Page 320 - Basic _ Clinical Pharmacology ( PDFDrive )

306 SECTION IV Drugs with Important Actions on Smooth Muscle

■ KININS
Activated blood
BIOSYNTHESIS OF KININS coagulation
factor XII
+
Kinins are potent vasodilator peptides formed enzymatically by
the action of enzymes known as kallikreins acting on protein sub- Plasma Plasma kallikrein
strates called kininogens. The kallikrein-kinin system has several prekallikrein
features in common with the renin-angiotensin system. +
HMW kininogen Bradykinin
Kallikreins
Kininases Inactive
Kallikreins are serine proteases present in plasma (plasma Aminopeptidases I and II fragments
kallikrein) and in several organs (tissue kallikrein), including the
kidneys, pancreas, intestine, sweat glands, and salivary glands. The LMW kininogen Kallidin
two groups are secreted as zymogens and are activated by proteo- +
lytic cleavage. Plasma prekallikrein is activated by activated blood
coagulation factor XII (FXIIa). The two groups differ in their Tissue kallikreins
gene structure, molecular weight, substrate specificity, and kinin
produced. Kallikreins can convert prorenin to active renin, but the
physiologic significance of this action is not known. Tissue prekallikreins

Kininogens
FIGURE 17–4 The kallikrein-kinin system. Kininase II is identical
Kininogens—the substrates for kallikreins and precursors of to converting enzyme peptidyl dipeptidase (ACE).
kinins—are present in plasma, lymph, and interstitial fluid. Two
kininogens are present in plasma: a low-molecular-weight form
(LMW kininogen) and a high-molecular-weight form (HMW PHYSIOLOGIC & PATHOLOGIC EFFECTS
kininogen). The two forms result from differential splicing of the OF KININS
kininogen gene to generate proteins that differ at the C-terminus.
About 15–20% of the total plasma kininogen is in the HMW Effects on the Cardiovascular System
form. It is thought that LMW kininogen crosses capillary walls
and serves as the substrate for tissue kallikreins, whereas HMW Kinins produce marked arteriolar dilation in several vascular beds,
kininogen is confined to the bloodstream and serves as the including the heart, skeletal muscle, kidney, liver, and intestine.
substrate for plasma kallikrein. In this respect, kinins are approximately 10 times more potent on
a molar basis than histamine. The vasodilation may result from a
direct inhibitory effect of kinins on arteriolar smooth muscle or
FORMATION & METABOLISM OF KININS may be mediated by the release of nitric oxide or vasodilator pros-
taglandins such as PGE and PGI . In contrast, the predominant
2
2
The pathway for the formation and metabolism of kinins is shown effect of kinins on veins is contraction; again, this may result from
in Figure 17–4. The two major kinins in humans are bradykinin direct stimulation of venous smooth muscle or from the release of
and Lys-bradykinin or kallidin. Bradykinin is released from venoconstrictor prostaglandins such as PGF . Kinins also pro-
2α
HMW kininogen by plasma kallikrein, whereas kallidin is released duce contraction of most visceral smooth muscle.
from LMW kininogen by tissue kallikrein. Kallidin can be con- When injected intravenously, kinins produce a rapid but brief
verted to bradykinin by an arginine aminopeptidase. The two kinins fall in blood pressure that is due to their arteriolar vasodilator
are present in plasma and urine. Bradykinin is the predominant action. Intravenous infusions of the peptide fail to produce a
kinin in plasma, whereas Lys-bradykinin is the major urinary form. sustained decrease in blood pressure; prolonged hypotension can
Kinins are metabolized rapidly (half-life < 15 seconds) by non- only be produced by progressively increasing the rate of infusion.
specific exopeptidases or endopeptidases, commonly referred to as The rapid reversibility of the hypotensive response to kinins is
kininases. Two plasma kininases have been characterized. Kininase I, due primarily to reflex increases in heart rate, myocardial contrac-
apparently synthesized in the liver, is a carboxypeptidase that tility, and cardiac output. In some species, bradykinin produces
releases the carboxyl terminal arginine residue. Kininase II is pres- a biphasic change in blood pressure—an initial hypotensive
ent in plasma and vascular endothelial cells throughout the body. response followed by an increase above the preinjection level. The
It is identical to angiotensin-converting enzyme (ACE, peptidyl increase in blood pressure may be due to a reflex activation of the
dipeptidase), discussed above. Kininase II inactivates kinins by sympathetic nervous system, but under some conditions, bradyki-
cleaving the carboxyl terminal dipeptide phenylalanyl-arginine. nin can directly release catecholamines from the adrenal medulla
Like angiotensin I, bradykinin is almost completely hydrolyzed and stimulate sympathetic ganglia. Bradykinin also increases
during a single passage through the pulmonary vascular bed. blood pressure when injected into the central nervous system, but