi-nant in the normal, conscious dog. Anotherapparently incompatible finding is that of

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METABOLIC EFFECTS OF ANGIOTENSIN

ADDISON'S DISEASE

E 37. 5 mgm. / day

5 HEALTHY PEOPLE

NIL

1.0

0.53

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I I

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I I

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2 4 6 8 10

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II

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FIG. 8.-Comparison of the long-term metaboliceffects of small quantities of angiotensin II in5 normal people and a patient with well-controlled Addison's disease.

Marieb and Mulrow (1964) who cannot stimu-late aldosterone or corticosterone secretionfrom the rat adrenal gland with pressor quanti-ties of angiotensin II. Yet, in the rat, whichsecretes increased amounts of aldosterone afterhemorrhage (Singer and Stack-Dunne, 1955),there is a positive correlation between thewidth of the zona glomerulosa and (a) theadministration of renin (Deane and Masson,1951), (b) granul,arity of the juxtaglomerularcells (Tobian, 1960), and (c) the extractablerenin content of the kidneys (Gross,Schaechtelin, Brunner and Peters, 1964). There

is also, of course, a negative correlation betweenthe width of the zona glomerulosa and the saltintake (Deane, Shaw and Greep, 1948).

If increased quantities of angiotensin circu-late in the blood of patients with secondaryhyperaldosteronism, one might expect hyper-tension to occur. But the blood pressure isusually normal in cedematous states whetherclinical or experimental. In man it is possiblethat subpressor quantities of angiotensin stimu-late aldosterone production (v. infra) but, inany case, cedematous states are associated witha remarkable resistance to the pressor effects

ANGIOTENSIIpgm. / minut

+1.

BODY WEIGF,&Kg

-1.

20(

URINE NanEq. /day

100

II

IIIII

I

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I I I -L.-JI

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492 POSTGRADUATE MEDICAL JOURNAL August, 1964

of angiotensin and noradrenaline (Johnstonand Jose, 1963; Laragh, Cannon, Bentzel,Sicinsky and Meltzer, 1963). Whether this isinherent or merely a result of diuretic therapyis controversial. Hypertensive patients treatedwith chlorothiazide are relatively resistant tothe pressor effects of noradrenaline (Freis,Wanko, Schnaper and Frohlich, 1960), and thisappears to be a direct effect of the drug onperipheral resistance vessels (Jackson andDuff, 1963).Whatever the final outcome, we now know

that aldosterone secretion will increase when-ever the circulating 'angiotensin concentrationincreases; whether the former is actually con-trolled by the latter under normal circum-stances must await further study. However, theidea that the renin-angiotensin system controlsaldosterone secretion is particularly attractivebecause it provides, at least potentially, bothaffector and effector mechanisms.

More direct effects of angiotensin on sodiumexcretionEven in amounts which have little or no

effect on the blood pressure, angiotensin pro-duces ran immediate sharp fall in the rate ofsodium excretion when infused into normalpeople (Bock, Dengler, Krecke and Reichel1958; Gill, Barbour, Slater and Bartter, 1964)which does not depend on the presence of theadrenal glands (Statius Van Eps, Smoren-Berg-Schoorl, Zurcher-Mulder, de Vries andBorst, 1962). This is illustrated in F,ig. 7.However, over la longer period of time theindirect effect of angiotensin on aldosteronemay outweigh the "direct" effects of angiotensinon the kidney. Fig. 6 shows the adrenal andmetabolic effects of sub-pressor amounts ofangiotensin II infused into normal people.Despite an average weight gain of just over1 kg. the rate of aldosterone excretion increasedwhen it would otherwise have been expectedto decrease. In the one patient with Addison'sdisease treated with cortisone who was insodium balance, a 4-day angiotensin infusionhad no metabolic effect, although pressorquantities were used (Fig. 8). This serves toemphasise that in small sub-pressor quantitiessuch as are likely to be found physiologically,the effect of angiotensin on sodium excretionis likely to be largely mediated by its effecton aldosterone production.

