The renin-angiotensin system (RAS) plays a crucial role in the organized mechanisms that regulate both electrolyte/ blood volume homeostasis and blood pressure. In general, factors reducing blood volume, renal perfusion pressure, or concentration of sodium in plasma lead to activation of the system, while factors increasing these parameters lead to suppression of its function. Although our understanding is still incomplete, the RAS is highly involved in the development, progression, and persistence of hypertension. Moreover, the RAS has also been implicated in the pathogenesis of chronic renal and heart failure. With these diseases, inappropriate activation of the RAS is also manifest. Therefore, the RAS has been defined as a key target for cardiovascular therapy.
This overview focuses primarily on the role of the RAS in hypertension. Historical background on the system will be provided, along with general considerations regarding hypertensive disease. Furthermore, a description ensues on the pathophysiological impact of angiotensin II (Ang II)—the effector peptide in the RAS—on various tissues. Also included is a discussion of the major clinical studies analyzing different drug classes that target distinct components of the RAS; for example, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin (AT1) receptor blockers, direct renin inhibition, and aldosterone receptor inhibitors.
THE RENIN-ANGIOTENSIN SYSTEM: HISTORY AND GENERAL ASPECTS
The RAS represents an endocrine system in which its main effector peptide Ang II is found systemically as a circulating hormone in plasma. Furthermore, Ang II has been shown to be locally produced and active in several tissues (tissue-RAS). The primary enzyme of the RAS cascade is renin. Renin was discovered as early as 1898 by the Finnish physiologist, Robert A. Tigerstedt and by his student, Per Gustav Bergman [1]. Their findings represented the starting point of long-lasting research efforts, finally leading to the acknowledgement of this system as an attractive pharmacological target in controlling blood pressure and associated cardiovascular diseases.
Tigerstedt and Bergman performed an essential experiment [1]. They demonstrated that venous injection of extracts, isolated from kidneys of rabbits, was capable of significantly increasing the blood pressure in other recipient rabbits. These findings led Tigerstedt and Bergman to the assumption that the kidney contains a pressor component, called renin. Moreover, following these observations, they located the origin of renin in the renal cortex. Nonetheless, their findings were not pursued by the scientific community for quite some time.
Following these initial discoveries more than 30 years later, and thereby finally establishing the RAS as a crucial blood pressure controlling system, Harry Goldblatt demonstrated induction of experimental hypertension in a dog animal model by clipping one or both renal arteries [2]. These findings paved the way for revitalization of investigations concerning pressor substances released by the kidney. Shortly after Goldblatt´s milestone methodological publications, two independent laboratories demonstrated that renin itself was not a pressor-controlling substance, but represented an enzyme catalyzing the release of a vasoconstrictor peptide, called angiotensin [3].
Subsequent research finally identified angiotensinogen as the substrate of renin. The RAS was ultimately established in main features by discovering angiotensin I (Ang I) as a decapeptide released from angiotensinogen. The assumption of Ang I being the effector pressor substance controlling blood pressure was refuted when ACE, giving rise to a further cleavage product, Ang II, was discovered in lung endothelial cells [4]. In the latter part of the 1950s, the last component of the nowadays termed renin-angiotensin-aldosterone system (RAAS) was discovered. Gross and colleagues were able to show release of aldosterone from adrenal glands following RA activation [5].
After being considered a systemic, plasma-circulating system, several observations suggested the existence of a local-acting RAS. For instance, a so-called tissue-RAS was described in the kidney itself, the adrenal glands, and the brain [6-8]. In addition, directly produced and acting RAS was detected in the vessel wall, and even salt-sensitive alterations in angiotensinogen production by the vasculature were demonstrated [9].
Biochemistry of the renin-angiotensin system
The starting point for the generation of Ang II, the major effector peptide of the RAS, represents enzymatic cleavage of angiotensinogen by renin, thereby producing release of Ang I. This decapeptide is subject to subsequent enzymatic processing by ACE, thus giving rise to Ang II. Ang II transduces cellular effects mainly via type 1 and type 2 receptors (AT1 receptor and AT2R). Figure 1 is a schematic overview of the RAS, including aldosterone, and the level of action of currently clinically available drug classes.
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Figure 1. Schematic overview of the renin-angiotensin-aldosterone system and the drugs targeting the system. |
Ang II may be converted by aminopeptidase A to Ang III (a heptapeptide: [2–8]-angiotensin II). Ang III causes qualitatively similar effects as Ang II (increasing blood pressure and augmenting aldosterone concentration), but is less potent [10]. Based on animal experiments, the pressor potency of Ang III is about 25% of that achieved by Ang II [11]. It has been suggested that Ang III might be responsible for central regulation of blood pressure [12].
By additional fragmentation, Ang III can further be converted into a hexapeptide by aminopeptidase N into [3–8]-angiotensin II, which is commonly known as Ang IV. Ang IV has been attributed to activation of endothelial nitric oxide (NO) synthase, however, without affecting the blood pressure after intravenous infusion [13]. Ang IV, finally, is degraded into small fragments.
Angiotensinogen
Angiotensinogen is currently the only known substrate of renin. It is a glycosylated protein with a molecular weight of approximately 60,000 Da, and belongs to the family of alpha2-plasma globulins. The major source of circulating (plasma) angiotensinogen, however, is the liver. Nonetheless, synthesis has been found in other organs/tissues, including the brain, heart, vessels, adrenal glands, ovaries, and testes.
The impact of an extrahepatic contribution to plasma levels is, at least in the adult organism, most likely minimal [14]. Panlobular synthesis of angiotensinogen in the liver is difficult to detect on the protein level because protein is not stored in hepatocytes but is rapidly released into the circulatory system [15]. Production of angiotensinogen has been shown to be regulated by various inducers. As an acute phase reaction, angiotensinogen plasma levels rise upon glucocorticoid stimulation (for instance, with dexamethasone) and, therefore, also in connection with Cushing`s syndrome [16]. The upstream region of the human angiotensinogen gene contains responsive elements for glucocorticoids, estrogen, and cyclic adenosine monophosphate (cAMP). Therefore, it is not surprising that plasma angiotensinogen levels were found to be increased during pregnancy [17]. In addition, thyroid hormones and Ang II were found to give rise to increased plasma angiotensinogen levels. Concerning the latter, a positive feedback loop is induced, which may be associated with clinical conditions [16].
Renin
Initially formed preprorenin is processed to the 57,000 Da protein prorenin [18]. Prorenin, the precursor of renin, had previously been considered to be functionally inactive, despite high circulating concentrations. Parts of prorenin are further cleaved to renin (molecular weight: 40,000 Da) [19]. Plasma levels of prorenin, however, normally exceed renin levels and are further increased under pathological conditions, such as diabetes mellitus [20,21]. Under physiological conditions, the ratio between secreted prorenin to renin is approximately 10 [22]. Only angiotensinogen has been described as a substrate of renin, giving rise to the production of the decapeptide Ang I.
Data demonstrated that prorenin, the inactive precursor of renin, seems to have a pathophysiological significance of its own and independent of Ang II generation. Prorenin contains a prosegment with a 43- amino-acid extension from the N terminus of mature renin [23]. This prosegment is folded in the active site cleft of renin and prevents interaction with angiotensinogen [23,24].
Prorenin can be activated in two ways: proteolytically or nonproteolytically [25]. Activation without proteolysis occurs in vitro by exposure to cold and/or low pH, or through binding of the pentameric “handle region” of prorenin to the prorenin receptor [26]. Thus, prorenin is not capable of generating Ang I in solution, but it gains enzymatic activity comparable to renin by binding to its receptor. This suggests that the receptor is able to unmask the catalytic activity of prorenin [27]. Proteolytic activation of prorenin occurs in the juxtaglomerular cells of the kidney, but has also been demonstrated in isolated cardiac and vascular cells [28-30].
While plasma renin concentrations in hypertensive patients have been shown to be associated with a higher incidence of acute myocardial infarction [31], plasma prorenin concentrations have been considered as early predictors for retinopathy, nephropathy, and microalbuminuria in patients with diabetes [32-34]. Importantly, prorenin-transgenic rats develop renal and vascular end-organ damage without activating the systemic RAS or inducing hypertension [35].
Renin belongs to the family of aspartyl proteases. Highest activity of renin is observed under conditions of neutral pH, as evident in the circulatory system. Renin has been detected during gestation in newly forming arterial branches. In the adult, renin is produced abundantly in the juxtaglomerular apparatus (JGA) of the kidney located in the vessel wall of the afferent arteriole. In general, it is assumed that cells of the JGA are metaplastically modified smooth muscle cells [36]. The primary source of active renin in the circulatory system is the kidney. Other tissues, however, including the brain, adrenal and submandibular gland, testis, and ovary, have also been shown to express renin [37].
