Journal of Human Hypertension (2000) 14, 649–666 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh REVIEW ARTICLE The renin-angiotensin system in the year 2000 MG Nicholls1 and JIS Robertson2 1Department of Medicine, Christchurch Hospital, Christchurch 1, New Zealand; 2Elmbank, Manse Road, Bowling, Glasgow, UK Keywords: renin-angiotensin system Introduction demonstrating almost certainly, as was later con- firmed, that renin is a protein. Their work further The beginning of the third millennium falls very suggested that renin was released into renal venous close to the centenary of the discovery of the renin- blood so as to cause its pressor effect; it is now angiotensin system. In 1898 Tigerstedt and 1 known that renin is indeed secreted into both the Bergman reported that they had obtained, in both renal vein and renal lymphatics.2 watery and alcoholic extracts of the renal cortex of rabbits, material which had a pressor effect on intra- venous injection. They named this substance ‘renin’. Goldblatt and renovascular hypertension A century later, the renin-angiotensin system is Little further work was performed on renin in the revealed as possessing remarkable biochemical and early years of the 20th century. Then Goldblatt et pharmacological complexity, aspects which have al,5 in 1934, showed that it was possible to produce profound evolutionary implications, as shall be dis- sustained hypertension by applying constricting cussed herein. This system is widely and deeply clamps to the renal arteries. Surprisingly, although involved in diverse physiological and pathological Goldblatt speculated that a humoral substance might processes, such that drugs designed to influence its be involved in the pathogenesis of this form of different aspects have extensive, and still increasing, experimental hypertension, he did not at first con- application. Whilst, just over a century following its sider renin to be a contender. Nevertheless, others discovery, the full physiological and pathological did, and once more renin was successfully extracted significance of the renin-angiotensin system remains from kidneys and partially purified.6 Even so, the even now in several respects imperfectly compre- role of the renin-angiotensin system in the causation hended, its importance cannot be in doubt. of renovascular hypertension eventuated as being remarkably complex, and more than 60 years of Historical review extensive study, and some fierce controversy, were required to clarify the situation, which in certain A historical review2 of advancing knowledge and respects remains still unresolved. These matters will understanding of the renin-angiotensin system was be considered in more detail later. proferred in a chapter of the two-volume study of the system that we edited and which was published in 1993;3 further details on various aspects appear Renin as an enzyme in relevant individual chapters therein. Additional perspectives are given in a celebratory centenary The possibility that renin was an enzyme was raised 7 8 volume.4 The following abbreviated account is larg- by Kohlstaedt et al and by Munoz et al in the late ely derived from those several sources. 1930s. Extensive studies consequently confirmed that renin itself did not have a direct pressor action, but that it acted upon a plasma substrate (now called The discovery of renin angiotensinogen) to form ultimately the vasoactive Tigerstedt and Bergman1 achieved remarkably material subsequently identified as the peptide detailed characterisation in their initial studies, angiotensin II (Figure 1). The comparatively slow and prolonged rise in arterial pressure when renin is injected intravenously is because of the require- ment for the generation of angiotensin II in vivo; this Correspondence: Dr MG Nicholls, Department of Medicine, Christchurch Hospital, Private Bag 4710, Christchurch, New contrasts with the more rapid and briefer rise in Zealand. E-mail: barbara.griffinȰchmeds.ac.nz pressure when preformed angiotensin II itself is Received and accepted 10 April 2000 given. The renin-angiotensin system in the year 2000 MG Nicholls and JIS Robertson 650 Figure 1 Outline of the biochemistry of the renin-angiotensin system (equine renin substrate is indicated, with the differences in composition in man immediately below). In man, the enzyme, renin, cleaves its substrate (angiotensinogen) between leucine and valine in positions 10 and 11 to form the decapeptide, Ang I. In several other species, both positions 10 and 11 of angiotensinogen are occupied by leucine. Converting enzyme removes residues 9 and 10 (histidine and leucine) to form the active octapeptide, Ang II. Removal of aspartic acid from position 1 forms the heptapeptide, Ang III. In the rat, the 2–10 