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(Circulation. 2001;103:904.)
© 2001 American Heart Association, Inc.
Cardiovascular Drugs |
Angiotensin II Type 1 Receptor Blockers
From the Division of Hypertension and Vascular Medicine, CHUV, Lausanne, Switzerland.
Correspondence to Prof M. Burnier, Division of Hypertension and Vascular Medicine, Hôpital Nestlé, Av P. Decker, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne/Switzerland. E-mail Michel.Burnier{at}chuv.hospvd.ch
Key Words: angiotensin • hypertension • heart failure • antihypertensive agents
 |
Introduction |
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Top
Introduction
The Renin-Angiotensin Cascade...In the 1970s, a series of observations demonstrated that angiotensin II has deleterious effects on the heart and kidney and that patients with high levels of plasma renin activity are at a higher risk of developing stroke or myocardial infarction than those with low plasma renin activity.1 2 Thereafter, the development of pharmacological probes that block the renin-angiotensin system helped define the contribution of this system to blood pressure control and to the pathogenesis of diseases such as hypertension, congestive heart failure, and chronic renal failure. Thus, the concept of treating hypertension and congestive heart failure by a specific blockade of the renin-angiotensin system was first established with the use of saralasin, a nonselective peptidic antagonist of angiotensin II receptors.3 4 5 6 7 8 9 With saralasin, it became possible to demonstrate that angiotensin II receptor blockade, alone or in combination with salt depletion, lowers blood pressure in hypertensive patients and improves systemic hemodynamics in patients with congestive heart failure.3 4 5 6 7 8 9 10 However, saralasin had many drawbacks. Because it is a peptide, it had to be administered intravenously. This characteristic limited its use to hours or a few days at maximum. In addition, at higher doses, saralasin had some partial agonist, angiotensin II–like effects.
The next major breakthrough in the understanding of the renin-angiotensin system was triggered by the development of orally active angiotensin-converting enzyme (ACE) inhibitors.10 11 12 13 14 15 Studies performed with these agents rapidly confirmed and reinforced the seminal clinical observations made with saralasin. ACE inhibitors are now recognized as an important therapeutic step to control blood pressure in hypertensive patients and to reduce morbidity and mortality in patients with congestive heart failure.16 In addition, because of their ability to lower proteinuria, ACE inhibitors have become an essential component of the treatment of chronic renal diseases to delay the progression of renal failure.17 ACE inhibitors are also very effective in reducing cardiovascular morbidity and mortality in patients with a high cardiovascular risk profile, including diabetics.18
ACE is an enzyme with multiple effects, not all of which are mediated through angiotensin receptors. Thus, the hope has been that angiotensin II receptor blockers would produce more specific actions and fewer side effects than ACE inhibitors. When ACE inhibitors became available, the more specific approach of blocking angiotensin II receptors was abandoned. Nevertheless, research continued. This resulted in the most recent therapeutic development of specific, nonpeptide, orally active angiotensin II receptor antagonists.19
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The Renin-Angiotensin Cascade and Angiotensin II Receptor Subtypes |
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The renin-angiotensin system is an enzymatic cascade that starts with the cleavage of angiotensinogen by renin to form the inactive decapeptide angiotensin I. Thereafter, angiotensin I is converted by ACE to form angiotensin II. Although there are other angiotensin peptides with biological effects, angiotensin II is the major end product of the system. However, angiotensins I and II can be generated by other enzymatic pathways.20 21 Thus, angiotensin I can be formed by nonrenin enzymes such as tonin or cathepsin, and angiotensin I can be converted to angiotensin II by enzymes such as trypsin, cathepsin, or the heart chymase. Today, the quantitative contribution of these alternative pathways to the generation of angiotensin II remains unclear.
ACE is also called kininase II, and it participates in metabolizing bradykinin to inactive peptides. The inhibition of ACE produces an increase in plasma bradykinin levels.22 23 This increase surely contributes to the side effects of ACE inhibitors (eg, angioedema) and may play a role in the organ-specific effects of ACE inhibitors.23 Whether bradykinin accumulation contributes to the antihypertensive efficacy of ACE inhibitors is less clear, despite some findings in experimental models of hypertension22 24 25 26 and some clinical results suggesting that bradykinin plays a role in the short-term blood pressure lowering effect of ACE inhibition in humans.27 28
The discovery of specific angiotensin II receptor
antagonists has confirmed the existence of various subtypes of
angiotensin II receptors.19
Angiotensin II type 1 (AT1) receptors are
selectively inhibited by losartan and are sensitive to dithiothreitol,
whereas type 2 (AT2) receptors are inhibited by
PD 123177 and related compounds but are insensitive to dithiothreitol.