In hypertensive patients, angiotensin infusionsoften produce an immediate increase ratherthan a decrease in the rate of sodium excretion(Brown and Peart, 1962). This reversal of thenormal response also occurs in patients receiv-ing salt and large quantities of mineralocorti-coid rand we have observed it over a longerperiod in a normotensive Addisonian patientovertreated with desoxycorticosterone. In short-term experiments it is impossible to disprovethe hypothesis that, under these conditions,angiotensin constricts the efferent arteriole toa relatively greater extent than the afferentarteriole. For example, Brown and Peart reportthat the GFR increases rather than decreasesin patients with hypertension. In cirrhosis ofthe liver, however, Laragh and others (1963)had shown that such a massive outpouringof salt can occur in response to large quanti-ties of angiotensin, despite minimal changesof GFR, that a tubular effect seems probable;and it appears from the stop-flow experimentsof Vander (1963) that angiotensin in normaldogs inhibits distal tubular sodium reabsorp-tion directly. This may also occur in the rat(Peters, 1963; Gross and others, 1964).These are some f-acts which will need to be

considered in formulating a hypothesis for themechanism of action of angiotensin but in viewof the already numerous biological effects of thepolypeptide, it is perhaps invidious to attemptone until we know more about which effectsare likely to be relevant physiologically.

ConclusionThis is a necessarily incomplete account of

the present state of our knowledge about thehormonal mechanisms controlling body sodium.An attempt has been made to stress principlesand to keep an exceedingly complex fielduncluttered with unresolved detail except whenthe problems themselves are likely to be stimu-lating rather than confusing. One importantfield, for example, which has not been discussed(largely because methodological problems stillabound) is the study of the precise factorswhich control renin release from the kidneys.Nevertheless, the discovery of the likely import-ance of the renin-angiotensin system in thecontrol of body sodium is perhaps one of themost exciting new developments in the realmof fluid balance since Verney's discovery ofthe physiological role of anti-diuretic hormone.

REFERENCESAUGUST, J. T., NELSON, D. H., and THoRN, G. W. (1958): Response of Normal Subjects to Large Amountsof Aldostorone, J. clin, Invest., 37, 1549,

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August, 1964 SLATER: The Hormonal Control of Body Sodium 493

BARGER, A. C., BERLIN, R. D., and TULENKO, J. F. (1958): Infusioai of Aldosterone, 9oc-Fluorohydro-cortisone and Antidiuretic Hormone into the Renal Artery of Normal and Adrenalectomised,Unanrsthetised Dogs: Effect on Electrolyte and Water Excretion, Endocrinology, 62, 804.

BARTrER, F. C. In discussion of BLAIR-WEST et al. (1963): Recent Progr. Hormone Res., 19, 370.BARTrER, F. C., GANN, D. S., and THOMAS, J. P. (1960): On the Mechanism of Sodium Retention in

Cardiac and Hepatic Disease. In 'The Human Adrenal Cortex'. Proc. Conf. Univ. Glasgow, 11thto 14th July, 1960. London: E. & S. Livingstone.

BARTrER, F. C., LIDDLE, G. W., DuNCAN, L. E., Jr., BARBER, J. K., and DELEA, C. (1956): The Regulationof Aldosterone Secretion in Man: The Role of Fluid Volume, J. clin. Invest., 35, 1306.

BARTrER, F. C., MILLS, I. H., BIGLIERI, E. G., and DELEA, C. (1959): Studies on the Control and Physio-logic Action of Aldosterone, Recent Progr. Hormone Res., 15, 311.

BARTTER, F. C., MILLS, I. H., and GANN', D. S. (1960): Increase in Aldosterone Secretion by CarotidArtery Constriction in the Dog and its Prevention by Thyrocarotid Arterial Junction Denervation, J. clin.Invest., 39, 1330.

BARTrER, F. C., PRONOVE, P., GILL, J. R., Jr., MACCARDLE, R. C. (1962): Hyperplasia of the Juxtaglomer-ular Complax with Hyperaldosteronism and Hypokalemic Alkalosis, Amer. J. Med., 33, 811.

BELL, N. H., SCHEDL, H. P., and BARTrER, F. C. '(1964): An Explanation for Abnorimal Water Retentionand Hyponatremia in Congestive Heart Failure, ibid, 36, 351.

BERLINER, R. W., KENNEDY, T. J., Jr., and HILTON, J. G. '(1950): Renal Mechanisms for Excretion ofPotassium, Anmer. J. Physiol., 162, 348.

BERNARD, C. See 'Claude Bernard and his Physiological Works' (1878) ART XVII for full references to hisreflections on physiological subjects, Amer. J. med. Sci., 76, 161.

BIGLIERI, E. G., and GANONG, W. F. (1961): Effect of Hypophysectomy on Adrenocortical Response toBilateral Carotid Constriction, Proc., Soc., exp. Biol., (N.Y.), 106, 806.

