Angiotensin
Angiotensin, a peptide, causes blood vessels to constrict, and drives blood pressure up. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex. Aldosterone promotes sodium retention in the distal nephron, in the kidney, which also drives blood pressure up.
Angiotensin is an oligopeptide in the blood that causes vasoconstriction, increasedblood pressure, and release of aldosterone from the adrenal cortex. It is a hormone and a powerful dipsogen. It is derived from the precursor molecule angiotensinogen, a serum globulin produced in the liver. It plays an important role in the renin-angiotensin system. Angiotensin was independently isolated in Indianapolis and Argentina in the late 1930s (as 'Angiotonin' and 'Hypertensin' respectively) and subsequently characterised and synthesized by groups at the Cleveland Clinic and Ciba laboratories in Basel , Switzerland
Precursor, and types of angiotensin
Angiotensinogen
Angiotensinogen is an α-2-globulin that is produced constitutively and released into the circulation mainly by the liver. It is a member of the serpin family, although it is not known to inhibit other enzymes, unlike most serpins. Plasma angiotensinogen levels are increased by plasma corticosteroid, estrogen, thyroid hormone, and angiotensin II levels.
Angiotensinogen is also known as renin substrate.
Human angiotensinogen is 452 amino acids long, but other species have angiotensinogen of varying sizes. The first 12 amino acids are the most important for activity.
Angiotensin I
ngiotensin I (CAS# 11128-99-7) is formed by the action of renin on angiotensinogen. Renin is produced in the kidneys in response to renal sympaticus activity, decreased intra-renal blood pressure at thejuxtaglomerular cells, or decreased delivery of Na+ and Cl- to the macula densa.[2] If less Na+ is sensed by the macula densa, renin release by juxtaglomerular cells is increased.
Renin cleaves the peptide bond between the leucine(Leu) and valine (Val) residues on angiotensinogen, creating the ten amino acid peptide (des-Asp) angiotensin I
Angiotensin I appears to have no biological activity and exists solely as a precursor to angiotensin 2.
Angiotensin II
giotensin I is converted to angiotensin II through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE, or kinase), which is found predominantly in the capillaries of the lung.[3] ACE is actually found all over the body, but has its highest density in the lung due to the high density of capillary beds there. Angiotensin II acts as an endocrine, autocrine/paracrine, and intracrine hormone.
ACE is a target for inactivation by ACE inhibitor drugs, which decrease the rate of angiotensin II production. Angiotensin II increases blood pressure by stimulating the Gq protein in vascular smooth muscle cells (which in turn activates contraction by an IP3-dependent mechanism). ACE inhibitor drugs are major drugs against hypertension.
Other cleavage products of ACE, 7 or 9 amino acids long, are also known; they have differential affinity for angiotensin receptors, although their exact role is still unclear. The action of angiotensin II itself is targeted by angiotensin II receptor antagonists, which directly blockangiotensin II AT1 receptors.
Angiotensin II is degraded to angiotensin III by angiotensinases that are located in red blood cells and the vascular beds of most tissues. It has a half-life in circulation of around 30 seconds, whereas, in tissue, it may be as long as 15–30 minutes.
Angiotensin III
ngiotensin III has 40% of the pressor activity of Angiotensin II, but 100% of the aldosterone-producing activity.
Angiotensin IV
Angiotensin IV is a hexapeptide that, like angiotensin III, has some lesser activity.
Effects
Angiotensins II, III & IV have a number of effects throughout the body:
Cardiovascular
They are potent direct vasoconstrictors, constricting arteries and veins and increasing blood pressure.
Angiotensin II has prothrombotic potential through adhesion and aggregation of platelets and production of PAI-1 and PAI-2.
When cardiac cell growth is stimulated, a local (autocrine-paracrine) renin-angiotensin system is activated in the cardiac myocyte, which stimulates cardiac cell growth through Protein Kinase C. The same system can be activated in smooth muscle cells in conditions of hypertension, atherosclerosis, or endothelial damage. Angiotensin II is the most important Gq stimulator of the heart during hypertrophy, compared to endothelin-1 and A1 adrenoreceptors.
