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Angiotensin II blockade in man by SAR ALA angiotensin II for understanding and treatment of high blood pressure
Abstract
Sar1-ala8-angiotensin II, the octapeptide competitive inhibitor of angiotensin II, was administered intravenously to twelve patients with either renovascular, advanced, or malignant hypertension, or with hypertension of pyelonephritis. In eight patients with increased plasma-renin, angiotensin blockade induced immediate striking and sustained reductions in blood-pressure to nearly normal levels. Large excesses of the drug never produced hypotension. This evidence suggests that angiotensin II was involved in sustaining the high blood-pressure. In contrast, in four patients with either low or normal plasma-renin, the angiotensin inhibitor did not alter blood-pressure. Efficacy of the drug was indicated by the striking increases in plasma-renin induced in all patients. Angiotensin blockade with its apparent lack of toxicity provides a new, safe, more specific and effective approach to diagnosis and treatment of hypertensive situations associated with high renin levels. Also, it seems useful for predicting surgical curability of renovascular hypertension.
... Nearly fifty years ago it was reported that minor structural modifications of AngII yielded peptides capable of acting as antagonists at the AT1 receptor subtype. Two of these compounds, saralasin (Sar1, Ala8-AngII) and sarile (Sar1, Ile8-AngII) were evaluated in clinical trials but were dismissed primarily because of their peptidic structures [104][105][106][107]. Even so these peptides have been useful as research tools that highlighted the importance of the RAS, and particularly the AT1 receptor, in mediating systemic blood pressure [65]. ...
Neurodegenerative diseases are unrelenting, unforgiving and cruel given the long duration of patient suffering due to the impact of progressive damage within specific brain locations. In the case of dementias, there is a direct impact on memory and cognitive processing, and the loss of personal dignity and worth. Ultimately, the patient loses the ability to maintain basic hygiene placing attentional responsibilities on family members and support staff. With respect to neurodegenerative diseases of the eye, the patient must deal with progressive deleterious changes in vision resulting from retinal damage. This review discusses the role of the Renin-Angiotensin System (RAS) in cardiovascular disease, Alzheimer’s and Parkinson’s diseases, Type 2-induced dementia, depression, glaucoma, macular degeneration and diabetic retinopathy. We conclude with a consideration of the challenges posed regarding the development of new drugs designed to treat dementias, depression, and neurodegenerative diseases of the eye. The use of small molecule agonist and antagonist analogs of RAS components is discussed. These analogs can be configured to pass the blood-brain barrier and target relevant receptor proteins in specific brain structures or they can be applied topically to the eye to discourage increases in intraocular pressure, decreased retinal microvascular blood flow, tissue inflammation and oxidative stress as well as the accumulation of extracellular material (drusen) that can disrupt normal vision. Along with suggested drug development strategies, several important drug targets are identified in an effort to focus attention, and facilitate research efforts, to improve drug efficacy and thus provide better clinical outcomes for these patients.
... Eight AT 1 R blockers (ARBs), which stabilize the receptor in an inactive state, have been approved by the FDA and are clinically utilized for the treatment of multiple cardiovascular diseases including heart failure. 153,154 The AT 1 R β-arrestin-biased ligand TRV027 was also recently proposed as pharmacotherapy for acute heart failure. However, TRV027 failed to improve the clinical status of patients with this condition in clinical trials. ...
G protein-coupled receptors (GPCRs), comprising the largest superfamily of cell surface receptors, serve as fundamental modulators of cardiac health and disease owing to their key roles in the regulation of heart rate, contractile dynamics, and cardiac function. Accordingly, GPCRs are heavily pursued as drug targets for a wide variety of cardiovascular diseases ranging from heart failure, cardiomyopathy, and arrhythmia to hypertension and coronary artery disease. Recent advancements in understanding the signaling mechanisms, regulation, and pharmacological properties of GPCRs have provided valuable insights that will guide the development of novel therapeutics. Herein, we review the cellular signaling mechanisms, pathophysiological roles, and pharmacological developments of the major GPCRs in the heart, highlighting the β-adrenergic, muscarinic, and angiotensin receptors as exemplar subfamilies.
... The evidence of involvement of angiotensin II receptor in sustaining high blood pressure explained by Brunner et al.(1973) as they found intravenous administration of the octapeptide competitive inhibitor Sar-1 Leu-8 ANG-II (Saralasin) to individuals with renovascular or hypertension due to pyelonephritis or malignant hypertension cause a rapid and persistent decrease in blood pressure to about normal values. Interestingly the over dose did not caused hypotension moreover blood pressure in individuals with low or normal renin level did not affected by this dose. ...
... E.g a learner would say "I buyed a shirt" or "He goed home" overgeneralizing the use of "ed" to form past tense form. According to [30], the ability to go beyond the information given, inexperience, and make overgeneralization, which can be used to understand and create a new form of experience, is fundamental to learning. Simplification: this third process of interlanguage, unlike the two earlier mentioned, is reductionist. ...
... Первым препаратом, блокирующим РААС, стал неселективный пептидный антагонист рецептора к ангиотензину II (АТ II), получивший название «саралазин». Саралазин -пептид, структурно сходный с АТ II, действовал как конкурентный ингибитор АТ [11]. Препарат не получил распространения, так как вводился только парентерально, мог применяться короткими курсами и вызывал дозозависимый АТ II-подобный эффект. ...
... With these agents, Brunner and Gavras again demonstrated that BP control was achievable with a combination of a RAS blocker and salt depletion using furosemide. 5,6 When captopril became available in the late 70's, 7 the same authors demonstrated that BP of hypertensive patients with chronic renal failure who were resistant to all previous therapies, could be normalised with the administration of captopril and furosemide. 8 At a time when severe hypertension was still treated with bilateral nephrectomy. ...