The regulation of renin release from the kidney is complex. Several factors have been described, resulting in increased renin release. Reduction in arterial perfusion pressure and renal blood flow results in a decrease in glomerular filtration rate. This leads to reduced fluid load to the distal nephron and macula densa with reduced sodium chloride concentration. Alteration of an electrolyte cotransporter follows, which finally leads to increased calcium concentration with subsequent activation of phospholipase A2 and formation of prostaglandins. Prostaglandins stimulate renin release in the afferent arteriole [38]. Besides intracellular calcium concentration, cAMP and cyclic guanosine monophosphate (cGMP) have been identified as controlling renin release. Not surprisingly, activation of beta-adrenergic receptors, known to increase cAMP levels, was demonstrated to rapidly increase renin secretion [39,40]. In addition, other substances leading to increase of cAMP, including dopamine and glucagon, were also shown to increase renin release [41].
Since the plasma activity of renin is generally considered to be the rate-limiting step of the RAS cascade, the positive effect of Ang II on renin liberation certainly makes ACEIs and AT1 receptor blockers important interfering pharmacological agents, exhibiting action on this initial step of the RAS. Furthermore, other agents altering renin release, including beta-adrenergic blockers and inhibitors of prostaglandin production, interfere significantly with the RAS with all its obvious clinical implications.
Angiotensin-converting enzyme
ACE (dipeptidyl-carboxypeptidase I/kininase II) is predominantly localized in the vascular endothelium, particularly at high levels on the endothelial surface of lung vessels. Other vascular and nonvascular cell types, however, have been described to express ACE (eg, renal epithelial cells, brain cells, smooth muscle cells, monocytes, and adipocytes) [42]. This enzyme with a molecular weight of over 150,000 Da catalyzes Ang I into the octapeptide Ang II. In addition to Ang II, ACE also catalyzes other circulating peptides. Therefore, ACE plays a significant role in bradykinin, enkephalin, and insulin metabolism [43,44]. In the case of bradykinin [45], reduced cleavage of bradykinin results in increased levels of NO and prostaglandins. These effects significantly contribute to the beneficial effects of ACEIs, but they have also been associated with major adverse effects, such as coughing and angioneurotic edema [46].
Under physiological and disease conditions, ACE is not only found in plasma, but also in other biological fluids such as cerebrospinal and bronchoalveolar fluids. Plasma ACE levels have been described as a significant risk factor for various cardiovascular diseases, including coronary artery disease, myocardial infarction, and stent restenosis [42]. While ACE levels are under genetic control, association studies on ACE polymorphisms have provided conflicting data [47].
Besides the capability of ACE cleaving not only Ang I, but several other substrates, Ang I is also the substrate to various other enzymes, thereby releasing Ang II. These Ang-II-producing enzymes include chymase, cathepsin G, and trypsin. Even though the impact of these enzymes for production of significant levels of Ang II in vivo is uncertain, they might play a significant clinical role when ACE is inhibited by pharmacological intervention.
Angiotensin receptors
Ang II exerts its actions via AT1 and AT2 receptor subtypes. A further subdivision (in rodents) of AT1 receptors into AT1A and AT1B subtypes is based on receptor binding studies. The AT1 receptor is a 7-transmembrane domain receptor, coupled to a guanosine-triphosphate-binding protein (G-protein). The receptor transduces various signals via intracellular proteins, including phospholipases A, C, and D, inositol phosphates, Src homology 2 domain-containing phosphatase-2, and a variety of tyrosine and serine/threonine kinases [48,49]. AT1 receptors are widely expressed in the adult organism, abundantly in organs and tissues involved in fluid/electrolyte homeostasis and blood pressure regulation (eg, vascular smooth muscle cells, adrenal glands, kidney, and heart).
Similar to the AT1 receptor, the AT2 receptor (AT2R) is also a 7-transmembrane glycoprotein. It shares only approximately 34% amino acid sequence homology with the AT1 receptor, however. The knowledge of precise signaling events induced by the AT2R activation is not yet complete. However, serine and tyrosine phosphatases (eg, Src homology 2 domain-containing phosphatase-1), phospholipase A2, NO, and cGMP have been implicated in AT2R signaling. In addition, direct protein interaction partners of the AT2R were identified, including promyelocytic zinc finger (PLZF) and AT2-binding protein (ATBP) [50,51].
While AT2R is highly expressed in the developing fetus, it shows only low expression in the cardiovascular system in the adult. Interestingly, it is reexpressed in cells in the neointima of vascular lesions [52,53]. In general, AT2R expression is significantly enhanced under conditions of traumatic injury or ischemia [54,55]. Intrinsically, higher expression is detectable in the uterus, ovary, adrenal medulla [56], and some areas of the brain (eg, the cerebellum and the inferior olive) [57,58].
Renin receptor
The classical role of prorenin and renin is believed to be their enzymatic activity, thus producing Ang I from angiotensinogen. There is accumulating evidence, however, that prorenin and renin also possess direct capability to bind to cellular targets, therefore constituting cellular effector hormones. A human renin receptor (RER) has been cloned, which specifically binds prorenin and renin. Expression of the RER has been detected in the heart, brain, and placenta [59,60].
The signaling events by the RER are complex. Upon binding of renin, the catalytic activity of renin is significantly enhanced. As briefly introduced earlier, evidence suggests that prorenin, the inactive precursor of renin, is enhanced in its enzymatic activity upon binding to the RER as well [27,61]. This concept proposes the possibility of RER-mediated unravelling of prorenins’ enzymatic activity. In addition to the receptors’ function to enhance (pro)renin activity, the RER transfers signaling events upon ligand binding. These signaling cascades include activation of mitogen-activated kinases Erk1 and Erk2 [27]. Significant pathophysiological implications are based on RER-mediated proliferative and antiapoptotic cellular responses as well [60]. Schefe et al identified the transcription factor PLZF as the first direct protein–protein interaction partner of the RER. Furthermore, a novel signaling pathway upon renin binding, involving RER, PLZF, and the PI3 kinase subunit p85α, was established [60].
Aldosterone receptor
The mineralocorticoid receptor, also called aldosterone receptor, exhibits high affinity for mineralocorticoids. It belongs to the steroid hormone receptor family. Ligands (eg, aldosterone) diffuse into cells and interact with the receptor, which results in signal transduction including (after translocation to the nucleus, homodimerization and binding to hormone response elements) altering specific gene expression. The gene for the aldosterone receptor, which is located on chromosome 4q31.1-31.2, encodes for a 107 kDa protein. Besides expression of the aldosterone receptor in the kidney, it is also found in various tissues, including the heart and central nervous system [62]. The aldosterone receptor is not only activated by aldosterone, but also by other mineralocorticoids such as deoxycorticosterone, as well as glucocorticoids, such as cortisol and cortisone.
Besides classical genomic actions of aldosterone via the mineralocorticoid receptor, nongenomic actions have been described in a variety of cell culture and in vivo systems. In contrast to the classical genomic effects on gene transcription, nongenomic actions occur rapidly within seconds to minutes after administration of aldosterone. The primary cause of these effects is still unknown. In particular, isolation of a nonclassical membrane receptor for aldosterone was unsuccessful. It has been suggested that rapid nongenomic effects of aldosterone on, for example, vascular smooth muscle cells and cardiomyocytes are mediated via classical mineralocorticoid receptors as well [63]. This does not, however, exclude the possibility of the rapid effects of aldosterone mediated by a yet unknown distinct membrane receptor.
HYPERTENSION: GENERAL ASPECTS
Persistent hypertension is one of the primary risk factors for heart failure, myocardial infarction, chronic renal failure, and stroke. Hypertension has been widely acknowledged as a leading cause of mortality worldwide. In particular, high blood pressure soundly beats other risk factors, which are often more in the focus of general health care discussions, such as alcohol and use of tobacco (Figure 2) [64]. Importantly, hypertension is not only of great significance for mortality in highly developed countries, but also in developing regions. Analyzing in more detail the age- and sex-dependent prevalence of hypertension, large variations become evident (Figure 3) [65]. While only between 5 to 15% of the population in established market economies suffer from hypertensive disease, more than two thirds have hypertension at an age over 70 years. Interestingly, the prevalence of hypertension shows some association with sex (Figure 3). Numerous studies have provided evidence that even moderate elevation of blood pressure leads to shortened life expectancy. Importantly, hypertension is a modifiable disease, including therapeutic drug interventions. The possible intervention regarding the RAS will be discussed in detail later.
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Figure 2. Global mortality 2000: Impact of hypertension and other health risk factors.
(Adapted with permission from Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. Selected major risk factors and global and regional burden of disease. Lancet 2002;360(9343):1347-1360) |
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Figure 3. Prevalence of hypertension by age and sex: Data for established market economies (US, Canada, Spain, England, Germany, Greece, Italy, Sweden, Australia, and
Japan).
