ATC code C09

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

ACE inhibitors, or inhibitors of Angiotensin-Converting Enzyme, are a group of pharmaceuticals that are used primarily in treatment of hypertension and congestive heart failure, in most cases as the drugs of first choice.

Indications for ACE inhibitors include:

• Prevention of cardiovascular disorders
• Congestive heart failure (CHF)
• Hypertension
• Left ventricular dysfunction
• Prevention of nephropathy in diabetes mellitus

In several of these indications, ACE inhibitors are used first-line as several agents in the class have been clinically shown to be superior to other classes of drugs in the reduction of morbidity and mortality.

ACE inhibitors are often combined with diuretics in the control of hypertension (usually a thiazide), when an ACE inhibitor alone proves insufficient; and in chronic heart failure (usually furosemide) for improved symptomatic control. Thus there exists, on the market, combination products combining an ACE inhibitor with a thiazide (usually hydrochlorothiazide) in a single tablet to allow easy administration by patients.

This system is activated in response to hypotension, decreased sodium concentration in the distal tubule, decreased blood volume and renal sympathetic nerve stimulation. In such a situation, the kidneys release renin which cleaves the liver derived angiotensinogen into Angiotensin I. Angiotensin I is then converted to angiotensin II via the angiotensin-converting-enzyme (ACE) in the pulmonary circulation. The system in general aims to increase blood pressure.

ACE inhibitors lower arteriolar resistance and increase venous capacitance; increase cardiac output and cardiac index, stroke work and volume, lower renovascular resistance, and lead to increased natriuresis (excretion of sodium in the urine).

Normally, angiotensin II will have the following effects:

• vasoconstriction (narrowing of blood vessels), which may lead to increased blood pressure and hypertension
• Ventricular remodeling of the heart, which may lead to ventricular hypertrophy and CHF
• stimulate 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.
• stimulate the posterior pituitary into releasing vasopressin (also known as anti-diuretic hormone (ADH)) which also acts on the kidneys to increase water retention.

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 patient suffering from the effects of rapidly decreasing their blood pressure (dizziness, fainting, etc).

Common adverse drug reactions (≥1% of patients) include: hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea, renal impairment.^[1]

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.^[2] 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, and is associated with their effect on angiotensin II-mediated homeostatic functions such as renal blood flow. Renal blood flow is 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 reduce GFR, a marker of renal function. Specifically, ACE inhibitors can induce or exacerbate renal impairment in patients with renal artery stenosis. This is especially a problem if the patient is also concomitantly taking an NSAID and a diuretic – the so-called “triple whammy” effect – such patients are at very high risk of developing renal failure.^[3]

ACE inhibitors may cause hyperkalemia, because angiotensin II increases aldosterone release. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors ultimately cause retention of potassium.

Some patients develop angioedema due to increased bradykinin levels. There appears to be a genetic predisposition towards this adverse effect in patients who degrade bradykinin slower than average.^[4]

ACE inhibitors can be divided into three groups based on their molecular structure:

• Captopril (trade name Capoten), the first ACE inhibitor

This is the largest group, including:

• Enalapril (Vasotec/Renitec)
• Ramipril (Altace/Tritace/Ramace/Ramiwin)
• Quinapril (Accupril)
• Perindopril (Coversyl/Aceon)
• Lisinopril (Lisodur/Lopril/Novatec/Prinivil/Zestril)
• Benazepril (Lotensin)

• Fosinopril (Monopril), the only member

Casokinins and lactokinins are breakdown products of casein and whey that occur naturally after ingestion of milk products, especially cultured milk. Their role in blood pressure control is uncertain.^[5]

Comparatively, all ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main point-of-difference lies with captopril, the first ACE inhibitor, which has a shorter duration of action and increased incidence of certain adverse effects (cf. captopril).

Certain agents in the ACE inhibitor class have been proven, in large clinical studies, to reduce mortality post-myocardial infarction, prevent development of heart failure, etc. While these effects are likely to be class-effects, good evidence-based medicine practice would direct the use of those agents with established clinical efficacy.

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)

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.^[1] In the U.S., ACE inhibitors are required to be labelled with a “black box” warning concerning the risk of birth defects when taking during the second and third trimester. It has also been found that use of ACE inhibitors in the first trimester is also associated with a risk of major congenital malformations, particularly affecting the cardiovascular and central nervous systems.^[6]

Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalaemic effect of ACE inhibitors.