... We are currently analysing our structural proteineprotein interaction databases to see how widespread this feature might be (Fig. 4) and whether it can provide useful clues about potentially druggable sites. Interactions involving the termini of a protein have also been exploited in the development of peptide PPI inhibitors, for example the angiotensin II receptor antagonists mimicking Angiotensinogen (Brunner et al., 1973). Further examples of the involvement of flexible extensions in PPI are found in the binding of HGF/SF to the Met tyrosine kinase receptor (Met), which initiates a number of downstream signalling events including cell proliferation, motility, angiogenesis, morphogenesis and invasiveness (Birchmeier et al., Fig. 3. Residue binding modes at pairwise PPI interfaces. ...
While protein-protein interfaces have promised a range of benefits over conventional sites in drug discovery, they present unique challenges. Here we describe recent developments that facilitate many aspects of the drug discovery process – including characterization and classification of interfaces, identifying druggable sites and strategies for inhibitor development.
... Interactions involving the termini of a protein have also been exploited in the development of peptide PPI inhibitors, for example the angiotensin II receptor antagonists mimicking Angiotensinogen (Brunner et al., 1973). Further examples of the involvement of flexible extensions in PPI are found in the binding of HGF/SF to the Met tyrosine kinase receptor (Met), which initiates a number of downstream signalling events including cell proliferation, motility, Fig. 3. Residue binding modes at pairwise PPI interfaces. ...
The transient assembly of multiprotein complexes mediates many aspects of cell regulation and signalling in living organisms. Modulation of the formation of these complexes through targeting protein-protein interfaces can offer greater selectivity than the inhibition of protein kinases, proteases or other post-translational regulatory enzymes using substrate, cofactor or transition state mimetics. However, capitalising on protein-protein interaction interfaces as drug targets has been hindered by the nature of interfaces that tend to offer binding sites lacking the well-defined large cavities of classical drug targets. In this review we posit that interfaces formed by concerted folding and binding (disorder-to-order transitions on binding) of one partner and other examples of interfaces where a protein partner is bound through a continuous epitope from a surface-exposed helix, flexible loop or chain extension may be more tractable for the development of "orthosteric", competitive chemical modulators; these interfaces tend to offer small-volume but deep pockets and/or larger grooves that may be bound tightly by small chemical entities. We discuss examples of such protein-protein interaction interfaces for which successful chemical modulators are being developed.
Copyright © 2015. Published by Elsevier Ltd.
... Twelve patients were studied, and the 8 with high peripheral renin activity levels (PRA) had dramatic falls in blood pressure with the saralasin infusion, whereas those with normal or low PRA did not respond with a fall in blood pressure. 12 An early patient studied was a 21-year-old female patient of mine who was admitted with malignant hypertension (Figure 1). At the time of infusion, her blood pressure was 210/135 mm Hg, and during the infusion it fell to 160/90 mm Hg. ...
... 2 In the 1970s, John and his colleagues Hans Brunner and Haralambos (Harry) Gavras first demonstrated that antagonizing Ang II receptors with sarcosine 1 -alanine 8angiotensin II (saralasin) or blocking Ang II formation with teprotide lowered blood pressure in patients with essential hypertension. 3,4 This groundbreaking work propelled the development of SQ-14225 (captopril), the first orally active ACE inhibitor, and was a major breakthrough in hypertension treatment. Gavras and Brunner, 5 as well as John and his colleagues, 6 independently demonstrated that ACE inhibition was effective in treating essential hypertension and set off a flurry of basic and clinical research using SQ-14225, including studies in our lab, 7 that quickly led to widespread use of this new and highly effective approach to treating hypertension. ...
John Laragh has been a great inspiration to me and many others in the field of hypertension research. His inquisitive mind, deep knowledge of physiology and medicine, and keen clinical insights led him to discoveries and innovation that were critical to our current understanding of the renin– angiotensin–aldosterone system (RAAS) and to the development of effective therapies for hypertension. I first met John in the 1970s during one of his visits to Mississippi, along with his research group, to meet with our Department of Physiology, led at that time by Arthur Guyton. My lab was engaged in basic research studies on the intrarenal actions of angiotensin II (Ang II) in regulating glomerular filtration rate, tubular reabsorption, and longterm control of blood pressure, and I was deeply impressed by the work of John and his colleagues at Cornell. Teprotide (SQ-20881), the peptide inhibitor of angiotensin-converting enzyme (ACE), and peptide antagonists of the ANG II type 1 receptor were just becoming available, and I was eager to use these compounds to investigate the intrarenal role of Ang II in long-term blood pressure regulation. One major reason for my interest was John’s previous studies that showed that low-dose Ang II infusions in humans had powerful effects on blood pressure that were not only sustained but also actually amplified during several days of infusion. 1 The progressive hypertensive effect of Ang II was related to sodium balance and was even more impressive than that of aldosterone. The effects of Ang II contrasted with those of norepinephrine, which had progressively weaker blood pressure effects during several days of infusion and caused either natriuresis or no change in sodium balance. 1 In a seminal series of studies in humans, John and his colleagues found that Ang II controls sodium balance and blood pressure not only through stimulation of aldosterone but also by direct actions on the kidneys. A paragraph in his 1965 paper in the Journal of Clinical Investigation 1 was especially enlightening:
While the role of Greeks in the development of early western medicine is well-known and appreciated, the contributions of modern Greek medical practitioners are less known and often overlooked. On the occasion of the 200-year anniversary of the Greek War of Independence, this review article sheds light onto the achievements of modern scientists of Greek descent in the development of cardiology, cardiac surgery, and cardiovascular research, through a short history of the development of these fields and of the related institutions in Greece. In the last decades, the Greek cardiology and Cardiac Surgery communities have been active inside and outside Greece and have a remarkable presence internationally, particularly in the United States. This article highlights the ways in which Greek cardiology and cardiovascular research has been enriched by absorbing knowledge produced in international medical centers, academic institutes and pharmaceutical industries in which generations of Greek doctors and researchers trained prior to their return to the homeland; it also highlights the achievements of medical practitioners and researchers of Greek descent who excelled abroad, producing ground-breaking work that has left a permanent imprint on global medicine.