(Adapted with permission from Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365[9455]: 217-223) |
A complete description and discussion of the pathogenesis of primary (essential) hypertension is beyond the scope of this overview; nonetheless, there is a large body of excellent textbook chapters and scientific publications that readers can research for further information. Certain aspects, however, will be briefly introduced.
In contrast to secondary mechanisms associated with hypertension, which are in general known in great detail, the mechanisms of primary hypertension are less well understood. It is known, however, that early in disease initiation, cardiac output is increased, while the peripheral resistance remains normal. During disease progression, cardiac output returns to normal values, while peripheral resistance is increased. These phenomena have been proposed to possibly result from the inability of kidneys to excrete sodium. Furthermore, an overactive RAS has been described, leading to vasoconstriction (enhanced peripheral resistance) and retention of sodium and water. As a consequence, blood volume is increased, which contributes to hypertension.
The sympathetic nervous system is crucial for short-term regulation of blood pressure and heart rate. While it buffers acute blood pressure changes, it may also contribute to the long-term maintenance of hypertension [66].
The role of dietary salt intake for hypertensive disease has been widely debated in the past. While several studies have established that salt-sensitive changes in arterial pressure exist in many individuals, some epidemiological and dietary interventional studies (that did not discriminate between putative salt-sensitive and salt-resistant individuals) argued against a pathogenic role of salt intake in hypertension. Nonetheless, small increases in plasma sodium have been observed in certain cases of hypertension, and these seem to be linked to the activation of the sympathetic nervous system [67].
Kidney disease is known to be a cause or a consequence of hypertension. In fact, sodium retention and activation of the RAS have been considered the most important mechanisms involved in the elevation of blood pressure in patients with kidney disease [68]. Furthermore, there is a high incidence of hypertension after kidney transplantation. While the pathogenesis of posttransplant hypertension is multifactorial, data suggest that patients with posttransplant hypertension can be treated effectively with inhibitors of the RAS, and that this treatment exhibits significant additional benefits beyond blood pressure control [69].
Finally, heritable (polygenic) factors have been postulated in the etiology of hypertension [70,71].
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM AND HYPERTENSION
When discussing the effects of RAS, one needs to distinguish three modes of actions: rapid activation of RAS-balancing hypotension and hypovolemia; short activation of the RAS interfering with salt homeostasis; and long-term activation of the RAS leading to structural alterations of target tissues, such as the vessel wall and the myocardium.
Renin-induced effects
Renin, which only recently can be targeted by pharmacological intervention, is an aspartic protease. It catalyzes the first and rate-limiting step in the cascade of the RAS, where it binds its substrate angiotensinogen with high specificity. Therefore, renin’s primary function is believed to increase blood pressure by activating the RAS, finally leading to restoration of renal perfusion pressure.
As introduced earlier, besides renin’s ability to catalyze the rate-limiting step in the synthesis of Ang II, amplified enzymatic activity and additional pathophysiological effects occur when renin (and prorenin) binds to the RER. Importantly, RER-mediated proliferative and antiapoptotic cellular responses may have significant pathophysiological implications under conditions of high renin–plasma concentrations [60,72].
Angiotensin-I-induced effects
Ang I is formed by the action of renin on angiotensinogen. In contrast to other angiotensin subtypes, in particular Ang II, Ang I appears to exhibit no significant biological activity. Thus, its main “function” is to represent the precursor to Ang II.
Angiotensin-II-induced effects
Vasoconstriction and blood pressure control
Immediate vasoconstriction induced by activation of the RAS is the result of hypovolemia and/or hypotension. This vasoconstriction particularly affects arterioles, thus increasing the peripheral vascular resistance and ultimately increasing blood pressure. Importantly, small doses of Ang II, which do not exhibit a strong immediate blood pressure response, may cause effects lasting a few days. This results, in particular, in a slow reduction of arteriolar compliance. As a consequence of these prolonged effects, an increase of aldosterone can be observed, in addition to the activation of the sympathetic nervous system, thus demonstrating a major cross-talk between blood pressure regulating systems with all their obvious pathological implications.
Salt and blood volume homeostasis
A major physiological function of the RAS is balancing electrolytes and, in particular, sodium levels to maintain body fluid homeostasis. The RAS regulates sodium homeostasis retention by directly affecting AT1 receptors in the proximal tubuli. These activated AT1 receptors by high levels of Ang II ultimately mediate retention of sodium. Ang II, however, alters sodium retention by releasing the mineralocorticoid aldosterone from the zona glomerulosa in the adrenal glands, which is also mediated via AT1 receptors. This, thereby, indirectly leads to sodium retention in the kidney.
Cellular responses
The long-term effects from an activated RAS represent significant alterations on a cellular and tissue-based level. These include various structural changes with pathophysiological consequences. The activation of vascular smooth muscle cells leads to enhanced contraction and increases in pressor sensitivity. In terms of Ang-II-mediated cellular alterations in the myocardium, cardiac output initially can be increased. Long-term effects of an activated RAS, however, account for worsening of vascular and cardiac performance, ultimately contributing to heart failure. Morphological alterations take place, particularly in the heart and the vessel wall, as well as in the kidney. In terms of these long-terms effects, the effector peptide Ang II exhibits (growth-actor-like) effects on various vascular and nonvascular cells, including vascular smooth muscle cells in the vessel wall and cardiac fibroblasts, as well as on cardiomyocytes. Consequently, Ang II contributes significantly to cardiac and renal fibrosis [73,74]. In addition, the impact of Ang II on vascular wall pathology, like that on atherosclerosis and restenosis, is well established [75]. Since these Ang-II-induced effects are attributed to the enhanced activation of the AT1 receptor, the rationale of ACE inhibition and/or AT1 receptor blockade is obvious, ultimately leading to inhibition of these harmful effects. Figure 4 is a schematic overview of the various (deleterious) effects of Ang II via the AT1 receptor, subsequently contributing to cardiovascular- related diseases [76].
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Figure 4. Angiotensin II (Ang II): Direct and indirect effects in target organ damage.
Numerous cardiovascular and renal pathologies have been implicated with Ang II via
angiotensin (AT1) receptors, which include cardiac left ventricular hypertrophy (LVH)
and structural alterations of the vasculature, heart, and kidney (for example, neointima
formation, postinfarct remodeling, and nephrosclerosis), by exhibiting growth-factor-like properties.
(Adapted with permission from Chung O, Unger T. Angiotensin II receptor blockade and
end-organ protection. Am J Hypertens 1999;12[12 Pt 1-2]:150S-156S) |
Effects of angiotensin II on different tissues and organs
Heart
In the adult heart, all components of the RAS are expressed [77]. This even includes transcripts for renin and angiotensinogen in cardiomyocytes. The general assumption is, however, that the majority of renin in the myocardium derives from the circulatory system [78]. Nonetheless, this raises the question of the stimulus for local renin expression in the heart. It is widely accepted that the decrease of sodium levels in plasma represents an important stimulus for increased expression of cardiac-derived renin. In contrast, angiotensinogen, as in the case of the liver, seems to be regulated by similar effects from glucocorticoids and hormones, such as thyroxine and estrogens. The next component in the RAS, the ACE, has also been detected in the heart. Main expression loci are not cardiomyocytes and cardiac fibroblasts, but rather the endothelium of the vasculature in the heart. In addition, expression of ACE has been demonstrated at the cardiac valves. Finally, angiotensin receptors are expressed primarily in cardiomyocytes, as well as in sympathetic nerves, but also in cardiac vascular endothelial cells [79].
Concerning the physiological and pathological impact of Ang II on the heart, different mechanisms need to be distinguished. Ang II increases cardiac output by increasing heart rate, as well as heart strength. These effects are mediated by Ang II activation of the AT1 receptor. Furthermore, the alteration of the sympathetic nervous system seems to be involved in these effects. This, among others, explains the deleterious proarrhythmic effects of Ang II via cardiac AT1 receptors, hence contributing to lethal arrhythmias (Figure 4).
Vessel wall
The physiology and integrity of the vessel wall is of crucial importance for the morbidity and mortality of patients. Vascular diseases, such as atherosclerosis and restenosis, are highly associated with stroke, myocardial infarction, and death. Thus, all interventional therapies, including pharmacological regimens, targeting the vessel wall integrity are of significant clinical importance.
The vessel wall is composed of multicellular layers and different components of extracellular matrices. This includes the vascular cells, such as endothelial cells, vascular smooth muscle cells, and fibroblasts, which are found in nondiseased vessels. Also included are the nonvascular cells—for example, inflammatory cells including monocytes and macrophages, which are found in the vessel wall under pathological circumstances.