ACE inhibitors share many common characteristics with another class of cardiovascular drugs called angiotensin II receptor antagonists, which are often used when patients are intolerant of the adverse effects produced by ACE inhibitors. ACE inhibitors do not completely prevent the formation of angiotensin II, as there are other conversion pathways, and so angiotensin II receptor antagonists may be useful because they act to prevent the action of angiotensin II at the AT₁ receptor.

While counterintuitive at first glance, the combination therapy of angiotensin II receptor antagonists with ACE inhibitors may be superior to either agent alone. This combination may increase levels of bradykinin while blocking the generation of angiotensin II and its activity at the AT₁ receptor. This ‘dual blockade’ may be more effective than using an ACE inhibitor alone, because angiotensin II can be generated via non-ACE-dependent pathways. Preliminary studies suggest that this combination of pharmacologic agents may be advantageous in the treatment of essential hypertension, chronic heart failure, and nephropathy.^[7][8] However, more studies are needed to confirm these highly preliminary results. While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking.^[9]

Patients with heart failure may benefit from the combination in terms of reducing morbidity and ventricular remodeling.^[10][11]

The most compelling evidence has been found for the treatment of nephropathy: this combination therapy partially reversed the proteinuria and also exhibited a renoprotective effect in patients afflicted with diabetic nephropathy,^[7] and pediatric IgA nephropathy.^[12]

The first step in the development of (ACE) inhibitors was the discovery of angiotensin converting enzyme (ACE) in plasma by Leonard T. Skeggs and his colleagues in 1956. The conversion of the inactive angiotensin I to the potent angiotensin II was thought to take place in the plasma. However, in 1967, Kevin K. F. Ng and John R. Vane showed that the plasma (ACE) was too slow to account for the conversion of angiotensin I to angiotensin II in vivo. Subsequent investigation showed that rapid conversion occur during its passage through the pulmonary circulation.^[13]

Bradykinin is rapidly inactivated in the circulating blood and it disappears completely in a single passage through the pulmonary circulation. Angiotensin I also disappears in the pulmonary circulation due to its conversion to angiotensin II. Furthermore, angiotensin II passes through the lungs without any loss. The inactivation of bradykinin and the conversion of angiotensin I to angiotensin II in the lungs was thought to be caused by the same enzyme.^[14] In 1970, Ng and Vane using bradykinin potentiating factor (BPF) provided by Sérgio Henrique Ferreira showed that the conversion of angiotensin I to angiotensin II was inhibited during its passage through the pulmonary circulation.^[15]

Bradykinin potentiating factor (BPF) is derived from the venom of the pit viper (Bothrops jararaca). It is a family of peptides and its potentiating action is linked to inhibition of bradykinin by ACE. Molecular analysis of BPF yielded a nonapeptide BPF teprotide (SQ 20,881) which showed the greatest (ACE) inhibition potency and hypotensinve effect in vivo. Teprotide had limited clinical value, due to its peptide nature and lack of activity when given orally. In the early 1970s, knowledge of the structure-activity relationship required for inhibition of ACE was growing. David Cushman, Miguel Ondetti and colleagues used peptide analogues to study the structure of ACE, using carboxypeptidase A as a model. Their discoveries led to the development of captopril, the first orally-active ACE inhibitor in 1975.

Captopril was approved by the United States Food and Drug Administration in 1981. The first non-sulfhydryl-containing (ACE) inhibitor enalapril was marketed two years later. Since then, at least twelve other ACE inhibitors have been marketed.

1. In renal artery stenosis, there is decreased perfusion of the kidney and increased release of renin by the juxtaglomerular apparatus. ACE inhibitors inhibit the synthesis of angiotensin II in this hypereninemic state.
2. In patients without renal artery stenosis, ACE inhibitors act via 6 mechanisms:
   • Inhibition of conversion of circulating angiotensin I to angiotensin II.
   • Reduce the secretion of aldosterone to induce natriuresis.
   • They induce renal vasodilation and enhance natriuresis.
   • The inactivation of vasodilatory bradykinins is reduced.
   • Inhibition of local formation of angiotensin II in vascular tissue and myocardium.
   • Indirect adrenergic modulation.
3. Quality of life. It has been claimed that angiotensin converting enzymes have a favorable side-effect profile and offer an improved quality of life compared with other anti-hypertensives. However, the comparative studies have used medications with central and sexual side-effects, namely methyldopa and Inderal and cough was not included in the analysis.

