Inhibitor SourceBook™ Second Edition

Nitric Oxide/Oxidative Stress
Guanylate Cyclase (GC) Inhibitors
Guanylyl cyclase (GC) catalyzes the formation of the
second messenger cyclic GMP (cGMP) from GTP and
exists in both the soluble and particulate fractions. The
soluble enzyme can be regulated by free radicals and
nitrovasodialators, whereas the particulate enzyme can
be regulated by various peptides. cGMP signaling is
mediated by cGMP-activated protein kinases, the cGMPregulated
phosphodiesterases and the cGMP-gated ion
channels. The action of cGMP is terminated by the action
of cGMP-degrading phosphodiesterases. GC is present
either as soluble (sGC) or as membrane-bound enzyme
linked to a receptor. sGC is activated by another second
messenger, nitric oxide (NO). Membrane-bound GC, on
the other hand, is activated by hormones. The prosthetic
heme group of sGC acts as the NO sensor, and binding of
NO induces conformational changes leading to an up to
200-fold activation of the enzyme. The organic nitrates
commonly used in the therapy of coronary heart disease
exert their effects via stimulation of this enzyme. Two
isoforms of the NO-sensitive heterodimeric enzyme have
been identified, the ubiquitous a1b1 isoform and the less
broadly distributed a2b1 isoform. These two forms differ
in their subcellular distribution.
Membrane-bound GCs are receptor-linked enzymes with
one membrane-spanning region. Although all of these
GCs share a conserved intracellular catalytic domain,
they differ in their extracellular ligand-binding domains
and are activated by different peptide hormones.
Guanylate Cyclase Inhibitors
The guanylyl cyclase A (GC-A) isoform acts as the
receptor for the natriuretic peptides, ANP and BNP,
and hormones that are involved in the regulation of
blood pressure as well as in the water and electrolyte
household. GC-B is mainly found in the vascular
endothelium and is thought to participate in smooth
muscle relaxation. It displays the highest affinity for the
natriuretic peptide of the C-type (CNP). GC-C is reported
to bind the peptide hormone guanylin found in the
intestine, where it is involved in salt and water balance.
GC-C is stimulated by the heat-stable enterotoxin
produced by E. coli.
References:
Friebe, A., and Koesling, D. 2003. Cir. Res. 93, 96.
Denninger, J.W., and Marletta M.A. 999. Biochim. Biophys. Acta 1411, 334.
Russwurm, M., and Koesling, D. 2002. Mol. Cell Biochem. 230, 59.
Koesling, D., and Friebe, A. 999. Rev. Physiol. Biochem. Pharmacol. 135, 35.
More online... www.calbiochem.com/inhibitors/GCI
Product Cat. No. Comments Size Price
LY 83583 440205 (6-Anilino-5,8-quinolinequinone)
A cell-permeable, competitive inhibitor of soluble guanylate cyclase
(IC 50 = 2 mM). Lowers the production of cGMP levels in a wide range of
tissues by blocking intracellular Ca 2+ release, with negligible effect on
cAMP levels. Inhibits nitric oxide-induced smooth muscle relaxation.
Methylene Blue 457250 [3,7-bis(Dimethylamino)phenothiazin-5-ium Chloride]
An inhibitor of soluble guanylate cyclase that acts as an organic spintrap.
Forms stable adducts with oxygen free radicals in solution.
NS 2028 492030 [4H-8-Bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one]
A potent, specific, and irreversible inhibitor of soluble guanylyl cyclase
(IC 50 = 30 nM for basal and 200 nM for NO-stimulated enzyme activity;
IC 50 = 7 nM for S-nitrosoglutathione-enhanced soluble guanylyl
cyclase activity in homogenates of mouse cerebellum).
ODQ 495320 (1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one)
A cell-permeable, potent and selective inhibitor of nitric oxide (NO)sensitive
soluble guanylyl cyclase (IC 50 = 20 nM). In cerebellum slices,
ODQ is shown to reversibly inhibit the NO-dependent cGMP response to
glutamate receptor agonists without affecting NOS activity.
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