Interaction of all cellular and noncellular components preserves vascular homeostasis, such as maintenance of contractile tonus, luminal area, and the balanced action on blood coagulation. Contraction of vessels is mediated by factors of the sympathetic nervous system (noradrenaline), by others produced primarily by the vascular wall itself (endothelin), or by components of the RAS (Ang II). Vasodilation is mediated mainly by factors released by endothelial cells, such as prostacyclin and NO. This also explains the high impact of endothelial dysregulation on initiation and progression of vascular disease. A dysbalanced action of vasoconstrictive and vasodilatative factors is of critical importance not only for the pathogenesis of atherosclerosis, but also for hypertension.
As demonstrated for other organs, a local RAS is also found in the vessel wall. Importantly, besides endothelial ACE, other enzymes catalyzing production of Ang II are expressed in vascular tissues. These include chymase, which is identical to chymostatin-sensitive angiotensin-generating enzyme (CAGE), and others. Of critical importance are the effects mediated by Ang II on vascular smooth muscle cells, significantly contributing to obstructive vascular disease, such as restenosis and atherosclerosis. Furthermore, Ang II has inflammatory properties supporting the inflammatory concept of atherosclerosis [80]. While these Ang-II-mediated actions are widely referred to enhanced action of the AT1 receptor, several lines of evidence exist for opposing effects via stimulation of the AT2R. This also includes experimental data regarding induction of vasodilatation via activation of the AT2R [81]. On a molecular level, effects of AT2 receptor stimulation have been linked to bradykinin and, subsequently, NO production [82].
Kidney
Due to the finding that circulating renin is largely produced by the kidney in the JGA and, to a minor extent, in other regions, the kidney is often referred to as the classical organ of the RAS. This is because important regulatory processes, including Ang-II-mediated water and salt retention, are located here. Furthermore, not only renin, but also other components of the RAS are expressed in the kidney. For instance, Ang II is locally produced by ACE, located at the proximal tubules of the nephrons. Here, the highest levels of Ang II are found. These levels, which increase as much as 1000-fold, exceed the regular levels found in the circulatory system. Obviously, a local tissue RAS plays a major role in the kidneys.
Various effects of Ang II have been described, including tubular sodium reabsorption. Furthermore, Ang II leads to vasoconstriction of the efferent arteriole of the glomerulus and, to a lesser extent, of the afferent arteriole. Importantly, due to changes on the tubular-glomerular feedback, a decrease of renal perfusion is observed upon RAS activation. Even though the RAS keeps blood pressure balanced, especially under conditions of reduced water and salt uptake, these important mechanisms may ultimately exhibit pathophysiological consequences, including development and/or progression of several cardiovascular diseases, such as hypertension, as well as renal fibrosis and renal failure.
Brain
As in cardiac and vascular tissues, also in the brain, all components of the RAS have been detected, however, to different extents. For instance, the AT1 receptor is primarily found in periventricular regions, but its expression has also been described in the pituitary gland [83] and in astroglial cells [84].
Direct stimulation of angiotensin receptors by intracerebroventricular Ang II injection induces several reactions, including alterations of the nervous system. Interestingly, the activation of cerebral AT1 receptors indirectly stimulates water retention by enhanced release of vasopressin in the circulatory system. Furthermore, several hormones are released from the pituitary gland upon AT1 receptor stimulation, including adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), and growth hormone (GH). Importantly, several lines of evidence suggest the reverse of these central actions by simulation of brain AT2Rs [85].
Differential effects of angiotensin II receptors and their pathophysiological impact
Opposing effects in cells and tissues have been described for the activation of AT1 and AT2 receptors. Regarding the current situation, AT1 receptor blockers are widely used for treatment of hypertension and chronic heart failure. In the future, however, further research regarding development of AT2R agonists is likely and anticipated. Therefore, a short summary follows regarding the differential effects of the AT1 receptor and that of the AT2R, including their pathophysiological impact.
Currently, most if not all effects mediated by Ang II regarding blood pressure and water and salt homeostasis have been attributed to the activation of the AT1 receptor. These AT1-receptor-mediated effects, such as vasoconstriction, release of aldosterone, and retention of sodium, are crucial under circumstances of low sodium and water intake. Because this is—at least in modern civilization—generally provided, the more deleterious effects caused by activation of the AT1 receptor take center stage.
The effects on cellular proliferation and growth of cardiovascular and renal cells, in addition to proinflammatory properties of Ang II via AT1 receptor stimulation, are of critical pathophysiological and clinical impact. This provides the rationale for pharmacological therapies targeting the AT1 receptor. In fact, AT1 receptor blockade has been shown to interfere with numerous cardiovascular diseases, such as cardiac hypertrophy and arrhythmias, obstructive vessel wall diseases, glomerulosclerosis, and stroke, thus, significantly impacting cardiovascular-related morbidity and mortality of patients.
In contrast to the abundant expression of the AT1 receptor, the AT2R is highly expressed in the developing fetus, but only low levels are detected in the adult. Under pathological conditions, however, the AT2R is extensively upregulated, possibly impacting significantly on various diseases, such as heart failure, atherosclerosis, and restenosis, and during repair mechanisms in the heart, skin, and brain. Here the AT2R seems to participate in cell differentiation, proliferation and apoptosis, wound healing, and tissue regeneration. Overall, under these pathophysiological circumstances, the activation of the AT2R might oppose the deleterious effects mediated by the AT1 receptor. Taken into consideration, pharmacological blockade of the AT1 receptor possibly leads to the activation of the AT2R under conditions of Ang II presence, since AT2Rs remain unblocked. Thus, the beneficial effects mediated by the AT2R, such as its vasodilatory effects, might be unmasked, possibly significantly enhancing the blood-pressure-lowering properties of AT1 receptor blockers. But other beneficial effects, including interference of proliferative cellular responses in the cardiovascular system, are likely.
Angiotensin-(1-7)
Angiotensin-(1-7)—Ang-(1-7)—is formed from Ang I and Ang II by several endopeptidases and carboxypeptidases. Ang-(1-7) binds to the Mas receptor and has been established as a vasodilator peptide with antihypertensive properties [86,87]. Potentially important from a clinical point of view, ACEIs and AT1 receptor blockers were shown to shift the balance from Ang II to increased formation of Ang-(1-7). These effects may contribute to the blood-pressure-lowering properties of RAS-inhibitors. For instance, Ang-(1-7) levels increase significantly under conditions of ACE inhibition [88].
Angiotensin-III/IV-induced effects
Angiotensin III (Ang III) exhibits less of the pressor activity of Ang II, but approximately the same aldosterone-producing activity [11,89]. Angiotensin IV (Ang IV), which is less well characterized, is a hexapeptide whose activity is similar to that of Ang III [13,90,91]. Besides effects of Ang III and Ang IV on blood pressure and aldosterone production, in vitro studies in rat endothelial cells and human adipocytes established both peptides as capable of stimulating plasminogen activator inhibitor-1 (PAI-1) release and secretion [92-94].
Some data suggest that Ang III is the main effector peptide of the RAS in the brain [95]. Furthermore, Ang III might be responsible for central regulation of blood pressure [12].
Aldosterone-induced effects
In epithelial tissues, activation of the aldosterone receptor leads to the expression of proteins regulating ionic and water transports (mainly the sodium channel, Na+/K+ pump), resulting in the reabsorption of sodium. The consequences are an increase in extracellular volume, increase in blood pressure, and excretion of potassium to maintain salt homeostasis.
OVERVIEW OF DRUGS TARGETING THE RENIN-ANGIOTENSIN SYSTEM
The first ACEI, captopril, was launched in 1981. The development of this drug was mainly based on academic efforts. The first AT1 receptor blocker was launched in the 1990s for the treatment of hypertension. Following spironolactone, eplerenone, a newer aldosterone antagonist, was approved by the US Food and Drug Administration (FDA) for treatment of hypertension in 2002. Several ACEIs, AT1 receptor blockers, and aldosterone receptor antagonists have also been approved for chronic heart failure treatment since then [96]. The latest drug class targeting the RAS are renin inhibitors. Currently only one inhibitor, aliskiren, is available, which was launched in 2007 for the treatment of hypertension.