Information defining the renin-angiotensin-aldosterone axis as a control system concurrently regulating salt balance and blood pressure has been applied to examine the role of renin in the causation of experimental and clinical forms of renovascular and renal hypertension and thence to develop criteria for differentiating these entities.
Experimentally there are two models of renovascular hypertension, one characterized by excess renin with reduced sodium (vasoconstrictor form) and the other by excess sodium with reduced renin (volume form). But with sodium depletion, the volume form switches to a vasoconstrictor form, illustrating how the two factors coordinate to maintain blood pressure. Human renovascular and renal hypertensions appear to be sustained by the same two mechanisms.
Experimental and clinical studies both indicate that curable renal hypertension is in fact a renin-dependent vasoconstrictor hypertension. Three criteria, derived from four renin measurements, identify this situation: (1) Hypersecretion of renin is reflected by a high peripheral level when referenced against sodium excretion. (2) Lateralization of renin secretion with contralateral suppression rules out occult bilateral disease. It is indicated by V-A = 0 from the uninvolved kidney. (3) A third criterion, (V-A)/A > 48 per cent from the ipsilateral kidney, identifies renal ischemia. These three criteria, when taken together in a combined scoring analysis, provide high precision in identifying the patient with the vasoconstrictor form of renal hypertension that is potentially reversible by appropriate surgery.
Absence of these criteria identifies hypertension associated with either occult or overt bilateral renal disease. In these patients, the volume factor often predominates and is expressed by some suppression of plasma renin levels. Here, removal of renal tissue is contraindicated.
Corroborative evidence to support these three criteria can be developed from the blood pressure response to angiotensin blocking drugs or to anti-renin therapy with propranolol. Thus in all of these renal hypertensions, the vasoconstrictor and volume factors can be identified using renin measurements and pharmacologic interventions.
This review deals with the following classes antihypertensive drugs: renin inhibinors, potassium channel openers, imidazoline (11)
receptor agonists, neutral endopeptidase inhibitors, endothelin antagonists, angiotensin II receptor antagonist of the ATI subtype.
Although aortic coarctation has been well known to pathologists for 100 years [1], the hypertension usually associated with coarctation has been appreciated only more recently. In 1912 Gossage [2] suggested that hypertension was essential in patients with coarctation to ‘overcome the difficulty of getting blood through the narrow arterial channels.’ By 1933 Lewis [3] was able to state in a review of a large number of cases of aortic coarctation that hypertension was present in the upper arms of all patients and that any patient with hypertension must be considered as possibly having coarctation. After reviewing 170 cases of coarctation, King [4] agreed that hypertension was usually present. Furthermore, it is the uncontrolled hypertension which leads to the demise of untreated patients with coarctation, whose average survival is 35 years [5]. Subarachnoid hemorrhage, acute aortic dissection and left heart failure account for the majority of the deaths, and all are directly related to the associated hypertension. It appears obvious that proper therapy of coarctation must be directed towards the relief of the hypertension.
Die renale Hypertonie als häufigste Form der sekundären Hypertonie hat einen Anteil am Gesamtkollektiv der Hypertoniker von 25–30%. Da bei der renalen Hypertonie prinzipiell die Möglichkeit der kausalen chirurgischen Therapie gegeben ist, ist ihre diagnostische Abgrenzung gegenüber anderen Formen der Hypertonie von therapeutischer Bedeutung. Voraussetzung dafür ist die Kenntnis der Pathophysiologie der renalen Hypertonie, deren Verständnis sich aus experimentellen und klinischen Befunden ergibt.
Renal hypertension is the most frequent form of secondary hypertension and accounts for 25% to 30% of hypertensive disease. Since renal hypertension is in principle amenable to causal surgical therapy, its diagnostic differentiation from other forms of hypertension is of therapeutic importance. For this, a knowledge of the pathophysiology of renal hypertension is required, derived on the basis of experimental and clinical findings.
Although hypertension is a common manifestation of renal parenchymal disease in most of its forms, and renal vascular hypertension represents the most common form of hypertension that can be cured by surgery, our emphasis in this chapter will be on essential hypertension and what has been learned that may be relevant to renin’s role in pathogenesis, in diagnosis, and in therapy. We will return to renal hypertension only when the implications of recent advances in pharmacological interruption of the rennin-angiotensin system provide new approaches to diagnosis and treatment, and to present what is now known of the potential of percutaneous transluminal angioplasty in reversing renovascular hypertension.
Measurement of the components of the mineralocorticoid hormone pathway to aldosterone and of the renin-angiotensin system (RAS) has now been coupled with the ability to measure an effective competitive antagonist of angiotensin II, a converting enzyme inhibitor, and smaller but active fragments of angiotensin II. This combination has permitted further in-depth probes of the system. The aldosterone-renin-angiotensin system (A-RAS) not only is a major effector of pathological disorders, but also can be the marker of events or substances that are more proximate causes of a specific disorder. The effectiveness of inquiries into the A-RAS as a regulator of blood pressure, electrolyte metabolism, and regulation of aldosterone secretion is examined herein.
Die Entwicklung von Substanzen zur pharmakologischen Beeinflussung des Renin-Angiotensin-Aldosteron-Systems stellen Meilensteine in der Ermittlung neuer therapeutischer Wirkprinzipien bei arterieller Hypertonie, myokardialer Dysfunktion und Herzinsuffizienz während der letzten 3 Jahrzehnte medizinischer Forschung dar. Etabliert sind: Angiotensin- Conversions-Enzym-Hemmer, Angiotensinrezeptorblocker, Aldosteronrezeptorantagonisten; in Entwicklung: Vasopeptidase-Inhibitoren, Endothelinrezeptorantagonisten, Reninantagonisten. Dieser Fortschritt ist untrennbar verknüpft mit der Erforschung des Renin-Angiotensin-Aldosteron-Systems.
