ACE: angiotensin-converting enzyme
ACEI: angiotensin-converting enzyme inhibitor
ACTH: corticotropin (formerly adrenocorticotropic hormone)
ARB: angiotensin receptor blocker
ATR: angiotensin receptor
BP: blood pressure
cAMP: cyclic AMP
CNS: central nervous system
DRI: direct renin inhibitor
FDA: Food and Drug Administration
GFR: glomerular filtration rate
GPCR: G protein–coupled receptor
LDL: low-density lipoprotein
MrgD: Mas-related G protein–coupled receptor D
NO: nitric oxide
NOS: nitric oxide synthase
NSAID: nonsteroidal anti-inflammatory drug
PAI-1: plasminogen activator inhibitor type 1
PI3K: phosphoinositide 3-kinase
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 RENIN-ANGIOTENSIN SYSTEM
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 27–29.
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 ...