Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from

POSTGRAD. MED. J. (1966), 42, 153 RENIN AND ANGIOTENSIN A survey of some aspects J. J. BROWN, B.Sc,. M.B., B.S., M.R.C.P. D. L. DAVIES, M.B., B.S. A. F. LEVER, 'B.Sc., M.B., B.S., M.R.C.P. J. I. S. ROBERTSON, 'B.Sc., M.B., B.S., M.R.C.P. St. Mary's Hospital, London, W.2. THE APPEARANCE of an article on renin and Wiberg, 1958; Cook & Pickering, 1959; Cook, angiotensin in a symposium devoted to hyper- 1960), although at present it remains undecided tension may suggest that these substances have whether the macula densa (Bing & Wiberg, a function in hypertension which is set apart 1958) or the granular cells of the afferent arteri- from their role in normal physiology. Any such ole (Hartroft, Sutherland & Hartroft, 1964) are impression would be misleading. Renin, angio- the major storage site (see reviews by Bing, tensin, aldosterone, sodium balance, and renal 1963; Cook, 1963). function remain closely inter-related irrespective Although the presence of renin in blood was of the height of the arterial pressure. We have, long disputed, it is now known that small therefore, attempted a wider survey in the hope quantities circulate in peripheral venous and that this may, in the process, clarify some arterial plasma (Lever, Robertson & Tree, 1963; aspects of hypertension. Lever & Robertson, 1964; Brown, Davies, This review is unbalanced in at least two Lever, Robertson & Tree, 1964 k,l). respects. Firstly, while the extent of the regions In blood samples taken simultaneously from which remain unexplored can only be surmised, a peripheral vein and from a renal vein, renin by copyright. it seems likely that a disproportionately detailed concentraltion was systematically higher in renal knowledge of the adrenocortical relationship of venous plasma. When peripheral venous renin renin and angiotensin has'been acquired as com- concentration was normal, the mean ratio of the pared with their possible intrarenal function. renal venous to peripheral venous concentration Secondly, we have deliberately considered in was 1.25 (33 pairs of observations in 17 most detail those aspects with which we have patients). 'In conditions in which the peripheral personal acquaintance. We have, however, renin ilevel was abnormally high, the difference attempted to give a guide to the very extensive between the renal venous and peripheral venous literature of the subject. Finally, while indulging plasma concentrations was usually considerably http://pmj.bmj.com/ in several speculations, we have tried to indicate greater (Brown, Davies, Lever & Robertson these clearly, since we do not intend them to unpuiblished observations). live longer than the facts permit. In similar studies in the dog, a higher renin Renin is an enzyme present in kidney extracts concentration was usually 'found in renal venous (Tigerstedt & Bergman, 1898; Pickering & than in renal arterial plasma (Skinner, Brown, Prinzmetal, 1938; Haas & Gold'blatt, 1963; Davies, Lever & Robertson, unpublished). Kemp & Rubin, 1962; Peart, Lloyd, Payne, 'Renin-like enzymes have also been demon- Stone, Thatcher & Lever, 1965), which acts on strated in renal lymph (Lever & Peart, 1962) on September 30, 2021 by guest. Protected a plasma substrate '(Braun-Menendez, 1956; and in urine (Brown, Davies, Lever, Lloyd, Skeggs, Lentz, 'Hochstrasser & Kahn, 1963; Robertson & Tree, 1964c; 1965b). 'Renin thus Lever, Robertson & Tree, 1964; Cook & Lee, has three possible routes of exit from the 1965) to form a decapeptide, angiotensin (Peart, kidney, all of w-hich must be taken into account 1955, 1956; Elliott & Peart, 1956; Skeggs, in estimating the rate of renin release. Marsh, Kahn & In mammals, renin-like enzymes have in Shumway, 1955). The decapep- addition been demonstrated in the uterus and tide is converted to octapeptide angiotensin by placenta (Stakemann, 1960; Gross, Schaechte- a peptidase (or peptidases) present in blood lin, Ziegler & Berger, 1963; Ferris & Mulrow, (Skeggs, Marsh, Kahn & Shumway, 1954; 1965), in arterial walls (Dengler, 1956; Gould Skeggs, Kahn & Shumway, 1956). & Skeggs, 1963), in salivary glands (Werle, In the mammalian kidney, renin is closely Baumeister & Schmal, 1962), and in amniotic associated with the vascular pole of the glomer- fluid (Brown, Davies, Doak, Lever, Robertson ulus (Cook, Gordon & Peart, 1957; Bing & & Tree, 1964b). Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from 154 POSTGRADUATE MEDICAL JOURNAL March, 1966 Pressor substances resembling mammalian (d) Release of Kinins. In the carcinoid syn- renin have also been extracted from the kidney drome, facial flushes, probably mediated by a and from the corpuscle of Stannius of the hormone, may be provoked by the intravenous European eel i(Chester Jones, Henderson, Chan, injection of small doses of several substances, Rankin, Mosley, Brown, Lever, Robertson & including catechol amines and angiotensin Tree, 1966). (Robertson, Peart & Andrews, 1962). Reasons Circulating angiotensin is less easy to detect have been advanced why the released hormone and its identity therefore less easy to establish is probably not serotonin, and since bradykinin than is renin, but its presence has been reported had earlier been shown to be released by adre- in blood (Kahn, Skeggs, Shumway & Wisen- naline and noradrenaline (Hilton & Lewis, 1956) baugh, 1952; Langford & Day, 1961; Scornik & it was considered a likely candidate (Robertson Paladini, 1961; Morris, Robinson & Scheele, and others, 1962). Subsequently, Oates, Mel- 1964); plasma (Boucher, Veyrat, de Champlain mon, Sjoerdsma, Gillespie & Mason (1964) pro- & Genest, 1964; Mulrow, 1964), and renal vided direct evidence of kinin release in these lymph I(Lever & Peart, 1962). circumstances. It is thus possible that angioten- Actions of Renin and Angiotensin sin may release kinins, and the timing of the As far as is known, the various physiological events in provoked carcinoid flushes suggests actions of renin are all mediated by angiotensin. that this action is not mediated via catechol Although decapeptide angiotensin has pharma- amines (Robertson and others, 1962). This cological effects on certain tissues (see Page & aspect has been somewhat neglected, but it Bumpus, 1961), the octapeptide form has the could be relevant to the hypotension which more prominent physiological actions. Some of follows infusions of renin and angiotensin (see the main effects which have been observed are Blacket, Depoorter, Pickering, Sellers & Wilson, summarised below, but we must emphasize that 1950; 'Brown, Chapuis & 'Robertson, 1963a; many of these are known to be closely inter- 1964a). related, and are far from independent of one (e) Effect on Adrenal Cortex. The recentby copyright. another. rapid advance in knowledge of this aspect of the (a) Pressor Action. The systemic pressor renin-angiotensin system resulted from the con- effect was first noted by Tigerstedt & Bergman vergence of several widely separated lines of (1898) and continued to attract most attention investigation. (see Pickering & Prinzmetal, 1938; Goldblatt, Deane & Masson '(1951) found that the ad- 1947, 1964; Pickering, 1955; Haas & Goldblatt, ministration of renin to rats led to histological 1964) until recently. A pressor action has been changes in the adrenal cortex suggestive of observed also in the pulmonary circulation (see increased activity.

