Key Points
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Hypertension is the most common modifiable risk factor for cardiovascular disease (CVD), and the risk of CVD events, including myocardial infarction, stroke, heart failure and end-stage renal disease, can be greatly reduced by lowering blood pressure.
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The best-known regulator of blood pressure and determinant of target-organ damage from hypertension is the renin–angiotensin–aldosterone system (RAAS). Overexpression of renin and its metabolic products predisposes to hypertension and related target-organ damage.
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Renin cleaves angiotensinogen to produce the inactive peptide angiotensin I. Cleavage of angiotensin I by angiotensin-converting enzyme (ACE) gives the active peptide angiotensin II (although there are alternative routes). Most of the known functions of the RAAS are mediated through the activation of the angiotensin II type 1 receptor (AT1 receptor) by angiotensin II, which leads to vasoconstriction, aldosterone release and other functions that tend to elevate blood pressure and cause hypertrophy or hyperplasia of target cells.
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Approved drugs that act on the RAAS that are discussed here include ACE inhibitors, AT1-receptor blockers (ARBs) and aldosterone-receptor antagonists (ARAs). These agents have been shown to be highly effective in lowering blood pressure and, particularly in the case of the ARBs, are extremely well tolerated. A novel class of combined ACE and neutral-endopeptidase inhibitors that are in development, called vasopeptidase inhibitors, are also discussed.
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Clinical-trial evidence is beginning to clarify some of the key issues in the use of ACE inhibitors and ARBs, such as clinical benefits beyond blood-pressure lowering. These drugs are also helping to better define the role of the RAAS in the pathogenesis of hypertension, stroke, myocardial infarction, heart failure and end-stage renal disease.
Abstract
Effective antihypertensive therapy has made a major contribution to the reductions in the morbidity and mortality of cardiovascular disease that have been achieved since the 1960s. However, blood-pressure control with conventional drugs has not succeeded in reducing cardiovascular disease risks to levels seen in normotensive persons. Drugs that inhibit or antagonize components of the renin–angiotensin–aldosterone system are addressing this deficiency by targeting both blood pressure and related structural and functional abnormalities of the heart and blood vessels, thus preventing target-organ damage and related cardiovascular events.
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Glossary
- MYOCARDIAL INFARCTION
-
Commonly known as a heart attack, this is the death of part of the heart muscle owing to a sudden loss of blood supply.
- HYPERTROPHY
-
An increase in the size of a tissue or organ resulting from an increase in the size of the cells present.
- HYPERPLASIA
-
An increase in the size of a tissue or organ resulting from an increase in the total number of cells present.
- ATHEROSCLEROSIS
-
A degenerative condition that is characterized by a narrowing of the arteries, owing to deposits of fatty substances, cholesterol, cellular waste products, calcium and other substances in the arterial inner lining.
- MINERALOCORTICOID
-
A corticosteroid that acts primarily on water and electrolyte balance by promoting the renal retention of sodium ions and excretion of potassium ions. Aldosterone is the most potent of the naturally occuring mineralocorticoids.
- FIBROSIS
-
The production of fibrous connective tissue as a consequence of chronic inflammation or healing.
- PROTEINURIA
-
The presence of protein in urine.
- ANGIOEDEMA
-
The development of tissue swelling, most commonly around the eyes and lips, which can lead to airway obstruction in rare cases.
- PRESSOR RESPONSE
-
An increase in blood pressure due to angiotensin II-induced activation of AT1 receptors.
- HYPERKALAEMIA
-
The presence in the blood of an abnormally high concentration of potassium.
- URICOSURIC ACTION
-
A tendency to promote urinary excretion of uric acid.
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Zaman, M., Oparil, S. & Calhoun, D. Drugs targeting the renin–angiotensin–aldosterone system. Nat Rev Drug Discov 1, 621–636 (2002). https://doi.org/10.1038/nrd873
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DOI: https://doi.org/10.1038/nrd873
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