Page 357 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 19 Nitric Oxide 343

Acetylcholine,
bradykinin
Lumen of blood vessel

Endothelial
Endoplasmic cell
reticulum
Ca 2+ Arginine
CaM eNOS
Ca •CaM NO
2+
Vascular
GTP smooth
Ca 2+ Soluble muscle
- guanylyl
- PKG cGMP cyclase cell
Contraction Phosphodiesterase
GMP

FIGURE 19–2 Regulation of vasorelaxation by endothelial-derived nitric oxide (NO). Endogenous vasodilators, eg, acetylcholine and
2+
bradykinin, cause calcium (Ca ) efflux from the endoplasmic reticulum in the luminal endothelial cells into the cytoplasm. Calcium binds to
calmodulin (CaM), which activates endothelial NO synthase (eNOS), resulting in NO synthesis from l-arginine. NO diffuses into smooth
muscle cells, where it activates soluble guanylyl cyclase and cyclic guanosine monophosphate (cGMP) synthesis from guanosine triphos-
phate (GTP). cGMP binds and activates protein kinase G (PKG), resulting in an overall reduction in calcium influx, and inhibition of calcium-
dependent muscle contraction. PKG can also block other pathways that lead to muscle contraction. cGMP signaling is terminated by
phosphodiesterases, which convert cGMP to GMP.

atheromatous plaques. This effect is due to the inhibitory effect of prevent the action of NO, such as the sGC inhibitor methylene
NO on the expression of adhesion molecules on the endothelial blue. Furthermore, knockout mice lacking a functional iNOS
cell surface. The antiatherogenic effect of NO may also involve gene are more resistant to endotoxin than wild-type mice.
an antioxidant effect, blocking the oxidation of low-density However, despite the ability of NOS inhibitors to ameliorate
lipoproteins and thus preventing or reducing the formation of hypotension in sepsis, there is no overall improvement in sur-
foam cells in the vascular wall. Plaque formation is also reduced vival in patients with gram-negative sepsis treated with NOS
by NO-dependent reduction of endothelial cell permeability to inhibitors. The absence of benefit may reflect the inability of
lipoproteins. The importance of eNOS in cardiovascular disease
is supported by experiments showing increased atherosclerosis in
animals treated with eNOS inhibitors. Atherosclerosis risk factors, TABLE 19–3 Some inhibitors of nitric oxide
such as smoking, hyperlipidemia, diabetes, and hypertension, are synthesis or action.
associated with decreased endothelial NO production, and thus
with a loss of the diverse antiatherogenic effects of NO. Inhibitor Mechanism Comment
ω
N -Monomethyl- Competitive inhibitor, Nonselective NOS
SEPTIC SHOCK l-arginine binds arginine-binding inhibitor
(l-NMMA)
site in NOS
ω
N -Nitro- Competitive inhibitor, Nonselective NOS
Sepsis is a systemic inflammatory response caused by infec- l-arginine methyl binds arginine-binding inhibitor
tion. Endotoxin components from the bacterial wall along with ester (l-NAME) site in NOS
endogenously generated tumor necrosis factor-α and other 7-Nitroindazole Competitive inhibitor, Partially selective for
cytokines induce synthesis of iNOS in macrophages, neutro- binds both tetrahydro- NOS-1 in vivo
phils, and T cells, as well as hepatocytes, smooth muscle cells, biopterin and arginine-
endothelial cells, and fibroblasts. This widespread generation binding sites in NOS
of NO results in exaggerated hypotension, shock, and, in some BBS-2 Inhibits iNOS Also weakly inhibits
cases, death. This hypotension is reduced or reversed by NOS dimerization nNOS and eNOS
inhibitors in humans as well as in animal models (Table 19–3). Hemoglobin NO scavenger
A similar reversal of hypotension is produced by compounds that BBS-2, a pyrimide imidazole; NOS, nitric oxide synthase.