de Bono, Lee, Mottram, Pickering, Brown, Hartroft & Hartroft (1953) and Tobian http://pmj.bmj.com/ Keen, Peart & Sanderson, 1963). (1960a) showed that sodium deprivation caused (b) Effect on Adrenal Medulla. T-he release histological changes in the juxtaglomerular of adrenaline 'by angiotensin was reported by apparatus which suggested increased secretory Braun-Menendez, Fasciolo, Leloir & Munoz function, whilst the converse occurred during (1940), Braun-Menendez, Fasciolo, Leloir, sodium loading. These and other observations Munoz & Taquini (1946), and Kaneto, MoCub- led Gross (1958, 1960) to postulate that renin bin & 'Page (1961), and has recently been further and angiotensin might serve to control sodium examined (Feldberg & Lewis, 1964). However, excretion by regulating aldosterone secretion. on September 30, 2021 by guest. Protected the excretion of vanillylmandelic acid (the chief Subsequently, Genest, Nowaczynski, Koiw, San- metabolite of adrenaline and noradrenaline) dor & Biron (1960) and iBiron, Koiw, Nowac- did not change during pressor in-fusions of zynski, Brouillet & Genest (1961) showed that angiotensin in 4 human subjects (Vincent, angiotensin caused an increase in aldosterone Kashemsant, Cuddy, Fried, Smulyan & Eich, excretion in man. Laragh, Angers, Kelly & 1965). Lieberman '(1960a), 'Mulrow & Ganong (1961a), Carpenter, Davis, Ayers & Casper (1961), Bart- (c) Neurological Actions. Lewis & Reit (1965) ter, Casper, Delea & Slater (1961), and Blair- have demonstrated that angiotensin is able to West, Coghlan, Denton, Goding, Monro, Peter- stimulate autonomic ganglia, whilst Laverty son & Wintour (1962) later demonstrated an (1963) and Benelli, Delia Bella & Gandini increase in aldosterone secretion rate on admini- (1964) have suggested that some of the effects tration of angiotensin to several species. of angiotensin may be mediated 'by the nervous Whether or not angiotensin stimulates the system. secretion of other corticosteroids under normal Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from March, 1966 BROWN, DAVIES, LEVER & ROBEIRTSON: Renin & Angiotensin 155 physiological conditions is disputed (see Davis, Page & Bumpus (1961), Haas & Goldblatt 1963; Slater, 1963; Slater, Barbour, Henderson, (1963), Peart i(1965), and Helmer (1965). Casper & Bartter, 1965), although there is little The Estimation of Renin and Angiotensin doubt that large (and possibly unphysiological) The different components of the system have doses are capable of such effects. In recent been assessed in such a wide variety of ways studies a rise in the peripheral venous plasma that it is necessary to emphasize the points of concentration of aldosterone was found within difference. Methods range from the purely 30 minutes of starting intravenous angiotensin qualitative to those whose quantitative accuracy administration to normal humans, and was has been accredited with various degrees of maintained throughout a 2-hour infusion. By reliability. contrast, neither plasma cortisol nor corticos- (a) Histological. In the first category are terone increased during these experiments (Fra- inferences based on the histological appearance ser, James, Brown, Isaac, Lever & Robertson, of the juxtaglomerular complex (see Goorma- 1965). ghtigh, 1945; Itskovitz, Hildreth, 'Sellers & (f) Efiect on Internal Distribution of Electro- Blakemore, 1963; Hess, 1963; Hartroft and lytes. Angiotensin may also have an influence others, 1964). on the distribution of electrolytes within the (b) Angiotensin. Angiotensin assays have body, promoting the movement of sodium into, been made on extracts of whole blood (Kahn, and potassium out of, vascular smooth muscle Skeggs, Shumway & Wisenbaugh, 1952; Lang- cells (see Friedman & Friedman 1964, 1965). ford & Day, 1961; Boucher, Biron & Genest, (g) Diuretic and Antidiuretic Effects. Both 1961; Scornik & Paladini, 1961; Morris & diuretic and antidiuretic responses to renin and Robinson, 1964), and of plasma (Boucher, Vey- angiotensin have been reported (Pickering & rat, de Champlain & Genest, 1964; Mulrow, Prinzmetal, 1940; Hughes-Jones, Pickering, San- 1964). The consistency of recovery through derson, Scarborough & Vandenbroucke, 1949; these methods, and characterisation of the Croxatto, Barnafi & Passi, 1952; Nijensohn, extracted material have varied considerably. by copyright. 1957; Peart, 1959; Gross & Turrian, 1960; Peart Each of these methods fails to detect circulating & Brown, 1961; Lauler & Hickler, 1962; Brown angiotensin in a proportion of normal subjects. & Peart, 1962; Brown, 1963; de Bono, Lee, Recently a superfusion assay technique of Mottram, Pickering, Brown, Keen, Peart & San- considerable sensitivity has ibeen developed for derson, 1963; Peters, 1962; Brown, Matthew & use in experimental animals (Regoli & Vane, Robertson, 1964m; Gantt & Carter, 1964; 1964). Healy, Barcena, O',Connell & Schreiner, 1965; (c) "Direct" Assay of Renin. Renin may be Langford & Pickering, 1965), natriuresis and assayed by means of its pressor effect on intra- antinatriuresis generally accompanying corres- venous injection into an intact animal (Tiger- http://pmj.bmj.com/ ponding changes in water excretion (see Lever, stedt & Bergman, 1898; Pickering & Prinzmetal, 1965). The nature of the renal response to 1938; Haas & Gold'blatt, 1964). This is a reli- infused angiotensin varies with the dose, the able, but relatively insensitive, method which duration of administration, the height of has been used, for example, in estimating the the arterial pressure, and some aspects of renin content of kidney extracts (Pickering, sodium (or steroid) balance (see Soghikian & Prinzmetal & Kelsall, 1942; Cook and others, Lameyer, 1963; Laragh, Cannon, Bentzel, Sicin- 1957). An interesting variant of this principle ski & Meltzer, 1963; Gantt & Carter, 1964). is the technique of isovolaemic cross-perfusion on September 30, 2021 by guest. Protected For reasons discussed in these papers it is developed by Rondell, McVaugh & Bohr unlikely that the diuretic or antidiuretic effects (1958), and later used also by Gross, Regoli & are a simple consequence either of angiotensin- Schaechtelin '(1963). All these "direct" assay methods involve calibration against a standard stimulated increases in aldosterone, or of acute preparation of renin. changes in renal artery pressure. (d) Plasma "Renin-activity". The term (h) Renin and Angiotensin as Local Hor- "renin-activity" estimation (Helmer. 1964; mones. The possibility raised in the previous Boucher, Veyrat, de Champlain & Genest, 1964) section-that renin and angiotensin may sub- has been applied to a group of techniques serve an intrarenal function-will be considered which, whilst differing in detail, have several later. features in common. A sample of plasma (or These and other actions of renin and angio- other biological fluid) is incubated in vitro for a tensin are also discussed in more general reviews fixed period, usually after angiotensinases have by Pickering (1955), 'Braun-Menendez (1956), been removed or inactivated. The reaction is Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from 156 POSTGRADUATE MEDICAL JOURNAL March, 1966 then stoppeed, and the angiotensin content is approach was developed by Leloir, Munoz, estimated i(Helmer, 1962; Helmer & Judson, Braun-Menendez & Fasciolo '(1940) who esti- 1963; Fasciolo, IRomero, de Vito & Cucchi, mated renin by measuring the consumption of 1964; Fitz & Armstrong, 1964; Boucher and substrate. others, 1964; Skinner, MoCubbin and Page, (f) Renin Concentration. The renin assay 1964; Kirkendall, Fitz & Armstrong, 1964; method we have used, and with which this Veyrat, de Champlain, Boucher & Genest, review is mainly concerned, differs from the 1964; Conn, Cohen & Rovner, 1964a). The techniques described above. Renin is extracted fact that a method of this type was one of from plasma (or other biological material), the first which was sufficiently sensitive to separated from endogenous substrate and angio- demonstrate consistently renin-like activity in tensinase, and incubated with a fixed concen- biological fluids '(Helmer, 1962) has tended to tration of a standard substrate. The initial velo- obscure the quantitative limitations. Firstly, the city of the reaction is measured 'by assaying the velocity of angiotensin production depends on angiotensin content of samples taken at varying both the renin concentration and the substrate intervals from the incubation mixture. The renin concentration; when neither is measured inde- concentration is then determined by reference to pendently, the relative contributions of renin a calibration curve prepared with serial dilutions and substrate cannot be determined. Secondly, of a standard renin of the appropriate species in none of the papers cited above are details (Lever and others, 1964; Brown, Davies, Lever, of 'the reoovery of either renin or substrate Robertson & Tree, 1964 k, 1). No activators or given, so that the relationship of their in vitro inhibitors have been detected in plasma extracts concentrations to those prevailing in vivo is in any of the situations discussed -below. unknown. The possible physiological importance The extracted enzyme is identifiable as renin of variation in substrate concentration has been on physico-chemical, enzyme kinetic, and stressed by Helmer 1(1964), whilst the need for pharmacological grounds; and the incubation accurate measurement of suibstrate recovery is product as angiotensin physico-chemically andby copyright. emphasized (by the results of Maebas'hi, Yosh- pharmacologically. inaga, Aida, Okuyama & Oikawa (1965). These The method is sufficiently sensitive to detect workers found that the substrate concentration renin in the peripheral venous plasma of normal of human plasma which had been adjusted to subjects, and in all cases of pathological de- pH 5.5 could vary over a very wide range. pression of renin concentration encountered so Thirdly, the influence in such assay systems of far, short of bilateral nephrectomy. Whilst it any co-factors or inhibitors present in plasma gives a measure of the in vivo plasma renin is not known (see Bumpus, 1965). Fourthly, in concentration within assessable limits of error,

these techniques only a single estimation of it is no more a measure of the in vivo activity http://pmj.bmj.com/ angiotensin in the incubation mixture is made, of the rate of angiotensin formation than any of and they can not therefore necessarily be re- the preceding techniques, since measurable sub- garded as measuring the initial velocity of the strate, activators, inhibitors and angiotensinase reaction. This is a serious theoretical objection are eliminated from the system. A similar to the quantitative accuracy of enzyme systems method has 'been used by Cook and Lee (1965) in general (see Dixon & Webb, 1958), and has for the measurement of renin in kidney extracts. been shown to be relevant in practice to this Intrarenal Variations in Renin particular reaction i(Lever, Robertson & Tree, Goormaghtigh (1939, 1945) observed that on September 30, 2021 by guest. Protected 1964). juxtaglomerular granulation was more marked Pickens, Bumpus, Lloyd, Smeby & Page in the superficial than in the deep zones of the (1965) have recently described a method in rabbit kidney, and proposed that this might which the problem of substrate concentration indicate differing quantities of a pressor has been partly met, and in which initial hormone in these regions. velocity measurement is probably achieved un- Assays on 'pooled glomeruli taken from differ- less renin is present in very high concentration. ent parts of the rabbit renal cortex subsequently These authors have preferred to retain the term suggested that more renin was associated with "'renin-activity", however, since they have evi- the superficial than with the deep glomeruli dence of co-factors or inhibitors in their incu- (Cook and others, 1957; Bing & Wiberg, 1958; bation system. This usage of the term "renin- Cook & Pickering, 1959). activity" thus has different connotations from The development of a more sensitive assay that of Boucher and others (1964). method permitted the estimation of extractable (e) Substrate Consumption. A rather different renin associated with single glomeruli. This Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from March, 1966 BROWN, DAVIES, LEVER & ROBERTSON: Renin & Angiotensin 157

Normal rabbit. Untouched Kidney

Subcapsulor 192 ~~~~surfocc.

17 (D~~~V~ Superficiol Superficial Deep < ~~~~Deep I1 ,X3

W (a) (b) FIG. I.- Diagrams of renin quantities associated wit«h single glomeruli alontg the course of an interlo- bular artery in the Tabbit. Clipped Kidney la. From n-ormnal raJbbit. by copyright. Ilb. & Ilc. From a rabbit wi,th a unilateral renal artery clip. '(lb. from untouched kidney; lc. from clipped kidney). Renin in units X 10,000. Quantities less than about 0.0017 units are undetectablep these are shown ,as 0. (Ia. 'by permission o-f the Journ-al of Physiology; lb. and Ic. Iby permission of C:linical Science). showed that there was a progressive rise in the renin associ,ated with glomerulli along the co-urse of an interlobular artery, renin being usually http://pmj.bmj.com/ undetectable in juxtamedullary, and greatest in -the most sulperficiaJl, tglo.merul1i (IFig. 1). This gradation in renin content was paralleled by increlasing granulari.ty in the afferent glomerular arteriole, and, rather less closely, iby differences in the staining characteristics of the macula densa !(Brown, Davies, ILever, Parker & Robert- on September 30, 2021 by guest. Protected son, 1963c, d, 1964d; 1965c). The application of la. unilateral renal artery clip was found to lead to an alteration in this distribution, both -the extractable renin and the Superficial juxtaglomerular granulation increasing in the Deep deep glomeruli distal to the constriction, whilst in the untouched kidney bo-th extractable renin and granulation were low, even in the superficial cor-tex I(Brown -and others, 1963c, d; Brown Davies, iLever & Robertson, 1964j; P-arker, I 1964; Bro-wn, Davies, Lever, Parker & Robert- slon, 1966g). These results, which had -been anticipated by earlier histological studies, and by renin assays (c) Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from 158 15POSTGRADUATE MEDICAL JOURNAL March, 1966 in whole kidney extracts (see Gross, 1960; subjects, renin values in peripheral venous Tobian, 1960b; Gross, Regoli & Schaechtelin, plasma being slightly higher during the day 1963) indicate that renin may be influenced by than in the night (Brown, Davies, Lever & local circulatory modifications, and that its dis- Robertson, 19661). Small variations also occur tribution is closely related to the anatomically in normal women during the menstrual cycle, complex intrarenal circulation (see Trueta, Bar- renin being highest during the luteal phase clay, Daniel, Franklin & Prichard, 1947; Moffat (Brown, Davies, Lever & Robertson, 1964h). & Fourman, 1963; Fourman & Moffat, 1964; Plasma concentration of renin is also increased Lever, 1965; Kriz & Lever, 1966). in some, but not all, normal subjects on tilting Possible intrarenal functions of renin and from the recumbent to the upright posture angiotensin have been considered by several (Brown, Davies, Lever, McPherson & Robert- workers (Goormaghtigh, 1937, 1939; Lever & son, 1966f). It is notable that in all of Peart, 1962; Schmid, 1962; Bing, 1963; Guyton, these situations with higher renin some 1963; Brown, Davies, Lever, Robertson, 1964; aspect of aldosterone production or plasma Brown, Davies, Lever, Lloyd, 'Robertson & aldosterone concentration has been shown to Tree, 1964c; Brown, Matthew & Robertson. be increased (Muller, Manning & Riondel, 1964m; Lever, 1965). Roles which have been 1958; Nowaczynski, Koiw, Biron, Chretien suggested are that renin is concerned in the & Genest, 1962; Reich, 1962; Wdlff & regulation of glomerular filtration rate (see Torbica, 1963; Bougas, Flood, Little, Tait, Tait Goormaghtigh, 1937, 1939 and 1945; Schmid, & Underwood, 1964). Plasma renin concentra- 1962; Thurau, 1964); in the control of sodium tion is increased to a variable extent in normal reabsorption by the renal tubule (Leyssac, pregnancy (Brown, Davies, Doak, Lever & 1964; Langford, 1964; Tobian, 1964; Vander Robertson, 1963b; 1966a). Aldosterone produc- & Miller, 1964); and in changes in the medul- tion has also been shown to be high in normal lary circulation l(Lever, 1965). pregnancy, although it is not certain that a