General pharmacological aspects
ACEIs were the first drug class developed to target the RAS (Figure 1). ACEIs specifically and selectively inhibit ACE by competitive antagonism. This results in reduction of Ang II release from the decapeptide Ang I, thus significantly impacting blood pressure. Decreasing Ang II levels is of obvious clinical benefit. Besides reduction of AT1 receptor activation, however, it also eliminates the possible activation of beneficial AT2Rs as a target of Ang II under pathophysiological conditions (Figure 5) [97]. Moreover, as outlined earlier, other peptides are processed by ACE, such as bradykinin. Therefore, ACEIs not only target the RAS, but also other vascular tone-controlling systems. Deleterious, but rather advantageous, consequences have been attributed to these inhibitory mechanisms [98,99].
 |
Figure 5. Selective angiotensin (AT1) blockade and its possible clinical benefit via AT2 receptor stimulation. Under conditions of AT1 receptor blockade, the AT2 receptor, which remains unblocked, is activated by Ang II. In some tissues, the AT2 receptor even induces an increase in nitric oxide (NO), which seems to depend on the release of endogenous
bradykinin.
(Adapted with permission from Steckelings UM, Kaschina E, Unger T. The AT2 receptor—a
matter of love and hate. Peptides 2005;26[8]:1401-1409) |
Of significant clinical importance is the unblocked production of Ang II via alternative pathways. Several other enzymes besides ACE are capable of producing Ang II, such as chymase and cathepsin G. Therefore, even under effective ACE inhibition in clinical settings, such as in heart failure and hypertension, notable levels of Ang II are still produced via these avenues. Upon consideration, the pharmacological rationale for directly antagonizing the AT1 receptor, and thereby more completely inhibiting the RAS, is obvious.
AT1 receptor blockers, also called ARBs or sartans, are widely prescribed for the treatment of hypertension. The first AT1 receptor blocker, losartan, was launched in 1995. In contrast to ACEIs, they block the activation of the AT1 receptor by Ang II via direct competition. While the AT1 receptor and AT2R at the receptor site have comparable affinities for Ang II, they clearly differ with regard to their molecular structure, signal transduction, and intracellular signal transducing and cellular effects. Therefore, blockade of the AT1 receptor is a significant difference when compared to ACE inhibition. In general, the affinity of AT1 receptor blockers for the AT1 receptor is about 10,000 times higher compared to their affinity to the AT2R. Thus, the AT2R is generally not affected by treatment with AT1 receptor blockers.
The rate-limiting step in the RAS cascade is the production of renin. Importantly, treatment with AT1 receptor blockers abolishes the Ang-II-mediated negative feedback for renin production, thereby leading to even higher Ang II levels under conditions of AT1 receptor blockade. This might also imply a significant and advantageous increase of AT2R activation. Obviously, these latter-mentioned effects are not evident from treatment with ACEIs. During chronic ACE inhibition, however, levels of renin are still increased and reactive increases in Ang II levels might occur due to compensatory stimulation of alternative pathways of Ang II formation (“Ang II escape”).
However, even though these significant pharmacological differences between ACEIs and AT1 receptor blockers exist, both drug classes seem to possess a comparable potential with regard to lowering blood pressure. In contrast, differences concerning impact on metabolic changes, end-organ damage, and adverse events might be evident. In particular, the results from large clinical trials (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial [ONTARGET] and Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease [TRANSCEND]), comparing the use of the AT1 receptor blocker telmisartan, the ACEI ramipril, or their combination, in patients at high cardiovascular risk, shed light on this debate [100]. While the results of ONTARGET were published in April 2008 and are described in detail later, the publication of TRANSCEND is awaited eagerly.
Spironolactone and eplerenone are two low-ceiling diuretics antagonizing aldosterone receptors. Both drugs are used in combination treatment of hypertension and heart failure. While spironolactone was associated with significant endocrine adverse reactions, tolerability of eplerenone seems markedly improved. Besides essential hypertension, aldosterone receptor antagonists obviously are recommended for treatment of hyperaldosteronism.
The renin inhibitor aliskiren is the latest drug class developed for targeting the RAS. It was approved for the treatment of hypertension by the FDA in March 2007 and in Europe in August 2007. While all available clinical studies, which have enrolled a few thousand patients, have shown the excellent blood-pressure-lowering capability of aliskiren during short-term treatment, large-scale and, in particular, long-term comparative studies are not currently available. They will provide evidence whether renin antagonism indeed exhibits benefits regarding morbidity and mortality of patients compared to established RAS inhibitors. Furthermore, numerous studies (eg, ALOFT: Aliskiren Observation of Heart Failure Treatment; AVOID: Aliskiren in the Evaluation of Proteinuria in Diabetes; and ALLAY: Aliskiren in Left Ventricular Hypertrophy) are being conducted to possibly unravel aliskiren’s potential in the management of several renal and cardiovascular diseases, such as diabetic nephropathy, heart failure, and postmyocardial infarction.
Adverse effects and contraindications of drugs targeting the renin-angiotensin system
Angiotensin-converting enzyme inhibitors
Common side effects associated with the use of ACEIs include cough, hypotension, hyperkalemia, and, rarely, angioneurotic edema. In particular, dry cough (possibly resulting from bradykinin accumulation, whose breakdown is also inhibited by ACEIs) often leads to withdrawal of the drug or noncompliance by the patient. In bilateral renal artery stenosis, intrarenal perfusion pressure is reduced. Glomerular filtration rate is maintained in part by an Ang- II-induced increase in resistance at the efferent (post-glomerular) arteriole. Therefore, blocking this response with ACEIs will sequentially relax the efferent arteriole, lower intraglomerular pressure, and reduce the glomerular filtration rate [101,102]. Bilateral renal artery stenosis, thus, represents a contraindication for the use of ACEIs. Furthermore, ACEIs are contraindicated in pregnancy, since they are associated with an increased incidence of fetal complications.
AT1 receptor blockers
The extremely high tolerance of treatment with AT1 receptor blockers has been documented in numerous clinical trials. In case of recommended use with regard to treatment intervals and doses, they virtually exhibit no characteristic adverse reactions and events (Figure 6). The rate of observed adverse effects in AT1 receptor blocker treatment does not seem to significantly differ from those observed with placebo treatment. For instance, coughing, a very common side effect of treatment with ACEIs (see earlier) occurs in patients treated with AT1 receptor blockers at a level seen with those under placebo treatment. The most dramatic and potentially life-threatening adverse reaction by an ACEI, the development of angioneurotic edema, occurs only very rarely from treatment with AT1 receptor blockers [103].
 |
Figure 6. Combined therapeutic efficacy, tolerability, and target organ damage reduction
of various antihypertensive drugs, including those discussed in this overview. The
launching year of the drugs is indicated on the x-axis.
(Adapted with permission from Unger T. [New options in the drug treatment of hypertension: claim and reality]. Deutsche medizinische Wochenschrift [1946] 2002;127[45]:2404-2406) |
Distinguishable from adverse effects, some cases of hypersensitivity to treatment with AT1 receptor blockers have been reported. In these cases, the use of AT1 receptor blockers for treatment of hypertension and chronic heart failure represents a contraindication. In addition, as with the use of ACEIs, treatment with AT1 receptor blockers during pregnancy and during lactation is contraindicated due to adverse effects on fetal development. Most importantly, treatment of AT1 receptor blockers should not be considered under circumstances where the activation of the RAS stabilizes the cardiovascular system. This includes conditions of hypotension and hypovolemia, as well as renal artery stenosis and higher levels of aortic or mitral valve stenosis. In addition, primary hyperaldosteronism represents a contraindication. Insufficiency of metabolizing and/or excretion organs—ie, the liver and kidneys—leads to the need for dose modifications.
Aldosterone receptor antagonists
Spironolactone and eplerenone are aldosterone antagonists approved for treatment of mineralocorticoid hypertension, ascites associated with portal hypertension, chronic heart failure, and hypertension. Both agents, however, differ significantly with regard to adverse effects. Spironolactone exhibits nonspecificity, due to its influence on other steroid hormone receptors. This leads to antiandrogenic and proestrogenic effects, including, for instance, development of gynecomastia in male patients at a considerable rate [104]. Based on these data, a second oral aldosterone antagonist with less adverse effects was developed. Eplerenone represents an aldosterone antagonist with less interference with other steroid hormone receptors. Spironolactone’s severe adverse effect—hyperkalemia—is also observed under eplerenone treatment, however. As true for other drugs targeting the RAS, there are no available adequate studies of eplerenone and spironolactone with pregnant women. Thus, pregnancy is regarded as a contraindication for aldosterone antagonists.