1. In congestive heart failure, there is a vicious cycle in which a diminished cardiac output decreases baroreceptor stimulation and increases SVR, further increasing the afterload on the failing myocardium.
2. Angiotensin converting enzymes work by reducing the SVR and minimizing afterload.
3. Patients with CHF are also at risk for VEA and ACE inhibitors may provide a benefit by increasing serum potassium and decreasing circulating norepinephrine levels. Specific studies, however, remain to be done to document this effect.
4. Therapy is usually initiated with a test dose of Captopril 6.25 mg because of its shorter half-life and overdiuresis is avoided to prevent a hypereninemic state prior to initiation of the therapy.
5. In patients with liver dysfunction Captopril may be preferable to Enalapril because Enalapril requires activation by the liver.
6. Diuretics remain the first line agent. ACE inhibitors do not appear to work well in the absence of diuretics and therefore are primarily second line agents.
7. Patients with a low sodium concentration ( i.e. below 130 meq/l ) are likely to be hypereninemic and may experience a precipitous fall in blood pressure.
8. Avoid hyperkalemia in patients already treated with potassium sparing diuretics or with potassium supplements especially if renal function is already impaired.

• Both experimental and clinical studies support the use of angiotensin converting enzymes inhibitors to decrease LV dilation post MI.

1. Exert a renal vasodilatory effect by dilating efferent arterioles and relieving intraglomerular pressure.
2. In diabetic nephropathy, Captopril has been shown to decrease proteinuria without changing creatinine which has been thought to be due to reduced intraglomerular hypertension i.e. reducing the filtered load.
3. The role of Captopril in other forms of renal failure is less clear.

1. Cough, dry, irritating, non-productive. Most common side effect. Patients with CHF frequently cough anyway. Cough was ignored in the “quality of life” study. Incidence may be as high as 10-15%. Thought to be secondary to increased formation of bradykinin and prostaglandins. NSAIDs may help, but at the expense of renal vasodilatory effects of ACE inhibitors.
2. Hypotension: When initial blood pressure is very low, further afterload reduction can cause hypotension and renal hypoperfusion.
3. Renal side effects: Again, hypotension can lead to renal failure which is usually temporary. 3 situations in which this is a possibility include
   • severe CHF
   • unilateral renal artery stenosis
   • bilateral renal artery stenosis
4. Occasionally irreversible renal failure has been precipitated in patients with bilateral renal artery stenosis and this is a contraindication.
5. To minimize these possibilities a low dose of short acting Captopril 6.25 mg is given to patients with CHF.
6. Angioedema rare, .1% life-threatening. No known method of prediction.

1. Avoid hyperkalemia with K+ sparing agents
2. Monitor plasma lithium levels
3. Combination with thiazide diuretics increases the hypotensive effects of ACE inhibitors.
4. Captopril increases digoxin levels.
5. ACE inhibitors and β blockers both decrease renin levels, but their is some evidence to suggest that the effect is additive.
6. ACE inhibitors and calcium channel blockers are a good combination because both are free of CNS effects.

1. The first ACE inhibitor
2. t1/2 = 2 to 3 hours
3. Dosing:
   • HTN: 25 to 50 mg bid
   • CHF: 75 to 150 mg daily in 2 to 3 divided doses. Test dose of 6.25 mg, particularly if recently diuresed
4. Improves proteinuria in diabetic nephropathy
5. Contraindications:
   • Bilateral renal artery stenosis
   • Unilateral renal artery stenosis in a single kidney
   • Immune-based renal disease (4/100 incidence of neutropenia in those with collagen vascular disease and renal impairment).
   • Cr > 1.6 mg/dl
   • Pre-existing neutropenia
   • Hypotension
6. Immune-based side-effects peculiar to captopril include taste disturbances (2-7%), skin rashes (4-10%) and neutropenia (1/8600). In patients with renal impairment at the time of initiation of therapy, then WBC counts need to be checked q 2 wks for 3 mos.
7. Proteinuria occurs in 1% of patients taking captopril and is due to immune mechanisms and decreased renal perfusion.