Neural
Angiotensin II increases thirst sensation (dipsogen) through the subfornical organ (SFO) of the brain, decreases the response of thebaroreceptor reflex, and increases the desire for salt. It increases secretion of ADH in the posterior pituitary and secretion of ACTH in the anterior pituitary. It also potentiates the release of norepinephrine by direct action on postganglionic sympathetic fibers.
Adrenal
Angiotensin II acts on the adrenal cortex, causing it to release aldosterone, a hormone that causes the kidneys to retain sodium and lose potassium. Elevated plasma angiotensin II levels are responsible for the elevated aldosterone levels present during the luteal phase of themenstrual cycle.
Renal
Angiotensin II has a direct effect on the proximal tubules to increase Na+ reabsorption. It has a complex and variable effect on glomerular filtration and renal blood flow depending on the setting. Increases in systemic blood pressure will maintain renal perfusion pressure; however, constriction of the afferent and efferent glomerular arterioles will tend to restrict renal blood flow. The effect on the efferent arteriolar resistance is, however, markedly greater, in part due to its smaller basal diameter; this tends to increase glomerular capillary hydrostatic pressure and maintain glomerular filtration rate. A number of other mechanisms can affect renal blood flow and GFR. High concentrations of Angiotensin II can constrict the glomerular mesangium reducing the area for glomerular filtration. Angiotensin II as a sensitizer to tubuloglomerular feedbackpreventing an excessive rise in GFR. Angiotensin II causes the local release of prostaglandins, which, in turn, antagonize renal vasoconstriction. The net effect of these competing mechanisms on glomerular filtration will vary with the physiological and pharmacological environment.
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors, are a group of pharmaceuticals that are used primarily in treatment of hypertension and congestive heart failure.
Clinical use
ACE inhibitors are used primarily in the treatment of hypertension, though they are also sometimes used in patients with cardiac failure, renal disease or systemic sclerosis ACEIs can also be used to treat diabetic nephropathy and left ventricular hypertrophy.
Mechanism of action
Angiotensin-converting enzyme inhibitors reduce the activity of the renin-angiotensin-aldosterone system.
The renin-angiotensin-aldosterone system (RAAS)
One mechanism for maintaining the blood pressure is the release of a protein called renin from cells in thekidney (to be specific, the juxtaglomerular apparatus). This produces another protein called angiotensin, which signals the adrenal gland to produce a hormone called aldosterone. This system is activated in response to a fall in blood pressure (hypotension) as well as markers of problems with the salt-water balance of the body, such as decreased sodiumconcentration in a part of the kidney known as thedistal tubule, decreased blood volume and stimulation of the kidney by the sympathetic nervous system. In such a situation, the kidneys release renin, which acts as an enzyme and cuts off all but the first 10amino-acid residues of angiotensinogen (a protein made in the liver, and which circulates in the blood). These 10 residues are then known as angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme (ACE) which removes a further 2 residues and is found in the pulmonary circulation as well as in the endothelium of many blood vessels.[1] The system in general aims to increase blood pressure by increasing the amount of salt and water the body retains, although angiotensin is also very good at causing the blood vessels to tighten (a potent vasoconstrictor).
Effects
ACE inhibitors block the conversion of angiotensin I to angiotensin II. They, therefore, lower arteriolar resistance and increase venous capacity; increase cardiac output, cardiac index, stroke work, and volume; lower renovascular resistance; and lead to increased natriuresis(excretion of sodium in the urine). Renin will increase in concentration in the blood due to negative feedback of conversion of AI to AII. Angiotensin I will increase for the same reason. AII will decrease. Aldosterone will decrease. Bradykinin will increase due to less inactivation that is done by ACE enzyme.