Renin inhibition
Studies with aliskiren have reported good tolerability and a low number of adverse effects. The most common adverse events are gastrointestinal disorders, fatigue, and headaches. Interestingly, no rise in the number of adverse events was reported when increasing the dose of aliskiren to 300 mg daily [105], while higher doses are associated with an increase of adverse events, such as diarrhea [106]. With regard to clinical laboratory findings, minor changes in red blood cell count and hematocrit have been observed when doses of 300 mg per day or more were given [106]. These findings, however, have also been reported in studies with ACEIs and AT1 receptor blockers. As with other pharmacological compounds targeting the RAS, pregnancy is an absolute contraindication of aliskiren. In addition, the impact of aliskiren during lactation is currently unknown.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND HYPERTENSION
Large clinical trials have been conducted with patients suffering from hypertension. In general, antihypertensive therapy should not only focus on the actual decrease in blood pressure, but should particularly analyze the impact on cardiovascular complications, that is, mortality and morbidity. Furthermore, blood-pressure-lowering drugs might result in beneficial effects in patients at increased cardiovascular risk with, and even without, hypertension. This has been demonstrated in the Heart Outcomes Prevention Evaluation (HOPE) trial [107]. In particular, it was proposed that ACEIs have the additional advantages of having a more favorable side-effect profile than do other antihypertensives, including beta-blockers and diuretics [108], and/or have beneficial effects regarding incidence of cardiovascular end points, such as myocardial infarction, death, stroke, and new-onset diabetes beyond blood-pressure-reducing capability.
Clinical trials
Captopril Prevention Project trial
In the Captopril Prevention Project (CAPPP) trial, 10,985 patients between the ages of 25 and 66 with a diastolic blood pressure of at least 100 mmHg were randomly assigned to either captopril (up to 100 mg per day) or conventional therapy (a diuretic and/or a beta-blocker) [109]. The primary end points were fatal and nonfatal myocardial infarction, stroke, and other cardiovascular deaths. Follow-up was performed for 6 years. The randomized groups were corrected for relative imbalances in the statistical analyses: for example, minor differences in blood pressure before treatment. At follow-up, the two treatment regimens had almost the same effect on blood pressure, while slightly higher values in the captopril group remained throughout the study. Interestingly, while no statistically significant difference was observed in the risk of cardiovascular events between the two treatment groups, subsequent subgroup analyses showed that patients with diabetes who were treated with captopril had a significant reduction (-40%) in the relative risk of all primary end points [110]. Thus, this trial provided evidence for beneficial effects of ACE inhibition beyond blood pressure control in a subgroup of patients.
Second Australian National Blood Pressure study
The Second Australian National Blood Pressure (ANBP2) study was a prospective study of 6083 elderly patients (ages between 65 and 84 years) with hypertension [111]. The patients were randomly assigned to an antihypertensive regimen with either an ACEI (with enalapril recommended, but every ACEI allowed) or a diuretic (with hydrochlorothiazide recommended, but also other diuretics allowed). The primary end point was all cardiovascular events, including initial and subsequent events, or death from any cause. Included were coronary events (such as myocardial infarction, sudden death from cardiac causes, and others), other cardiovascular outcomes (such as heart failure, death from vascular causes, and others), and cerebrovascular events (such as stroke and transient ischemic attacks).
The mean initial blood pressures were the same for the ACEI and diuretic groups (167/91 and 168/91 mmHg, respectively). The therapeutic goal was a reduction in systolic and diastolic pressure of at least 20/10 mmHg to less than 160/90 mmHg. As in the aforementioned CAPPP trial, similar blood pressure reduction was observed in either treatment arm at the study end (median of 4.1 years; blood pressure decrease by 26/12 mmHg). Monotherapy was given to approximately two thirds in both arms. The group treated with ACEIs showed a lower incidence of the primary end point (all cardiovascular events or death from any cause) compared with the group treated with diuretics (hazard ratio of 0.89, 95% confidence interval [CI], 0.79- 1.00). Because there was no difference in mortality between the two groups, the benefit was due to a decrease in the rate of nonfatal events with ACEIs. There was a significant difference regarding male and female patients: the benefits with ACEI therapy were fully restricted to men, as the hazard ratios for the primary end point were 0.83 (95% CI, 0.71-0.97) for men and 1.00 (95% CI, 0.83-1.21) for women.
In summary, the ANBP2 study demonstrated that antihypertensive therapy with ACEIs, compared with diuretics, was superior regarding certain cardiovascular outcomes in elderly men.
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [112] was a randomized prospective, multicenter study of 33,357 patients >55 years old with hypertension and one additional risk factor for coronary heart disease (previous myocardial infarction or stroke, left ventricular hypertrophy, type 2 diabetes, current cigarette smoking, hypercholesterolemia, or atherosclerotic cardiovascular disease. Mean follow-up was 4.9 years. The study was designed to evaluate whether the incidence of adverse cardiovascular events differed among patients randomly assigned to the diuretic chlorthalidone (12.5 to 25 mg per day compared to the calcium channel blocker amlodipine (2.5 to 10 mg/dL), and the ACEI lisinopril (10 to 40 mg/dL). Primary outcomes were combined fatal coronary heart disease or nonfatal myocardial infarction. Secondary outcomes were all-cause mortality, stroke, combined coronary heart disease (primary outcome, coronary revascularization, or angina with hospitalization), and combined cardiovascular disease (combined coronary heart disease, stroke, treated angina without hospitalization, heart failure, and peripheral arterial disease).
Initial mean blood pressure levels were similar in the three treatment groups. At a mean follow-up of almost 5 years, each of the antihypertensive drugs lowered blood pressure. However, compared with chlorthalidone, the mean systolic blood pressure was slightly higher when treated with amlodipine or lisinopril, while the diastolic blood pressure was lower under amlodipine treatment (133.9/75.4 mmHg for chlorthalidone, 134.7/74.6 mmHg for amlodipine, and 135.9/75.4 mmHg for lisinopril). While no significant differences between the treatment groups were found in terms of the primary end points (incidence: 11.5%, 11.3% and 11.4%, respectively), there were differences in favor of chlorthalidone treatment in the secondary end points regarding “stroke incidence” and “occurrence of heart failure,” but not regarding “total mortality.”
While the authors of ALLHAT concluded a superiority of chlorthalidone in the prevention of one or more major forms of cardiovascular disease, numerous concerns have been raised against this interpretation. This is also reflected by the enormous amount of comments and discussions about ALLHAT. In general, ALLHAT did not confirm many of the results of major clinical studies from the past.
At no point was the blood pressure in the three treatment groups reduced to the same level. In particular, the systolic blood pressure of the chlorthalidone treatment group throughout the entire study was at least 2 to 3 mmHg below that measured in the lisinopril group. Already these blood pressure differences significantly affect stroke incidence and coronary mortality [113], which makes the ALLHAT findings difficult to interpret. Furthermore, the blood pressure values at the beginning of the study were quite low for a hypertensive population (mean blood pressure in all three groups: 146/84 mmHg). In addition, the blood pressure control achieved during the study was amazingly good when compared to other large hypertension studies [114]. This may indicate a selective patient population, which responded particularly well to diuretics.
In addition, significant differences appeared with regard to prevalence of new diabetes (fasting glucose ≥126 mg/dL/≥7.0 mmol/L) and hypokalemia (serum potassium <3.5 mEq/L), in favor of lisinopril and amlodipine treatment as compared to that with chlorthalidone. Prevalence of new diabetes at 4 years follow-up was 11.6% for chlorthalidone, 9.8% for amlodipine, and 8.1% for lisinopril. Furthermore, the rate of hypokalemia was increased eight-fold (vs lisinopril) and five-fold (vs amlodipine) in the chlorthalidone group. Thus, these results suggest beneficial effects of ACE inhibition beyond blood pressure control.
In summary, the principal finding of ALLHAT was that the antihypertensive drugs amlodipine, lisinopril, and chlorthalidone provided similar protection from coronary heart disease, death, and nonfatal myocardial infarction among the investigated patient group. But considering the aforementioned concerns about the study design [115,116], interpretations are difficult to draw.
Conclusion
There is a large body of evidence that ACE inhibition is very effective in the treatment of hypertension. Furthermore, numerous studies, including those discussed earlier (ie, CAPPP trial and ANBP2 study), have shown that ACE inhibition exhibits additional properties beyond that of simple blood pressure reduction, thus leading to improved morbidity and mortality regarding cardiovascular-related diseases.
AT1 RECEPTOR BLOCKERS AND HYPERTENSION
The benefit of blood pressure reduction due to AT1 receptor blockers in patients at high cardiovascular risk has been investigated in several major clinical trials, including Losartan Intervention for Endpoint Reduction in Hypertension (LIFE), Valsartan Antihypertensive Long-term Use Evaluation (VALUE), and Study on Cognition and Prognosis in the Elderly (SCOPE).
