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The Renin-Angiotensin System and the Heart: a Historical Review Heart: First Published As 10.1136/Hrt.76.3 Suppl 3.7 on 1 November 1996

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The Renin-Angiotensin System and the Heart: a Historical Review Heart: First Published As 10.1136/Hrt.76.3 Suppl 3.7 on 1 November 1996 Heart (Supplement 3) 1996;76:7-12 7 The renin-angiotensin system and the heart: a historical review Heart: first published as 10.1136/hrt.76.3_Suppl_3.7 on 1 November 1996. Downloaded from Stephen J Cleland, John L Reid Early observations on a possible link effect but was in fact an enzyme. The names between the kidney and the "hypertensin""l and "angiotonin"12 were given cardiovascular system to the pressor substance formed from the renin In 1836 an English clinician Richard Bright substrate by the enzymatic action of renin. observed that patients dying with contracted Subsequently, it was agreed that the term kidneys often had a hard, full pulse and cardiac "angiotensin" would be used to describe this hypertrophy.' In 1889 Brown-Sequard, the substance. During this period the potential for "father" of endocrinology, showed that injec- pathological effects of renin was recognised. tions of extracts from guinea pig testicles were Winternitz described necrotising arteriolar able to produce systemic effects of vigour and lesions in animals which had undergone renal the perception of rejuvenation.2 On this back- artery ligation and also in nephrectomised ani- ground, in 1896 the Finnish physiologist mals which had been given kidney extracts.'3 Robert Tigerstedt and his student Per Finally, the relevance of renal control of blood Bergman began to explore the possibility that pressure in man was described by Young who, kidney extracts from rabbits may have some in 1936, cured a case of malignant hyperten- systemic effects on the cardiovascular system. sion by removing an ischaemic kidney.'4 In 1898 their classic paper was published showing that intravenous injection of these renal extracts exerted a pressor effect. The elucidation of the renin-angiotensin Moreover they postulated that the substance system responsible for this effect was a protein which In 1956, Elliott and Peart'5 and Skeggs and they named renin. They further suggested that colleagues'6 discovered that the product of renin was released from the kidney into the renin action was a decapeptide which required blood to produce an effect on blood vessels at a further enzymatic breakdown to form the distance: another of the earliest ideas on blood active pressor substance, an octapeptide. Based borne chemical messengers.34 Eight years later on these results the terms angiotensin I, Tigerstedt described a pressor effect of renal angiotensin II, and angiotensin converting venous blood although he admitted that the enzyme (ACE) were coined. In the following evidence for this was weak.5 Other groups year the structure of renin substrate was shown http://heart.bmj.com/ could not reproduce Tigerstedt's results, prob- to be a tetradecapeptide'7 which was later ably because they failed to prevent proteolysis referred to as angiotensinogen. Concurrent in the preparation of the renal extracts. with the discovery of the structure for Therefore enthusiasm for the concept of renin angiotensinogen, angiotensin II was synthe- as a pressor substance waned. Tigerstedt died sised'8 which enabled further definition of its in 1923 without any real acknowledgment of actions. However, it was not until the early the significance of his contribution to the fields 1970s that the mechanism of action of renin, of both endocrinology and cardiovascular as an acid protease with very narrow substrate on September 28, 2021 by guest. Protected copyright. homeostasis. In fact for 30 years there were few specificity, was described.'9 references to the pressor effects of renin in the Meanwhile the idea of a relation between literature. In 1925, the histologist Ruyter was the renin-angiotensin system and the adrenal the first to describe granulated cells in the walls cortex was evolving. In 1953, aldosterone was of the glomerular arterioles.6 The significance discovered.20 The following year Gross showed of this was realised by Goormaghtigh in 19397 an enhanced pressor response to renin in ani- after the concept of renin as a hormone had mals with bilateral nephrectomy and in those been rekindled. with "DOCA-salt" induced hypertension. Another group observed that the amount of granules in the juxtaglomerular apparatus cor- The rediscovery of renin as a pressor related with the width of the zona glomerulosa hormone of the adrenal cortex.2' In 1956, Gross showed Department of In 1934, Goldblatt showed in animal models that the amount of renin in the juxtaglomerular Medicine and Therapeutics, that clamping of the renal arteries raised blood apparatus was inversely proportional to the Gardiner Institute, pressure.8 This stimulated a series of