Under normal conditions, angiotensin II will have the following effects:
§ vasoconstriction (narrowing of blood vessels), which may lead to increased blood pressure and hypertension
– constriction of the efferent arterioles of the kidney, leading to increased perfusion pressure in the glomeruli.
§ Contribute to ventricular remodeling and ventricular hypertrophy of the heart.
§ stimulation of the adrenal cortex to release aldosterone, a hormone that acts on kidney tubules to retain sodium and chloride ions and excrete potassium. Sodium is a "water-holding" molecule, so water is also retained, which leads to increased blood volume, hence an increase in blood pressure.
§ stimulation of the posterior pituitary to release vasopressin (also known as anti-diuretic hormone (ADH)), which also acts on the kidneys to increase water retention.
§ decrease renal protein kinase C.
With ACE inhibitor use, the effects of angiotensin II are prevented, leading to decreased blood pressure.
Epidemiological and clinical studies have shown that ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effect. This action of ACE inhibitors is utilised in the prevention of diabetic renal failure.
ACE inhibitors have been shown to be effective for indications other than hypertension even in patients with normal blood pressure. The use of a maximum-dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, prophylaxis of cardiovascular events) is justified because it improves clinical outcomes, independent of the blood pressure-lowering effect of ACE inhibitors. Such therapy, of course, requires careful and gradual titration of the dose to prevent the effects of rapidly decreasing blood pressure (dizziness, fainting, etc.).
ACE inhibitors have also been shown to cause a central enhancement of parasympathetic activity in healthy volunteers and patients with heart failure.[4][5] This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials.
The ACE inhibitor enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure. Cachexia is a poor prognostic sign in patients with chronic heart failure. ACE-inhibitors are now used to reverse frailty and muscle wasting in elderly patients without heart failure
Adverse effects
Common adverse drug reactions include: hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea, and renal impairment.[8]There is also some evidence to suggest that ACE inhibitors might increase inflammation-related pain.[
A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in bradykinin levels produced by ACE inhibitors, although the role of bradykinin in producing these symptoms remains disputed by some authors.[ Patients who experience this cough are often switched to angiotensin II receptor antagonists.
Rash and taste disturbances, infrequent with most ACE inhibitors, are more prevalent in captopril and is attributed to its sulfhydryl moiety. This has led to decreased use of captopril in clinical setting, although it is still used in scintigraphy of the kidney.
Renal impairment is a significant adverse effect of all ACE inhibitors. The reason for this is still unknown. Some suggest that it is associated with their effect on angiotensin II-mediated homeostatic functions such as renal blood flow. Renal blood flow may be affected by angiotensin II because it vasoconstricts the efferent arterioles of the glomeruli of the kidney, thereby increasing glomerular filtration rate (GFR). Hence, by reducing angiotensin II levels, ACE inhibitors may reduce GFR, a marker of renal function. To be specific, ACE inhibitors can induce or exacerbate renal impairment in patients with renal artery stenosis. This is especially a problem if the patient is concomitantly taking anNSAID and a diuretic. When the three drugs are taken together, there is a very high risk of developing renal failure.
ACE inhibitors may cause hyperkalemia. Suppression of angiotensin II leads to a decrease in aldosterone levels. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors ultimately cause retention of potassium.
A severe allergic reaction that rarely can affect the bowel wall and secondarily cause abdominal pain can occur. This "anaphylactic" reaction is very rare as well.
Some patients develop angioedema due to increased bradykinin levels. There appears to be a genetic predisposition toward this adverse effect in patients that degrade bradykinin more slowly than average.
