Smooth Myocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 442

effectors of -adrenoceptors signaling that modulates activity of certain ion channel

to initiate a vasodilation. In vascular smooth myocytes, AC6 is the predominant
isozyme involved in the Gs-ACase-cAMP-PKA axis triggered by

β

β -adrenoceptors

( 60% of the response) [ 817 ]. Activated cAMP-dependent protein kinase PKA

phosphorylates many types of K + channels, in particular ATP-sensitive K + channel.
The latter causes the hyperpolarization primed by stimulated

∼

-adrenoceptors.
Isoform AC3, which is involved in signaling primed by PGe2 in vascular smooth
myocytes, has a minor role in

β

β -adrenoceptor signaling; AC5 subtype does not play

a significant role.

Nitric Oxide

Nitric oxide is a vasodilator that inhibits vasoconstrictor influences. Nitric oxide is
produced by vascular endothelial and smooth myocytes, among others.
Nitric oxide synthase catalyzes the conversion of L arginine to NO and L citrulline.
Two major NOS types exist: constitutive (cNOS [NOS1 and NOS3]) and inducible
(iNOS or NOS2).
Calcium-calmodulin-dependent NOS localizes to endothelial cells (constitutive
endothelial eNOS or NOS3) and smooth myocytes. Nitric oxide synthase NOS3 is
a plasmalemmal protein that yields a basal release. The continuous NO production
is enhanced by multiple stimuli. Inducible NOS2 is expressed in endothelial cells in
the presence of cytokines (cytokine-inducible NOS2).
Pro-inflammatory cytokines increase the activity of cyclohydrolase GTP ,therate-
limiting enzyme for tetrahydrobiopterin production, a cofactor for nitric oxide
synthase. In arteriolar smooth myocytes, nitric oxide operates via cGMP and cGMP-
dependent protein kinase-G.
The NO-cGMP-PKG axis influences Ca 2 + signaling. Calcium-induced Ca 2 +
release can indeed be attenuated because [ 818 ]: (1) NO inhibits adenosine diphos-
phoribose cyclase and (2) activated K Ca 1 (BK) channel counteracts KCl-induced
depolarization.
In uterine vascular smooth myocytes, large-conductance, Ca 2 + -activated K +
channel (K Ca 1.1) is activated by the upregulated NO-cGMP pathway to adapt the
uteroplacental blood flow during the last trimester of pregnancy [ 819 ]. In addition,
changes in 1-subunit stoichiometry

modify the functional features of uterine vascular smooth muscle.
Nitric oxide can be produced during the reduction of nitrite by deoxygenated
erythrocytes to cause vasodilation. However, nitrite-induced vasodilation caused by
red blood cells during hypoxemia can rely on release of adenosine triphosphate to
produce vasodilation [ 820 ]. Once liberated, ATP can target endothelial nucleotide
receptors that stimulate endothelial nitric oxide synthase (NOS3).

α -subunit isoform of K Ca 1.1 channels and α : β