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

Aldosterone
Xanthine
oxldase
Cholesterol
Synthesis
Angiotensin II
Angiotensin I
807
MR antagonist
G6PD
XO-I
Mevalonate
pathway
Statin
ARB
ACE
inhibitor
O 2 O 2
– H 2 O 2
eNOS ONOO –
NO
Endothelial cell
NO
Impaired vascular reactivity
cGMP
sGC
Vascular smooth muscle cell
O 2
–
NO-insensitive
sGC
BAY58-2667
Figure 28–7. Preserving normal vascular reactivity is a target of evolving priority in the treatment of patients with chronic congestive
heart failure. Increased levels of reactive oxygen species (ROS), including superoxide (O 2−
) and hydrogen peroxide (H 2
O 2
) that are generated
in both endothelial cells (EC) and vascular smooth muscle cells (VSMC) impair key cell signaling pathways necessary for normal
vascular function. Specifically, hyperaldosterone- induced decreased antioxidant enzyme activity in EC, such as glucose-6-phosphate
dehydrogenase (G6PD), results in increased ROS formation (Leopold et al., 2007). Likewise, increased xanthine oxidase (XO) activity,
AT 1
receptor activation, and upregulation of signaling pathways associated with cholesterol metabolism create a cellular environment
favorable for ROS formation. In EC, elevated levels of ROS impair vascular reactivity, in part, by decreasing endothelial nitric
oxide synthase (eNOS) activity and increasing peroxynitrite (ONOO − ) formation to decrease bioavailable nitric oxide (NO) levels. In
VSMC, oxidant stress decreases NO levels and impairs soluble guanylyl cyclase (sGC) sensitivity to NO, thereby decreasing cyclic GMP
levels that are necessary for normal VSMC relaxation. Mineralacorticoid (MR)-receptor antagonists, XO inhibitors (XO- I), HMGcoA–reductase
inhibitors (statin), AT 1
receptor blockers (ARBs), and angiotensin- converting enzyme (ACE) inhibitors block various
cellular reactions associated with elevated levels of ROS and impaired vascular reactivity. The BAY compounds (e.g., BAY 58-2667;
figure inset), in turn, are a novel group of direct sGC activators that increase enzyme activity despite oxidant stress- induced sGC modifications
that convert the enzyme to an NO- insensitive state. XO-I, xanthine oxidase inhibitor.
NO
sGC
cGMP
CHAPTER 28
PHARMACOTHERAPY OF CONGESTIVE HEART FAILURE
Xanthine Oxidase and Vascular Dysfunction. Xanthine
oxidase (XO) is necessary for normal purine metabolism
and catalyzes the oxidation of hypoxanthine to
xanthine and xanthine to uric acid in a reaction that generates
superoxide. Elevated levels of uric acid are associated
with clinically evident CHF (Hare et al., 2008).
For example, epidemiologic data support a positive,
graded association between impaired exercise capacity
and circulating uric acid levels (Doehner et al., 2001).
Although the myocardium is rich in XO, vascular
endothelial cells also contain high concentrations of
XO, an observation that ultimately lead to the hypothesis
that increased XO- generated superoxide impairs
vascular reactivity in CHF patients (Hare et al., 2008).
Early studies suggested allopurinol (300 mg/day), an XO
inhibitor, effectively decreases generation of free oxygen radicals
and improves peripheral arterial vasodilation and blood flow in hyperuricemic
patients with mild- to- moderate CHF from systolic dysfunction
(Doehner et al., 2002). Interestingly, probenecid, which decreases
circulating urate levels by enhancing its elimination rather than by
inhibiting XO activity, has not been shown to influence vascular reactivity.
In patients with advanced CHF, allopurinol- induced serum uric