Die renale Hypertonie als häufigste Form der sekundären Hypertonie hat einen Anteil am Gesamtkollektiv der Hypertoniker von ca. 15%. Da bei der renalen Hypertonie prinzipiell die Möglichkeit der kausalen chirurgischen Therapie gegeben ist, ist ihre diagnostische Abgrenzung gegenüber and eren Formen der Hypertonie von therapeutischer Bedeutung. Voraussetzung dafür ist die Kenntnis der Pathophysiologie der renalen Hypertonie, deren Verständnis sich aus experimentellen und klinischen Befunden ergibt.
Renovascular hypertension, which probably accounts for between 1% and 2% of an unselected hypertensive population1, not only constitutes the dual threat of severe hypertension with its complications and progressive renal insufficiency, but may also be a marker of widespread vascular disease. Until recently, the therapeutic options were limited to medical treatment with antihypertensive drugs, reconstructive surgery, or nephrectomy. Conventional drug therapy often proves inadequate for the optimal control of hypertension associated with renovascular disease, while polypharmacy and unwanted side-effects contribute to poor patient compliance. The introduction of angiotensin converting enzyme inhibitors provided a means of effectively controlling hypertension in most patients with renal artery stenosis2,3. Successful medical therapy, however, was associated in some instances with a decrease in renal function4,5, and patients with bilateral renal artery stenoses or severe stenosis in a solitary functioning kidney ran the risk of developing acute oliguric renal failure6,7.
Angiotensin II (Ang II), the active component of the renin-angiotensin system (RAS), is one of the most important hormones involved in the regulation of body fluid and cardiovascular homeostasis (1). The rate-limiting step in the synthesis of Ang II is the release of the enzyme renin from the juxtaglomerular cells of the kidney. Renin is an aspartyl protease composed of two polypeptide chains linked by disulfide bridges (2), which produces a conformation similar to that of other proteases. Prorenin, which is a 47-kDa protein, is released in a constitutive fashion directly from the Golgi apparatus or may also be packaged into mature granules and released from the kidney in a regulated pathway as the active 41-kDa protein renin. The concentration of prorenin in plasma is approximately 10 times greater than renin. Conversion to the active enzyme requires the removal of 46 amino acids from the N-terminus of the enzyme. The protease responsible for this cleavage in vivo is unknown but has been proposed to be cathepsin B, because this enzyme is colocalized with renin in both immature and mature secretory granules (3,4).
Etwa 50 Millionen Amerikaner haben eine Hypertonie. Bei den meisten Patienten ist die Ursache unbekannt, man bezeichnet die Erkrankung deshalb als essentielle Hypertonie. Bei 5–15% der Patienten mit Hypertonie ist eine Nierenerkrankung ursächlich beteiligt. Man spricht hier von renaler Hypertonie. Ein renaler Hypertonus kann vaskulär bedingt sein (d.h. infolge einer Nierenarterienerkrankung (s. Tabelle 35.1)), er kann auf eine renale Nierenparenchymerkrankung zurückzuführen sein (Tabelle 35.2), oder er kann die Folge einer Kombination aus beiden sein. Viele Fälle einer renalen Hypertension sind reversibel, wenn sie richtig diagnostiziert und behandelt werden.
Die renovaskuläre Hypertonie (RVH) stellt, an anderen für einen Hochdruck verantwortlichen Ursachen gemessen, mit ca. 5% aller Hypertoniker einen relativ hohen Anteil. Da sie in die Kategorie der chirurgisch heilbaren Hochdruckformen gehört, verdient sie besondere Beachtung. Trotz umfangreicher diagnostischer Bemühungen ist es nach wie vor schwierig, die endokrine Signifikanz einer angiographisch nachgewiesenen Nierenarterienstenose (NAS) festzulegen.
Blockade of the renin angiotensin system by the angiotensin analogue saralasin may have both diagnostic and therapeutic applications. Response to this investigational drug appears to provide a noninvasive means of identifying patients with renovascular and some other 'angiotensinogenic' hypertensions. It is also seen as potentially useful in the management of hypertensive crises or states exacerbated by angiotensin excess.
This chapter discusses the development and clinical studies of antihypertensive agents. Clonidine is effective at low doses without postural hypotension or lasting sedative side effects in two long term studies. A comparison with reserpine illustrated clonidine's lack of depressive reactions and the combination with chlorthalidone were even more effective than clonidine alone. The danger of hypertensive rebound and other side effects on sudden withdrawal from clonidine was noted. Minoxidil is a useful hypotensive agent in uremic patients with severe hypertension or those with malignant or accelerated hypertension refractory to conventional drugs. Compared to hydralazine, the drug was more potent, longer acting, and showed no signs of tolerance development. It causes a marked increase in serum renin activity, cardiac hyperactivity and sodium retention but co-administration of a β-blocker and a diuretic counteracts this side effect. The clinical trials of propranolol continue to illustrate its utility as a hypertensive with activity improved by addition of a vasodilator such as hydralazine in severe hypertension or with hydrochlorthiazide in mild to moderate hypertension. The antihypertensive effect of prostaglandin A, in man is thought mainly due to its effect on renal circulation where it causes vasodilatation and excretion of water and sodium.
Since its introduction as an experimental antihypertensive agent, captopril (Capoten, SQ 14225) has been shown to lower blood pressure effectively in a considerable proportion of patients with essential and renovascular hypertension (1–5). The drug was designed as a specific, potent competitive inhibitor of angiotensin-converting enzyme (6) and, following oral administration to human subjects, it can block almost completely the effects of in-fused angiotensin I (7). Long-term administration of captopril to hypertensive patients results in a sustained reduction in aldosterone secretion, concomitant potassium retention and, in most cases, natriuresis (8)—effects that can be ascribed to a drug-induced reduction in circulating angiotensin II. Despite these findings, there has been considerable controversy regarding the extent to which its antihypertensive effect is mediated by blockade of the renin-angiotensin system.
