The renin-angiotensin system (RAS) plays a crucial role in the Welcome, UpToDate Marketing Professional Angiotensin II mediates vasoconstriction as well as aldosterone Congestive heart failure in renal transplant recipients: risk factors, outcomes, and relationship with ischemic heart disease. blood pressure. Furthermore, the aldosterone-to-renin ratio, an indicator of support the relation between genetically programd. ALDOS acti vity .. Spironolactone. The first of these drugs to be brought to market, almost. Renin is an enzyme that controls aldosterone production. Aldosterone and renin tests help diagnose primary (Conn syndrome) and secondary.
Because of the inability to sample at these extravascular sites of action, the more meaningful tissue-based half-life cannot be determined. This is particularly the case for the ARBs, since AT1Rs are found in multiple extravascular locations and blocking these receptors, may, in an as-of-yet undefined fashion, influence the manner in which BP is reduced [ ].
With the above in mind, the pharmacokinetic half-life of an ARB will roughly approximate its duration of effect as long as the plasma concentration of an ARB remains above the threshold for a BP-lowering effect. Several of the ARBs, such as candesartan, olmesartan, telmisartan, and irbesartan, are considered once-daily compounds in pharmacokinetic terms.
The true impact of pharmacologic half-life for these compounds probably lies more so in the fact that the drug is available for a longer period and thereby binds to additional AT1Rs as they are formed during the latter portion of a dosing interval.
Differentiation of one ARB from the other requires that drugs be studied in the same patient types and therein variable responses sought. Without a homogeneous population, heterogeneity weights results toward more non-responders, which is both a phenotypically and genotypically difficult state to characterize.
ARBs are fairly equivalent at their low-end and high-end doses, with the probable exception of losartan.
If a patient is a responder to an ARB, it is evident even at low-end doses. Thus, in those studies where BP is not the most important determinant of response, the results are then more so a matter of the specific dosing with a particular compound.
A pertinent example of this is found in the Valsartan Heart Failure Trial Val-HeFT wherein valsartan was administered at a maximum dose of mg twice daily [ ]. The primary end point was all-cause mortality and the secondary end point was sudden death or resuscitated arrest. The study did not have a superior outcome with losartan; however, losartan was administered only once daily at a low-end dose and this was believed by many to be the basis for the comparable response between captopril and losartan [ ].
These findings could be interpreted to represent an intraclass difference when in point-of-fact they represent inadequate dosing. This is another of the vagaries in attempting to unravel the issue of class effect for individual ARBs [ ]. Recently, another possible beneficial effect of telmisartan on metabolic syndrome has been described.
In fact, this ARB can function as a partial agonist of peroxisome proliferator-activated receptor [ ]. The clinical significance of these differences among members of the class remains to be determined in outcome trials.
ARBs can thus be characterized as having a wide therapeutic window, with virtually no dose-dependent side effects. This finding, taken together with some data of improved outcomes at higher doses, suggests higher doses might provide better target organ protection. However, in those studies exploring the efficacy of such combinations in order to control BP in patients with type 2 diabetes mellitus did not showed any increased risk of mortality [ ].
Renoprotection with both drugs have invariably shown that their renoprotective benefit is mainly explained by their specific antiptoteinuric effects. This is consistent with the view that proteins, once leaked through the glomerular barrier, act as mediators of ongoing renal fibrosis [ ].
Thus in patients with renal disease reducing albuminuria remain an important strategy for renal and cardiovascular protection.
The experimental demonstration that the blockade of AII with an ACEI slowed the progressive loss of renal in a number of animal models or renal diseases, including diabetic nephropathy, offered the opportunity, for the first time, to devise a treatment strategy that was not limited to passively accompany patients to their destiny of dialysis, but was aimed to preserve renal function as long as possible .
Based in these circumstances and several experimental and clinical studies emerged the concept of renoprotection [ ]. The development of a new class of the drugs, the ARBs has offered another opportunity to further improve the renoprotection.What is Customer Relationship Marketing: Building Motherhood Brands
In fact the near complete abolition of AII activity is instrumental to achieve full renal protection. Thus the combination of the two drugs, an ACEI and an ARB, in an experimental model of chronic nephropathies was associated with greater reduction of proteinuria and a trend toward less renal injury than with each drug alone [ ].
Until now, it has considered as the main goal of current treatments the arrest of renal disease progression, however, the kidney has a great potential of regeneration after injury.
Experimental evidence is accumulating that there is potential for regression of renal scarring, as shown in a paper by Fogo, in which the mechanisms of regeneration are reviewed [ ]. Of note, the potential antifibrotic role of drugs that block the RAAS system is underlined [ ]. Despite many uncertainties and as yet unknown factors, regression of human kidney disease now represents a realistic potential clinical target.