BING, J., and KAZIMIERCZAK, J. (1962): Renin Content of Different Parts of the Juxtaglomerular Apparatus,Acta path. microbiol. Scand., 54, 80.

BIRON, P., KIow, E., NOWACYNSKI, W., BROUILLET, J., and GENEST. J. (1961): The Effects of IntravenousInfusions of Valine-5-angiotensin II and other Pressor Agents on Urinary Electrolytes and Cortico-steroids including Aldosterone, J. clin. Invest., 40, 338.

BLACK, D. A. K., PLATT, R., and STANBURY, S. W. (1950): Regulation of Sodium Excretion in Normaland Salt-deplated Subjects, Clin. Sci., 9, 205.

BLAIR-WEST, J. R., COGHLAN, J. P., DENTON, D. A., GODING, J. R., MUNRO, J. A., PETERSON, R. E., andWINTOUR, M. (1962): Humoral Stimulation of Adrenal Cortical Secretion, J. clin. Invest., 41, 1606.

BLAIR-WEST, J. R., COGHLAN, J. P., DENTON, D. A., GODING, J. R., WINTOUR, M., and WRIGHT, R. D.(1963): The Control of Aldosterone Secretion, Recent. Progr. Hormone Res., 19, 311.

BOCK, K. D., DENGLER, H., KRECKE, H. J., and REICHEL, G. (1958): Untersuchungen uber die Wirkungvon Synthetischem Hypertensin II auf Elektrolythaushalt, Nierenfucktich und Kreislauf beim Menschen,Klin. Wschr., 36, 808.

BOUCHER, R., VEYRAT, R., DE CHAMPLAIN, J., and GENEST, J. i(1964): New Procedures for Measurementof Human Plasma Angiotensin and Renin Activity Levels, Canad. med. Ass. J., 90, 194.

BROWN, J. J., DAVIES, D. L., LEVER, A. F., and ROBERTSON, J. I. S. (1964): Variations in Plasma ReninConcentration in Several Physiological States, ibid, 90, 201.

BROWN, J. J., and PEART, W. S. (1962): The Effect of Angiotensin on Urine Flow and Electrolyte Excretionin Hypertensive Patients, Clin. Sci., 22, 1.

CARPENTER, C. C. J., DAVIS, J. O., and AYERS, C. R. (1961): Concerning the Role of Arterial Baroreceptorsin the Control of Aldosterone Secretion, J. clin. Invest., 40, 1160.

CARPENTER, C. C. J., DAVIS, J. O., and AYERS, C. R. (1961): Relation of Renin, Angiotensin II, and Experi-mental Renal Hypertension to Aldosterone Secretion, J. clin. Invest., 40, 2026.

CHALMERS, T. M., LEWIS, A. A. G., and PAWAN, G. L. S. (1952): The Effect of Acute Reduction of theGlomerular Filtration Rate on Sodium Excretion in Man, J. Physiol., 117, 218.

COGHLAN, J. P., DENTON, D. A., GODING, J. R., WRIGHT, R. D. (1960): The Control of AldosteroneSecretion, Postgrad. med. J., 36, 76.COOK, W. F., and PICKERING, G. W. (1959): The Location of Renin within the Kidney, J. Physiol., 149,

526.CRABBE, J., Ross, E. J., and THORN, G. W. (1958): The Significance of the Secretion of Aldosterone

during Dietary Sodium Deprivation in Normal Subjects, J. clin. Endocr., 18, 1159.DAVIS, J. 0. (1960): Mechanisms of Salt and Water Retentio_ in Congestive Heart Failure, Amer. J. Med.,

24, 486.DAVIS, J. O., BAHN, R. C., YANKOPOULOS, N. A., KLIMAN, B., and PETERSON, R. E. (1959): Acute Effects

of Hypophysectomy and Diencephalic Lesions on Aldosterone Secretion, Amer. J. Physiol., 197, 380.DAVIS, J. O., CARPENTER, C. C. J., AYERS, C. R., and BAHN, R. C. (1960): Relation of Anterior pituitary

Function to Aldosterone and Corticosterone Secretion in Conscious Dogs, Amer. J. Physiol., 199, 212.DAVIS, J. O., CARPENTER, C. C. J., AYERS, C. R., HOLMAN, J. E., and BAHN, R. C. (1961): Evidence

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Documents

THE HORMONAL CONTROL OF BODY SODIUM · change of GFR does not appear to disrupt sodium homeostasis (Surtshin, Rolf and White, 1951). There-fore, tubular reabsorption must also change,