Captopril is the newly developed orally active inhibitor of the enzyme that controls formation of the pressor hormone, angiotensin II, from its inactive precursor, angiotensin I. Based on previous experience with an intravenously given nonapeptide inhibitor, the compound was developed as a potential antihypertensive agent, and, as described in this volume, it has proven to be extremely potent. This treatment focuses once more on the renin-angiotensin system as a vital participant in sustaining the blood pressure of hypertensive patients.
A sustaining or causal role for renin in essential hypertension has at least begun to gain credence along with the concept that essential hypertension is not a single clinical entity. Indeed, only recently has renin secretion been implicated in renovascular hypertension; renin measurements were not included even in the broad 1972 evaluation of renovascular hypertension formulated by the National Cooperative Study Group (1).
Angiotensin II Receptor Antagonists (AIIRA) are the most recent introduced pharmacological class in hypertension and heart failure treatment. Shortly after their commercialization a great number of clinical trials demonstrated not only their ability in reducing blood pressure values, but also a reduction in primary cardiovascular end points. On the same time their absolute tolerability was also endorsed, thus explaining the long term high compliance with this drug therapy. The most important data deriving from these trials concern the fact that AIIRAs protective effect may be independent from their blood pressure lowering effect, depending on the contrary on their ability to block completely the renin-angiotensin-aldosteron system. Very recently the FDA allowed the commercialization of olmesartan, the newest among the seven AIIRAs that are presently used in therapy: its peculiar characteristics are here briefly reviewed.
The current drugs and strategy for treating hypertension are the result of truly remarkable advances during the past 20 years. The pathways to discovery of new antihypertensive drugs have been varied. The vasodilators were developed largely as a result of systematic searches for compounds that lower blood pressure in experimental animals. By contrast, there was no evidence from investigations in animals that the beta-adrenergic blockers, methyldopa, Clonidine, or the oral diuretics could lower blood pressure. Importantly, each of these drugs had been developed for the purpose of affecting a biological system of sufficient importance to merit their investigation in man. Only after they were introduced into clinical investigation was their antihypertensive action discovered.
The existence of a renal pressor hormone was first suggested in 1898 by Tigerstedt and Bergman (1), who gave it the name “renin.” During the next 80 years, the renin system, as it later became to be known, went through alternating periods of glamour and complete oblivion. As soon as it was discovered, renin was forgotten until 1934, when Dr. Goldblatt reported his classic experiment (2). This experiment opened up a new era for the renin system. Its various components were rapidly characterized (3–9), and it was believed that it played a predominant role in the pathogenesis of hypertensive diseases. The tide changed somewhat during the early 1960s, when methods became available to measure renin activity in the plasma of hypertensive patients. It was then found that renin was only rarely elevated (10, 11) and, so it became somewhat of a curiosity as a pathogenetic factor seeming only to contribute to rare forms of hypertension, such as renovascular hypertension.
Originally, a chapter on the renin-angiotensin system (RAS) was not planned for inclusion in this volume on antihypertensive agents. However, in view of the recent development of various competitive antagonists to angiotensin II, as well as of other drugs which interfere with the activity of the RAS, it was necessary to refer to the possibilities of lowering blood pressure in cases in which hypertension is renin dependent. To improve understanding this chapter gives a short review of the biochemistry and pathophysiology of the RAS (Fig. 1). The discussion is limited to those aspects necessary for the understanding of mechanisms underlying the pathogenesis of renin-dependent forms of high blood pressure and to drugs that may interfere at various levels with the RAS. The inhibitory effect of β-adrenergic blockers on the release of renin from the kidney is discussed in Chapter 13, p. 602. Only a limited number of the recent references and reviews on that topic are quoted in this context.
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Proper blood pressure control is an essential prerequisite to longevity for patients on maintenance dialysis. Over the last decade, the refinement of extracorporeal hemodialysis and peritoneal dialysis techniques, the development of continuous ambulatory peritoneal dialysis and the release of a number of new pharmacological agents have allowed for greater ease of modification of blood pressure abnormalities.
The kidneys are frequently involved in PSS; clinical renal involvement carries a grave prognosis with a mean survival of one month from onset of disease to death.
Malignant or mild hypertension, proteinuria, azotaemia and microangiopathic haemolytic anaemia constitute the clinical expression of renal disease, but not all need be present (particularly hypertension) simultaneously.
Magnification renal arteriography is a useful method to demonstrate the vascular abnormalities. A spotted nephrogram probably results from the renal ischaemia and is pathognomonic of renal scleroderma in the absence of large vessel disease.
Histologically, a proliferative intimal lesion in the interlobular arteries is the hallmark of renal scleroderma. The proliferating cell type is thought to originate from the medial smooth muscle cells which migrate to the intima following endothelial injury.
Vascular spasm, in addition to the structural lesions produced by repeated renal vascular insults, leads to luminal narrowing. The coagulation cascade may be triggered by the intimal lesion, leading to fibrin deposition, reduced blood flow and local ischaemia, which in turn triggers the rennin–angiotensin system, leading to further vasoconstriction, systemic hypertension and renal failure.
Aggressive medical management of hypertension may arrest the progressive course of the disease. When medical treatment fails, early nephrectomy, haemodialysis and renal transplantation are justified and provide the optimal setting for survival.
Early detection of renal scleroderma, prior to the onset of clinically evident disease, is not feasible at this time. However, application of new approaches such as stimulated renin activity is promising. Early detection and therapeutic intervention (B-adrenergic blockers) may change the natural history of renal scleroderma, and prove of long-lasting benefit.