In rodents, AT1 receptors have been further
subdivided into AT1A and
AT1B. In amphibians and in neuroblastoma cell
lines, an angiotensin II receptor inhibited neither by losartan nor by
PD 123177 has been classified as AT3. Both the
AT1 and the AT2 receptors
have been
cloned.29 30 31
They belong to the superfamily of G-protein–coupled receptors that
contain 7 transmembrane regions. Their amino acid sequence seems to be
highly conserved across species and across tissues within a species.
AT1 and AT2 receptors
share only 
34% homology and have distinct signal transduction
pathways.
AT1 receptors have been localized in the kidney, heart, vascular smooth muscle cells, brain, adrenal gland, platelets, adipocytes, and placenta. AT2 receptors are abundant in the fetus, but their number decreases in the postnatal period.19 In adult tissues, AT2 receptors are present only at low levels, mainly in the uterus, the adrenal gland, the central nervous system, the heart (cardiomyocytes and fibroblasts), and the kidney.19 AT2 receptors seem to be re-expressed or upregulated in experimental cardiac hypertrophy, myocardial infarction, and vascular and wound healing.32 33 34
As shown in
Table 1
, all the known clinical effects of
angiotensin II are mediated by the AT1 receptor.
The physiological role of AT1 receptors is very
well documented experimentally and clinically.
AT1A receptor knockout mice are characterized by
a low blood pressure and high circulating renin
levels.35 These mice were
also recently shown to display less left ventricular remodeling and an
improved survival after myocardial
infarction.36 The
physiological role of the AT2 receptor is only
partially understood. In recent years, several new functions have been
attributed to AT2 receptors, including
inhibition of cell growth, promotion of cell differentiation, and
apoptosis.37 38 39 40
Thus, AT2 receptors could have an important role
in counterbalancing some of the effects of angiotensin II mediated by
AT1 receptors. However, this topic remains a
matter of debate because controversial results have been
published.41 42
More recent data also suggest that AT2 receptors
could mediate the production of bradykinin, nitric oxide, and perhaps
prostaglandins in the
kidney.43 Additional studies
are now needed to confirm these multiple roles of
AT2 receptors in humans.
|
|
Pharmacology of AT1 Receptor Blockers |
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In recent years, numerous orally active, selective AT1 receptor antagonists have been synthetized.44 Today 6 of them have been accepted by the US Food and Drug Administration and can be used in the United States and various European countries for the treatment of hypertension. Other compounds may be launched in the future. As shown in Table 2
, these antagonists share some pharmacological
characteristics. First, they have a high affinity for
AT1 receptors (in the low nanomolar range) and
almost no affinity for AT2 receptors. Second,
all antagonists display very high protein binding. Finally, when
studied in vitro, most (if not all) AT1 receptor
antagonists induce, to a variable degree, an "insurmountable
blockade." This behavior describes the nonparallel displacement of
the angiotensin II response curves seen during in vitro studies.
Surmountable/insurmountable antagonism describes the interaction with
the antagonist after a preincubation step, whereas
competitive/noncompetitive antagonism is related to experimental
conditions in which ligand and antagonist are added simultaneously.
Studies have convincingly demonstrated that all
AT1 receptor antagonists are competitive, with a
very slow dissociation from the
receptor.45 46
Because insurmountable blockade is difficult to achieve at the doses
used clinically, it will not be discussed in more detail. Studies
performed in normotensive subjects have demonstrated consistently that
AT1 receptor antagonists dose-dependently block
the pressor response to exogenous angiotensin
II.47 48 49 50
|
Losartan
Losartan was the first orally active
AT1 receptor antagonist available on the market,
and it is the antagonist with which the greatest clinical experience
has been accumulated. It represents the prototype of a highly selective
AT1 receptor antagonist and was derived from the
Takeda series of 1-benzylimidazole-5-acetic acid derivatives recognized
to be weak angiotensin II
antagonists.19 In vitro,
losartan competes with the binding of angiotensin II to
AT1 receptors; the concentration that inhibits
50% of the binding of angiotensin II (IC50) is
20 nmol/L. Losartan has a major active metabolite, EXP 3174.