1. Longer half-life (4 to 5 hours in HTN and 7 to 8 hours in CHF)
2. Requires hydrolysis of the pro-drug to the active drug, enalaprilat in the liver, thus in liver disease requires higher dosing.
3. Does not have the sulfhydryl group and therefore less of a risk of immune-based side effects.
4. 95% renal excretion
5. Peak antihypertensive effect in 4 to 6 hours after the initial dose.
6. Dosing:
   • HTN: 2.5 to 20 mg daily as 1 or 2 daily doses
   • CHF: Initial dosing 2.5 mg to avoid the risk of hypotension and renal failure
   • If GFR < 30 ml/min, then reduce the dose
7. Side-effects: neutropenia less frequent. Cough still occurs. Can be safe when captopril causes a rash. Regular neutrophil monitoring is not required.

1. Is not a pro-drug, excreted unchanged by the kidney.
2. t1/2 = 12 – 14 hours.
3. No sulfhydryl group, therefore few immune-based side effects.
4. Dosing similar to enalapril.

1. Studied in 95 american studies.
2. The prodrug is benazepril, the esterified form.
3. Benazepril is hydrolyzed in the liver to the active unesterified form, benazeprilat.
4. Initial dose: 10 mg PO qd. Chronic dosing: 20 mg or 40 mg PO qd. Occasionally a patient will require 40 mg PO bid.
5. Five most common side effects in 3,500 patients were headache, dizziness, fatigue, cough (3.4% in treatment group compared with 1.3% in placebo arm), and nausea.
6. In patients with a creatinine clearance less than 30 ml/min a reduction in the initial dosage is decreased.
7. No need to reduce dose in cirrhosis.
8. No dose reduction in the elderly.

Template:WikiDoc Sources CME Category::Cardiology

Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys.

An oligopeptide, angiotensin is a hormone and a dipsogen. It is derived from the precursor molecule angiotensinogen, a serum globulin produced in the liver. Angiotensin was isolated in the late 1930s (first named ‘angiotonin’ or ‘hypertensin’) and subsequently characterized and synthesized by groups at the Cleveland Clinic and Ciba laboratories.^[1]

Angiotensinogen is an α-2-globulin 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.

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-…

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu | Val-Ile-…

Angiotensin I (CAS# 11128-99-7), also called proangiotensin, is formed by the action of renin on angiotensinogen. Renin cleaves the peptide bond between the leucine (Leu) and valine (Val) residues on angiotensinogen, creating the decapeptide (ten amino acid) (des-Asp) angiotensin I. Renin is produced in the kidneys in response to renal sympathetic activity, decreased intrarenal blood pressure (<90mmHg systolic blood pressure^[2] ) at the juxtaglomerular cells, or decreased delivery of Na+ and Cl- to the macula densa.^[3] If a reduced NaCl concentration^[4] in the distal tubule is sensed by the macula densa, renin release by juxtaglomerular cells is increased. This sensing mechanism for macula densa-mediated renin secretion appears to have a specific dependency on chloride ions rather than sodium ions. Studies using isolated preparations of thick ascending limb with glomerulus attached in low NaCl perfusate were unable to inhibit renin secretion when various sodium salts were added but could inhibit renin secretion with the addition of chloride salts.^[5] This, and similar findings obtained in vivo,^[6] has led some to believe that perhaps “the initiating signal for MD control of renin secretion is a change in the rate of NaCl uptake predominantly via a luminal Na,K,2Cl co-transporter whose physiological activity is determined by a change in luminal Cl concentration.”^[7]

Angiotensin I appears to have no direct biological activity and exists solely as a precursor to angiotensin II.

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe

Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE), primarily through ACE within the lung (but also present in endothelial cells, kidney epithelial cells, and the brain). Angiotensin II acts on the CNS to increase vasopressin production, and also acts on venous and arterial smooth muscle to cause vasoconstriction. Angiotensin II also increases aldosterone secretion, therefore, it acts as an endocrine, autocrine/paracrine, and intracrine hormone.

ACE is a target of 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 an IP3-dependent mechanism leading to a rise in intracellular calcium levels and ultimately causing contraction). In addition, angiotensin II acts at the Na⁺/H⁺ exchanger in the proximal tubules of the kidney to stimulate Na reabsorption and H⁺ excretion which is coupled to bicarbonate reabsorption. This ultimately results in an increase in blood volume, pressure, and pH.^[8] Hence, ACE inhibitors are major anti-hypertensive drugs.