The sections in this article are:
Historical Background
Renin
Aldosterone
A Coordinated Renal‐Adrenal Hormonal System: Renin, Angiotensin, and Aldosterone
Comparative Aspects
Brief Overview of the Renin‐Angiotensin‐Aldosterone System
Biochemistry and Molecular Biology of the Renin System
Prorenin
Renin
Renin Substrate
Angiotensins I and II
Angiotensin‐Converting Enzyme
Aldosterone
Methods of Measurement
Physiology
Prorenin
Renin
Renin Substrate
Angiotensin II
Aldosterone
Cybernetics of the System
Coordinated Regulation of Sodium, Potassium, and Blood Pressure
Use of the Renin System to Understand Blood Pressure Control and Disorders of Pressure‐Volume Homeostasis
Two Forms of Vasoconstriction: Vasoconstriction‐Volume Analysis
Three Basic Tenets Concerning Plasma Renin Measurements
The Sodium—Calcium Connection
Dynamic Reciprocity of Two Forms of Vasoconstriction
The Sympathetic Nervous System and Modulation of the Two Forms of Arteriolar Vasoconstriction
Human Disorders of the Renin System
Hypertensive Disorders
Renin System Abnormalities in Edematous States
Hypokalemic Normotensive States
Summary
Alzheimer's (AD) and Parkinson's (PD) diseases are neurodegenerative diseases presently without effective drug treatments. AD is characterized by general cognitive impairment, difficulties with memory consolidation and retrieval, and with advanced stages episodes of agitation and anger. AD is increasing in frequency as life expectancy increases. Present FDA approved medications do little to slow disease progression and none address the underlying progressive loss of synaptic connections and neurons. New drug design approaches are needed beyond cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists. Patients with PD experience the symptomatic triad of bradykinesis, tremor-at-rest, and rigidity with the possibility of additional non-motor symptoms including sleep disturbances, depression, dementia, and autonomic nervous system failure. This review summarizes available information regarding the role of the brain renin-angiotensin system (RAS) in learning and memory and motor functions, with particular emphasis on research results suggesting a link between angiotensin IV (AngIV) interacting with the AT4 receptor subtype. Currently there is controversy over the identity of this AT4 receptor protein. Albiston and colleagues have offered convincing evidence that it is the insulin-regulated aminopeptidase (IRAP). Recently members of our laboratory have presented evidence that the brain AngIV/AT4 receptor system coincides with the brain hepatocyte growth factor/c-Met receptor system. In an effort to resolve this issue we have synthesized a number of small molecule AngIV-based compounds that are metabolically stable, penetrate the blood-brain barrier, and facilitate compromised memory and motor systems. These research efforts are described along with details concerning a recently synthesized molecule, Dihexa that shows promise in overcoming memory and motor dysfunctions by augmenting synaptic connectivity via the formation of new functional synapses.
The health significance of essential hypertension “high blood pressure of undefined origin” is well established. It is a major factor contributing to coronary heart disease, stroke, and kidney failure. It directly affects about one in five Americans. Factors which are known to be associated with blood pressure include: body composition as it relates to overall mass and fat mass; physiological variables involving the sympathetic and parasympathetic nervous systems; biochemical variables such as renin, aldosterone, kallikrein, lipids, and lipoproteins, etc.; environmental variables such as sodium intake, heavy metals, and noise; and psychological variables involving personality type and mental stress.
There is a definite, well-established genetic involvement in hypertension, but specific genetic mechanisms remain a mystery. Familial aggregation occurs for many of the associated traits listed above. For some, specific polymorphic major genes have been identified, but for others genetic factors are unidentified. Essential hypertension is undoubtedly a heterogeneous group of diseases with the common end result of elevated blood pressure. Because of its health significance, there is considerable interest in identifying genetic mechanisms resulting in essential hypertension. One area that currently shows some potential for the identification of a specific genetic mechanism is related to the transmembrane transport of sodium and potassium cations.
The availability of orally active specific angiotensin receptor antagonists (AT 1 antagonists) has opened new therapeutic choices and provided probes to test the specific role of the renin‐angiotensin system in the pathogenesis of cardiovascular disease.
The data available so far suggest that the antihypertensive efficacy of angiotensin receptor antagonists is comparable to that of angiotensin‐converting enzyme (ACE) inhibitors. This provides further evidence that this latter class of drugs exerts its effect mainly through blockade of the renin‐angiotensin enzymatic cascade. As expected, the association of a diuretic exerts an equally strong additive effect to the antihypertensive efficacy of both classes of drugs.
The most common side effect of ACE inhibitors, dry cough, does not occur with AT 1 antagonists, which confirms the long‐held view that this untoward effect of the ACE inhibitors is due to renin‐angiotensin‐independent mechanisms.
Long‐term studies with morbidity/mortality outcome results are needed, before a definite position can be assigned to this newcomer in the orchestra of modern antihypertensive drugs. Notwithstanding, this new class of agents already represents an exciting new addition to our therapeutic armamentarium.
The proteolytic processing of neuropeptides has an important regulatory function and the peptide fragments resulting from the enzymatic degradation often exert essential physiological roles. The proteolytic processing generates, not only biologically inactive fragments, but also bioactive fragments that modulate or even counteract the response of their parent peptides. Frequently, these peptide fragments interact with receptors that are not recognized by the parent peptides. This review discusses tachykinins, opioid peptides, angiotensins, bradykinins, and neuropeptide Y that are present in the central nervous system and their processing to bioactive degradation products. These well-known neuropeptide systems have been selected since they provide illustrative examples that proteolytic degradation of parent peptides can lead to bioactive metabolites with different biological activities as compared to their parent peptides. For example, substance P, dynorphin A, angiotensin I and II, bradykinin, and neuropeptide Y are all degraded to bioactive fragments with pharmacological profiles that differ considerably from those of the parent peptides. The review discusses a selection of the large number of drug-like molecules that act as agonists or antagonists at receptors of neuropeptides. It focuses in particular on the efforts to identify selective drug-like agonists and antagonists mimicking the effects of the endogenous peptide fragments formed. As exemplified in this review, many common neuropeptides are degraded to a variety of smaller fragments but many of the fragments generated have not yet been examined in detail with regard to their potential biological activities. Since these bioactive fragments contain a small number of amino acid residues, they provide an ideal starting point for the development of drug-like substances with ability to mimic the effects of the degradation products. Thus, these substances could provide a rich source of new pharmaceuticals. However, as discussed herein relatively few examples have so far been disclosed of successful attempts to create bioavailable, drug-like agonists or antagonists, starting from the structure of endogenous peptide fragments and applying procedures relying on stepwise manipulations and simplifications of the peptide structures.