nonapeptide is present in blood, and Ang III can be formed directly from this nonapeptide by the action of converting enzyme. (From Robertson2,3 with permission.) The renal juxtaglomerular cells renin splits off first a decapeptide, the inactive angiotensin I. Angiotensin I is then cleaved by The Belgian histologist and physiologist Goormagh- angiotensin-converting enzyme (ACE) to form the tigh9 in 1945 recognised the juxtaglomerular cells on main active component of the sytem, the octapep- the renal afferent arteriole to be the principal source tide angiotensin II (Figure 1). The amino acid of renin, as has since been thoroughly confirmed. sequences of bovine and equine angiotensin were elucidated respectively by Elliott and Peart,14 and by Long-term pressor effect of renin Skeggs et al.15 Angiotensin was shortly afterwards 16 Pickering perceived that renin was well suited to synthesised by Schwyzer and colleagues. serve as a long-term regulator of the circulation, and he and his colleagues10 executed experiments of Renin and aldosterone considerable difficulty given the apparatus then 17 available in 1950, demonstrating that intravenous Gross in 1958 formulated the hypothesis that infusion of renin for up to 18 days’ duration could renin, via angiotensin II, was an important stimulus initiate and then sustain hypertension throughout and hence regulator of adrenocortical aldosterone that period. secretion. This notion owed much to the aforemen- tioned histological observations of Goormaghtigh,9 since distinct changes in the prominence and con- The slow pressor effect of angiotensin II figuration of the juxtaglomerular cells were found to Thus far, the pressor action had been studied at take place with alterations in sodium balance. doses sufficient to raise arterial pressure immedi- Gross’s suggestion was thoroughly vindicated by ately, presumably via direct vasoconstriction. In several groups proceeding roughly simultaneously, 1963 Dickinson and Lawrence11 observed that the including those of Davis,18 Genest,19 Laragh,20 and intravenous infusion of angiotensin II at low doses, Mulrow and Ganong.21 having no immediate effect on arterial pressure This discovery gave much impetus to the study of would, over the course of several days, result in a many aspects of the renin-angiotensin system. One gradual, and eventually very marked, rise in press- demerit, however, was that the more important ure. Angiotensin II could thus be shown to elevate range of direct actions of angiotensin II on renal its own acute pressure dose-response curve, such function22 tended for a time to be neglected. that a direct response could be superimposed on a slow rise that had reached a plateau, the combined Renin, angiotensin, and sodium balance effect exceeding that of the maximum simple initial direct response.12 Following closely on the recognition of the renin- angiotensin-aldosterone connection, it was demon- strated23 that sodium restriction caused a rise in Structure of angiotensin plasma renin and angiotensin II, while, conversely, Skeggs et al13 found that the essential component sodium loading depressed plasma renin. of angiotensinogen is a tetradecapeptide from which The physiological relevance of this observation Journal of Human Hypertension The renin-angiotensin system in the year 2000 MG Nicholls and JIS Robertson 651 was then further emphasised by the finding24,25 that (and often remain today) rarely standardised, quan- sodium restriction enhanced the stimulant effect of titative comparison of results over time, or between angiotensin II on aldosterone secretion, while simul- laboratories, was hardly ever possible. taneously depressing the pressor effect, both A different problem arose with some early phenomena obviously helping to promote sodium methods for the assay of plasma renin concentration conservation at a time of its deficiency. (PRC).32,33 During extraction, inactive prorenin could be activated, and such procedures thus gave a measure of total, rather than of active, renin con- Renin and plasma sodium concentration centration. An inverse association between plasma sodium con- While studies employing those early PRA and centration within the last week of life and sub- PRC assays provided much valuable information, sequent granularity of the juxtaglomerular cells at their limitations have inevitably become more post mortem was demonstrated in 24 patients with obtrusive. diverse medical conditions.26 Subsequent workers showed that plasma levels of renin and sodium were Circulating inactive renin (prorenin) related inversely in patients with hypertension and heart failure.27 These associations pointed to func- As mentioned in the foregoing paragraphs, it became tional interactions between activity of the renin-