Role of Nitric Oxide in Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 62

of blood to pass through easily. The NO/superoxide (O 2− ) balance is also a key
regulator of endothelial function. O 2− levels are elevated in many forms of cardiovas-
cular disease; therefore, decreasing O 2− should improve endothelial function.
Interactions between NO and the sympathetic nerve system, that is, norepinephrine,
are of importance in the regulation of vascular tone. There is also a possible association
of NO and endocannabinoid signaling with the vascular relaxation response, a
physiological counterpart of the stress response. Because a fractional amount of
guanylyl cyclase is sufficient to mediate vasorelaxation at higher NO concentra-
tions, it is concluded that the majority of NO-sensitive guanylyl cyclase is not
required for cGMP-forming activity but as NO receptor reserve to increase sensitiv-
ity toward the labile messenger NO in vivo (Mergia et al. 2006 ).
Mice whose genes for the eNOS found in endothelial cells has been “knocked out”
suffer from hypertension. Nitroglycerine (glyceryl trinitrate, GTN), which is often
prescribed to reduce the pain of angina, does so by generating NO, which relaxes
the walls of the coronary arteries and arterioles. However, the identity of the cel-
lular mechanisms through which GTN elicits NO-based signaling to dilate blood
vessels remains controversial. Recent evidence suggests an unexpected role for
mitochondria. Bioconversion by mitochondria of clinically relevant concentrations
of GTN results in activation of guanylate cyclase, production of cGMP, vasodila-
tion in vitro, and lowered blood pressure in vivo, which are eliminated by genetic
deletion of the mitochondrial aldehyde dehydrogenase (mtALDH). Thus, mtALDH
is required for vasoactivity derived from therapeutic levels of GTN and mitochon-
dria can serve as a source of NO-based cellular signals that may originate indepen-
dently of NOS activity (Chen et al. 2005 ). A genetically encoded high-sensitive
indicator for visualizing physiological nanomolar dynamics of NO in living cells
has shown that approx 1 nM of NO, which is enough to relax blood vessels, is
generated in vascular endothelial cells even in the absence of shear stress (Sato
et al. 2005 ). The nanomolar range of basal endothelial NO thus revealed appears to
be fundamental to vascular homeostasis.
Several studies have attempted to determine whether NO is responsible for the
“unexplained” limb vasodilation seen with body heating, limb ischemia, exercise,
and mental stress. There are at least two independent mechanisms contributing to
the rise in skin blood flow during nonpainful local heating: a fast-responding vasodi-
lator system mediated by the axon reflexes and a more slowly responding vasodila-
tor system that relies on local production of NO. Ultrasound induces vasorelaxation
almost completely by time-dependent endothelial NO and prostacyclin release,
which appears unrelated to tissue heating or endothelial architectural disruption.
These observations are relevant to pain relief by application of heating pads to
muscles and potential application for relief of intermittent claudication due to
peripheral vascular insufficiency.
SIRT1 protein deacetylase mediates many of the effects of calorie restriction
(CR) on organismal lifespan and metabolic pathways. Reduced caloric intake
decreases arterial blood pressure in healthy individuals and improves endothelium-
dependent vasodilation in obese and overweight individuals. A study has shown
that SIRT1 promotes endothelium-dependent vasodilation by targeting eNOS for