Whilst the precise nature of any such intra- strict parallel between renin and aldosterone by copyright. renal function remains undecided, largely from exists throughout all stages (see Watanabe, the absence hitherto of sufficiently sensitive Meeker, Gray, Sims & Solomon, 1963, *for assay techniques, the general concept is one references; also Tait, 1964). which appears to us extremely attractive. The (b) Sodium Restriction and Repletion. The signiificance of a 'local effect is that it might be relationship between renin and aldosterone is achieved by alterations in the concentrations of seen most closely in connection with sodium renin and angiotensin which would be insuffi- balance in normal subjects, and this provides cient to affect more distant target organs such some of the strongest evidence that the renin- as the adrenal cortex or medulla. This carries angiotensin system includes among its normal the further implication that the systemic functions the regulation of aldosterone produc- http://pmj.bmj.com/ actions of renin and angiotensin may have tion. In man, both aldosterone excretion evolved as secondary (and possibly supplemen- (Luetscher & Axelrad, 1954; Luetscher & Cur- tary) effects. tis, 1955; Hernando, Crabbe, Ross, Reddy, In this context it is of interest that the adrenal Renold, Nelson & Thorn, 1957; Johnson, cortex of amphibians such as Necturus (Chase, Lieberman & Mulrow, 1957; Venning, Dyren- 1923; Hartman & Brownell, 1949) is partly furth, Giroud & Beck, 1957; Bartter, Mills, embedded within the substance of the kidney Biglieri & Delea, 1959) and secretion (Ulick, on September 30, 2021 by guest. Protected close to the glomerulus, a relationship which Laragh & Lieberman, 1958; Mills, 1962) are suggests that a hormone released in the kidney inversely related to sodium intake. Sodium might stimulate the adrenal cortex without restriction leads to a rise in plasma renin entering the general circulation. It is further concentration, whilst oral sodium loading causes possible that steroids liberated in this way could plasma renin to fall (Brown, Davies, Lever & also act locally. Bott (1962) has discussed this (Robertson, 1963e, 1964g). If a rapid loss of possibility in relation to the abrupt fall in urinary sodium is induced with intravenous sodium concentration occurring in the early frusemide, a concomitant rise in both plasma distal tubule. renin and aldosterone is seen within an hour, Changes in Plasma Renin Concentration in whilst neither plasma cortisol nor corticosterone Relation to Sodium Balance and Aldosterone increase (Fraser and others, 1965). Homoeo- Production static mechanisms limit the extent of sodium (a) Physiological Variations. A diurnal cycle loss which can be induced in normal persons by of plasma renin concentration occurs in normal sodium restriction (McCance. 1936), and, prob- Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from

March, 1966 BROWN, DAVIES, LEVEiR & ROBERTSON: Renin & Angiotensin 159 ably in consequence, the rise in renin which can Urquhart & Davis, 1963; Sanders & Melby, be induced in this way is not great (Brown and 1964). others, 1964g). Since the metabolic clearance of aldosterone (c) Addison's Disease. Sodium homoeostasis may be impaired in patients with hepatic con- is lost in patients with primary adrenocortical gestion secondary to cardiac failure (Luetscher, insufficiency, in which very high concentrations Camargo, Cohn, Dowdy & Callaghan, 1963; of plasma renin are found. These return to Camargo, Dowdy, Hancock & Luetscher, 1965; normal, or near to normal, with steroid replace- Tait, Bougas, Little, Tait & Flood, 1965), it is ment therapy (Brown, Davies, Lever & Robert- theoretically possible for a high plasma aldos- son, 1963g, 1964f). terone concentration to be achieved with a In a recent study of a patient with previously normal or even low aldosterone secretion rate, untreated Addison's disease (Brown, 'Fraser, and hence a low plasma renin concentration. James, Lever, McCusker & iRobertson, 1966c), However, in the few cases in which we have administration of oral cortisol and 9-a-fluoro- studied both, plasma renin and plasma aldos- cortisol was accompanied by a rise in plasma terone have been in close correspondence. sodium, in total exchangeable sodium, and in (f) Other Diseases. Other pathological situa- plasma volume, whilst plasma potassium and tions in which we have found renin concentra- renin concentration fell from very high values tion increased are hepatic cirrhosis with ascites to normal. External potassium balance and total (Brown and others, 1963g, 1964f); some, but not exchangeable potassium were not, however, all, cases of nephrotic syndrome; and following greatly altered by treatment. a large, but not a small, haemorrhage (Brown (d) Sodium-losing Renal Disease. In Addi- and others, 1964k; Brown, Davies, Lever, son's disease the renin-angiotensin system may Robertson & Verniory, 1966m). In more recent be studied in isolation from the adrenal cortex. studies of experimental haemorrhage in the dog, Changes in plasma steroids as well as renin made in collaboration with Drs. J. R. Vane and may be observed in patients whose ability to R. D. Lowe, concomitant increases in plasmaby copyright. retain sodium is impaired because of renal renin concentration and angiotensin generation disease. For example, in a patient with bilateral were found. renal calculi and recurrent urinary infections, Again, evidence of increased aldosterone urinary sodium output was undiminished during production has 'been observed in all these three days of sodium restriction. During this situations '(Farrell, Rosnagle & Rauschkolb, time there was a very marked rise in both 1956; Genest 1957; Dyrenfurth, Stacey, Beck plasma renin and aldosterone concentration, & Venning, 1957; Wolff, Koczorek & Buchborn, with a smaller increase in plasma corticosterone 1958; Muller, 1958; Mulrow & Ganong, 1961b; during the more severe stages of sodium deple- Davis, 1962). http://pmj.bmj.com/ tion (Fig. 2). There was no appreciable rise in Variations in plasma renin concentration in plasma cortisol in these circumstances, afthough a wide range of circumstances in which arterial the response to ACTH was normal (Fraser, pressure is normal (or low) are thus in accord James, Brown, Davies, Lever & Robertson, with the concept of the renin-angiotensin system 1966). subserving the regulation of aldosterone secre- (e) Congestive Cardiac Failure. We have ob- tion and sodium balance.

served two distinct patterns in untreated Renin and Angiotensin in Hypertension on September 30, 2021 by guest. Protected congestive failure. More commonly, renin con- The role of the renin-angiotensin system in centration has been normal or low, rising with hypertension is closely involved with its physio- therapeutic diuresis. In other instances, renin logical functions in the regulation of sodium has initially been high, and has fallen with treat- balance and aldosterone secretion. ment. In both treated and untreated cases, there (i) Relation between Renin and Sodium in has been a general inverse relationship between Hypertension plasma sodium and renin concentration (Brown, Survey of a large series of patients with Davies, Johnston, Lever & Robertson, 1966e). 'hypertension revealed an inverse relationship Measurement of aldosterone excretion, secre- between plasma sodium and renin concentration and metabolic clearance in car- which extended through the normal range of tion congestive both, and was independent of aetiology, of the diac failure have given variable results (Deming severity of the hvpertension, of complicationis, & Luetscher, 1950; Muller, Riondel, Manning and of treatment (Brown, Davies, Lever & & iMach, 1956a; Wolff, Koczorek & Buchborn, Robertson, 1965g, h; 1966d, k) (Fig. 3). The 1957; Ulick and others, 1958; Laragh, 1962b; extremes of thlis spectrum were represented 'by Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from

160 160 POSTGRADUATE MEDICAL JOURNAL March, 1966 Neg. Na 25b mEq. bO0 A PLASMA 40 RENIN UNITS/ 1. 20. . 0 300 PLASMA 200 ALDOSTERONE mpq °h 100 0 PLASMA CORTICO- 'oo1 STERONE pjq 0%25% 0 PLASMA 20 CORTISOL jjq% 0

138 4., PLASMA Na 134. mEq/l. 130' 126 I Ii:::?~~~. L., PLASMA K 403 o- °*i~SLT 30 mEq/l. 5 10 I. H. by copyright. 77 BODY. Wt. Kg. 72 38q HAEMATOCRIT % 0 33 0 150 BRP mm.Hq. 110

70 I I http://pmj.bmj.com/

I I I) 25 30 DAYS FIG. 2.-Changes in plasma renin and steroids during dietary sodium restriction in a woman with sodium-losing renal disease. on September 30, 2021 by guest. Protected (By permission of Journal of Endocrinology).

two distinct syndromes, both of which were tem was probably the drive to aldosterone secre- accompanied by increased aJdosterone secretion tion (Brown and others, 1965g; Barraclough, and hypokalaemia. Bacchus, Brown, Davies, Lever & Robertson, In one, severe, frequently malignant, hyper- 1965). tension, and usually either renal artery stenosis The converse situation of elevated plasma or some other form of renal disease (see Brown sodium concentration with depression of renin and others, 1965g) were found in association was seen in primary hyperaldosteronism with hyponatraemia and raised plasma renin. (Brown, 'Davies, Lever & {Robertson, 1963f, The correspondence between the raised plasma 1964f; Brown, Davies, Lever, Peart & renin concentration and aldosterone secretion Robertson, I1964e, 1965d) rate found in a group of patients with this syn- These two syndiromes are contrasted in drome indicated that the renin-angiotensin sys- Fig. 5. Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from March, 1966 BROWN, DAVIES, LEVER & ROBERTSON: Renin & Angiotensin 161

Relationship between Plasma Renin and Plasma Na+

70 - Entire Hypertensive Series.

