15homology with mammalian NOS was confirmed, but no reductase domain identi-
fied (Gusarov et al. 2008 ). Later, an alternative bNOS homolog that contains both
oxygenase and reductase was characterized in Sorangium cellulosum (Agapie
et al. 2009 ).
2.1.2 NO’s Medical Use: From Nitroglycerin to Viagra
NO is considered an effective antianginal drug for alleviating ischemic pain
(angina) because it causes vasodilation and decreases cardiac workload.
NO-releasing drugs such as nitroglycerin (NG) can lower arterial pressure and
left ventricular filling pressure by dilating the veins. NG has been used for over
130 years as a vasodilator for treatment of angina and chronic heart failure.
Although NG was known for long time to be converted to NO, the conversion-
responsible enzyme mitochondrial aldehyde dehydrogenase has not been identified
until 2005 (Chen et al. 2005 ). Another drug, amylnitrite, can also release NO in
vivo and serve as a NG-like vasodilator. Besides, a sequential reduction of dietary
nitrate from nitrate-rich vegetables, such as spinach, arugula, and beetroot, can
also provide NO to reduce the blood pressure in prehypertensive persons (Webb
et al. 2008 ).
The endothelium of blood vessels uses NO to direct surrounding smooth mus-
cles relaxation and vasodilation, thereby increasing blood flow. NO was therefore
originally known as an “endothelium-derived relaxing factor”. NO activates gua-
lylate cyclase (GC) that catalyzes the formation of cGMP. As a secondary messen-
ger, cGMP can activate protein kinase G that accelerates Ca^2 + reuptake. Low-level
Ca^2 + ensures that myosin is no longer phosphorylated by myosin light chain
kinase, hence halting the cross-bridge cycle and leading to smooth muscle relaxa-
tion (Rhoades and Tanner 2003 ).
Sildenafil citrate, popularly known by its trade name Viagra, stimulates penis
erection by inhibiting cGMP-specific phosphodiesterase type 5, an enzyme that
promotes the degradation of cGMP. It is clear that both NO and Viagra can main-
tain a high level of cGMP even though NO accelerates cGMP production, whereas
Viagra inhibits cGMP degradation (Webb et al. 1999 ). Since becoming commer-
cially available in 1998, Viagra has been used as a prime drug for improving erec-
tile function in men.
2.1.3 A “Double-Edged Sword”: Physiological
and Pathological Views on NO
NO contributes to vessel homeostasis by inhibiting vascular smooth muscle con-
traction and growth, platelet aggregation, and leukocyte adhesion to the endothe-
lial tissue (Roszer 2012 ). The constitutively expressed eNOS is a primary NO
2.1 NO and NOS