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Abstract

Nitric Oxide: A Small molecule with diversifying impacts

Nitric oxide (NO), a colorless and odorless gas was discovered in 1980 as a chemical entity known as endothelial derived relaxing factor (EDRF) [1]. Since then the molecule has become one of the most highly studied and important biological molecules. It has been evolved as an important physiological mediator involved in cellular signaling in the cardiovascular, gastrointestinal, genitourinary, respiratory and nervous system [2]. The imbalance of NO in tissues has been indicated for the development of several disease state. Hence the production of NO and its inhibition can lead to the development of many therapeutic molecule [3]. Nitric oxide is biosynthesized from amino acid L-arginine, that is present in high concentrations in blood, in extracellular fluid, and as well even at higher concentrations within the cells. The synthesis of NO is the outcome of a series of oxido-reductive events involving a large number of co-factors, which binds to the specific binding sites on the NO synthase that work as a catalyzer [4]. The NO synthase has three different isoforms as they are tailored for the location and stimuli where the NO is required. The main areas of its involvement are in neurotransmission, non-specific immunity and inflammatory response and its regulation in blood pressure [5]. The most beneficial effects of NO involves the inhibition of leukocyte adhesion, protection against tumor necrosis factor, and also its role an as antioxidant such as offering protection against hydrogen peroxide, alkyl hydroperoxide and superoxide induced free radical damage. Nitric oxide plays an important role in vascular biological, immuno surveillance system, renal function, bronchodilation, cellular adhesion [6]. In addition to these NO has been shown to be involved in the oxidation war chest of the immune system by virtue of involvement of anti-tumor and anti-pathogen host response [7]. Besides its therapeutic implications, the synthesis of NO is seen as a source of oxygen free radicals either alone or via the formation of peroxy nitrite, which has been generated as the resultant end product of the reactions between NO and superoxide. These generated oxygen free radicals have been suggested to be responsible for some the cytotoxic effects of these molecules. There are several deleterious effect of NO such as, inhibition of enzyme functions, induction of DNA damage [8, 9], induction of lipid peroxidations, the depletion of antioxidants stores and also it increases the susceptibility to radiations, alkylating agents and toxic metals. The susceptibility of cell by cytotoxic agents are enhanced when NO per se is present. Still there is confusion regarding the NO’s involvement in the physiologic derailment because of its multifaceted and paradoxical action in various cytotoxic mechanisms. [10]. On the basis of enormous work that has been done on NO’s suggests that they can regulate cellular and the whole body activity in a surprisingly versatile way. This uniquely acts as a double edge sword mediator, which has beneficial physiological effects as well as detrimental pathological effect making its development into a drug quite challenging. So there is a tremendous potential in the field of NO research, so that NO can be further regulated by pharmaceuticals and can be further exploited for treatment using NO or the regulators of NO. References: Cirino G. Nitric Oxide releasing drugs: from bench to bedside. Digestive and Liver Disease 2003; Suppl 2:S2-S8.Watts SW. Endothelin receptors: what’s new and what do we need to know? Am J Physiol Regul Integr Comp Physiol 2010; 298: R254–R260.Low SY. Applications of pharmaceuticals to nitric oxide. Molecular Aspects of Medicine 2005; 26:97-138.Palmer RM, Rees DD, Ashton DS, Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation.  Biochem. Biophys. Res. Commun 1988; 153:1251-1256.Bruckdorfer R. The basics about nitric oxide. Molecular Aspects of Medicine 2005; 26:3-31.Nevin BJ, Broadley KJ. Nitric oxide in respiratory diseases. Pharmacol. Ther 2002; 95:259-293.Transforming growth factor-β regulation of Immune responses. Li MO, Wan YY, Sanjabi S, Robertson AKL, Flavell RA. Annual Review of Immunology 2006; 24:99-146.Pacher P, Beckman JS, Liaudet L. Nitric Oxide and Peroxynitrite in Health and Disease. Physiol Rev 2007; 879(1):1315-1324. Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry & Cell Biology 2007; 39:44-84. 10.  Park HC, Yasuda K, Ratliff B, Stoessel A, Sharkovska Y, Yamamoto I, et al. Postobstructive regeneration of kidney is derailed when surge in renal stem cells during course of unilateral ureteral obstruction is halted. Am J  Physiol Renal 2010;298(2):F357-F364


Author(s): Arun Kumar, Minaketan Tripathy

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