DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

70 of cyclic GMP are also increased by activation of the
transmembrane BNP receptor (BNP-R), whose guanylate
cyclase activity is increased when BNP binds. BNP
is released from cardiac muscle in response to increased
filling pressures. The contractile state of the arteriole is
thus regulated acutely by a variety of physiological
mediators working through a number of signal transduction
pathways. In a patient with hypertension, SMC
tone in an arteriole may be elevated above normal due
to one or more changes in endogenous ligands or signaling
pathways. These include elevated circulating
concentrations of AngII, increased activity of the sympathetic
nervous system, and decreased NO production
by endothelial cells. Pharmacotherapy might include
the use of one or more drugs to block or counteract the
acute pathological changes in blood pressure as well as
to prevent long-term changes in vessel wall structure
due to stimulation of SMC proliferation and alterations
in SMC gene expression.
Drugs commonly used to treat hypertension include
β 1
antagonists to reduce secretion of renin (the rate-limiting
first step in AngII synthesis), a direct renin inhibitor
(aliskiren) to block the rate-limiting step in AngII production,
angiotensin-converting enzyme (ACE) inhibitors
(e.g., enalapril) to reduce the concentrations of circulating
AngII, AT 1
receptor blockers (e.g., losartan) to block
AngII binding to AT 1
receptors on SMCs, α 1
adrenergic
blockers to block NE binding to SMCs, sodium nitroprusside
to increase the quantities of NO produced, or a Ca 2+
channel blocker (e.g., nifedipine) to block Ca 2+ entry into
SMCs. β 1
antagonists would also block the baroreceptor
reflex increase in heart rate and blood pressure elicited by
a drop in blood pressure induced by the therapy. ACE
inhibitors also inhibit the degradation of a vasodilating
peptide, bradykinin (Chapter 26). Thus, the choices and
mechanisms are complex, and the appropriate therapy in
a given patient depends on many considerations, including
the diagnosed causes of hypertension in the patient,
possible side effects of the drug, efficacy in a given
patient, and cost.
Some of the mediators that cause coronary vasoconstriction
and hypertension, such as AngII and NE,
can also have chronic effects on the vascular wall
through mechanisms involving alterations in SMC gene
expression. These effects on gene expression can alter
the biochemical and physiological properties of the
SMC by stimulating hypertrophy, proliferation, and
synthesis of proteins that remodel the extracellular
matrix. The pathways involved in these chronic effects
include many of the same pathways used by growth factor
receptors, such as PDGF which can also be involved
SECTION I
GENERAL PRINCIPLES
in the vascular wall remodeling that occurs in neointimal
hyperplasia associated with coronary artery
restenosis. One of the beneficial effects of using ACE
inhibitors and AT 1
receptor blockers in the treatment of
hypertension is their ability to prevent the long-term
pathological remodeling of the vascular wall that results
from chronic activation of AT 1
receptors by AngII.
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