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ACE: angiotensin-converting enzyme

ACEI: angiotensin-converting enzyme inhibitor

Ac-SDKP: N-acetyl-seryl-aspartyl-lysyl-proline

ACTH: corticotropin (formerly adrenocorticotropic hormone)

Ang: angiotensin

ARDS: acute respiratory distress syndrome

ARNi: angiotensin receptor–neprilysin inhibitors

ARB: angiotensin receptor blocker

BP: blood pressure

cAMP: cyclic AMP

CoV: coronavirus

COVID-19: coronavirus disease 2019

COX: cyclooxygenase

DRI: direct renin inhibitor

ECM: extracellular matrix

GFR: glomerular filtration rate

GI: gastrointestinal

GPCR: G protein-coupled receptor

GRK: G protein-coupled receptor kinases

HFrEF: heart failure with reduced ejection fraction

IRAP: insulin-regulated aminopeptidase

JG: juxtaglomerular

LDL: low-density lipoprotein

MD: macula densa

MI: myocardial infarction

MRGPRD: Mas-related G protein–coupled receptor D

NE: norepinephrine

NO: nitric oxide

NOS: nitric oxide synthase

NSAID: nonsteroidal anti-inflammatory drug

PAI-1: plasminogen activator inhibitor type 1

PG: prostaglandin

PI3K: phosphoinositide 3-kinase

PL: phospholipase

PRA: plasma renin activity

PRC: plasma renin concentration

(pro)renin: renin and prorenin

PRR: (pro)renin receptor

RAS: renin-angiotensin system

RBF: renal blood flow

ROS: reactive O2 species

SARS: severe acute respiratory syndrome

TGF: transforming growth factor

TPR: total peripheral resistance


The renin-angiotensin system (RAS) participates in the pathophysiology of numerous clinical disorders, including diabetic nephropathy, hypertension, congestive heart failure, and myocardial infarction (MI). This role has led to extensive study of the RAS and development of multiple ways to inhibit its actions. This chapter discusses the physiology, biochemistry, and cellular and molecular biology of classical and novel RAS components and pathways. The chapter also discusses the pharmacology and clinical utility of drugs that inhibit the RAS. Therapeutic applications of drugs covered in this chapter are also discussed in Chapters 31, 32, 33. The RAS is sometimes identified as the renin-angiotensin-aldosterone system. Aldosterone, a mineralocorticoid, is discussed in Chapter 50.


In 1898, Tiegerstedt and Bergman found that saline extracts of the kidney (ren-) contained a pressor substance that they named renin. In 1934, Goldblatt and colleagues found that renal artery constriction produced persistent hypertension in dogs. In 1940, Braun-Menéndez and colleagues in Argentina and Page and Helmer in the U.S. reported that renin was an enzyme that acted on a plasma protein substrate to catalyze the formation of a pressor peptide, which the Argentinian investigators named hypertensin and Page and Helman named angiotonin. This peptide was ultimately renamed angiotensin, and its plasma substrate was called angiotensinogen.

In the 1950s, two forms of angiotensin (Ang) were identified: a decapeptide (AngI) and an octapeptide (AngII) formed by the cleavage of AngI by angiotensin-converting enzyme (ACE), a zinc metalloproteinase discovered by Skeggs in 1956. AngII was the more active form; its synthesis by Schwyzer and Bumpus in 1957 made it available for study. Later research showed that the kidneys are an important site of aldosterone action; angiotensin stimulates its production in humans, and renin secretion increases with depletion of Na+. Thus, the RAS became recognized as a mechanism that stimulates aldosterone synthesis and secretion and an important ...

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