In pregnant women, ACE inhibitors taken during the first trimester have been reported to cause major congenital malformations, stillbirths, and neonatal deaths. Commonly reported fetal abnormalities include hypotension, renal dysplasia, anuria/oliguria, oligohydramnios,intrauterine growth retardation, pulmonary hypoplasia, patent ductus arteriosus, and incomplete ossification of the skull.[13]
Contraindications and precautions
The ACE inhibitors are contraindicated in patients with:
§ Previous angioedema associated with ACE inhibitor therapy
§ Renal artery stenosis (bilateral, or unilateral with a solitary functioning kidney)
§ Hypersensitivity to ACE inhibitors
ACE inhibitors should be used with caution in patients with:
§ Impaired renal function
§ Aortic valve stenosis or cardiac outflow obstruction
§ Hypovolemia or dehydration
§ Hemodialysis with high-flux polyacrylonitrile membranes
ACE inhibitors are ADEC Pregnancy category D, and should be avoided in women who are likely to become pregnant.[8] In the U.S.
Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic effect of ACE inhibitors.
Angiotensin II receptor antagonist
ngiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. Their main use is in hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure.
Structure
Losartan, irbesartan, olmesartan, candesartan and valsartan include the tetrazole group (a ring with four nitrogen and one carbon).
Losartan, irbesartan, olmesartan, candesartan, and telmisartan include one or two imidazole groups.
Losartan, irbesartan, olmesartan, candesartan, and telmisartan include one or two imidazole groups.
Mechanism of action
These substances are AT1-receptor antagonists – that is, they block the activation of angiotensin II AT1 receptors. Blockade of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, reduces production and secretion of aldosterone, amongst other actions – the combined effect of which is reduction of blood pressure.
The specific efficacy of each ARB within this class is made up of a combination of three pharmacodynamic and pharmacokinetic parameters. For these three key PD/ PK areas that indicate efficacy, it is important to see that one needs a combination of all three at an effective level; the parameters of the three characteristics will need to be compiled into a table similar to one below, eliminating duplications and arriving at consensus values; the latter are at variance now.
Pressor inhibition
Pressor inhibition at trough level - this clinically important measurement relates to the amount of blockade or inhibition of the BP raising effect of angiotensin II. Pressor inhibition is not a measure of blood pressure efficacy, though. The rates as listed in the US FDA Package Inserts for inhibition of this effect at the 24th hour for the ARBs are as follows: (all doses listed in PI are included)
§ Valsartan 80 mg 30%
§ Telmisartan 80 mg 40%
§ Losartan 100 mg 25–40%
§ Irbesartan 150 mg 40%
§ Irbesartan 300 mg 60%
§ Olmesartan 20 mg 61%
§ Olmesartan 40 mg 74%
AT1 affinity
AT1 affinity vs AT2 is not a meaningful efficacy measurement of blood pressure response. The specific AT1 affinity relates to how specifically attracted the medicine is for the correct receptor, the US FDA Package Insert rates for AT1 affinity are as follows:
§ Losartan 1000 fold
§ Telmisartan 3000 fold
§ Irbesartan 8500 fold
§ Olmesartan 12500 fold
§ Valsartan 20000 fold
Biological half life
The third area that completes the overall efficacy picture of an ARB is its biological half life. The half-lives from the US FDA Package Inserts are as follows:
§ Valsartan 6 hours
§ Losartan 6–9 hours
§ Irbesartan 11–15 hours
§ Olmesartan 13 hours
§ Telmisartan 24 hours
Uses
Angiotensin II receptor antagonists are primarily used for the treatment of hypertension where the patient is intolerant of ACE inhibitortherapy. They do not inhibit the breakdown of bradykinin or other kinins, and are thus only rarely associated with the persistent dry cough and/or angioedema that limit ACE inhibitor therapy. More recently, they have been used for the treatment of heart failure in patients intolerant of ACE inhibitor therapy, particularly candesartan. Irbesartan and losartan have trial data showing benefit in hypertensive patients with type II diabetes, and may delay the progression of diabetic nephropathy. Candesartan is used experimentally in preventive treatment of migraine.
The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing blood pressure effects at the maximal doses.[2] When used in clinical practice, the particular agent used may vary based on the degree of blood pressure response required.