Administered intravenously, EXP3174 is 10 to 20 times more potent than
losartan and has a longer duration of action than losartan. However,
the oral bioavailability of EXP 3174 is very low. Thus, the drug on the
market is losartan, but most of losartan’s effect is due to EXP 3174.
The main pharmacokinetic characteristics of losartan and EXP 3174 are
presented in
Table 2
. Losartan and its metabolite are excreted by the
kidney and in bile. Neither compound is dialysed.
Valsartan
Valsartan is a nonheterocyclic antagonist in which the
imidazole of losartan has been replaced with an acylated amino acid. It
is also a potent AT1 antagonist
(IC50 of 2.7 nmol/L on rat aorta). Valsartan
does not need to be metabolized to be effective, and it is excreted
both by the bile (70%) and the kidneys (30%). There is only one
inactive metabolite. Food decreases drug absorption by 40%. Like
losartan, valsartan lacks affinity for adrenergic, histamine, substance
P, muscarinic, and serotonin receptors.
Irbesartan
Irbesartan is a longer acting
AT1 receptor antagonist than losartan and
valsartan
(Table 2). It also has a high affinity for the
AT1 receptor (IC50 of 1.3
nmol/L in rat liver) and no affinity for AT2
receptors. Structurally, it contains an imidazolinone ring in
which a carbonyl group functions as a hydrogen bond acceptor in place
of the C5 hydroxymethyl group of losartan. In contrast to losartan,
irbesartan has no active metabolite. It is cleared predominantly by the
bile (80%) and partly by the kidney (20%). Irbesartan has a large
volume of distribution (53 to 93 L versus 12 L for EXP 3174 and 17 L
for valsartan). Clinically, irbesartan has been evaluated at doses up
to 900 mg/d. Irbesartan induced a dose-related blood pressure response,
with a plateau at 300
mg.51
Candesartan Cilexetil
Candesartan is a also a long-acting angiotensin II
receptor antagonist. To overcome a poor oral absorption, a series of
ester prodrugs was synthesized, and candesartan cilexetil was
identified as the compound that provided the best angiotensin II
antagonistic activity profile after oral administration. Thus,
candesartan cilexetil is a prodrug that is rapidly and completely
converted to the active compound candesartan during gastrointestinal
absorption. Candesartan AT1 binding affinity in
the rabbit aorta is 80 times greater than that of losartan and 10 times
greater than that of EXP 3174, the active metabolite of losartan. In
vivo, candesartan has a relatively long half-life (9 hours), which
seems to be somewhat longer in the elderly (9 to 12 hours). Candesartan
is eliminated principally by the kidneys (60%) and to a lesser
extent through the bile (40%). There is no significant drug
accumulation in patients with mild renal impairment. At doses >12
mg/d, an accumulation of candesartan cilexetil may be observed in
patients with severe renal dysfunction. The mean extraction ratio for
candesartan from dialysed blood is low.
Telmisartan
Telmisartan is the longest acting angiotensin II
AT1 receptor antagonist currently available. Its
mean elimination half-life is 24 hours in patients with mild to
moderate hypertension who receive 20 to 160 mg/d telmisartan for 4
weeks. Telmisartan is directly active; it undergoes minimal
transformation and is excreted almost completely by the feces
(98%).
Eprosartan
Eprosartan is the latest angiotensin II receptor
antagonist. Eprosartan has the shortest half-life of the 6 antagonists
currently available (elimination half-life of 5 to 7 hours), and most
of the initial clinical studies have been conducted using a twice a day
regimen at doses up to 400 mg BID. In vivo, both biliary (90%) and
renal (10%) excretion pathways contribute to the elimination of
eprosartan. Depending on the formulation, the absorption of eprosartan
may be reduced by 25% and retarded by 1.5 hours when the drug is
administered with
food.52 The renal
clearance of eprosartan seems to be slowed in subjects with renal
insufficiency.52 However,
because only a small fraction of eprosartan is cleared by the kidney,
no dose adjustment seems to be necessary in patients with chronic renal
failure.