60 -

< 50 -

D 40 - c c , 30 - 0 E 20 - a

10 -

0 - <132 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 >147 Plasma Na+ mEq/I. FIG. 3.-Relationship between renin and sodium in hypertensive patients. Mean and S.E.M. shown for renin (By permission of British Medical Journal). by copyright. (ii) Renin in Relation to the Aetiology of the Brown, Owen, Peart, Robertson & Sutton, 1960; Hypertension Stamey, Nudenlman, Good, Schwentker & (a) Renal Artery Stenosis. In a group of Hendricks, 1961). This does not, however, hypertensive patients with renal artery stenosis imply that renin 'measurement has no prognos- (on the combined evidence of arteriographic, tic value in relation to renal artery surgery. pyelographic, and ureteric catheterisation While the number of cases studied so far is studies), a scatter of renin levels from low insufficient to provide a definite answer, we normal to a hundred times normal was found. have some evidence suggesting that the patients

Throughout this wide range renin was closely with renal artery stenosis and elevated renin http://pmj.bmj.com/ related inversely to plasma sodium, and directly, may respond better -than those with normal although less closely, to the severity of the renin to renal artery surgery (Brown and others, stenosis. In cases with retinal evidence of the 1966k). However, Mulrow (1964) reported malignant phase plasma renin was invariably successful surgical results in a small number high and sodium low; these comprised all the of patients, despite normal preoperative patients with severe stenoses (Brown and others, measurements of angiotensin and aldosterone. 165£f, g, h) JFig. 4). with (b) Other Renal Lesions. Patients hyper- on September 30, 2021 by guest. Protected It is noteworthy that roughly 25 per cent of tension due to other forms of renal disease ailso the patients with hypertension and renal artery showed a wide range of plasma renin concen- stenosis had renin values within the normal tration. Again, this was closely related inversely range (Fig. 4). This observation is in agreement to plasma sodium, and at the higher levels of with the finding of normal renin values in a plasma renin were encountered cases with the proportion of both rabbits (Lever & Robertson, malignant phase, hypokalaemia, and other 1964) and dogs (Verniory, Enderle, Potvliege, features of the hyponatraemic syndrome (Brown Primo, Gregoire, Vereerstreeten & Stuckens, and others, 1965h). 1965; Reinert, Davey, Brown, Davies, Lever & Robertson, 1966) with experimental renal (c) "Essential" Hypertension; Coarctation; hypertension, and indicates that plasma renin Phaeochromocytoma. Plasma renin concentra- measurement is a rather less sensitive index tion was not abnormal in a small group of of renal artery stenosis than are pyelography, cases with hypertension due -to phaeochromocy- arteriography, and ureteric catheterization toma or to coarctation of the aorta. iRenin was studies (see Schiegel, SaVlov & Gabor, 1959; also in the normal range in a group of patients Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from 162 POSTGRADUATE MEDICAL JOURNAL March, 1966

RENAL ARTERY STENOSIS. > 50 50 -

RETINOPATHY NO RETINOPATHY 40 - * >50 - * z 50 - Z 30- z LLI

20 - 40- e 0

10 - _1) 0. I- 30- 0 0- z 0 Z 0 w 0t 20- Increased Aldosterone FIG 5.-Plasma renin concentrations in

hyper- by copyright. 2 S.D. tensive patients with increased aldosterone 10- I S.D. secretion rate or increased plasma aldosterone Normal _ _ * concentration. Normal mean 1 & 2 S.D. Mean indicated for renin. The group with high Irenin I S.D. levels all had renal disease, evidence of the malignant phase, and low plasma sodium levels. 2 S.D The group with low renin are examples of 0- primary hyperaldosteronism; adrenocortical adenomata have subsequently been removed from of FIG 4.-Renin values in hypertensive patients with ten these. renal stenosis and retinal

artery haemorrhages http://pmj.bmj.com/ and exudates; and in similar cases without retinal lesions. renin concentration was no higher than in (By permission of British Medical Journal). normal pregnancies of comparable duration although still above the non-pregnant range. with hypertension of undetermined cause The most severely hypertensive patients gener- (Brown and others, 1965h). ally showed the lowest renin levels (Brown, (d) Hypertension due to Adrenal Cortical Davies, Doak, Lever, Robertson & Trust, The and low 1965a, Davies, Overactivity. hyperatraemia plas- 1966b; Bonar, Brown, Lang- on September 30, 2021 by guest. Protected ma renin concentration in patients with primary ford, Lever & IRobertson, 1966). hyperaldosteronism have already been men- (iii) Renin in Relation to the Complications of tioned in this review, and have been previously Hypertension discussed in detail in a series of papers (Brown (a) Malignant Phase. Since a raised plasma and others, 1963f, g; 1964e, f; 1965d, g, h; renin concentration is found in the hyponatrae- 1966d). mic hypertensive syndrome, in which evidence Renin and sodium were normal in three of the malignant phase is also extremely com- patients with Cushing's syndrome and hyperten- mon (see Brown and others, 1965g; 1966d), it sion, but in a fourth case, where sodium was follows that many patients with malignant abnormally high, renin was low (Brown and hypertension will have elevated plasma renin. others, 1965h). However, in patients who did not have a low (e) Hypertensive Disease of Pregnancy. As plasma sodium we observed both retinal and we have noted above, circulating renin is in- histological evidence of the malignant phase in creased in normal pregnancy (Brown and others, association with either normal or abnormally 1963b). In "pre-eclamptic toxaemia" plasma low renin concentration i(Brown and others, Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from March, 1966 BROWN, DAVIES, LEVER & ROBE'RTSON: Renin & Angiotensin 163 by a fall in plasma renin concentration to very 220 low levels (Brown and others, 1966d). B.P. ISO _ (iv) Eflect of Treatment of the Hypertension on m1 Hg 140 I Plasma Renin Concentration 'I II (a) Hyponatraemic Hypertensive Syndrome: Where this combination of features was associa- 141 ted with renal artery stenosis, surgical correction PLASMA Na 139_ of the lesion was seen to be followed by eleva- mEq/I.9ql* 137[ tion of the low plasma sodium and low plasma potassium, and reduction of the increased plas- 135 ma renin concentration, aldosterone secretion 40 rate, and blood pressure to normal, with resolu- PLASMA 30 tion of the lesions of the malignant phase RENIN 20 UNITS/L (Brown and others, 1965f; 1966k; Barraclough 10 _ and others, 1965; Barraclough, 1966). Similar results were also observed following unilateral O _ nephrectomy. Furthermore, effective drug 240 SODIUM treatment may ibe achieved in these cases, INTAKE 120_ and we have observed a fall in renin and rise mEq/Day _ in sodium to normal during guanethidine ther- I I I I I I apy before operation in one patient with a renal DAYS artery stenosis. In another patient with uni- FIG 6.-Effect of oral sodium loading on plasma lateral renal artery occlusion, mild hypo- renin and plasma sodium in a paitien.t with severe natraemia, and elevated plasma renin concen- hypertension, renal artery Atenosis, hyper- tration, oral sodium loading corrected the natraemia and hypokalaemia. plasma electrolytes and renin, although arterialby copyright. 1966d). Our results are thus in accord with the pressure was unaffected (Fig. 6). view that the vascular lesions of malignant (b) Primary Hyperaldosteronism. Removal hypertension are a consequence of increased of an aldosterone-producing adrenal tumour intra-arterial pressure (Wilson & Pickering, may be followed by a fall in plasma 1938; Wilson & Byrom, 1939; Pickering, 1955; aldosterone and plasma sodium, and a rise Byrom, 1963), and do not support the sugges- in plasma renin concentration to normal tions made by Laragh, Cannon & Ames (1963) (Brown and others, 1964e, 1965d). Of much and Conn, Knopf & Nesbit (1964b), that greater theoretical interest is the observation the combination of increased circulating angio- that spironolactone treatment, while leaving http://pmj.bmj.com/ tensin and aldosterone is required to produce aldosterone secretion unaltered, can correct the the malignant phase. It is, 'however, possilble other abnormalities, including blood pressure that a raised plasma renin, and -hence increased and plasma renin concentration (Brown and angiotensin concentration, might facilitate the others, 1963f, g; 1964e, f; 1965d; 1966k). occurrence of lesions in the retina more readily Spironolactone therapy also has practical than at other sites, possibly because of focal application in this condition as an alternative retinal anoxia (Brown and others, 1966d). whiich may be preferable -to total adrenalectomy (b) Hypertensive Heart Failure: Hyperten- ('Relman, 1963; Slaton & Biglieri, 1965) in cases on September 30, 2021 by guest. Protected sive 'heart failure conformed to the pattern most where the adrenal tumour cannot be located at commonly seen in other forms of congestive operation (Brown and others, 1963f, g, 1964e, failure, in which plasma renin concentration f, 1965d, f, 1966k). was low initially, rising, sometimes to abnor- c) Drug Treatment of Hypertension. The use mally high levels, with vigorous diuretic therapy of thiazides or spironolactones as adjuncts to (Brown and others, 1966d). other forms of hypotensive therapy may lead to (c) Chronic Renal Failure: In patients with an elevation of plasma renin, irrespective of hypertension and chronic renal failure, a wide aetiology. The inverse relationship between range of plasma renin concentration was seen, plasma renin and sodium was close in these probably reflecting the instability of sodium patients, whereas no significant correlation with balance in these patients. It was notable that plasma potassium was found (Brown and high plasma renin values might occur even with others, 1965g). grossly impaired excretory function. In two Diuretics apart, successful drug treatment of patients, bilateral nephrectomy was -followed hypertension tended to restore renin to the Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from 164 POSTGRADUATE MEDICAL JOURNAL March, 19;66 normal range if it was raised before treatment, already referred to the inverse relationship and to leave it unchanged if it was initially between plasma renin and sodium concentration normal (Brown and others, 1966k). found in hypertension (Brown and oithers, 1965 g), cardiac fa-ilure (Brown and others, The Control of Plasma Renin Concentration 1966 e), Addison's disease (Brown and others, As discussed earlier, renin enters the kidney 1963 g, 1964 f, 1966 c), and sodium-losing in renal arterial blood, and leaves in the venous renal disease (Brown and others, 1965f; Fraser blood, lymph and urine. Setting aside the and others, 1966); (Fig. 2). Plasma sodium question of the relative distribution of the has been found to be relatively low in several enzyme between red cells and plasma, of the other situations in which an increase in estimation of the net rate at which renin is renin occurs, such as dietary sodium restriction, released into renal venous plasma requires cirrhosis with ascites, the luteal phase of the measurement of the renin concentration in menstrual cycle, and normal pregnancy (see both renal arterial and venous plasma, and McCance, 1936; Sherlock, 1963; Fawcett and also of the renal plasma flow. It should, in Wynn, 1956; Gray, Munro, Sims, Meeker, addition, be emphasized that as "renin activity" Solomon and Watanabe, 1964). determinations (see earlier) do not measure the These data suggest 'that the plasma level of concentration of renin, such methods cannot sodium may be one factor controlling the validly be used to compute either arteriovenous plasma renin concentration; alternatively, renin differences of the enzyme or its rate of secretion. could be affected by some other aspect of sodium balance of which the plasma sodium Moreover, as we have stressed before (Brown concentration is merely an indicator. Plasma and others, 1964k, 1, 1966m), it cannot be sodium, however, cannot be the sole deter- inferred that changes in the concentration of minant of plasma renin, since renin increased renin in peripheral plasma are necessarily the with the sodium diuresis following intravenous result of changes in the rate at which renin frusemide although plasma sodium was not by copyright. is released. Alterations in the rate of clearance altered detectably (Fraser and others, 1965); from blood could also be important. At present and the hyponatraemia of inappropriate over- it is undecided whether changes in plasma secretion of ADH is not accompanied by a renin concentration are achieved by modifi- corresponding irise in plasma renin concentration cations of renin secretion rate, or in its disposal, (Brown, Davies, Lever and Robertson, 1965 e). or by a combination of events. It is, never- (c) Plasma or ECF Volume. The work of theless, possible to consider some of the Bartter, Liddle, Duncan, Barber and Delea influences on plasma renin concentration. (1956), Bartter and others (1958), and