Some of these drugs have a uricosuric effect.
In 2008 they were reported to have a remarkable negative association with Alzheimer's disease (AD). A retrospective analysis of five million patient records with the US Department of Veterans Affairs system found that different types of commonly used anti-hypertensive medications had very different AD outcomes. Those patients taking angiotensin receptor blockers (ARBs) were 35—40% less likely to develop AD than those using other anti-hypertensives. (Preliminary unpublished data)
Adverse effects
This class of drugs is usually well-tolerated, with common adverse drug reactions (ADRs) including: dizziness, headache, and/orhyperkalemia. Infrequent ADRs associated with therapy include: first dose orthostatic hypotension, rash, diarrhea, dyspepsia, abnormal liver function, muscle cramp, myalgia, back pain, insomnia, decreased hemoglobin levels, renal impairment, pharyngitis, and/or nasal congestion.
While one of the main rationales for the use of this class is the avoidance of dry cough and/or angioedema associated with ACE inhibitor therapy, they may still rarely occur. Additionally, there is also a small risk of cross-reactivity in patients who have experienced angioedemawith ACE inhibitor therapy.
Myocardial Infarction: the controversy
The question of whether or not Angiotensin II receptor antagonists slightly increase the risk of heart attack (myocardial infarction) is currently being investigated. Some studies have demonstrated that ARBs can increase the risk of myocardial infarction. However, other studies have found that ARBs do not increase the risk of myocardial infarction. To date, there is no consensus on whether ARBs have a tendency to increase the risk of myocardial infarction, and further investigations are underway.
Indeed, as a consequence of AT1 blockade, ARBs increase Angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating Angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition upregulated. Unfortunately, recent data suggest that AT2 receptor stimulation may be less beneficial than previously proposed and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis, and hypertrophy , as well as proatherogenic andproinflammatory effects.
Cancer Risk Factors
A study published in 2010 determined that "...meta-analysis of randomised controlled trials suggests that ARBs are associated with a modestly increased risk of new cancer diagnosis. Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug. These findings warrant further investigation."
Longevity Promotion
Knockout of the Agtr1a gene that encodes AT1 results in marked prolongation of the life span of mice by 26 percent compared to controls by reducing oxidative damage especially to mitochondria and over-expression of renal pro-survival genes and the ARBs seem to have the same effect.
Fibrosis Regression
Losartan and other ARBs regress liver, heart, lung and kidney fibrosis.
Angiotensin II Type-1 Receptor Blocker Valsartan Enhances Insulin Sensitivity in Skeletal Muscles of Diabetic Mice
Angiotensin II has been shown to contribute to the pathogenesis of insulin resistance; however, the mechanism is not well understood. The present study was undertaken to investigate the potential effect of an angiotensin II type-1 (AT1) receptor blocker, valsartan, to improve insulin resistance and to explore the signaling basis of cross-talk of the AT1 receptor- and insulin-mediated signaling in type 2 diabetic KK-Ay mice. Treatment of KK-Ay mice with valsartan at a dose of 1 mg/kg per day, which did not influence systolic blood pressure, significantly increased insulin-mediated 2-[3H]deoxy-D-glucose (2-[3H]DG) uptake into skeletal muscle and attenuated the increase in plasma glucose concentration after a glucose load and plasma concentrations of glucose and insulin. In contrast, insulin-mediated 2-[3H]DG uptake into skeletal muscle was not influenced in AT2 receptor null mice, and an AT2 receptor blocker, PD123319, did not affect 2-[3H]DG uptake and superoxide production in skeletal muscle of KK-Ay mice. Moreover, we observed that valsartan treatment exaggerated the insulin-induced phosphorylation of IRS-1, the association of IRS-1 with the p85 regulatory subunit of phosphoinositide 3 kinase (PI 3-K), PI 3-K activity, and translocation of GLUT4 to the plasma membrane. It also reduced tumor necrosis factor-
(TNF-) expression and superoxide production in skeletal muscle of KK-Ay mice. Specific AT1 receptor blockade increases insulin sensitivity and glucose uptake in skeletal muscle of KK-Ay mice via stimulating the insulin signaling cascade and consequent enhancement of GLUT4 translocation to the plasma membrane.