Primarily hypervolaemic, high output forms of hypertension, with features indicating or strongly suggesting fluid overload as the cause of elevated cardiac output, resulting from renal disease with reduced glomerular filtration rate causing sodium retention, renal tubular causes of sodium retention, greatly excessive sodium intake and low renin hypertension, can be treated by reduction of sodium intake and potentiation of its excretion by diuretic therapy, removal of the cause (e.g. aldosteronoma), and calcium antagonists.
Excessive vasoconstriction resulting from noradrenaline (norepinephrine) in neurogenic hypertension, phaeochromocytoma, orthostatic hypertension and a-adrenergic drug administration; angiotensin excess due to renal ischaemia brought about by aortic coarctation, renal arterial and arteriolar stenosis, intraluminal obstruction, external renal compression, renin-producing tumours, intrinsic kidney diseases and excessive renin substrate; and vascular structural disorders such as atherosclerosis, arteriolitides and fibrosis with or without calcification of major arteries may also induce hypertension.
Secondary hypertension of uncertain mechanism may occur in hyperparathyroidism, hyper-or hypothyroidism, or acromegaly. All are best treated by appropriate correction of the endocrine excess or deficiency. It may also occur in pregnancy, where the mechanism may involve prostaglandin-thromboxane imbalance or calcium deficiency; calcium deficiency with some evidence of benefit from calcium supplements; and the recumbent hypertension paradoxically associated with autonomic failure. Excellent responses to specific correction of the underlying cause or pathogenetic mechanism is usual in young individuals but less frequent in older patients.
Overactivity of the renin-angiotensin-aldosterone system occurs in the syndrome of congestive cardiac failure. Aldosterone overactivity is crucially involved in maintaining the oedematous state as evidenced by its often complete correction by adrenalectomy, or by aldosterone antagonists, in both experimental and clinical heart failure.
The hyperaldosteronism of heart failure can also be attacked by angiotensin-converting enzyme (ACE) inhibition, which not only blocks the angiotensin drive to aldosterone, but also unloads the heart by blocking renin-angiotensin-mediated vasoconstriction. Accordingly, ACE inhibition alone, if continued in full dosage, can often reduce or obviate the need for daily thiazide diuretic therapy. This specific, two-pronged therapy with fewer side effects emerges as a primary strategy for the treatment of congestive heart failure.
To learn more about why and how the renin system becomes involved in heart failure, the renal functional abnormalities have been re-examined. The effects of sodium administration on central haemodynamics and on the activity of the renin system have also been studied. This research has led to a consideration of the role of atrial natriuretic hormone in this pathophysiological interplay.
The study recharacterised renal haemodynamic patterns and indicated that in congestive heart failure there is a disproportionate diversion of blood away from the kidneys because of afferent vasoconstriction. However, the glomerular filtration rate is maintained by concurrent efferent arteriolar constriction, expressed by a rising filtration fraction. As heart failure advances, the filtration fraction can no longer rise. At this point, the glomerular filtration rate becomes flow-dependent and falls commensurately with the declining cardiac output. These intrarenal patterns may be mediated in part by increased intrarenal renin activity resulting from heart failure and diuretic therapy.
A further study of the abnormal renin system activity operating in heart failure has shown it to be very sensitive to dietary salt intake. Thus, consuming modest amounts of salt (100 mEq/day) was sufficient to markedly suppress renin and aldosterone values. However, since peripheral resistance was not changed, another non-renin, sodium-related mechanism must take over to sustain increased arterial constriction. The fact that captopril challenge evoked no response before and a large response after sodium depletion supports this concept.
Preliminary data suggest that atrial natriuretic hormone may also be important in congestive heart failure by opposing renin system activity at 4 sites. More research to define often crucial endocrine and renal abnormalities of heart failure could provide even more specific therapies.
The renin system: Variations in man measured by radioimmunoassay or bioassay. Using a basic incubation procedure followed by either pressor bioassay or radioimmunoassay of angiotensin I, normal values for plasma renin activity (PRA) were defined in 52 normal subjects over the range of physiological variation which occurs in relation to changes in sodium balance. Complete interchangeability of results derived from the two different methods was achieved by the application of a correction factor based on the observed lower pressor activity of angiotensin I. Plasma renin activity exhibits a consistent dynamic relationship to the daily rate of urinary sodium excretion. The values ranged from 0.5 to 2.8 ng/ml/hr when sodium excretion was above 150 mEq/day, from 1.4 to 6.3 ng/ml/hr when sodium excretion was between 50 and 150 mEq/day, and up to 21 ng/ml/hr when sodium excretion was below 50 mEq/day. However, a more precise index derives from using limits inscribed by the whole curve as a nomogram. Plasma renin substrate measurements did not vary with changes in sodium balance. Its concentration measured by radioimmunoassay ranged from 900 to 2200 ng/ml but intra-individual variation was small. These values are considerably higher but closer to the true value than previously reported assays which erroneously compared angiotensin I generated during the incubation with the more pressor angiotensin II. Renin substrate “reactivity”, an arbitrary index derived from adding a fixed amount of purified human renin to plasma, also did not vary with changes in sodium balance but it did vary directly with the absolute substrate concentration. In normal subjects the mean reaction velocity was 59 × 103 ng/ml/hr/GU renin and this ranged from 35 to 89 ng/ml/hr/GU. These observations are in keeping with first order kinetics in which both enzyme and substrate concentrations are rate limiting. However, the study demonstrates that physiologically, changes in substrate concentration are not normally determinants of the rate of angiotensin generation since there was no relationship between substrate concentration and the endogenous level of plasma renin activity. Systemic arterio-venous differences in plasma renin were not observed. However, in 43 patients with benign essential hypertension, net and fairly equal secretion of renin by the two kidneys was demonstrated. Mean renal vein renin activity exceeded arterial levels by 0.48 ng/ml/hr when the mean arterial renin activity was 1.62 ng/ml/hr.