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AT1 Receptor Blockers in Hypertension |
|---|
Numerous studies have evaluated the antihypertensive efficacy of angiotensin II receptor antagonists in patients with mild to moderate or severe hypertension.53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 In these studies, angiotensin II receptor antagonists have been compared with ACE inhibitors, calcium antagonists,
-blockers, and
diuretics.53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80
The efficacy and tolerability of AT1 receptor
antagonists has also been evaluated in various populations and age
groups when administered either alone or in combination with diuretics.
Overall, the results of these studies show that the 6 angiotensin II
antagonists are as effective as ACE inhibitors, calcium antagonists,
-blockers, and diuretics. In monotherapy, angiotensin II antagonists
induce a similar decrease in blood pressure in young and elderly
patients and in men and women. Administered as monotherapy, angiotensin
II antagonists, like ACE inhibitors, are less effective in reducing
blood pressure in black patients, but this is not the case when
angiotensin II antagonists are combined with a diuretic. The
antihypertensive efficacy of angiotensin II receptor antagonists is
potentiated by the addition of a small dose of a thiazide
diuretic. |
Tolerability of Angiotensin II Receptor Antagonists |
|---|
Clinically, all angiotensin II receptor antagonists have an excellent tolerability profile, with an incidence of side effects that is not different from placebo.* They81 do not produce first-dose hypotension. Because plasma angiotensin II levels increase markedly during angiotensin II receptor blockade, rebound hypertension was initially a matter of concern if drug therapy was withdrawn quickly. No rebound hypertension has been demonstrated on withdrawal of losartan. Unlike ACE inhibitors, angiotensin II receptor antagonists do not produce a cough.82 83 84 Some cases of angioedema have been reported with the administration of losartan.85 However, because angioedema may occur with many substances, including drugs and some food products, it is difficult to ascertain whether these published cases of angioedema are really linked to the administration of the antagonist. Like ACE inhibitors, all angiotensin II receptor antagonists are contraindicated during pregnancy.
Angiotensin II antagonists have no major effect on routine laboratory parameters. Like ACE inhibitors, they have been shown to lower hematocrit in post-transplant erythrocytosis.86 87 Losartan has been shown to increase urinary uric acid excretion.88 89 The uricosuric effect of losartan is due to a specific effect of losartan potassium on urate transport in the renal proximal tubule and is independent of angiotensin II receptor blockade.90 It has not been observed with other angiotensin II blockers. In the Evaluation of Losartan In the Elderly (ELITE) trial, no difference in the incidence of renal dysfunction among elderly patients receiving losartan (50 mg daily) and those treated with the ACE inhibitor captopril (50 mg TID) was found.91
Occasionally, minor and transient increases in liver enzyme activity (particularly alanine aminotransferase) have been observed with angiotensin II receptor antagonists.81 In vivo, telmisartan causes a variable increase in digoxin serum levels. Thus, plasma digoxin levels should be monitored when telmisartan is combined with digoxin. Warfarin levels may also be reduced during coadministration with telmisartan.
