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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

ARB: angiotensin receptor blocker

ATR: angiotensin receptor

BP: blood pressure

cAMP: cyclic AMP

CNS: central nervous system

COX: cyclooxygenase

DRI: direct renin inhibitor

FDA: Food and Drug Administration

GFR: glomerular filtration rate

GI: gastrointestinal

GPCR: G protein–coupled receptor

HCTZ: hydrochlorothiazide

JG: juxtaglomerular

LDL: low-density lipoprotein

MrgD: 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

PCP: prolylcarboxylpeptidase

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

TGF: transforming growth factor

TPR: total peripheral resistance




The RAS participates in the pathophysiology of hypertension, congestive heart failure, myocardial infarction, and diabetic nephropathy. This realization has led to a thorough exploration of the RAS and the development of new approaches for inhibiting its actions. This chapter discusses the physiology, biochemistry, and cellular and molecular biology of the classical RAS and novel RAS components and pathways. The chapter also discusses the basic pharmacology of drugs that interrupt the RAS, and the clinical utility of inhibitors of the RAS. Therapeutic applications of drugs covered in this chapter are also discussed in Chapters 2729.




In 1898, Tiegerstedt and Bergman found that crude saline extracts of the kidney contained a pressor substance that they named renin. In 1934, Goldblatt and his colleagues demonstrated that constriction of the renal arteries produced persistent hypertension in dogs. In 1940, Braun-Menéndez and his 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 the actual pressor material, a peptide, that was named hypertensin by the former group and angiotonin by the latter. Ultimately, the pressor substance was renamed angiotensin, and the plasma substrate was called angiotensinogen.


In the mid-1950s, two forms of angiotensin were recognized, a decapeptide (AngI) and an octapeptide (AngII) formed by proteolytic cleavage of AngI by an enzyme termed ACE. The octapeptide was the more active form, and its synthesis in 1957 by Schwyzer and by Bumpus made the material available for intensive study. Later research showed that the kidneys are an important site of aldosterone action, and that angiotensin potently stimulates the production of aldosterone in humans. Moreover, renin secretion increased with depletion of Na+. Thus, the RAS became recognized as a mechanism to stimulate aldosterone synthesis and secretion and an important homeostatic mechanism in the regulation of blood pressure and electrolyte composition.


In the early 1970s, polypeptides were discovered that either inhibited the formation of AngII or blocked ...

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