important sodium balance; two years later he went on to Western Infirmary, papers over the next six years. Pickering suggest that the renin-angiotensin system par- Glasgow, Scotland S J Cleland described the partial purification of renin and ticipated in a negative feedback mechanism J L Reid its ability to increase blood pressure.9 Landis with the adrenal cortex to control sodium Correspondence to: also showed that renal extracts had a pressor metabolism.22 Subsequent studies confirmed Dr Stephen J Cleland, 40 year old this hypothesis. Renin and angiotensin II were Department of Medicine and effect,'0 confirming Tigerstedt's Therapeutics, Gardiner results. Braun-Menendez and colleagues" and shown to stimulate aldosterone secretion in Institute, Western Infirmary, and colleagues'2 that renin itself sheep23 and in dogs.24-26 Laragh found Glasgow G1 1 6NT, Page proposed United Kingdom. was not directly responsible for its pressor increased urinary aldosterone excretion in man 8 Cleland, Reid during infusion of angiotensin II.27 Brown and In 1975, it was shown that renin release in colleagues showed that a low sodium diet in dogs was modulated by cardiopulmonary man led to a raised plasma renin concentra- receptors.47 Further studies revealed that intra- tion28 and vice versa. They also described a venous injections of rat atrial extract induced Heart: first published as 10.1136/hrt.76.3_Suppl_3.7 on 1 November 1996. Downloaded from plasma renin concentration of 10 times that of natriuresis.48 Results from these studies led to normal concentrations in a patient with the isolation of atrial natriuretic factor (ANF) Addison's disease.29 which was found to modulate renin release in a The increasing ability to accurately measure dose dependent fashion. The modulation of the various components of the renin- renin release by ANF was dependent upon angiotensin-aldosterone system allowed further underlying sodium balance and renal func- studies to be conducted to confirm Gross's tion.49 In the context of congestive cardiac fail- hypothesis. Assays for plasma aldosterone lev- ure high concentrations of ANF have been els30 and plasma renin activity3' were described found in man.50 and the development of radioimmunoassays to Two concepts started to emerge concerning measure angiotensin I, angiotensin II, and the link between the renin-angiotensin system plasma renin concentrations followed.3233 and cardiac function. First, myocardial func- Using these techniques, studies performed in tion was affected by the renin-angiotensin sys- the human showed that salt depletion resulted tem directly and not simply as an indirect in increased plasma levels of angiotensin II34 as result of blood pressure changes. Second, the well as sensitising the secretion of aldosterone heart was able to modulate renin release to angiotensin II.3 through ANF and therefore played an integral Through these studies, which spanned a role in the homeostatic control of intravascular period of 25 years, the concept became estab- volume and sodium balance. lished that the renin-angiotensin system was an endocrine pathway linked to aldosterone secre- tion by the adrenal cortex. This pathway pro- The contribution of antagonists and vided a homeostatic control mechanism for inhibitors to the understanding of the sodium balance, intravascular volume, and renin-angiotensin system therefore blood pressure. It also became appar- In 1965, it was noted that venom from a ent that angiotensin II influenced blood pres- Brazilian viper potentiated the effects of sure directly by its vasoconstrictor effect and bradykinin.5' An enzyme had been described a also by an independent more slowly developing few years earlier which inactivated bradykinin52 pressor mechanism.3637 leading to the presumption that substances contained in the snake venom were kininase Early evidence ofa link between the renin- inhibitors. Meanwhile it was found that pep- angiotensin system and cardiac function tides from the same venom were able to inhibit In 1956 it was shown that patients who had ACE.53 From this work emerged the nonapep- suffered a myocardial infarction had increased tide teprotide, which was the first widely used amounts of urinary aldosterone.38 Thirty years ACE inhibitor. Teprotide was shown to lower http://heart.bmj.com/ later it was confirmed that the renin-angio- blood pressure in rats with induced hyperten- tensin system is stimulated in man following sion54 and in sodium depleted dogs.55 The race myocardial infarction, although it was shown to develop an orally active agent began and that there was a delay in this stimulation with a eventually SQ14225 emerged, later to be peak at approximately three days after the known as captopril. In the early 1 970s it infarction.39 In 1972, a study was published became clear that ACE and kininase were the which suggested that patients with essential same enzyme,56 a finding which may have hypertension
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