Ganong's Review of Medical Physiology, 23rd Edition

566 SECTION VICardiovascular Physiology

disease), apparently because the cells that normally form the
myenteric plexus fail to migrate to the distal colon. In addition,
endothelins play a role in closing the ductus arteriosus at birth.

SYSTEMIC REGULATION

BY HORMONES

Many circulating hormones affect the vascular system. The
vasodilator hormones include kinins, VIP, and ANP. Circu-
lating vasoconstrictor hormones include vasopressin, norepi-
nephrine, epinephrine, and angiotensin II.

KININS

Two related vasodilator peptides called kinins are found in the
body. One is the nonapeptide bradykinin, and the other is the
decapeptide lysylbradykinin, also known as kallidin (Figure
33–11). Lysylbradykinin can be converted to bradykinin by
aminopeptidase. Both peptides are metabolized to inactive
fragments by kininase I, a carboxypeptidase that removes the
carboxyl terminal arginine (Arg). In addition, the dipeptidyl-
carboxypeptidase kininase II inactivates bradykinin and ly-
sylbradykinin by removing phenylalanine-arginine (Phe-Arg)
from the carboxyl terminal. Kininase II is the same enzyme as
angiotensin-converting enzyme (see Chapter 39), which re-
moves histidine-leucine (His-Leu) from the carboxyl terminal
end of angiotensin I.
Bradykinin and lysylbradykinin are formed from two pre-
cursor proteins: high-molecular-weight kininogen and low-
molecular-weight kininogen (Figure 33–12). They are
formed by alternative splicing of a single gene located on
chromosome 3. Proteases called kallikreins release the pep-
tides from their precursors. They are produced in humans by
a family of three genes located on chromosome 19. There are
two types of kallikreins: plasma kallikrein, which circulates
in an inactive form, and tissue kallikrein, which appears to
be located primarily on the apical membranes of cells con-
cerned with transcellular electrolyte transport. Tissue kal-
likrein is found in many tissues, including sweat and salivary
glands, the pancreas, the prostate, the intestine, and the kid-
neys. Tissue kallikrein acts on high-molecular-weight kinino-
gen to form bradykinin and low-molecular-weight kininogen

to form lysylbradykinin. When activated, plasma kallikrein

acts on high-molecular-weight kininogen to form bradykinin.

Inactive plasma kallikrein (prekallikrein) is converted to

the active form, kallikrein, by active factor XII, the factor that

initiates the intrinsic blood clotting cascade. Kallikrein also

activates factor XII in a positive feedback loop, and high-

molecular-weight kininogen has a factor XII-activating action

(see Figure 32–13).

The actions of both kinins resemble those of histamine.

They are primarily tissue hormones, although small amounts

are also found in the circulating blood. They cause contrac-

tion of visceral smooth muscle, but they relax vascular

smooth muscle via NO, lowering blood pressure. They also

increase capillary permeability, attract leukocytes, and cause

pain upon injection under the skin. They are formed during

active secretion in sweat glands, salivary glands, and the exo-

crine portion of the pancreas, and they are probably responsi-

ble for the increase in blood flow when these tissues are

actively secreting their products.

Two bradykinin receptors, B 1 and B 2 , have been identified.

Their amino acid residues are 36% identical, and both are

coupled to G proteins. The B 1 receptor may mediate the pain-

producing effects of the kinins, but little is known about its

distribution and function. The B 2 receptor has strong homol-

ogy to the H 2 receptor and is found in many different tissues.

NATRIURETIC HORMONES

There is a family of natriuretic peptides involved in vascular
regulation, including atrial natriuretic peptide (ANP) secreted
by the heart, brain natriuretic peptide (BNP), and C-type
natriuretic peptide (CNP). They are released in response to
hypervolemia. ANP and BNP circulate, whereas CNP acts pre-
dominantly in a paracrine fashion. In general, these peptides
antagonize the action of various vasoconstrictor agents and
lower blood pressure. ANP and BNP also serve to coordinate
the control of vascular tone with fluid and electrolyte homeo-
FIGURE 33–11 Kinins. Lysylbradykinin (top) can be converted stasis via actions on the kidney.
to bradykinin (bottom) by aminopeptidase. The peptides are inacti-
vated by kininase I (KI) or kininase II (KII) at the sites indicated by the
short arrows.

Lys

Aminopeptidase

KII KI

KII KI

ProGlyPheSerProPheArg

ProGlyPheSerProPhe

Pro

Pro

Arg

ArgArg Arg

FIGURE 33–12 Formation of kinins from high-molecular-

weight (HMW) and low-molecular-weight (LMW) kininogens.

XII XIIa Clotting

Plasma

kallikrein Prekallikrein

HMW kininogen Bradykinin

LMW kininogen

Tissue

kallikrein

Lysylbradykinin