Other cleavage products of ACE, seven 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 AII itself is targeted by angiotensin II receptor antagonists, which directly block angiotensin II AT₁ receptors.

Angiotensin II is degraded to angiotensin III by angiotensinases 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 II results in increased inotropy, chronotropy, catecholamine (norepinephrine) release, catecholamine sensitivity, aldosterone levels, vasopressin levels, and cardiac remodeling and vasoconstriction through AT1 receptors on peripheral vessels (conversely, AT2 receptors impair cardiac remodeling). This is why ACE inhibitors and ARBs help to prevent remodeling that occurs secondary to angiotensin II and are beneficial in CHF. ^[7]

Asp | Arg-Val-Tyr-Ile-His-Pro-Phe

Angiotensin III has 40% of the pressor activity of angiotensin II, but 100% of the aldosterone-producing activity. Increases mean arterial pressure.

Arg | Val-Tyr-Ile-His-Pro-Phe

Angiotensin IV is a hexapeptide that, like angiotensin III, has some lesser activity. Angiotensin IV has a wide range of activities in the central nervous system.^[9][10]

The exact identity of AT4 receptors has not been established. There is evidence that the AT4 receptor is insulin-regulated aminopeptidase (IRAP).^[11] There is also evidence that angiotensin IV interacts with the HGF system through the c-Met receptor.^[12][13]

Synthetic small molecule analogues of angiotensin IV with the ability to penetrate through blood brain barrier have been developed.^[13]

See also Renin–angiotensin system#Effects

Angiotensins II, III and IV have a number of effects throughout the body:

Angiotensins “modulate fat mass expansion through upregulation of adipose tissue lipogenesis … and downregulation of lipolysis ” ^[14]

They are potent direct vasoconstrictors, constricting arteries and veins and increasing blood pressure. This effect is achieved through activation of the GPCR AT1, which signals through a Gq protein to activate Phospholipase C, and subsequently increase intracellular calcium.^[15]

Angiotensin II has prothrombotic potential through adhesion and aggregation of platelets and stimulation of PAI-1 and PAI-2.^[16][17]

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 α1 adrenoreceptors.

Angiotensin II increases thirst sensation (dipsogen) through the area postrema and subfornical organ of the brain,^[18][19][20] decreases the response of the baroreceptor reflex, increases the desire for salt, increases secretion of ADH from the posterior pituitary, and increases secretion of ACTH from the anterior pituitary.^[18] It also potentiates the release of norepinephrine by direct action on postganglionic sympathetic fibers.

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 the menstrual cycle.

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 is a sensitizer to tubuloglomerular feedback, preventing 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.

Direct Renal effects of angiotensin II (not including aldosterone release)

Target	Action	Mechanism[21]
renal artery & afferent arterioles	vasoconstriction (weaker)	VDCCs → Ca2+ influx
efferent arteriole	vasoconstriction (stronger)	(probably) activate Angiotensin receptor 1 → Activation of Gq → ↑PLC activity → ↑IP3 and DAG → activation of IP3 receptor in SR → ↑intracellular Ca2+
mesangial cells	contraction → ↓filtration area	activation of Gq → ↑PLC activity → ↑IP3 and DAG → activation of IP3 receptor in SR → ↑intracellular Ca2+ VDCCs → Ca2+ influx
proximal tubule	increased Na+ reabsorption	adjustment of Starling forces in peritubular capillaries to favour increased reabsorption efferent and afferent arteriole contraction → decreased hydrostatic pressure in peritubular capillaries efferent arteriole contraction → increased filtration fraction → increased colloid osmotic pressure in peritubular capillaries increased sodium–hydrogen antiporter activity
tubuloglomerular feedback	increased sensitivity	increase in afferent arteriole responsiveness to signals from macula densa
medullary blood flow	reduction

Wikimedia Commons has media related to Angiotensin.

• The MEROPS online database for peptidases and their inhibitors: I04.953
• Angiotensins at the US National Library of Medicine Medical Subject Headings (MeSH)
• Human AGT genome location and AGT gene details page in the UCSC Genome Browser.

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