Clinical trials
Losartan Intervention for Endpoint Reduction in Hypertension trial
The LIFE study [114] was a randomized, double-blind study of 9193 patients with hypertension (inclusion criteria: systolic blood pressure of 160 to 200 mmHg and/or diastolic blood pressure of 95 to 115 mmHg after 2 weeks of placebo treatment). In addition, patients were characterized by left ventricular hypertrophy and were treated for an average of 4.8 years with losartan or the beta-blocker atenolol (50 mg daily). In patients where blood pressure was not decreased below 140/90 mmHg after 2 months of treatment, an additional 12.5 mg of hydrochlorothiazide daily was given. If the target blood pressure of 140/90 mmHg could not be achieved after an additional 2 months, the dose of either primary drug was doubled. After another 2 months, those patients still above the target blood pressure received additional hydrochlorothiazide or another open-label medication (diuretics or calcium channel blockers, but no other AT1 receptor blockers, ACEIs, or beta-blockers). The primary end point was composite cardiovascular morbidity and mortality (myocardial infarction, cerebral stroke, or cardiovascular death).
Losartan prevented more cardiovascular morbidity and mortality than did treatment with atenolol, despite similar reduction in blood pressure. In addition, losartan was better tolerated. This superiority was mainly due to a decreased incidence of cerebral stroke. Thus, the finding that an AT1 receptor blocker (losartan) could exhibit significant effects on hypertension-associated diseases above blood pressure substantiated the findings of the placebo-controlled HOPE trial [107], which was not conducted as a pure hypertension study. This trial demonstrated that ACEIs also are protective against stroke beyond their blood-pressure-reducing capability.
Furthermore, one additional observation should merit high attention: reduced new-onset diabetes in the losartan-treated group (25% lower incidence compared with the atenolol-treated patients group). This finding, again, demonstrates the beneficial effects of RAS inhibition. In the LIFE study, this benefit could result from increased protection against the detrimental effects of Ang II, or from specific effects of losartan [117].
Valsartan Antihypertensive Long-Term Use Evaluation trial
Like the LIFE study, the randomized, double-masked, prospective VALUE trial [118,119] analyzed the impact of an AT1 receptor blocker with another antihypertensive drug in regard to primary cardiovascular end points. The study enrolled 15,245 patients at high cardiovascular risk who were >50 years with an untreated blood pressure of 160 to 200/≤110 mmHg. The patients received either the AT1 receptor blocker valsartan or the calcium-channel blocker amlodipine.
Interestingly, no significant difference in primary end points and cardiovascular mortality was observed between the two study arms. Fatal and nonfatal myocardial infarction, however, showed a relative risk reduction of 19% (p = .02) in the amlodipine group. These data are difficult to interpret because systolic blood pressure after 1 month of treatment was 4.0 mmHg lower in the amlodipine group than it was in the valsartan group, and after 6 months it was 2.1 mmHg lower. Therefore, when comparisons were made on the basis of equal blood pressure reduction, these differences were not further evident. In addition, valsartan was shown to be superior in reducing heart failure [119]. Importantly, as in the LIFE study, valsartan treatment was associated with a significant reduction in new-onset diabetes compared to treatment with the calcium channel blocker amlopdipine.
Study on Cognition and Prognosis in the Elderly
The SCOPE trial [120] included approximately 5000 patients (with an average age of 76 years, mean study follow-up of 3.7 years). Inclusion criteria were systolic blood pressure of 160 to 179 mmHg and/or a diastolic blood pressure of 90 to 99 mmHg. Treatment was performed with candesartan versus placebo. However, the study was conducted with open-label active antihypertensive therapy added if needed. Therefore, in the control group an active additional antihypertensive therapy was used in 84% of patients. Primary end points were major cardiovascular events, a composite of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction. Secondary outcome measures were total mortality, cardiovascular death, nonfatal and fatal stroke, nonfatal and fatal myocardial infarction, cognitive function, and dementia.
Blood pressure was significantly reduced with candesartan (-3.2 mmHg systolic/1.6 mmHg diastolic vs the control group). No significant difference, however, between candesartan treatment and the control group was observed regarding composite stroke incidence, myocardial infarction, and cardiovascular death (primary end point). In contrast, the candesartan group was characterized by a significant reduction of the relative risk for incidence of nonfatal stroke (secondary end point). Thus, the primary end point was not significantly altered due to candesartan treatment, whereas one of the secondary end points reached significance (risk reduction of 27.8%; 95% CI, 1.3–47.2).
Ongoing clinical trials
ONTARGET [100,121] is the largest trial comparing an AT1 receptor blocker and ACE inhibition therapy in high-risk patients with controlled blood pressure. It is anticipated that the results, which were released in April 2008, will significantly impact future treatment regimens and guidelines regarding cardiovascular disease.
The patients’ characteristics are similar to those in the HOPE trial [107,122], except for greater ethnic diversity and the slightly older age of the patients in the ONTARGET trial. Furthermore, the baseline characteristics of the patients differed in regard to the higher number of patients treated with statins and beta-blockers, for example. The primary outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The main secondary outcome was a composite of death (from cardiovascular causes), myocardial infarction, or stroke, and was therefore similar to the primary outcome in the HOPE trial. Further secondary outcomes included new heart failure, atrial fibrillation, diabetes mellitus, nephropathy, revascularization procedures, and cognitive decline or dementia. A total of 25,620 patients were included in this study at 733 centers in 40 countries. The patients were randomly assigned to either 10 mg of the ACEI ramipril, 80 mg of the AT1 receptor blocker telmisartan, or to combination therapy. The study was designed to prove noninferiority of the AT1 receptor blocker telmisartan to the ACEI ramipril (at a dose that had previously been shown to be effective for the primary outcome). In addition, it was to test whether the combination therapy was superior to ACE inhibition alone with regard to prevention of vascular events in high-risk patients with cardiovascular disease or diabetes mellitus, but who did not have heart failure. At a median follow-up of 56 months, the primary outcome occurred in 16.5% of the ramipril group and in 16.7% of the telmisartan group (relative risk 1.01; 95% CI, 0.94-1.09), thus demonstrating noninferiority (p <.006) of telmisartan in this patient group. There was, however, a significant reduction of cough (1.1% of telmisartan group vs 4.2% of ramipril group) and angioedema (0.1 vs 0.3%) in the patient group treated with telmisartan. This benefit was partially offset by significantly higher rates of hypotensive symptoms, but not syncope. Concerning the combination treatment, the primary outcome occurred in 16.3% (relative risk, 0.99; 95% CI, 0.92-1.07). There were no significant differences in the rates of secondary outcomes concerning ramipril versus telmisartan, and ramipril versus combination therapy, except for renal dysfunction. The combination therapy group had a significant increase in the relative risk for renal impairment (compared to ramipril treatment), occurring in 13.5% of the patients, compared to 10.2% in those using ramipril, and 10.6% in those using telmisartan. Furthermore, the combination was associated with significantly higher rates of hypotensive symptoms and syncope as compared to the ramipril group, and led to significantly higher potassium levels >5.5 mmol/L.
Taken together, this trial demonstrated noninferiority of telmisartan in patients with vascular disease or high-risk diabetes. Furthermore, telmisartan treatment was associated with significantly less angioedema and cough. The combination of ramipril and telmisartan (which led to an average blood pressure reduction of 2.4/1.4 mmHg in comparison to ramipril) did not produce an additional clinical benefit, but was associated with more adverse events. This absence of a further benefit besides reduction of blood pressure is “puzzling” [100]. Possibly, the addition of full doses of multiple drugs against the RAS can only lead to minor—if any—further clinical benefit. Moreover, adverse effects of full doses of ACEIs and AT1 receptor blockers possibly offset potential advantages. Combination therapy might be superior only in specific patient populations, such as in heart failure patients [123,124].
As a part of the ONTARGET/TRANSCEND clinical trial program, ONTARGET patients who were intolerant of ACE inhibition at baseline were randomized in the TRANSCEND study [125]. This trial recruited 5926 patients with cardiovascular disease or diabetes with organ damage, many of whom were on stable concomitant therapies, proven to confer cardiovascular protection. After a 3-week run-in period, eligible patients were randomized to receive either telmisartan (80 mg/day) or placebo treatment. The primary outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The median duration of follow-up was 56 months. Throughout the entire study, the mean blood pressure was lower in those patients randomized to receive telmisartan as compared to those randomized to placebo. At the end of the study period, no significant difference was observed for the incidence of the primary outcome between telmisartan and placebo arms. Although a significant reduction in the incidence of one component of the secondary end point (a composite of cardiovascular death, myocardial infarction, and stroke) was observed in favor of telmisartan as compared to placebo, this latter did not achieve statistical significance after adjustment for multiplicity of comparisons and overlap with primary outcome. Fewer patients receiving telmisartan-based strategy, however, were hospitalized for cardiovascular reasons as compared to those patients in the placebo arm. Fewer patients also permanently discontinued study medication in the telmisartan group than in the placebo group, with hypotensive symptoms the most common reason for permanent discontinuation. Overall, telmisartan was well tolerated in patients unable to tolerate ACE inhibitors, although it modestly reduced the risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke [126].
