Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 39

Regulation of Extracellular Fluid Composition & Volume 671

patients treated with ACE inhibitors (see Clinical Box 39–2).
Most of the converting enzyme that forms angiotensin II in
the circulation is located in endothelial cells. Much of the con-
version occurs as the blood passes through the lungs, but con-
version also occurs in many other parts of the body.
ACE is an ectoenzyme that exists in two forms: a
somatic
form found throughout the body and a
germinal
form found
solely in postmeiotic spermatogenic cells and spermatozoa
(see Chapter 25). Both ACEs have a single transmembrane
domain and a short cytoplasmic tail. However, somatic ACE
is a 170-kDa protein with two homologous extracellular
domains, each containing an active site (Figure 39–8). Germi-
nal ACE is a 90-kDa protein that has only one extracellular
domain and active site. Both enzymes are formed from a sin-

gle gene. However, the gene has two different promoters, pro-

ducing two different mRNAs. In male mice in which the ACE

gene has been knocked out, blood pressure is lower than nor-

mal, but in females it is normal. In addition, fertility is

reduced in males but not in females.

METABOLISM OF ANGIOTENSIN II

Angiotensin II is metabolized rapidly; its half-life in the circu-

lation in humans is 1 to 2 min. It is metabolized by various

peptidases. An aminopeptidase removes the aspartic acid

(Asp) residue from the amino terminal of the peptide (Figure

39–7). The resulting heptapeptide has physiologic activity and

is sometimes called

angiotensin III.

Removal of a second ami-

no terminal residue from angiotensin III produces the

hexapeptide sometimes called angiotensin IV, which is also

said to have some activity. Most, if not all, of the other peptide

fragments that are formed are inactive. In addition, ami-

nopeptidase can act on angiotensin I to produce (des-Asp

1

)

angiotensin I, and this compound can be converted directly to

angiotensin III by the action of ACE. Angiotensin-metaboliz-

ing activity is found in red blood cells and many tissues. In ad-

dition, angiotensin II appears to be removed from the

circulation by some sort of trapping mechanism in the vascu-

lar beds of tissues other than the lungs.

Renin is usually measured by incubating the sample to be

assayed and measuring by immunoassay the amount of angio-

tensin I generated. This measures the

plasma renin activity

(PRA)

of the sample. Deficiency of angiotensinogen as well as

renin can cause low PRA values, and to avoid this problem,

exogenous angiotensinogen is often added, so that

plasma

renin concentration (PRC)

rather than PRA is measured. The

normal PRA in supine subjects eating a normal amount of

CLINICAL BOX 39–2

Pharmacologic Manipulation

of the Renin–Angiotensin System

It is now possible to inhibit the secretion or the effects of

renin in a variety of ways. Inhibitors of prostaglandin synthe-

sis such as

indomethacin

and

β

-adrenergic blocking drugs

such as

propranolol

reduce renin secretion. The peptide

pepstatin

and newly developed renin inhibitors such as

enalkiren

prevent renin from generating angiotensin I. An-

giotensin-converting enzyme inhibitors (ACE inhibitors) such

as

captopril

and

enalapril

prevent conversion of angioten-

sin I to angiotensin II.

Saralasin

and several other analogs of

angiotensin II are competitive inhibitors of the action of an-

giotensin II on both AT

1

and AT

2

receptors.

Losartan

(DuP-

753) selectively blocks AT

1

receptors, and PD-123177 and

several other drugs selectively block AT

2

receptors.

FIGURE 39–7
Structure of the amino terminal end of angiotensinogen and angiotensins I, II, and III in humans.
R, remainder of pro-
tein. After removal of a 24-amino-acid leader sequence, angiotensinogen contains 453 amino acid residues. The structure of angiotensin II in dogs,
rats, and many other mammals is the same as that in humans. Bovine and ovine angiotensin II have valine instead of isoleucine at position 5.

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

Renin splits this bond

Angiotensinogen

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

Aminopeptidase splits this bond

Angiotensin II

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

Angiotensin-converting enzyme splits this bond

Angiotensin I

Angiotensin III