A relevant body of evidence, based in experimental and clinical studies, indicates that, by mechanism yet to be define, the glomerular capillary network can sometimes undergo a process of both structural and functional regeneration [ ].
In relation to the regression phenomena in chronic nephropathies, there are three main issues open for investigation. First, it is still a matter of controversy whether regression can be achieved in a consistent percentage of patients and to what extent . Second, there are some disparities between the extent of the observed regression of structural changes and its translation into effective improvement of kidney function.
At present, we know that controlling proteinuria seems to be a relevant factor for the progression of the disease [ ]. The third refers to that the regression of renal lesions can be achieved in all progressive forms of glomerulopathies, or will only some types of renal diseases respond [ ].
Recent clinical data showed that for patients at low renal risk and with low levels of albuminuria, RAAS inhibition might not offer any renal benefit [ ]. In these patients agents that blocks RAAS should be used sparingly, doses should be titrated to individual needs and kidney function should be monitored closely.
Although RAAS blockade is thought to have major nephroprotective properties in individuals with diabetes, attention should be devoted to the identification of patient subgroups that can profit most from this treatment regimen. In addition, results from the RASS study, performed in type 1 diabetes mellitus patient with normal BP and normoalbuminuria, strongly suggest that trials of RAAS blockade in patients with diabetes and a low CV burden require a much longer follow-up period than is usually assumed [ ].
Such trials of longer duration are needed to establish whether such a treatment regimen offers clinical benefit in the primary prevention of both microvascular and CV complications, which remain the major cause of morbidity and mortality in patients with diabetes [ ]. This suggests that treatments suppressing the RAAS might exert an additional specific cardioprotective effect compared to non-RAAS inhibiting antihypertensive medications.
In the general population as well as in specific high-risk patient subgroups ACEIs are the antihypertensive agents with the best risk-benefit profile. They also improve survival of patients with HF or left ventricular dysfunction, previous myocardial infarction, stroke, or transient ischemic attack or with peripheral vascular disease and diabetes [ 9294]. Studies have shown the efficacy of ACEIs in all symptomatic classes of systolic HF patients including those patients with some degree of renal dysfunction.
Thus, a meta-analysis of five randomized trials of ACEI therapy in patients with HF showed that although the proportion of patients who developed renal dysfunction was higher in the ACEI groups than in the placebo groups, drug discontinuation was required in only a small percentage of patients, and renal function returned to baseline in most patients even without dose adjustment [ 92 ].
A retrospective analysis of the studies of left ventricular dysfunction SOLVD has shown that the use of ACEIs was associated with a reduced risk of mortality, even at moderately and severely depressed levels of GFR, and did not have an adverse impact on kidney function [ ].
Therefore, in patients with chronic HF CHFmild-to-moderate renal insufficiency should not be viewed as a contraindication to ACEI therapy, and a mild and nonprogressive worsening of renal function during initiation of therapy should not be considered an indication to discontinue treatment, as the drug may offer the dual benefit of reducing disease progression in both the heart and the kidney [ ].
In patients with moderate or severe renal insufficiency, therapy with low doses of ACEIs should be initiated and the dose should be increased gradually with careful monitoring of renal function and serum electrolytes. First, ACEIs should be discontinued, and the patients should be evaluated for conditions causing renal hypoperfusion in which the use of ACEIs may result in acute renal failure, such as excessive depletion of circulating volume due to intensive diuretic treatment, concurrent administration of vasoconstrictor agents eg, nonsteroidal anti-inflammatory drugs- NSAIDs and severe bilateral renal artery stenosis.
Unless renal vascular disease is present, therapy with an ACEI can be reinstituted after correction of the underlying cause of reduced renal perfusion [ ]. The risk of hyperkalemia associated with the use of ACEIs in patients with HF and renal dysfunction is also a source of concern. Several measures may be used to minimize the risk of hyperkalemia in such patients, including discontinuation of drugs known to interfere with renal potassium excretion e. NSAIDs, including cyclooxygenase-2 inhibitorsadministration of a low potassium diet, as well as sodium bicarbonate in patients with metabolic acidosis [ ].
An augmented activity of these local pathways may lead to increased production of AII in patients with HF, and AII is a major adverse influence of cardiac remodeling and dysfunction.
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Although the ELITE Evaluation of Losartan in the Elderly trial [ ] found a mortality benefit in favor of losartan compared with captopril, the larger ELITE-2 trial that followed did not confirm this finding; rather, it found no difference [ ].
Unfortunately, patients who experience hyperkalemia or worsened renal function while taking ACEIs are likely to have the same complications with an ARB [ ]. An important area of interest corresponds to the role of atrial fibrillation AF as a factor on CV risk. Patients with AF have a mortality risk that is twofold than those without [ ].