(a) Aldosterone. Studies of several conditions Mutller, Riondel and tMach I(1956b) suggested http://pmj.bmj.com/ show that plasma renin concentration is not that aldosterone secretion might 'be related governed directly by either the plasma con- to plasma (or extracellular fluid) volume. centration of aldosterone or by the aldosterone Whilst a diminution in plasma volume secretion rate. Thus we found the intravenous might, similarly, result in an elevation of infusion of aldosterone in two subjects (1000 plasma irenin concentration (and vice versa), pg. in 5 hours) did not lower plasma renin this again cannot be the sole influence on concentration. Similarly, the treatment of plasma renin, as changes in plasma volume primary hyperaldosteronism with a spironolac- and renin are not inversely related in normal on September 30, 2021 by guest. Protected tone leads to elevation of the initially low pregnancy (see Hytten and Paintin, 1963; Low, plasma renin concentration to normal or high Johnson and McBride, 1965), or in patients normal levels, whilst the raised aldosterone with inappropriate oversecretion of ADH secretion rate can remain unchanged (Brown (Brown and others, 1965 e). Furthermore, and others, 1963 f, g, 1964 e, 1965 d). Further, spironolactone treatment of a patient with an when the normal renal response to aldosterone aldosterone-secreting adrenal adenoma restored is impaired because of renal disease, both aldo- abnormally low plasma renin into the normal sterone and renin concentrations in plasma may range, although the volumes of -both plasma rise together (Fraser and others, 1966; Fig. 2). and extracellular fluid remained well above A concomitant rise in plasma renin and aldo- the predicted normal values (Brown and others, sterone has also been observed following the 1965 d). administration of frusemide to normal subjects These observations suggest that plasma (Fraser and others, 1965). volume and plasma sodium concentration (or (b) Plasma Sodium Concentration. We have some other aspects of fluid distribution and of Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from

March, 1966 BROWN, DAVIES, LEVER & iROBERTSON: Renin & Angiotensin 165 sodium balance of which these are indices) centration are received remains undecided. may independently affect plasma renin con- Both the macula densa (Goormaghtigh, 1937, centration, so that renin is high when both 1939; Hess and Gross, 1959; Fisher, 1961; plasma volume and plasma sodium are low Latta, Maunsbach and Cook, 1962; Guyton. (as in sodium depletion), renin is low when both 1963; Brown and others, 1964 g; Thurau, 1964; are increased (as in primary hyperaldosteron- Vander and Miller, 1964) and the afferent ism), and renin may be normal in the rather less glomerular arterioles (Tobian, 1960 a, b; common circumstances when plasma volume Skinner, McCubbin and Page, 1964; Brown and sodium concentration move in opposite and others, 1964 g) have been considered, as directions '(as in patients with excess ADH). also have more complex functions of renal (d) Changes in Renal Circulation. Renin may distensibility (Ogden, 1944; Swann, Railey and also be influenced by changes in the renal Carmignani, 1959; Lowe, 1964). circulation, since there is evidence that the It is possible on the present evidence that renin concentration of renal lymph (Lever both the afferent glomerular arterioles and the and Peart, 1962), of peripheral arterial plasma macula densa may receive supplementary or (Lever and Robertson, 1964), and of renal alternative signals. Lever (1965) has proposed venous plasma (Skinner and others, unpub- a mechanism based on the relation of the lished) may increase following the application capillary circulation to the renal tubule, by of a renal artery constriction. The duration of which changes in sodium balance and renal these effects has not, however, been established. artery pressure might both influence plasma We have found no evidence to date of any renin via the osmolality of the fluid bathing simple relationship between arterial pressure the macula densa (see also Brown and others, and plasma renin concentration. Thus in 1964 g, 1965 c). Several of these points have experimental haemorrhage, the increase in been discussed in more detail in a previous plasma renin concentration was closely related paper i(Brown, Davies, Lever and Robertson, to the extent of the blood loss (in ml./Kg. body 1966 h). by copyright. weight), and could not be correlated with changes in mean arterial pressure '(Brown and Other Possible Relationships Between Plasma others, 19,66m). 'Further, there was no evidence Sodium and Plasma Renin Concentration of depression of renin in patients with hyper- So far, elevation of plasma renin concentration tension due to adrenal medullary tumours has been discussed mainly as a possible con- (Brown and others, 1965 h). However, sequence of hyponatraemia. The converse intrarenal circulatory changes may not parallel relationship, that elevation of plasma renin (and alterations in systemic blood pressuire. hence angiotensin) may contribute to a fall in

(e) Potassium. Although data have been plasma sodium also requires consideration. http://pmj.bmj.com/ obtained in both the dog and the sheep There are several ways in which -this might indicating that increases in plasma (or serum) occur. potassium may stimulate aldosterone excretion Inappropriate Urine Concentration with or secretion (see Laragh and Stoerk, 1957; Water Retention Blair-West and others, 1962; Davis, Urquhart Lever (1965) has suggested that the effects and Higgins, 1963; Wright, 1963 a, b), we have of renin '(and angiotensin) on the composition not so far observed 'in man evidence of a direct of the urine may partly be due to actions on influence of potassium on plasma renin. the renal medullary blood vessels. on September 30, 2021 by guest. Protected Certainly, sodium seems of greater importance Black (1964a) had earlier proposed that a in several of the situations studied (Brown and decrease in medullary blood flow might lead others, 1964 e, f, 1965 g, 1966 c, k). to the formation of urine which was over- Plasma renin concentration thus seems to concentrated in relation to the osmolality of be sensitive either to a variety of different body-fluid, and suggested this as one of the stimuli, or to an as yet unidentified common causes of hyponatraemia in cardiac failure. stimulus. The high plasma renin levels found in (f) Intrarenal Aspects of the Control of hyponatraemic heart failure thus raise the Plasma Renin. Despite extensive work, the possibility of a renin-mediated selective precise location of renin within the kidney reduction of medullary blood-flow (see Black, remains uncertain '(see Bing, 1963; Cook, 1963; 1965; Lever, 1965; Brown and others, 1966 e); Hartroft and others, 1964; Brown and others, a similar mechanism might operate in hepatic 1965 c). Furthermore, the site at which the cirrhosis with ascites (see Brown and others, hypothetical signals to increased renin con- 1963 g; 1964 f). Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from 166 POSTGRADUATE MEDICAL JOURNAL March, 1966 Inappropriate urine concentration with Sicinski and Meltzer, 1963). The natriuretic retention of water and hyponatraemia also effect of angiotensin in hypertensive patients occurs in patients with bronchial carcinoma may occur independently of acute increases in and excess of a vasopressin-like hormone systemic arterial pressure (Brown and Peart, (Schwartz, Bennett, Curelop and Bartter, 1957). 1962); it has also been observed in both kidneys, The administration of angiotensin can, like the even in cases with severe unilateral renal artery giving of exogenous ADH, lead to a decrease stenosis (Brown and others, 1964 m). in volume and an increase in osmolality of the A raised renal artery perfusion pressure per urine of patients with diabetes insipidus (Peart, se can also cause natriuresis (see Selkurt, 1961), 1959; IDel Greco, 1962; de Bono and others, and might thus contribute to the hyponatraemia 1963; Gill, Barbour, Slater and Bartter, 1964). of severe hypertension. Lever (1965) has cited this as evidence in Extracellular sodium depletion could, in favour of a similar intrarenal vascular action addition, be enhanced by a movement of sodium of angiotensin and ADH. into cells under the influence of angiotensin Possible Ef7ects of Endogenous Renin and (Friedman, Butt and Friedman, 1957; Friedman Angiotensin in Diabetis Insipidus. These and Friedman, 1964). observations encouirage speculations on the Observations on the Hyponatraemic possible contribution of renin to "thiazide Hypertensive Syndrome antidiuresis" and related phenomena in patients Many of the foregoing observations appear with diabetes insipidus. Meyer (1905) and relevant to the hyponatraemic syndrome of Bauer and Aschner (1924) noted that diuretics severe 'hypertension which is, as we have could reduce the polyuria of diabetes insipidus. mentioned previously, the one form of clinical Thiazides, theophylline, mersalyl, and spirono- hypertension in which plasma renin concentra- lactone i(Meyer, 1905; Kennedy and Crawford tion is consistently raised (see Brown and

1959); Havard and Wood, 1960, 1961) have all others, 1965 f, g). by copyright. been observed to produce this effect, which can In several reported cases of the syndrome be partly prevented by salt replacement (Havard urinary sodium loutput has appeared inappro- and Wood, 1961). The polyuria may also be priately high for the depressed plasma sodium diminished by dietary sodium restriction (Fitz, concentration (Holten and Petersen, 1956; 1914; Beaser, 1947). Laidlaw, Yendt and Gornall, 1960; Laragh, Since plasma renin concentration increases Ulick, Januszewicz, Deming, Kelly and during sodium deprivation, and following Lieberman, 1960 b), alithough this may not be treatment with thiazides or spironolactone (see invariable (Fitzgerald, Fourman, James and above), it is possible that these antidiuretic Scarborough, 1957). responses in diabetes insipidus may at least in Measurements of blood- or plasma-volume http://pmj.bmj.com/ part be the result of an increase in endogenous have given normal or reduced values, in angiotensin (Brown, Lever and Robertson, 1965 contrast to the typically increased plasma- j). When we made this suggestion, we pointed volume of primary hyperaldosteronism (Yam- out that the phenomenon has been observed in auchi, Biglieri and Hopper, 1961; Slaton and both vasopressin-sensitive and vasopressin-re- Biglieri, 1965). In the cases reported by Fitz- sistant diabetes insipidus. Very shortly after this, gerald and others (1957) and by Goldiberg and