(TNF-) expression and superoxide production in skeletal muscle of KK-Ay mice. Specific AT1 receptor blockade increases insulin sensitivity and glucose uptake in skeletal muscle of KK-Ay mice via stimulating the insulin signaling cascade and consequent enhancement of GLUT4 translocation to the plasma membrane.Renin inhibitor
enin inhibitor, or inhibitors of renin, are a new group of pharmaceuticals that are used primarily in treatment of hypertension.
They act on the juxtaglomerular cells of kidney, which produce renin in response to decreased blood flow.
Why target Renin
Renin is an enzyme that plays a major role in the Renin-Angiotensin System, a regulatory system in the body, which is responsible to maintain homeostasis of blood pressure. The enzyme belongs to the family of aspartic proteases and is responsible for the conversion of inactive angiotensinogen to angiotensin I (Ang I). Angiotensin I by itself is inactive. However, when acted upon by angiotensin converting enzyme (ACE) it gets converted to angiotensin II, which is active and is responsible for most of the pressor effects. Conversion of angiotensinogen to angiotensin I is the rate determining step of the system. The catalytic role played by renin is thus crucial in mediating blood pressure by the Renin-Angiotensin System.
Development of Renin Inhibitors
Direct renin inhibition offers another pharmacological tool in the treatment of hypertension. Early inhibitors of renin were monoclonal antibodies, which were excellent probes of enzyme function. However, they were in no ways suitable for use as medication as most were immunogenic and had to be administered via parenteral route. Transition state analogs in the form of statins were first synthesized and were found to be potent inhibitors of renin. However, they had drawbacks because of their peptide like nature and their lack of oral bioavailability. Modifications of these statins led to the development of CGP38560, a compound with reduced peptidic character and of smaller size (MW=730). Optimization of this compound by Novartis led to the development of Aliskiren- the only direct renin inhibitor which is clinically used as an antihypertensive drug
Aliskiren, is a first-in-class oral renin inhibitor, developed by Novartis in conjunction with the biotech company Speedel[1]. It was approved by the US Food and Drug Administration in 2007. It is an octanamide, is the first known representative of a new class of completely non-peptide, low-molecular weight, orally active transition-state renin inhibitors. Designed through the use of molecular modeling techniques, it is a potent and specific in vitro inhibitor of human renin (IC50 in the low nanomolar range), with a plasma half-life of ≈24 hours. Aliskiren has good water solubility and low lipophilicity and is resistant to biodegradation by peptidases in the intestine, blood circulation, and the liver. It was approved by the United States FDA on 6 March 2007, and for use in Europe on 27 August 2007. Its trade name is Tekturna in the USA , and Rasilez in the UK
While Novartis was developing inhibitors by modification of the peptide-like inhibitors of renin, Hoffman-La Roche started developing renin inhibitors, which were completely different in structure, having a piperidine ring. Screening of the Roche compound libraries led to the identification of rac-2(molecule a) (piperidine structure) which was selective in inhibiting renin over other aspartic proteases. Hoffman-La Roche pursued the development of these compounds until 2001 advancing to pre-clinical stage. Based on the piperidine structure, Pfizer pursued the task of designing ketopiperazine-based renin inhibitors which have shown greater potential(molecule b). More recently a new series of renin inhibitors based on the ketopiperazine structure was developed by Actelion Pharmaceuticals. These molecules have a 3,9-diazabicyclo[3.3.1] nonene group in place of the ketopiperazine group (molecule c). Another group of chemists from Vitae Pharmaceuticals has developed orally bioavailable alkyl amines based solely on a computational structure-based design
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