Left ventricular hypertrophy and dilation are invariably associated with reduced diastolic left ventricular compliance and secondary increase in left atrial pressure and size. These changes contribute to structural and electrical remodeling of the atria that eventually lead to an increased risk of AF.
It has been described that those patients with a higher prevalence of CV risk showed an increased atrial expression of ACE and the AT1R, in addition to activation of AII-dependent downstream signalling pathways involved in fibrogenesis, that have been found to affect electrophysiological properties of the myocardium and the pulmonary veins [ ]. Recent data suggest that AT1Rs are located in close proximity to potassium channels within the membrane and that AII inhibits outward potassium currents that are involved in the pathophysiology of AF [ ].
CV Physiology | Renin-Angiotensin-Aldosterone System
On the basis of the above findings, RAAS blockade might be a rational approach for the prevention and treatment of AF. A recent meta-analysis of 23 randomized controlled trials including 87, patients showed that RAAS inhibition is effective in the primary and secondary prevention of AF [ ].
Blocking the generation of AII also reduces the proinflammatory, profibrotic and oxidative effects of this peptide. Since there became available, ARBs have shown in prospective, randomized studies to attenuate the progression of renal disease in patients with type 1 and type 2 diabetes mellitus and advanced diabetic nephropathy [ ].
Consequently, plasma renin activity PRA is substantially increased in patients taking these drugs. By contrast, activation of the ATR2 could have vasodilatory and antiproliferative effects. As an example, in patients with congestive HF who were treated with ACEIs, the addition of an ARB was beneficial despite being associated with an increased incidence of hypotension, diminished renal function and hyperkalemia [ ]. However, in some patients treated with ACEIs, plasma Aldo concentrations return to normal levels over a variable period of weeks or months [ ].
Whether the addition of a MCR antagonist would have beneficial effects in patients who experience this phenomenon remains unknown; however, large trials using non-natriuretic doses of MCR antagonists showed an improved survival in patients with either severe CHF or congestive HF secondary to acute myocardial infarction [ 51 ].
These data suggest that the downstream effects of Aldo-increased inflammation, fibrosis, apoptosis, and oxidative injury—could potentially be blocked by concurrent therapy with aldosterone-receptor antagonists ARAs [ ].
Atriopeptins are potent endogenous vasodilators whose actions are similar in many respects to BK; both hormones have short plasma half-lives and stimulate the NO-cyclic guanosine monophosphate vasodilator cascade in VSM [ ]. There are three major atriopeptin isoforms synthesized in the heart: All are vasodilators that also cause natriuresis. ANP and BNP inhibit a variety of vasoconstrictors such as endothelin, cause inhibition of sympathetic nervous and RAAS activity, and blunt cell proliferation and hypertrophy.
All three atriopeptins are removed from the circulation primarily as a result of enzymatic degradation by NEP and to a lesser extent through clearance by the natriuretic clearance receptor [ ]. The natriuretic peptide system can be viewed as the endogenous inhibitor of the RAAS.
Moreover, the structural similarities in the active sites of both NEP and ACE had made the simultaneous inhibition of these two enzymes an attractive target for drug development. A number of such dual VPIs entered preclinical and clinical development in the s. Of the dual VPI, omapatrilat has been the most extensively studied in clinical trials. In early studies with this compound, it was shown to be superior to ACEIs as an antihypertensive agent and in the treatment of heart failure [ ].
Although initially attributed to benefits beyond ACE inhibition, omapatrilat was shown to be a weak diuretic, with thiazide diuretics providing additional BP reduction. These findings led to the conclusion that the efficacy of omapatrilat in hypertension and HF may be attributable in large part to the potentiation of kinins.
Despite the immense enthusiasm generated by initial studies, larger definitive studies were ultimately unsuccessful. Also, the high incidence of angioedema, when compared to enalapril reported in subjects treated with omapatrilat in the Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril OCTAVE trial, might limit its use. Whether this adverse-effect profile is shared by other members of the VPI class that are under development remains to be determined [ ].
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In OCTAVE, omapatrilat use was associated with a significantly higher overall incidence of nonfatal angioedema compared to enalapril, a problem that was amplified in African Americans. The mechanisms for these differences remain unknown but are presumed to be related to abnormal bradykinin metabolism [ ]. The endothelium and the neurohumoral system play a key role in modulating both vascular tone and structure by producing vasoactive substances, and in the modulation of blood cell adhesion.
Although the neurohormonal systems are essential in vascular homeostasis, they become maladaptive in conditions such as hypertension, diabetes and HF.
In this sense, VIPs represent a new and attractive therapeutic strategy for the treatment of CVD, although if this drugs add an incremental benefit over already proven therapy, with an acceptable side-effect profile is questionable [ ]. However, in the complex equilibrium among RAAS, sympathetic nervous and natriuretic peptide systems, omapatrilat, would offer some theorical advantages, by blocking a pro-fibrotic mechanism and stimulating an anti-fibrotic phenomenon [ ].