Brodehl and Gellisen (1966) reported a case of McCurdy (1963) the hyponatraemia could not on September 30, 2021 by guest. Protected vasopressin-resistant diabetes insipidus in which be explained on the basis of the external -balance angiotensin infusion reduced polyuria and in- of electrolytes or water. Whilst the exchangeable creased urine osmolality. potassium was distinctly low in the patient of Extracellular Sodium Depletion Fitzgerald and olthers (1957), exchangeable A rather different explanation of the hypo- sodium was more nearly normal. The sodium natraemia observed in some diseases could be content of skeletal muscle was abnormally high that it represents a loss of sodium from the in this case, whilst potassium was markedly extracellular compartment. reduced. Infused angiotensin is natriuretic in severe hypertension (Nijensohn, 1957; Peart, 1959; Speculations on the Pathogenesis of the Peart and Brown, 1961; Brown and Peart, 1962; Hyponatraemic Hypertensive Syndrome Brown and others, 1964 m), in cirrhotic ascites, In order to understand the pathogenesis of and in normal subjects deprived of sodium this syndrome, detailed studies during its (Laragh, 1 962a; Laragh, Cannon, Bentzel, development and resolution are required since Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from

March, 1966 BROWN, DAVIES, LEVER & ROBERTSON: Renin & Angiotensin 167 compensatoiry mechanisms probably obscure may remain within the normal range in patients the picture in the established condition. How- with hypertension and hyponatraemia (Fitz- ever, the hyponatraemia in this syndrome may gerald and others, 1957; Brown and colleagues, be explained by one or more of the following unpublished observations), suggests that a mechanisms. marked loss of sodium from the body is (i) External Loss of Sodium: Although not the sole factor in the development of this metabolic balance data in these patients are condition. Furthermore, the observation of a scanty, the urinary excretion of sodium seemed marked fall in plasma sodium concentra;tion in inappropriately high in several reported cases. severely hypertensive patients, without a This observation raises the possibility that the corresponding change in external sodium hyponatraemia is related to a negative external balance (Fitzgerald and others, 1957), implies sodium balance, and that the raised plasma an internal redistribution of sodium, and/or renin concentnation is a secondary event, which water. This suggestion is supported 'by the in turn leads to an increase in aldosterone report that the sodium content of skeletal secretion, ito restriction of further sodium loss muscle was abnormally high in a patient with and to potassium depletion. In favour of this this syndrome (Fitzgerald and others, 1957) suggestion is the report that blood and plasma and by the observation that the sodium content volume are reduced in patients of this type of arterial or arteriolar walls is increased in (Slaton and Biglieri, 1965). both experimental and clinical hypertension (see Tobian, 1960 b). This change might be An increased excretion of sodium in these a consequence of the high plasma renin patients might be explained by the observation concentration since, in the rat, infusion of that an experimental increase in mean renal angiotensin leads to an increase in arterial wall artery pressure leads to an increase in sodium sodium (Friedman and Friedman, 1964). The excretion (Selkurt, 1951), and that, in man, rising blood levels of aldosterone might also sodium excretion and arterial blood pressure contribute to internal movemen-ts of sodium andby copyright. are correlated (Green and Ellis, 1954). This potassium (see Woodbury and Koch, 1957; mechanism would provide a ready explanation Bush, 1962). As far as we are aware, the plasma for the additional observation that the plasma concentration of ADH has not been measured in concentration of both sodium and renin can an increase be returned to normal when the blood pressure these patients, but (see below) could is lowered by surgical treatment (Goldberg and also contribute ito a movement of sodium into McCurdy, 1963; Barraclough and others, 1965; cells (Friedman and Friedman, 1964). Brown and others, 1966 k), or -by hypotensive (iii) Dilutional Hyponatraemia. It might be

drugs in patients with severe hypertension due argued that water retention due to the action http://pmj.bmj.com/ to several causes, including unilateral renal of ADH could contribute to the observed artery stenosis (Gill, George, Solomon and hyponatraemia, since blood volume is reduced Bartter, 1964; Brown, Davies, Lever and in patients of this type (Slaton and Biglieri, Robertson, 1966 k). 1965), and there is evidenoe that 'this change As an alternative explanation, it could be leads to an increase in circulating vasopressin argued that the hyponatraemia follows the rise (Weinstein, Bern and Sachs, 1960; Share, 1962). in plasma renin concen-tration, since a sodium However, measurements of urine and plasma diuresis occurs during brief angiotensin osmolality in these patients (Goldberg and on September 30, 2021 by guest. Protected infusions in patients with severe hypertension McCurdy, 1963) do not suggest vasopressin (Nijensohn, 1957; Brown and Peart, 1962). activity, although interpretation is difficult since, It should be noted, however, that in these in general, patients with hypokalaemia are experiments, the increase in urine volume relatively insensitive to vasopressin. exceeded that required for solute excretion, so Dilution due to increased fluid intake may that the hyponatraemia cannot be explalined also contribute to the fall in plasma sodium by this mechanism alone. Furthermore, when since many authors have remarked on the small amounts of angiotensin were infused into development of exoessive thirst in various hypo- hypertensive patients during periods varying natraemic syndromes (McCance, 1936; see also from 1-10 days, the diuretic response was not Strauss, 1957 and Wolf, 1958), including that maintained, and a fall in plasma sodium was associated with severe hypertension (Goldberg not observed (Brown, 1963). and ;McC-urdy, 1963. Furthermore, many des- (ii) Internal Movement of Sodium. The criptions of clinical potassium depletion mention demonstration that total exchangeable sodium thiirst witth the other symptoms (Black, 1964 b). Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from 168 POSTGRADUATE MEDICAL JOURNAL March, 1966 Relationship Between Plasma Renin Con- angiotensin) required to produce an increase centration and the Pressor Sensitivity to in arterial pressure are positively related. This Injected Renin and Angiotensin inter-connexion might be anticipated also from In recent years studies of the renin- the observation (see Gaddum, 1959; Blacket angiotensin-aldosterone system have brought and others, 1950) that the pressor effect of an into prominence two associations. Plasma renin administered substance varies with the logarithm concentration has been shown to be inversely of the dose*. Thus small absolute increments related to sodium balance (and usually, but not in plasma renin concentration might affect the invariably, to plasma sodium conoentration); blood pressure in conditions in which renin is while the state of sodium balance is positively low (such as primary hyperaldosteronism), related to the pressor effect of infused (or whilst a large increase in renin would be needed injected) renin and angiotensin* (see Fried- to produce a pressor effect when the circulating man, Butt and Friedman, 1957; Johnston renin was high (as in Addison's disease). and Jose, 1963; Brown and others, 1963 f, g, Kaplan and Silah (1964) similarly suggested 1964 f, 1965 f, Imbs and others, 1966; Fried- that the sensitivity to infused angiotensin might man and Friedman, 1964; Ostrovsky and Gorn- reflect its plasma concentration. It must, how- all, 1964; Halpern, Meyer, Mililiez and Lagrue, ever, be emphasized that an explanation of 1964; Kuchel, Horky, Pazourek and Gregorova, this kind presupposes that the concentration 1964 a; Kuchel, 'Horky, Kapitola and Motlik. of renin in plasma is within a range capable 1964 b; Ames, Borkowski, Sicinski and Laragli, of affecting blood pressure. 1965). A third relationship therefore implied is This important proviso has recently been that the amount of renin or angiotensin required tested in experiments in which pressor infusions to produce a given rise in arterial pressure is of renin into the rabbit (Imbs, Brown, Davies, related positively to 'the prevailing plasma con- Lever and Robertson, 1966) and of angio- centrations of these substances. tensin into man i(Mulrow, 1964) were associated This is supported by several observations. with three-fold ito four-fold increases in the by copyright. It has been suggested, for example, that patients plasma concentrations of these substances, with primary hyperaldosteron;ism, and normal changes which !are not large in relation to the subjects replete with sodium, are particularly wide range of plasma level found in different sensitive to the pressor effects of angiotensin clinical circumstances. These infusions were, (see Biron and others, 1962; Kaplan and Silah, of course, acute experiments performed in 1964). Plasma renin concentration has been conditions of normal sodium balance. shown to be depressed in both these situations Conclusions (see Brown and others, 1963 e, f, g, 1964 e, f, g). It seems entirely possible on the present

Conversely, ithe pressor effects of angiotensin evidence that renin and angiotensin may be http://pmj.bmj.com/ are apparently reduced in several conditions- responsible in several ways, (including a direct pregnancy (see Chesley, 1965), cirrhotic ascites pressor action) for the maintenance of a normal (Johnston and Jose, 1963; Laragh and others, blood pressure and for the development of renal 1963; Kaplan and Silah, 1964), sodium hypertension, despite the wide range of plasma deprivation (Ames and others, 1965), Addison's levels found in various circumstances. disease (Kuchel and others, 1964 a), and the Several lines of research have indicated that syndromes reported by Bartter, Pronove, Gill, sodium is tan important factor in the pathogene- MacCardle and Diller (1962) and Desmit sis of hypertension, and a number of attempts on September 30, 2021 by guest. Protected (1964) (see also Bryan, Kliman, Gill and have been made in recent years to synthesize the Bartter, 1964; and Fraser and others, 1966)- in all of which plasma renin concentration has *It should be borne in mind that the infusion of a been shown to be raised. very large dose of renin or angiotensin results in Where measurements are available therefore, an initial rise in arterial pressu!re which is, however, it is seen that the plasma renin concentration not sustained, the pressure rapidly declining to and the quantity of exogenous renin (or basal levels as the infusion continues (see Braun- Menendez, 1956; Taggart and Drury, 1940; Blacket and others, 1950; Langford and Allison, 1961; Brown, 1963; Brown, Chapuis and Robertson, 1964a). *While it must be appreciated that changes in plasma This failure of pressor responsiveness, which has renin concentration do not necessarily cause parallel been termed "tachyphylaxis" cannot, at least in changes in angiotensin, in order to simplify the the rabbit, be due to changes in external sodium following discussion it has been assumed that in balance, since we have observed it after bilateral most of the conditions mentioned renin and nephrectomy (Brown, Davies, Doak, Lever and angiotensin levels move in the same direction. Robertson, unpublished). Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from

