Discovery of the nitric oxide signaling pathway and targets for drug development

Abstract

Nitric oxide is a multifunctional signaling molecule, intricately involved with maintaining a host of physiological processes including but not limited to host defense, neuronal communication and the regulation of vascular tone. Many of the physiological functions first ascribed to NO are mediated through its primary receptor, soluble guanylyl cyclase. Endogenous production of NO is a highly complex and regulated process involving the 5-electron oxidation of L-arginine requiring numerous substrates and cofactors. The production of a highly reactive and diffusible free radical gas further complicates our established concept and model of specific and targeted receptor-ligand interaction to elicit cell signaling events. Hence there are many steps in the endogenous pathway for altered production of NO and subsequent activation of sGC that may be targets for drug development as well as other molecular targets for NO. The following review will highlight the current state of the art of NO-sGC research and illustrate disease processes which may benefit from novel drug development exploiting the NO-sGC pathway as well as NOS and cGMP-independent pathways.

Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells

“…The NOS pathway is ubiquitous in the adult mammal, with endothelial, neuronal, and inducible NOS isoforms playing critical roles in every organ system, in particular cardiovascular homeostasis, thrombosis, neurotransmission, and immunity [ 24 ]. With respect to vascular reactivity and structure, NO plays a dominant role as a vasodilation factor that also potently inhibits vascular smooth muscle proliferation, leukocyte infi ltration, and platelet adherence and aggregation [ 25 ].…”

Nitrergic Neurons in the Spinal Cord of the Bottlenose Dolphin (Tursiops truncatus)

“…Three NOS isoforms have been identified and distinguished by their tissue distribution: neuronal (nNOS), inducible (iNOS), and endothelial (eNOS). The nNOS (Type I) is located in a discrete neuronal populations of the central (CNS) and peripheral (PNS) nervous system; the iNOS (Type II) is expressed by different cell types in response to inflammatory stimuli; the eNOS (Type III) has been identified in endothelial cells and astrocytes (Garthwaite, 1991;Bredt and Snyder, 1992;Dawson and Dawson, 1996;Moncada et al, 1997;Bredt, 1999;Davis et al, 2001;Ahern et al, 2002;Calabrese et al, 2007;Bryan et al, 2009). Interestingly, the nNOS is also present in macrophages and endothelial cells, in which it is probably involved in the basal modulation of vascular tone (Seddon et al, 2008).…”

Enhanced Oxygen Saturation in Optic Nerve Head of Non-Human Primate Eyes Following the Intravitreal Injection of NCX 434, an Innovative Nitric Oxide-Donating Glucocorticoid

“…Two of these are constitutive enzymes (neuronal NOS or NOS-I and endothelial NOS or NOS-III) requiring intracellular Ca ++ accumulation and are expressed in many cell types within the ocular compartment, 14 whereas the third isoform (NOS-II or iNOS) is mainly expressed in immune cells, is induced in response to pro-inflammatory stimuli, and produces large amounts of NO in a Ca ++ -independent manner. 14,15 It has been reported that a low physiological amount of NO activates soluble guanylyl cyclase and vascular relaxation, 15,16 favors neuronal transmission, and modulates gene transcription through nuclear factor NF-kappa B signaling. 17,18 Conversely, large quantities are thought to result in abnormal neuronal activity and central sensitization, 19 activate proinflammatory cytokines, and promote tissue-specific oxidative and nitrosative stress.…”