Page 321 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 17 Vasoactive Peptides 307

the physiologic significance of this effect is not clear, since it is Other Effects
unlikely that kinins cross the blood-brain barrier. (Note, however,
that bradykinin can increase the permeability of the blood-brain There is evidence that bradykinin may play a beneficial, protective
barrier to some other substances.) Kinins have no consistent effect role in certain cardiovascular diseases and ischemic stroke-induced
on sympathetic or parasympathetic nerve endings. brain injury. On the other hand, it has been implicated in cancer
The arteriolar dilation produced by kinins causes an increase in and some central nervous system diseases.
pressure and flow in the capillary bed, thus favoring efflux of fluid
from blood to tissues. This effect may be facilitated by increased KININ RECEPTORS & MECHANISMS OF
capillary permeability resulting from contraction of endothelial
cells and widening of intercellular junctions, and by increased ACTION
venous pressure secondary to constriction of veins. As a result of
these changes, water and solutes pass from the blood to the extra- The biologic actions of kinins are mediated by specific receptors
cellular fluid, lymph flow increases, and edema may result. located on the membranes of the target tissues. Two types of kinin
The role that endogenous kinins play in the regulation of receptors, termed B and B , have been defined based on the rank
1
2
blood pressure is not clear. They do not appear to participate in orders of agonist potencies; both are G protein-coupled receptors.
the control of blood pressure under resting conditions but may (Note that B here stands for bradykinin, not for β adrenoceptor.)
play a role in postexercise hypotension. Bradykinin displays the highest affinity in most B receptor
2
systems, followed by Lys-bradykinin. One exception is the B
2
Effects on Endocrine & Exocrine Glands receptor that mediates contraction of venous smooth muscle; this
appears to be more sensitive to Lys-bradykinin. Recent evidence
As noted earlier, prekallikreins and kallikreins are present in suggests the existence of two B -receptor subtypes, which have
2
several glands, including the pancreas, kidney, intestine, salivary been termed B and B .
2A
2B
glands, and sweat glands, and they can be released into the B receptors appear to have a very limited distribution in
1
secretory fluids of these glands. The function of the enzymes mammalian tissues and have few known functional roles. Studies
in these tissues is not known. Since kinins have such marked with knockout mice that lack functional B receptors suggest that
1
effects on smooth muscle, they may modulate the tone of sali- these receptors participate in the inflammatory response and may
vary and pancreatic ducts, help regulate gastrointestinal motility, also be important in long-lasting kinin effects such as collagen
and act as local modulators of blood flow. Kinins also influence synthesis and cell multiplication. By contrast, B receptors have
2
the transepithelial transport of water, electrolytes, glucose, and a widespread distribution that is consistent with the multitude of
amino acids, and may regulate the transport of these substances biologic effects that are mediated by this receptor type. Agonist
in the gastrointestinal tract and kidney. Finally, kallikreins may binding to B receptors sets in motion multiple signal transduc-
2
play a role in the physiologic activation of certain prohormones, tion events, including calcium mobilization, chloride transport,
including proinsulin and prorenin. formation of nitric oxide, and activation of phospholipase C,
phospholipase A , and adenylyl cyclase.
2
Role in Inflammation & Pain
Bradykinin has long been known to produce the four classic DRUGS AFFECTING THE KALLIKREIN-
symptoms of inflammation—redness, local heat, swelling, and
pain. Kinins are rapidly generated after tissue injury and play a KININ SYSTEM
pivotal role in the development and maintenance of these inflam-
matory processes. Drugs that modify the activity of the kallikrein-kinin system are
Kinins are potent pain-producing substances when applied to a available. Considerable effort has been directed toward develop-
blister base or injected intradermally. They elicit pain by stimulat- ing kinin receptor antagonists, since such drugs have considerable
ing nociceptive afferents in the skin and viscera. therapeutic potential as anti-inflammatory and antinociceptive
2
agents. Competitive antagonists of both B 1 and B receptors are
available for research use. Examples of B receptor antagonists
1
Role in Hereditary Angioedema are the peptides [Leu -des-Arg ]bradykinin and Lys[Leu -des-Arg ]
8
8
9
9
Hereditary angioedema is a rare autosomal dominant disorder that bradykinin. The first B receptor antagonists to be discovered
2
results from deficiency or dysfunction of the C1 esterase inhibi- were also peptide derivatives of bradykinin. These first-generation
tor (C1-INH), a major inhibitor of proteases of the complement, antagonists were used extensively in animal studies of kinin recep-
coagulation, and kallikrein-kinin systems. C1-INH deficiency tor pharmacology. However, their half-life is short, and they are
results in activation of kallikrein and increased formation of almost inactive on the human B receptor.
2
bradykinin, which by increasing vascular permeability and other Icatibant is a second-generation B receptor antagonist. It is a
2
actions, causes recurrent episodes of angioedema of the airways, decapeptide with an affinity for the B receptor similar to that of
2
gastrointestinal tract, extremities, and genitalia. Hereditary angio- bradykinin and is absorbed rapidly after subcutaneous administra-
edema can be treated with drugs that inhibit the formation or tion. Icatibant has been shown to be effective in the treatment of
actions of bradykinin (see below). hereditary angioedema. It may also be useful in other conditions