The intravenous administration of large doses of angiotensin II (0·9-1·8 μg. per kg. per minute) for 3 days to rabbits consistently produced acute renal failure with uræmia and a fall in urine/serum-urea ratio. Oliguria, however, occurred only occasionally. Extensive histological lesions of " circulatory " ("ischæmic") tubular necrosis were found in 8 out of 10 infused animals. These features were independent of changes in sodium balance. Myocardial infarction was found in 6 of 7 angiotensin-infused rabbits in which the heart was examined post mortem. These findings support the hypothesis that pathological increases in renin and angiotensin may be important in the genesis of acute circulatory renal failure. The results may have important clinical significance, since they suggest that measures likely to increase renin and angiotensin (such as diuretic administration) should be avoided in acute (and certain examples of chronic) renal failure.
In 219 patients with essential hypertension, aldosterone excretion and plasma renin activity were related to daily sodium excretion and compared to a nomogram drawn from 52 normal volunteers studied over the same continuous range of sodium balance. Plasma renin activity was subnormal in 27 per cent, normal in 57 per cent and elevated in 16 per cent. Further study showed eight patterns of renin and aldosterone secretion. Patients with normal or high renin had an 11 and 14 per cent frequency respectively of heart attacks or strokes. However, during a similar period of observation, none of 59 low renin patients had any of these complications. They appear protected despite similar hypertension, similar left ventricular enlargement, and despite higher mean age. Plasma renin activity emerges as a potential risk factor for patients with essential hypertension — useful for identifying etiologies, determining prognosis and applying therapy.
Experiments with rabbit aortic strips and pithed rats indicated that 1-Sar-8-Ala-angiotensin II (Sar-Arg-Val-Tyr-Val-His-Pro-Ala) is a specific competitive antagonist of the vascular action of angiotensin II. Norepinephrine-induced hypertension was not affected by infusions of 1-Sar-8--Ala-angiotensin II which evoked a dose-related reduction of angiotensin II-induced hypertension in conscious rats. Infusions of 1-Sar-8-Ala-angiotensin II that caused a dose-related reduction of the blood pressure of conscious rats in the acute phase of unilateral renal hypertension were ineffective during the chronic phase of such hypertension. Infusions of 1-Sar-8-Ala-angiotensin II lasting 1 hour did not reduce the blood pressure of normotensive, spontaneously hypertensive, or metacorticoid hypertensive conscious rats. These data indicate that, under certain experimental conditions, the blood pressure of rats during the acute phase of unilateral renal hypertension is maintained hy the endogenous angiotensin II previously demonstrated to he present in the plasma in supernormal concentrations. The blood pressure of normotensive, spontaneously hypertensive, metacorticoid hypertensive, and chronic unilateral renal hypertensive rats previously shown to have normal plasma levels of renin and angiotensin II appeared to be independent of the pres.sor action of endogenous angiotensin II. This is additional direct evidence implicating the pressor action of angiotensin II in the etiology of renal hypertension.
Antibody to angiotensin 11, or a specific peptide competitive inhibitor of angiolensin II, was used to investigate the role
of the renin-angiotensin system in two types of renal hypertension in rats. The data indicate that angiotensin II is in fact
critically involved in the pathogenesis of the form of renal hypertension in which one renal artery is clamped and the contralateral
kidney is left in place, but that it probably plays no significant role in the maintenance of experimental renal hypertension
in which the opposite kidney has been removed.
A specific inhibitor of angiotensin II was used in rats to investigate whether angiotensin is involved in the maintenance
of blood pressure in one-kidney Goldblatt hypertension, in which plasma renin levels are not usually increased. The inhibitor
produced marked falls in blood pressure, often down to normal levels in the hypertensive animals only when they were depleted
in sodium and not after sodium repletion. Much lesser but still significant falls in blood pressure were also produced in
normotensive sodium-depleted rats but not in repleted rats. We conclude that the importance of angiotensin for maintaining
blood pressure is largely determined by its relation to available sodium or fluid volume, since the renin component in maintenance
of either the hypertensive or the normotensive state could be exposed only by sodium deprivation. Therefore, volume expansion
per se or other pressor factors may be involved in maintaining blood pressure of these sodium-replete normotensive or hypertensive
animals.
Classification of patients with essential hypertension according to their renin levels in relation to sodium excretion has exposed subgroups which appear to have different physiological and epidemiological features. Low renin hypertensive patients appear relatively protected from heart attacks and strokes. Physiologically they exhibit a blunted aldosterone response to sodium deprivation which is associated with subtle potassium retention and an increase in plasma bicarbonate levels. These patients are older, but they also exhibit lower blood urea levels than the other two groups, suggesting a normal renal circulation. Hypertensive blacks below age 30 practically always fall into the normal renin subgroup, while those over age 50 with more benign hypertensive disease practiclly always exhibit low renin levels. Such results indicate that this renin subgrouping may provide a useful guide for deciding when and how to treat. Thus, all patients in the normal or high renin subgroups, and particularly young blacks, may require early and diligent treatment.
The antihypertensive effect and mechanism of propranolol were studied in 47 hypertensive patients classified according to high, normal, or low plasma renin activity. The drug was uniformly effective in 13 patients with high renin activity and malignant, renovascular, or essential hypertension, producing a mean fall in diastolic pressure of 30 mm of mercury. In 22 with normal renin, propranolol reduced mean diastolic pressure by 20 mm of mercury, but individual responses were less consistent. In contrast, the drug was uniformly ineffective in the 12 patients with low-renin essential hypertension. In all three groups, the action of propranolol closely correlated with both the control renin levels and the degree of renin suppression produced. Propranolol usually suppressed aldosterone secretion but to a lesser extent than it did renin, perhaps because of a hyperkalemic effect of the drug. These special effects of propranolol in renin-dependent hypertensions point to the possibility of an associated ...