Therefore, despite the immense theoretical appeal of blocking both ACE and NEP, the limited incremental benefit of this drug class along with the greater possibility of angioedema has limited its potential utility. However, the fact that newer VPI, such as M Sanofi Aventis, Paris, France are currently entering early phase human trials suggests that this class of drug may still have a future in the clinic.
Direct renin inhibitors DRIs Renin long has been recognized as the preferred, logical target for RAAS blockade because it corresponds to the first, highly regulated and rate-limiting step of the system.
Renin also has a remarkably high specificity for only one known substrate, angiotensinogen contrary to ACE. The clinical development of the first transition-state synthetic analogs capable of inhibiting renin has faced a number of technical problems. The oral administration of these renin inhibitors in human beings ie, remikiren and zankiren did not meet all the necessary criteria for these drugs to be considered clinically useful.
Molecular modeling and determination of the structure of the active site of renin have led to the identification of new renin inhibitors DRIs [ ]. The first representative of this class of nonpeptide drugs is aliskiren, a potent hydrophilic transition-state mimetic alkane carboxamide renin inhibitor with a very high binding affinity for renin, resulting in selectivity for this enzyme [ ].
It is a potent competitive renin inhibitor that binds strongly to renin and is highly specific for human renin.
However, with a renin inhibitor, the catalytic activity of the renin molecules newly released from the kidney is inhibited completely throughout the day, resulting in very low circulating levels of AI, AII, and other AI—derived peptides, thereby rendering the RAAS quiescent.
In contrast, the renin molecules newly released from the kidney remain enzymatically active after administration of an ARB or an ACEI, resulting in high circulating levels of AI, with variable levels of AII depending on the drug used. This counter-regulatory renin release could offset the pharmacologic inhibition of the RAAS at the end of each dosing interval, when the amount of competitive inhibitor or antagonist on the ACE or AT1R is decreasing [ 82 ].
Aliskiren does not affect cytochrome P, so this agent has few drug interactions and its dose need not be adjusted even in patients with advanced CKD due that is eliminated by the hepatobiliary route without being metabolized. This agent has a long half-life, which might enable improved 24 h BP control, particularly in obese patients with diabetes mellitus and in individuals with CKD whose BP does not show a nocturnal dip. This study showed that the combination of ARB and aliskiren substantially reduced the urinary albumin excretion and this effect seemed to be independent of BP control [ ].
Beta1-adrenoceptors located on the JG cells respond to sympathetic nerve stimulation by releasing renin. Specialized cells macula densa of distal tubules lie adjacent to the JG cells of the afferent arteriole. The macula densa senses the concentration of sodium and chloride ions in the tubular fluid. When NaCl is elevated in the tubular fluid, renin release is inhibited. In contrast, a reduction in tubular NaCl stimulates renin release by the JG cells. When afferent arteriole pressure is reduced, glomerular filtration decreases, and this reduces NaCl in the distal tubule.
Aldosterone acts on the tubules e. This increases blood volume and, therefore, increases blood pressure. In exchange for the reabsorbing of sodium to blood, potassium is secreted into the tubules, becomes part of urine and is excreted. Angiotensin II causes the release of anti-diuretic hormone ADH also called vasopressin — ADH is made in the hypothalamus and released from the posterior pituitary gland. As its name suggests, it also exhibits vaso-constrictive properties, but its main course of action is to stimulate reabsorption of water in the kidneys.
ADH also acts on the central nervous system to increase an individual's appetite for salt, and to stimulate the sensation of thirst. These effects directly act together to increase blood pressure and are opposed by atrial natriuretic peptide ANP. Local renin—angiotensin systems[ edit ] Locally expressed renin—angiotensin systems have been found in a number of tissues, including the kidneysadrenal glandsthe heartvasculature and nervous systemand have a variety of functions, including local cardiovascular regulation, in association or independently of the systemic renin—angiotensin system, as well as non-cardiovascular functions.
Medications aimed at the systemic system may affect the expression of those local systems, beneficially or adversely. Renin levels are high in the fetus, while angiotensin II levels are significantly lower; this is due to the limited pulmonary blood flow, preventing ACE found predominantly in the pulmonary circulation from having its maximum effect. Clinical significance[ edit ] Flowchart showing the clinical effects of RAAS activity and the sites of action of ACE inhibitors and angiotensin receptor blockers.
ACE inhibitors —inhibitors of angiotensin-converting enzyme are often used to reduce the formation of the more potent angiotensin II. Captopril is an example of an ACE inhibitor. ACE cleaves a number of other peptides, and in this capacity is an important regulator of the kinin—kallikrein systemas such blocking ACE can lead to side effects.