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,