|
Angiotensin II Receptor Antagonists in Renal and Congestive Heart Failure |
|---|
In experimental and small clinical studies, angiotensin II receptor antagonists had renal effects similar to ACE inhibitors. Thus, angiotensin II receptor antagonists seem to have no influence on glomerular filtration rate and to increase renal blood flow; hence, the filtration fraction decreases.89 92 93 94 Angiotensin II antagonists induce also a natriuretic response that may contribute to their antihypertensive efficacy.89 92 Preliminary experimental and clinical studies obtained with the angiotensin II receptor antagonists on small groups of patients suggest that these agents can decrease the filtration fraction and reduce urinary albumin excretion.93 95 96 97 98 99 This may suggest a favorable influence on renal function in patients with chronic renal failure. Finally, preliminary results suggest that, as with ACE inhibitors, acute renal failure may occur with angiotensin II antagonists when administered to patients with renal artery stenosis or diffuse intrarenal vascular stenosis.81
Because the use of ACE inhibitors is a recommended approach for the management of patients with heart failure and an effective treatment to induce the regression of left ventricular hypertrophy in hypertensive patients, several studies have investigated the effect of angiotensin II receptor blockade in these clinical indications. Thus, a recent study has demonstrated that valsartan produces a significant regression of left ventricular hypertrophy in previously untreated patients with essential hypertension.100 In heart failure, several short-term studies indicate that AT1 receptor antagonists have beneficial, systemic hemodynamic effects and are well-tolerated drugs.101 102 103 104 105 For these indications, preliminary studies have suggested that AT1 receptor antagonists are at least as efficacious as ACE inhibitors but have a more favorable side-effect profile. In the ELITE trial, one of the secondary end points (ie, combined mortality and hospitalization for heart failure) was surprisingly lower in the losartan group.91 These positive preliminary results were not confirmed in ELITE II, which involved more patients. Indeed, ELITE II confirmed that patients treated with losartan had significantly fewer side effects than those on captopril, but losartan was not superior to captopril in reducing morbidity and mortality.106 Nonetheless, although the actual data suggest that angiotensin II receptor blockers have no clear advantage over ACE inhibitors in heart failure, except for their better tolerability, one should be careful before concluding that the class of angiotensin receptor antagonists is less effective than ACE inhibitors in the treatment of congestive heart failure based on the results of ELITE II. Additional studies are ongoing, and their results will have to be taken into account to evaluate the place of angiotensin II receptor antagonists in heart failure.
|
Are There Differences Between Angiotensin II Receptor Antagonists? |
|---|
Angiotensin II receptor antagonists share the same mechanism of action. However, they have different pharmacokinetic profiles, which may account for potential differences in efficacy. In addition, the selected starting dose may have been chosen using different criteria, thus resulting in noncomparable degrees of blockade of the renin-angiotensin system.107 The relative antihypertensive efficacy of angiotensin II receptor antagonists was evaluated in a recent meta-analysis of 43 randomized, placebo-controlled trials.108 This comprehensive analysis suggests comparable antihypertensive efficacy within the angiotensin II receptor antagonist class. However, several double-blind, head-to-head comparative studies have evaluated the relative antihypertensive efficacy of some angiotensin II receptor antagonists in patients with mild to moderate hypertension.109 110 111 112 113 114 Their results suggest that longer acting angiotensin II antagonists such as irbesartan, candesartan, and telmisartan may be more effective than losartan, particularly at trough, thus providing better 24-hour control of blood pressure. The difference between antagonists seems mainly related to the dose selected and to the duration of action of the respective drugs. Nevertheless, additional studies are needed to assess whether these differences are really clinically relevant when examining end points such as morbidity and mortality.
|
Who Should be Treated With an Angiotensin II Receptor Antagonist? |
|---|
Angiotensin II receptor antagonists provide a more specific blockade of the renin-angiotensin system and have better tolerability when compared with ACE inhibitors. In addition, the evidence available thus far for this new class of antagonists has established that their efficacy is equal to that of ACE inhibitors in hypertension. Therefore, it is conceivable that angiotensin II receptor blockers will take a growing place in the management of hypertensive patients. However, the place of angiotensin II antagonists in the management of hypertension will, of course, depend on the results of morbidity and mortality trials. Three studies have included patients with slightly different clinical profiles (Table 3
). The Losartan Intervention For Endpoint Reduction
in Hypertension (LIFE) trial compared a losartan-based and an
atenolol-based regimen in patients with high cardiovascular risk who
had electrocardiographic evidence of left ventricular
hypertrophy.115 In the
Valsartan Antihypertensive Long-Term Use Evaluation (VALUE)
trial, >14 000 patients were enrolled on the basis of age plus 1 to 3
other cardiovascular risk factors. In this study, valsartan was
compared with amlodipine. Finally, in the Study on Cognition and
Prognosis in the Elderly (SCOPE), the effects of candesartan were
compared with those of a placebo in an older hypertensive population
(70 to 89 years).
