Page 318 - Basic _ Clinical Pharmacology ( PDFDrive )

304 SECTION IV Drugs with Important Actions on Smooth Muscle

Central Nervous System Up-regulation occurs in some disease states including heart failure
and myocardial infarction. In animal studies, activation of AT
In addition to its central effects on blood pressure, ANG II acts receptors has been reported to produce anti-inflammatory, anti- 2
on the central nervous system to stimulate drinking (dipsogenic proliferative, antihypertrophic, antifibrotic, proapoptotic, and
effect) and increase the secretion of vasopressin and adrenocorti- vasodilatory effects. These effects could help to counterbalance the
cotropic hormone (ACTH). The physiologic significance of these detrimental effects of excessive ANG II mediated via AT recep-
effects is not known. 1
tors, and thereby protect against the progression of organ damage.
Cell Growth Prorenin Receptors

ANG II is mitogenic for vascular and cardiac muscle cells and
may contribute to the development of cardiac hypertrophy. It also For many years, prorenin was considered to be an inactive precursor
exerts a variety of important effects on the vascular endothelium. of renin, with no receptor or function of its own, despite its high levels
Indeed, overactivity of the renin-angiotensin system has been in the circulation. However, a novel receptor has been described. This
implicated as one of the most significant factors in the develop- receptor binds both renin and prorenin and is therefore referred to as
ment of hypertensive vascular disease. Considerable evidence the (pro)renin receptor. It is a ubiquitously expressed 350-amino acid
now indicates that inhibition of the renin-angiotensin system protein with a single transmembrane domain that binds prorenin to
(see below) slows or prevents morphologic changes (remodeling) a large N-terminal extracellular domain.
following myocardial infarction that would otherwise lead to heart When prorenin binds to the (pro)renin receptor, the prorenin
failure. The stimulation of vascular and cardiac growth by ANG II undergoes a conformational change and becomes enzymatically
is mediated by other pathways, probably receptor and nonrecep- active without cleavage of the prosegment. This is referred to as
tor tyrosine kinases such as the Janus tyrosine kinase Jak2, and by nonproteolytic to distinguish it from the proteolytic activation
increased transcription of specific genes (see Chapter 2). with prosegment removal that occurs in the kidney. Binding of
prorenin to the receptor activates intracellular signaling pathways
that differ depending on the cell type. For example, in mesangial
ANGIOTENSIN RECEPTORS & and vascular smooth muscle cells, prorenin binding activates MAP
kinases and expression of profibrotic molecules. Thus, elevated
MECHANISM OF ACTION prorenin levels (as occur, for example, in diabetes mellitus) might
have adverse effects via angiotensin-dependent and -independent
Angiotensin Receptors pathways (Figure 17–3).

ANG II receptors are widely distributed in the body. Like the Renin inhibitors such as aliskiren (see below) do not block
receptors for other peptide hormones, ANG II receptors are G (pro)renin-induced signaling. However, a synthetic peptide named
protein-coupled and located on the plasma membrane of target handle region peptide (HRP), which consists of the amino acid
cells, and this permits rapid onset of the various actions of ANG sequence corresponding to the “handle” region of the prorenin
II. Two distinct subtypes of ANG II receptors, termed AT and prosegment, has been synthesized and shown to competitively
1
AT , have been identified. ANG II binds equally to both subtypes. inhibit binding of prorenin to the (pro)renin receptor. HRP has
2
The relative proportion of the two subtypes varies from tissue to been reported to have beneficial effects in the kidneys of diabetic
tissue: AT receptors predominate in vascular smooth muscle. rats. A newer putative (pro)renin receptor antagonist, PRO20,
1
Most of the known actions of ANG II are mediated by the AT which corresponds to the first 20 amino acids of the prosegment
1
receptor, a G protein-coupled receptor. Binding of ANG II to of mouse prorenin, has been reported to lower blood pressure in
q
AT receptors in vascular smooth muscle results in activation of an animal model of hypertension.
1
phospholipase C and generation of inositol trisphosphate and Note that the concentration of prorenin required to activate
diacylglycerol (see Chapter 2). These events, which occur within (pro)renin receptors is very high, much higher than that occurring
seconds, result in smooth muscle contraction. under physiologic conditions.
The AT receptor has a structure and affinity for ANG
2
II similar to those of the AT receptor. In contrast, however,
1
stimulation of AT receptors causes vasodilation that may serve INHIBITION OF THE RENIN-
2
to counteract the vasoconstriction resulting from AT receptor ANGIOTENSIN SYSTEM
1
stimulation. AT receptor-induced vasodilation appears to be
2
nitric oxide-dependent and may involve the bradykinin B In view of the importance of the renin-angiotensin system in
2
receptor-nitric oxide-cGMP pathway. AT receptors are present cardiovascular disease, considerable effort has been directed to
2
at high density in all tissues during fetal development, and may developing drugs that inhibit it. A wide variety of agents that
play an important role in regulating cellular differentiation and block the formation or action of ANG II is now available. Some
organ development by virtue of their high abundance in fetal of these drugs block renin release, but most inhibit the enzymatic
mesenchymal tissues. AT expression declines rapidly to an unde- action of renin, inhibit the conversion of ANG I to ANG II
2
tectable level in many tissues after birth, but low levels remain in (ACE inhibitors), or block angiotensin AT receptors (angioten-
1
the heart, adrenal gland, kidney, brain, and reproductive tissues. sin receptor blockers [ARBs]).