**2.1 Nitric oxide (NO)**

NO is a reactive, diffusible gaseous free radical whit strong intrinsic oxidant properties. It is produced locally at ECs by three different isoforms of NO synthase (NOS) enzymes, each with unique expression and functional properties: neuronal NOS (nNOS, NOS1), inducible NOS (iNOS, NOS2), and endothelial NOS (eNOS, NOS3) [5].

Elevated levels of intracellular Ca2+, acting through calmodulin, activates nNOS and eNOS respectively; iNOS is less susceptible to Ca2+, but around 1000 times more inducible by inflammatory stimuli such as TNF- α, IL-1β, and IFN-γ [6]. The NOS produced NO by catalyzing the oxidation of the nitrogen guanide of the L-arginine and O2 producing L-citrulline and NO (**Figure 1**) [5, 6]. The NO activates soluble guanylyl cyclase (sGC), which at binding creates an augmentation of the Vmax of sGC and, consequently, rising the cellular cyclic guanosine monophosphate (cGMP) [6].

The cGMP vascular effects are mediated by several mechanisms, being the activation of protein kinase G (PKG) one of the main processes, conducting vasodilatation by means of release inhibition of Ca2+ mediated by inositol 1,4,5-trisphosphate (IP3) [6].

#### **Figure 1.**

*The graphic shows the activation of NOS mediated by Calmodulin/Ca+2. Subsequently, NOS produced NO and L-citrulline starting from L-arginine and O2 . Original graphic created with BioRender.com.*

*DOI: http://dx.doi.org/10.5772/intechopen.107481 Endothelial Dysfunction, Molecular Biology, Physiopathology, Diagnosis, and Treatment*