|
In patients with congestive heart failure, there is no evidence at present that angiotensin II receptor blockers are superior to ACE inhibitors. However, because of their excellent tolerability profile, angiotensin II receptor blockers may be considered in patients developing an ACE-inhibitor–induced cough. Ongoing trials, such as the Valsartan–Heart Failure Trial (Val-HeFT) and the Candesartan in Heart Failure Assessment in Reduction of Mortality (CHARM) trial, will provide more insight regarding the potential of angiotensin II receptor blockade in heart failure. They will also address several practical issues such as dosing (once versus twice daily and monotherapy versus combination) and efficacy in different populations (ACE-inhibitor naive, ACE-inhibitor intolerant, and diastolic dysfunction). Two additional studies, the Optimal Trial in Myocardial Infarction With the Angiotensin II Antagonist Losartan (OPTIMAAL) and the Valsartan in Acute Myocardial Infarction (VALIANT) trial, will be conducted in patients after a myocardial infarction. In both trials, the effects of the angiotensin II blocker (losartan in OPTIMAAL and valsartan in VALIANT) will be compared with captopril. In OPTIMAAL, losartan is given once daily as monotherapy, whereas in VALIANT, valsartan is given twice daily and in combination with an ACE inhibitor. Again, the results of these 2 trials will establish whether combination therapy is useful for optimum clinical effect.
Thus far, there is also no evidence that angiotensin II
receptor blockers are superior to ACE inhibitors in treating patients
with diabetic and nondiabetic nephropathies. Therefore, at the present
time, ACE inhibitors must be considered the first-line choice in these
indications, with angiotensin II receptor blockers as a valuable
substitute in cases of intolerance to ACE inhibitors. Several trials
are now exploring the potential of angiotensin II receptor blockers in
patients with renal diseases. In a study on renal protection and
losartan, the Reduction of End Points in Non–Insulin-Dependent
Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL)
trial, losartan was compared with the usual care in patients
with type II diabetes and diabetic nephropathy. Usual care comprises
diuretics, vasodilators, and/or -blockers to achieve a target blood
pressure of <140/90 mm Hg. The Irbesartan Diabetic Nephropathy Trial
(IDNT) has a comparable objective but, in this trial, irbesartan was
compared with amlodipine and usual therapy in 3 parallel groups.
Finally, the Appropriate Blood Pressure Control in Diabetics
(ABCD-2V) trial will evaluate the impact of valsartan in the
treatment of normotensive and hypertensive patients with
non–insulin-dependent diabetes mellitus.
|
Future Developments |
|---|
In the management of patients with congestive heart failure and those with renal diseases, high doses of ACE inhibitors are often necessary to block the renin-angiotensin system completely and, hence, to obtain the maximal benefits of blocking the renin-angiotensin system. In these situations, the combination of an ACE inhibitor and an AT1 receptor antagonist could seem attractive to improve the overall blockade of the system.116 However, except for economic reasons, it seems questionable to attempt complete blockade of the renin-angiotensin system by a combination of an ACE-inhibitor with an AT1 receptor antagonist if the same result could be achieved by a higher dose of an AT1 receptor antagonist alone without adding the side effects inherent to all ACE inhibitors. Several studies were conducted in patients with hypertension, renal diseases, and heart failure to evaluate the combination of an ACE inhibitor and AT1 receptor antagonist.117 118 119 120 121 These studies have provided conflicting results: some studies suggested a beneficial effect of the combination, whereas others did not. The main limitation of these early studies is that the full dosing ranges of the AT1 receptor blockers and/or ACE inhibitors were not explored. Thus, one cannot ascertain that the same effect could have been obtained with a higher dose of the antagonist alone. Some of the large clinical trials discussed previously will address this specific question, particularly in heart failure.
|
Conclusions |
|---|
There is now convincing evidence that the new class of specific, angiotensin II receptor antagonists is as effective as ACE inhibitors,
-blockers, calcium antagonists, and diuretics in
treating patients with mild to moderate hypertension. However, these
antagonists are characterized by a better tolerability profile. In
contrast to most other recent classes of antihypertensive drugs, a
large number of outcome trials have been initiated to evaluate
angiotensin II antagonists. Their results will demonstrate whether
angiotensin II receptor antagonists can prevent target organ damage and
reduce cardiovascular morbidity and mortality. They will also enable
the more appropriate definition of the role of these antagonists in the
management of patients with hypertension, heart failure, or renal
diseases.
|
Acknowledgments |
|---|
Dr M. Burnier has received research grants from Merck Sharp and Dohme, Novartis, AstraZeneca, Bristol Myers Squibb, Sanofi Synthelabo, and Boehringer Ingelheim.
