A physiologically relevant role for NO stored in vascular smooth muscle cells: A novel theory of vascular NO signaling

S-nitrosothiols (SNO), dinitrosyl iron complexes (DNIC), and nitroglycerine (NTG) dilate vessels via activation of soluble guanylyl cyclase (sGC) in vascular smooth muscle cells. Although these compounds are often considered to be nitric oxide (NO) donors, attempts to ascribe their vasodilatory activity to NO-donating properties have failed. Even more puzzling, many of these compounds have vasodilatory potency comparable to or even greater than that of NO itself, despite low membrane permeability. This raises the question: How do these NO adducts activate cytosolic sGC when their NO moiety is still outside the cell? In this review, we classify these compounds as ‘nitrodilators’, defined by their potent NO-mimetic vasoactivities despite not releasing requisite amounts of free NO. We propose that nitrodilators activate sGC via a preformed nitrodilator-activated NO store (NANOS) found within the vascular smooth muscle cell. We reinterpret vascular NO handling in the framework of this NANOS paradigm, and describe the knowledge gaps and perspectives of this novel model.