March. 1966 BROWN. DAVIES. LEVER & ROBERTSON: Renin & Anviotensin 169 available evidence into a uniform concept (see BENELLI, G., DELLA BELLA, D. and GANDINI, A. & Richardson, Borst (1964): Angiotensin and Peripheral Sympathetic Floyer 1961; Dahl, 1963; Nerve Activity, Brit. J. Pharmaeol., 22, 211. & IBorst-de Geus, 1963; Borst, Smorenberg- BING, J. and WIBERG, B. (1958): Localisation of Schoorl, van Leeuwen & de Vries, 1963; Wil- Renin in the Kidney, Acta path. microbiol. scand., son, 1963; Langford, 1963; Ledingham, 1964; 44, 138. & Cohen, The relation of BING, J. (1963): Morphological and Histochemical Ledingham 1964). Aspects of the Renin-angiotensin System. Boer- these ideas to the present suggestions will be haave Symposium: Hypertension. 'Edited !by J. discussed in more detail elsewhere (Brown, de Graeff, pp. 3-21. Leyden University. Lever & Robertson, 1966j), but it is probable BIRON, P., KOIW, E.,NOWACZYNSKI, W., BROUILLET, for reasons one in J., and GENEST, J. (1961): The Effects of Intra- that, already given, way venous Infusions of Valine-5 Angiotensin II and which sodium retention may provoke hyper- other Pressor Agents on Urinary Electrolytes and tension is by "sensitising" the animal to the Corticosteroids, including Aldosterone, J. clin. pressor effects of angiotensin. The pressor sensi- Invest., 40, 338. thus is as as the ab- BIRON, P., CHRETIEN, M., KOIW, E., and GENEST, J. tivity probably important (1962): Effects of Angiotensin Infusions on solute level of renin or angiotensin. Aldosterone and Electrolyte Excretion in Normal This work was 'supported Iby grants from the Subjects and Patients with Hypertension and Medical Research Coundil, the British Heart Founda- Adrenocortical Disorders, iBrit. med. J., 1, 1569. tion, the Wellcome Trust, Ithe Endowment Fund, BLACK, D. A. K. (1964a): Cardiac Edema, Amer. St. Mary's IHospital, an'd Pfizer Limited. Heart J., 68, 435. We are gratefull to IDrs. Jill IM'cCusker, P. iB. Doak, BLACK, D. A. K. (1964b): Essentials of Flu'id V. Johnston, IM. Davey, H. !Reinert, W. Kriz, S. L. Balance, 3rd Edn. Oxford: IBlackwell. Skinner, tR. D. Lowe and J. (R. Vane for allowing BLACK, D. A. K. (1965): Renal Rete Mirabile, Lancet us to refer to collaborative 'studies not yet published. ii, 1141. ,REFERENCES BLACKET, R. B., DEPOORTER, A., PICKERING, G. W., AMES, R. P., (BORKOWSKI, A. 'J., SICINSKI, A. 'M. and SELLERS, A. L. and WILSON, G. M. (1950): LARAGH, J. H. (1965): Prolonged Infusions of Hypertension Produced in the Rabbit by Long Angiotensin II and Norepinephrine and Blood Continued Infusions of Renin, Clin. Sci., 6, 295. Pressure, Electrolyte Balance, and Aldosterone BLAIR-WEST, J. R., COGHLAN, J. P., DENTON, D. A., by copyright. and Cortisol Secretion in Normal Man and in GODING, J. R. MUNRO, J. A., PETERSON, R. E. Cirrhosis with Ascites, J. clin. Invest., 44, 1171. and WINTOUR, M. i(1962): Humoral Stimulation BARRACLOUGH, M. A., BACCHUS, B., BROWN, J. 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Homoeostatic Reaction to Deficient Sodium Churchill. Excretion. Boerhaave Symposium: Hypertension. BARTTER, F. C., CASPER, A. G. T., DELEA, C. and Ed. J. de Graeff, pp. 118-135. Leyden University. SLATER, J. D. M. 1(1961): On the Role of the BoTT, P. A. (1962): Micropuncture Study of Renal Kidney in the Control of Adrenal Steroid Excretion of Water, K, Na, and Cl in Necturus, Production, Metabolism, 10, 1006. Amer. J. Physiol., 203, 662. BARTTER, F. C., LIDDLE, G. W., DUNCAN, L. E., BOUCHER, R., BIRON, P. and GENEST, J. (1961): BARBER, J. K. and DELEA, C. (1956): The Procedure for Isolation and Determination of on September 30, 2021 by guest. Protected Regulation of Aldosterone Secretion in Man; Human IBlood Angiotensin, Canad. J. Biochem., the Role of Fluid Volume, I. clin. Invest., 35, 39, 581. 1306. BOUCHER, R., VEYRAT, R. DE CHAMPLAIN, J. and BARTrER, F. C., MILLS, I. H., BIGLIERI, E. G. and GENEST, J. (1964): New Procedures for Measure- DELEA, C. (1959): Studies on the Control and ment of Human Plasma Angiotensin and Renin Physiologic Action of Aldosterone, Recent Progr. Activity Levels, Canad. Med. Ass. J., 90, 194. Hormone Res., 15, 311. BOUGAS, J., FLOOD, C., LITTLE, B., TAIT, J. F., TAIT, BARTTER, F. C., PRONOVE, P., GILL, J. R., S. A. S. and UNDERWOOD, R. (1964): Dynamic MACCARDLE, R. C. and DILLER, E. (1962): Aspects of Aldosterone Metabolism. Aldosterone, Hyperplasia of the Juxtaglomerular Complex with Edited by E. E. Baulieu and P. Robel, pp. 25-50. Hyperaldosteronism and Hypokalaemic Alkalosis, Oxford: Blackwell. Amer. J. Med., 33, 811. BRAUN-MENENDEZ, E., FASCIOLO, J. C., LELOIR, L. F. BAEUR, J. and ASCHNER, B. (1924): Die and MUNOZ, J. M. (1940): Farmacologia de la Therapeutische Wirkung des Novasurols bei Hipertensina, Rev. Soc. argent. Biol., 16, 398. Diabetes Insipidus,Zbl. inn. Med., 45, 682. BRAUN-MENENDEZ, E., FASCIOLO, T. C., LELOIR, L. F., BEASER, S. B. (1947): Renal Excretory Function and MUNOZ, J. M., and TAQUINI, A. C. (1946): Renal Diet in Diabetes Insipidus, Amer. J. med. Sci., 213, Hypertension. Translated by L. Dexter. Springfield, 441. Illinois: Charles C. Thomas. Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from 170 POSTGRADUATE MEDICAL JOURNAL March, 1966 BRAUN-MENENDEZ, E. (1956): Pharmacology of ROBERTSON, J. I. S. (1964 f): Variations in Plasma Renin and Angiotensin, Pharmacol. Rev., 8, 25. Renin Concentration in Several Physiological and BRODEHL, J., and GELLISSEN, K. (1966): Die Pathological States, Canad. med. Ass. J., 90, 201. antidiureti,sche Wirkung des Angiotensins beim BROWN, J. J., DAVIES, D. L., LEVER, A. F. and Diabetes insipidus, Klin. Wschr., 44, 101. ROBERTSON, J. I. S. (1964 g): Influence of Sodium BROWN, J. J., OWEN, K., PEART, W. S., ROBERTSON, Deprivation and Sodium Loading on the Plasma- J. I. S. and SUTTON, D. (1960): The Diagnosis and renlin in Man, J. Physiol. (Lond.), 170, 408. Treatment of iRenal Artery Stenosis, Brit. med. J., BROWN, J. J., DAVIES, D. L., LEVER, A. F. and ii, 327. ROBERTSON, J. I. S. (1964 h): Variations in Plasma BROWN, J. J. and PEART, W. S. (1962): Effect of Renin During the Menstrual Cycle, Brit. med. J., Angiotensin on Urine Flow and Electrolyte ii, 1114. Excretion in Hypertensive Patients, Clin. Sci., 22, 1. BROWN, J. J., DAVIES, D. L., LEVER, A. F. and BROWN, J. J. (1963): Actions of Angiotensin on the ROBERTSON, J. I. S. (1964 j): The Assay of Renin Circulation, Mem. Soc. Endocrin. No. 13 in Single Rabbit Glomeruli, J. Physiol. (Lond.), "Hormones and the Kidney". Edited by P. C. 171, 32P. Williams, pp. 303-316. London: Academic Press. BROWN, J. J., DAVIES, D. L., LEVER, A. F., BROWN, J. J., CHAPUIS, G. and ROBERTSON, J. I. S. ROBERTSON, J. I. S. and TREE, M. (1964 k): The (1963 a): Effect of Long-continued Intravenous Estimation of Renin in Human Plasma, Biochem. Infusions of Angiotensin in the Rabbit, Lancet, 1, /., 93, 594. 1356. BROWN, J. J., DAVIES, D. L., LEVER, A. F., BROWN, J. J., DAVIES, D. L., DOAK, P. B., LEVER, ROBERTSON, J. I. S. and TREE, M. (1964 1): The A. F. and ROBERTSON, J. I. S. (1963b): Plasma- Estimation of Plasma Renin Concentration in the renin in Normal Pregnancy, Lancet, ii, 900. Dog, Biochem. J., 93, 3C. BROWN, J. J., DAVIES, D. L., LEVER, A. F., PARKER, BROWN, J. J., MATrHEW, 'G. K. and ROBERTSON, J. R. A. and 'ROBERTSON, J. I. S. ('1963c): Assay I. S. (1964 m): The Effect of Angiotensin on the of Renin in Single Glomeruli, Lancet, ii, 668. Function of the Separate Kidneys in Patients with BROWN, J. J., DAVIES, D. L., LEVER. A. F., PARKER, Unilateral Renal Artery Stenosis, Clin. Sci., 26, R. A. and ROBERTSON, J. I. S. (1963d): Renin 381. Distribution in ,the Normal Rabbit Kidney. Boer- BROWN, J. J., DAVIES, D. L., DOAK, P. B., LEVER, haave Symposium: Hypertension, Ed. J. de Graeff, A. F., ROBERTSON, J. I. S. and TRUST, P. (1965 a):