|
Footnotes |
|---|
1 References 55–59, 61, 63–68, 71–73, 75, 78, 80, 81.
|
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 A. Prasad and A. A. Quyyumi Renin-Angiotensin System and Angiotensin Receptor Blockers in the Metabolic Syndrome Circulation, September 14, 2004; 110(11): 1507 - 1512. [Full Text] [PDF]
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 N. Tejera, D. Gomez-Garre, A. Lazaro, J. Gallego-Delgado, C. Alonso, J. Blanco, A. Ortiz, and J. Egido Persistent Proteinuria Up-Regulates Angiotensin II Type 2 Receptor and Induces Apoptosis in Proximal Tubular Cells Am. J. Pathol., May 1, 2004; 164(5): 1817 - 1826. [Abstract] [Full Text] [PDF]
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 Y.-H. Liu, X.-P. Yang, E. G. Shesely, S. S. Sankey, and O. A. Carretero Role of angiotensin II type 2 receptors and kinins in the cardioprotective effect of angiotensin II type 1 receptor antagonists in rats with heart failure J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1473 - 1480. [Abstract] [Full Text] [PDF]
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 M. Auger-Messier, M. Clement, P. M. Lanctot, P. C. Leclerc, R. Leduc, E. Escher, and G. Guillemette The Constitutively Active N111G-AT1 Receptor for Angiotensin II Maintains a High Affinity Conformation Despite Being Uncoupled from Its Cognate G Protein Gq/11{alpha} Endocrinology, December 1, 2003; 144(12): 5277 - 5284. [Abstract] [Full Text] [PDF]
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A. Stanton, C. Jensen, J. Nussberger, and E. O'Brien Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren Hypertension, December 1, 2003; 42(6): 1137 - 1143. [Abstract] [Full Text] [PDF]
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L. Barki-Harrington, L. M. Luttrell, and H. A. Rockman Dual Inhibition of {beta}-Adrenergic and Angiotensin II Receptors by a Single Antagonist: A Functional Role for Receptor-Receptor Interaction In Vivo Circulation, September 30, 2003; 108(13): 1611 - 1618. [Abstract] [Full Text] [PDF]
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A. Nap, J. C Balt, M. Pfaffendorf, and P. A van Zwieten No involvement of the AT2-receptor in angiotensin II-enhanced sympathetic transmission in vitro Journal of Renin-Angiotensin-Aldosterone System, June 1, 2003; 4(2): 100 - 105. [Abstract] [PDF]
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A. Stanton Review: Potential of renin inhibition in cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, March 1, 2003; 4(1): 6 - 10. [Abstract] [PDF]
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 P. Manohar and I. L. Pina Therapeutic Role of Angiotensin II Receptor Blockers in the Treatment of Heart Failure Mayo Clin. Proc., March 1, 2003; 78(3): 334 - 338. [Abstract] [PDF]
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A. Forclaz, M. Maillard, J. Nussberger, H. R. Brunner, and M. Burnier Angiotensin II Receptor Blockade: Is There Truly a Benefit of Adding an ACE Inhibitor? Hypertension, January 1, 2003; 41(1): 31 - 36. [Abstract] [Full Text] [PDF]
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S. Ito, K. Komatsu, K. Tsukamoto, K. Kanmatsuse, and A. F. Sved Ventrolateral Medulla AT1 Receptors Support Blood Pressure in Hypertensive Rats Hypertension, October 1, 2002; 40(4): 552 - 559. [Abstract] [Full Text] [PDF]
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 Y. Shimoni Inhibition of the formation or action of angiotensin II reverses attenuated K+ currents in type 1 and type 2 diabetes J. Physiol., November 15, 2001; 537(1): 83 - 92. [Abstract] [Full Text] [PDF]
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J. W. Auer, R. Berent, B. Eber, and M. Burnier Angiotensin II Type 1 Receptor Blockers and Congestive Heart Failure Response Circulation, October 9, 2001; 104 (15): e82 - e82. [Full Text] [PDF]
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R. N. Re On Not Being the Last to Give Up the Old or the First to Adopt the New Hypertension, October 1, 2001; 38(4): 759 - 760. [Full Text] [PDF]
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