Conclusion
As with ACE inhibition, clinical trials with AT1 receptor blockers have provided evidence for potent blood pressure reduction. Importantly, AT1 receptor blockers exhibit less side effects compared to ACEIs. Beyond its excellent profile for controlling blood pressure, AT1 receptor blockade was associated with clinical benefits regarding cardiovascular disease progression, thus protecting against new-onset diabetes and (nonfatal) stroke.
RENIN INHIBITION AND HYPERTENSION
Renin inhibition by aliskiren is the latest development in RAS-targeting pharmacological intervention. In contrast to ACEIs and AT1 receptor blockers, however, available clinical data on renin inhibition rely on rather short-term treatment analyses (usually 8-weeks treatment with aliskiren). In addition, the number of patients or control subjects enrolled in clinical trials using aliskiren up to now is rather low (less than 10,000) compared to studies with ACEIs and AT1 receptor blockers. Therefore, no large-scale and, in particular, no long-term trials are currently available on mortality and morbidity in hypertensive patients receiving renin inhibition treatment. Nonetheless, the efficacy and safety of aliskiren has been evaluated in several clinical trials, a summary of which follows.
The development of an inhibitor of renin was largely hampered by poor pharmacokinetic and pharmacodynamic properties—for example, side effects and low bioavailability. With the discovery of aliskiren, the first nonpeptide drug specifically inhibiting human renin became available [127]. The long half-life of 20 to 45 h overcomes the rather poor bioavailability (2 to 3%), which is sufficient for good blood-pressure-lowering potency. Remarkably, aliskiren is extremely well tolerated with a side-effect profile near placebo, and no influence of renal or liver function. This potentially makes aliskiren very attractive for treatment of hypertension in the elderly, where comorbidities are frequently apparent.
Approximately 12% of patients with hypertension are characterized by elevated plasma renin activity, which is associated with increased risk for myocardial infarction [128]. Aliskiren inhibits approximately 40 to 80% of renin activity [129-131], and therefore reduces significantly the production of Ang I and Ang II, as well as aldosterone synthesis. Consequently, aliskiren exhibits potentially great therapeutic effective blockade of the RAS. However, renin concentration when being treated with aliskiren is increased [132]. The significance of this constellation— reduced plasma renin activity with increased renin concentration—on general cardiovascular risk is controversial [133,134].
Clinical trials
Gradman et al, Oh et al, and Kushiro et al [129,135,136] have all published double-blind, randomized, placebo-controlled, 8-week trials with aliskiren treatment varying between 75 and 600 mg daily with a total of 1779 enrolled patients. Each study demonstrated significant reductions in systolic and diastolic blood pressure compared to placebo treatment.
In a study using aliskiren either alone (aliskiren 75, 150, or 300 mg) or in combination with a diuretic (hydrochlorothiazide 6.25, 12.5, or 25 mg) for 8 weeks, or with placebo (instead of aliskiren), aliskiren proved significantly better in terms of blood pressure reduction [131]. Furthermore, combination treatment was superior to both drugs’ monotherapies. Also, the combination of the AT1 receptor blocker valsartan 320 mg with aliskiren 300 mg demonstrated good tolerability and superiority over either monotherapy alone (diastolic blood pressure reduction for aliskiren 9.0 mmHg, valsartan 9.7 mmHg, placebo 4.1 mmHg, combination aliskiren and valsartan 12.2 mmHg). In a pooled analysis summarizing the clinical data of trials enrolling more than 7000 patients on aliskiren, the antihypertensive efficacy appeared to be independent of sex, race, or age [106].
Conclusion
Aliskiren exhibits a new pharmacological concept by targeting the first step in the RAS cascade. It has the potential to largely improve the pharmacological intervention for treatment of hypertension. The pharmacokinetic and pharmacodynamic properties result in effective blood pressure control over 24 h, therefore working in the early morning hours as well. Another advantage clinically in the treatment of the elderly seems to be that aliskiren metabolism is independent of renal and liver function. Based on currently available clinical data, which rely on 8-week-long trials, it is impossible to determine what the long-term effects will be. Only the future will tell whether aliskiren exhibits benefits with regard to morbidity and mortality when large-scale and long-term comparative trials comparing aliskiren with other RAS targeting drugs become available. In addition, currently performed clinical trials (ALLAY, AVOID, and ALOFT) concerning aliskiren treatment for the management of other cardiovascular diseases, such as chronic heart failure and diabetic nephropathy, may lead to further indications, as is already true for other drugs targeting the RAS (ACEIs, AT1 receptor blockers, aldosterone receptor antagonists).
ALDOSTERONE RECEPTOR ANTAGONISTS AND HYPERTENSION
Primary, nonsuppressible hypersecretion of aldosterone is rare, but represents an underdiagnosed cause of hypertension. The classic signs of primary hyperaldosteronism are hypertension and hypokalemia. Many subtypes of primary aldosteronism have been described since Conn’s original report of the aldosterone-producing adenoma [137].
Besides surgery, the administration of an aldosterone receptor antagonist represents an effective alternative in patients who refuse or are not candidates for surgery. Interestingly, to date, trials comparing spironolactone and eplerenone in patients with primary aldosteronism have not been published. Based on “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure” (JNC VII), spironolactone and eplerenone are recommended as oral antihypertensives for treatment of hypertension [138].
Clinical trials
As is true for renin inhibition, no large-scale clinical trials are available concerning the long-term effects of aldosterone receptor inhibitors on morbidity and mortality of patients with hypertension. Undoubtedly, aldosterone receptor antagonism plays a significant role in the treatment of patients with resistant hypertension. For instance, in an analysis of 1411 patients in the Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT), spironolactone was administered as an additional antihypertensive agent to patients with continued hypertension (157/85 mmHg) despite three antihypertensive agents [139]. The mean blood pressure was significantly lowered (decrease of 22/10 mmHg) with spironolactone at a mean dose of 25 mg daily at 6 weeks and a decrease of 25/12 mmHg at 6-months follow-up. Importantly, the reduction was similar in subjects with or without primary aldosteronism. Furthermore, the effects were additive to the use of ACEIs, AT1 receptor blockers, and diuretics.
The efficacy of eplerenone was tested for the treatment of patients with low-renin hypertension [140]. The rationale for this study was that sodium retention and volume expansion, mediated in part by aldosterone, are prominent features in low-renin hypertension (defined as active renin ≤25 pg/mL [≤42.5 mU/L]). Eplerenone treatment was tested in a 16-week, double-blind, parallel-group, titration-to-effect trial with a total of 168 enrolled patients. The effects of eplerenone (100 to 200 mg per day) were compared to those of the AT1 receptor blocker losartan (50 to 100 mg per day). Add-on therapy with hydrochlorothiazide 12.5 to 25 mg daily was allowed for those patients with a diastolic blood pressure ≥90 mmHg after 8 weeks of monotherapy. After treatment for 8 weeks, eplerenone reduced blood pressure greater than losartan (decrease of systolic/diastolic blood pressure: 15.8/9.3 mmHg vs 10.1/6.7 mmHg, eplerenone vs losartan, respectively). Furthermore, significantly fewer patients in the eplerenone treatment group required add-on therapy with hydrochlorothiazide compared to the losartan-treated group (32.5 vs 55.6 %, eplerenone vs losartan).
Conclusion
Besides effective blood pressure control due to aldosterone receptor antagonism, no large-scale clinical data are available on long-term effects regarding cardiovascular disease morbidity and mortality in hypertensive patients. Data, however, are known for treatment of heart failure patients, where spironolactone or eplerenone was given as an add-on therapy in patients receiving optimal heart failure therapy including diuretics, beta-blockers, and ACE-inhibition/AT1 receptor blockers [104,141]. These data led to implementation of aldosterone receptor antagonism for the treatment of chronic heart failure in current guidelines and recommendations [96].
CONCLUDING REMARKS
Robert Tigerstedt and Per Gustav Bergman most likely did not anticipate the effects of their initial discovery of renin. Based on the tremendous knowledge on renin and the RAS, which has been gathered during the past 110 years, it seems easy to imagine that they would be both amused and bemused. Nonetheless, the book on RAS and its importance for blood pressure control and for a variety of cardiovascular and noncardiovascular diseases is far from being closed. Besides the effective treatment options, we nowadays have to potently target different components of the RAS, thereby significantly altering blood pressure and other diseases—further discoveries that will also lead to clinical relevance and practice. For instance, targeting other Ang II receptor subtypes may be a future treatment regimen. In addition, while ACEIs and, in particular, AT1 receptor blockers come very close to being optimal antihypertensive drugs in terms of combined therapeutic efficacy and tolerability (Figure 6) [142], time will tell where aliskiren will be plotted on this asymptotic curve. It may even be possible to find better antihypertensive agents that target the RAS than those currently clinically available.
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