pp. 222-226. Leyden University. Plasma Renin in the Hypertensive Disease ofby copyright. BROWN, J. J., DAVIES, D. L., LEVER, A. F. and Pregnancy, Lancet, ii, 1219. ROBERTSON, J. I. S. i(1963e): Influence of Sodium BROWN, J. J., DAVIES, D. L., LEVER, A. F., LLOYD, Loading and Sodium Depletion on Plasma-renin A. M., ROBERTSON, J. I. S. and TREE, M. (1965 b): in Man, Lancet, ii, 278. Renin-like Enzyme in Normal Human Urine, Urol. BROWN, J. J., DAVIES, D. L., LEVER, A. F. and Digest, 4, 18. ROBERTSON, J. I. S. (1963f): Plasma Renin in BROWN, J. J., DAVIES, D. L., LEVER, A. F., PARKER, Hypertension, Boerhaave Symposium: Hyper- R. A. and ROBERTSON, J. I. S. (1965 c): The tension. Ed. J. de Graeff, pp. 44-48. Leyden Assay of Renin in Single Glomeruli in ,the Normal University. Rabbit and the Appearance of ,the Juxtaglomerular BROWN, J. J., DAVIES, D. L., LEVER, A. F. and Apparatus, J. Physiol. t(Lond.), 176, 418. J. I. S. Plasma Renin in J. D. A. ROBERTSON,, (1963 g): BROWN, J., DAVIES, L., LEVER, F., PEART, http://pmj.bmj.com/ Relation to Alterations in Sodium Metabolism, W. S. and ROBERTSON, J. I. S. (1965 d): Plasma Boerhaave Symposium: Hypertension, Ed. J. de Concentration of Renin in a Patient with Conn's Graeff, pp. 216-221. Leyden University. Syndrome with Fibrinoid Lesions of the Renal BROWN, J. J., CHAPUIS, G. and ROBERTSON, J. I. S. Arterioles; the Effect of Treatment with Spirono- (1964 a): The Effect of Prolonged Intravenous lactone, J. Endocr., 33, 279. Infusion of Angiotensin in the Rabbit, Clin. Sci., BROWN, J. J., DAVIES, D. L., LEVER, A. F. and 26, 165. ROBERTSON, J. I. S. (1965 e): Plasma Renin in BROWN, J. J., DAVIES, D. L., DOAK, P. B., LEVER, Hypertension and in a Patient with Oversecretion A. F., ROBERTSON, J. I. S. and TREE, M. (1964 b): of ADH, J. Endocr., 32, v-vii. The Presence of Renin in Human Amniotic Fluid, BROWN, J. J., DAVIES, D. L., LEVER, A. F. and on September 30, 2021 by guest. Protected Lancet, ii, 64. ROBERTSON, J. I. S. (1965 f): Relationship between BROWN, J. J., DAVIES, D. L., LEVER, A. F. LLO\'D, Sodium Balance, Renin and Aldosterone in A. M., ROBERTSON, J. I. S. and TREE, M. (1964 c): Physiological and Pathological Situations in Man. A Renin-like Enzyme in Normal Human Urine, CIHTA Symposium on Hypertension. Ed. P. Lancet, ii, 709. Tdherdakoff. Paris: Expansion Scientifique. BROWN, J. J., DAVIES, D. L., LEVER, A. F., PARKER, BROWN, J. J., DAVIES, D. L., LEVER, A. F. and R. A. and ROBERTSON, J. I. S. (1964 d): ROBERTSON, J. I. S. (1965 g): Plasma Renin Distribution of the Juxtaglomerular Granulation Concentration in Human Hypertension. I. Relation- and the Renin Content by Assay of Single ship between Renin, Sodium, and Potassium, Brit. Glomeruli in the Rabbit, Ned. T. Geneesk., 108, med. J., ii, 144. 2378. BROWN, J. J., DAVIES, D. L., LEVER, A. F. and BROWN, J. J., DAVIES, D. L., LEVER, A. F., PEART, ROBERTSON, J. I. S. (1965 h). Plasma Renin W. S. and ROBERTSON, J. I. S. (1964 e): Plasma Concentration in Human Hypertension. II. Renin Renin in a Case of Conn's Syndrome with Fibrinoid in Relation to Aetiology, Brit. med. J., ii, 1215. Lesions: Use of Spironolactone in Treatment, BROWN, J. J., LEVER, A. 'F. and ROBERTSON, J. I. S. Brit. med. J., ii, 1636. (1965 J): Renin in Diabetes Insipidus, Lancet, ii, BROWN, J. J., DAVIES, D. L., LEVER, A. F. and 1349. Postgrad Med J: first published as 10.1136/pgmj.42.485.153 on 1 March 1966. Downloaded from March, 1966 BROWN, DAVIES, LEVER & ROBERTSON: Renin & Angiotensin 171 BROWN, J. J., DAVIES, D. L., DOAK, P. B., LEVER, LUETSCHER, J. A. (1965): Decreased Plasma A. F. and ROBERTSON, J. I. S. (1966 a): Changes Clearance and Hepatic Extraction of Aldosterone in Plasma Renin Concentration throughout Normal in Patients with Heart Failure, J. clin. Invest.. Pregnancy and Following Parturition, J. Endocr. 44, 356. in Press. CARPENTER, C. C. J., DAVIS, J. O., AYERS, C. R. BROWN, J. J., DAVIES, D. L., DOAK, P. B., LEVER, and CASPER, A. (1961): Relation of Renin, Angio- A. F., ROBERTSON, J. I. S. and TRUST, P. (1966 b): tensin II and Experimental Renal Hypertension to Plasma Renin Concentration in the Hypertensive Aldosterone Secretion, J. clin. Invest., 40, 2026. Disease of Pregnancy, J. Obstet. Gynaec. Brit. CHASE, S. W. (1923): The Mesonephros and Uro- Cwlth. (in press). genital Ducts of Necturus Macalosus, Rajinesque, BROWN, J. J., FRASER, R., JAMES, V. H. T., LEVER, J. Morph., 37, 457. A. F., MCCUSKER, J. and ROBERTSON, J. I. S. (1966 CHESLEY, L. C. (1965): Renal Function in Pregnancy, c): The Effect of Steroid Replacement Therapy Bull. N.Y. Acad. Med., 41, 811. on Electrolyte Balance and Plasma Renin in CHESTER JONES, I., HENDERSON, I. W., CHAN, D. K. Addison's Disease (in preparation). O., RANKIN, J. C., MOSLEY, W., BROWN, J. J., BROWN, J. J., DAVIES, D. L., LEVER, A. F. and LEVER, A. F., ROBERTSON, J. I. S. and TREE, M. ROBERTSON, J. I. S. (1966d.): Plasma Renin (1966): Pressor Activity in Extracts of the Concentration in Human Hypertension. III. Renin Corpuscles of Stannius of the European Eel, J. in Relation to Complications of Hypertension, Endocr., 34, (in press). Brit. med. J., i, 505. CONN, J. W., COHEN, E. L. and ROVNER, D. R. BROWN, J. J., DAVIES, D. L., JOHNSTON, V., LEVER, (1964 a): Suppression of Renin Activity in Primary A. F. and ROBERTSON, J. I. S. (1966 e): Plasma Aldosteronism, J. Amer. med. Ass., 190, 213. Renin Concentration in Cardiac Failure. (In CONN, J. W., KNOPF, R. F. and NESBIT, R. M. preparation). (1964 b): Primary Aldosteronism: Present BROWN, J. J., DAVIES, D. L., LEVER, A. F., Evaluation of its Clinical Characteristics and of MCPHERSON, D. and ROBERTSON, J. I. S. (1966 f): the Results of Surgery. Aldosterone. Eds. E. E. Effect of Posture on Plasma Renin Concentration, Baulieu and P. Robel. pp. 327-352. Oxford: Clin. Sci., 30, 279. Blackwell. BROWN, J. J., DAVIES, D. L., LEVER, A. F., PARKER, COOK, W. F., GORDON, D. B. and PEART, W. S. R. A. and ROBERTSON, J. I. S. (1966 g): The (1957): The Location of Renin in the Rabbit Assay of Renin in Single Glomeruli and the J. Kidney, Physiol. (Lond.), 135, 46P. by copyright. Appearance of the Juxtaglomerular Apparatus in COOK, W. F. and PICKERING, G. W. (1959): The the Rabbit following Renal Artery Constriction, Location of Renin in the Rabbit Kidney, J. Physiol. Clin. Sci., 30, 223. (Lond.), 149, 526. BROWN, J. J., DAVIES, D. L., LEVER, A. F. and COOK, W. F. (1960): Further Observations on the ROBERTSON, J. I. S. (1966 h): Factors Controlling Location of Renin in the Rabbit Kidney, J. Physiol. the Concentration of Renin in Plasma. Proceedings (Lond.), 152, 27P. of the German Speaking Society for Nephrology COOK, W. F. ((1963): Renin and the Juxtaglomerular (in press). Apparatus, Mem. Soc. Endocrin. No. 13 BROWN, J. J., LEVER, A. F. and ROBERTSON, J. I. S. 'Hormones and the (1966 j): IRenin. London: Edward Arnold. To be Kidney" Edited by P. C. published. Williams. pp. 247-254. London: Academic Press. J. COOK, W. F. and LEE, M. R. (1965): The Preparation BROWN, J., DAVIES, D. L., LEVER, A. F. and of http://pmj.bmj.com/ ROBERTSON, J. I. S. (1966 k): Plasma Renin Rabbit Renin Substrate for the Assay of Minute Concentration in Human Hypertension. IV. Renin Amounts of Renin, Biochem. J., 96, 413. in Relation to Treatment, Brit. med. J. (in press). CROXATTO, H., BARNAFI, L. and PASSI, J. (1952): BROWN, J. J., DAVIES, D. L., LEVER, A. F. and Effect of Renin on Diuresis in Rats, Science, 116, ROBERTSON, J. I. S. ,(1966 1): Variation of Plasma 507. Renin Concentration during a 24 hour Period, J. DAHL, L. K. (1963): Metabolic Aspects of Hyper- Endocr., 34, 129. tension, Ann. Rev. Med., 14, 69. BROWN, J. J., DAVIES, D. L., LEVER, A. F. DAVIS, J. 0. (1962): The Control of Aldosterone ROBERTSON, J. I. S. and VERNIORY, A. (1966 m): Secretion, Physiologist, 5, 65. Effect of Haemorrhage on Plasma Renin Concen- DAVIS, J. 0. (1963): The Importance of the Renin- on September 30, 2021 by guest. Protected tration in Man and the Dog, J. Physiol. (Lond.) angiotensin System in the Control of Aldosterone 182, 1649. Secretion. Mem. Soc. Endocrin. No. 13 "Hormones BRYAN,, G. T., KLIMAN, B., GILL, J. R., and BARTTER, and the Kidney". Ed. P. C. Williams. pp. 325-339. F. C. (1964): Effect of Human Renin on Aldo- London: Academic Press. sterone Secretion Rate in Normal Man and in DAVIS, J. O., URQUHART, J. and HIGGINS, J. T. Patients with the Syndrome of Hyperaldosteronism, (1963): The Effects of Alterations of Plasma Juxtaglomerular Hyperplasia, and Normal Blood Sodium and Potassium Concentration on Aldo- Pressure, J. clin. Endocr., 24, 729. sterone Secretion, J. clin. Invest., 42, 597. BUMPUS, F. M. (1965): Factors Affecting Formation DEANE, H. W., and MASSON, G. M. C. (1951): Adrenal and Destruction of Angiotensin. 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