Role of Nitric Oxide in Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 61

Acetylcholine

Cardiac myocyte

M 2

sGC

CRC

SERCA

Caveolin-3

GTP

cGMP

L-Arg

SR

NO

+

PKG

nNOS

PDE2 eNOS

Ca L

NO

−
-

L-Arg

cAMP ATP

Ca L

+

PKA

AC

β1

Noradrenaline

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Fig. 3.2 Role of NOS in functions of the cardiac myocyte. Postsynaptically, acetylcholine (Ach)
binds to ACh receptors (M2) on the sinoatrial-node pacemaker cells and, via second messenger
pathways, modulates ion channels to reduce heart rate. NO is generated in the pacemaker cell
following M2-receptor activation via caveolin-3 and eNOS to inhibit flow of Ca 2+ through L-type
Ca channels. When noradrenalin binds to the b1-adrenoceptor, nNOS localized in the sarcoplas-
mic reticulum can regulate Ca 2+ fluxes via SR-Ca 2+ ATPase (SERCA), Ca L and ryanodine-sensitive
Ca 2+ release channels (CRC)] to minimize the effect of excessive sympathetic stimulation.
AC adenylate cyclase, PKA protein kinase A, PKG protein kinase G, PDE2 phosphodiesterase 2,
sGC soluble guanylate cyclase

autonomic control of cardiac rate must be examined. Reflex control of cardiac rate
depends on afferent input from various types of visceral afferent, with baroreceptors
playing the most important role. It has been demonstrated that NO can affect periph-
eral afferent excitability but there are two other sites for NO modulation: the nucleus
tractus solitarius (the brainstem termination site for baroreceptor afferents) and car-
diac autonomic efferents at the level of the heart. At both these sites, there is exten-
sive anatomical evidence to support sophisticated NO-mediated interactions.

NO and Vasodilatation

NO relaxes the smooth muscle in the walls of the arterioles. At each systole, the
endothelial cells that line the blood vessels release a puff of NO. This diffuses into
the underlying smooth muscle cells causing them to relax and thus permit the surge