Mini-Reviews in Medicinal Chemistry, 2008, 8, 000-000 1 1389-5575/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Role of Nitric Oxide in Physiology and Pathology of the Gastrointestinal Tract A. Stanek 1,* , A. Gadowska-Cicha 1 , K. Gawron 2 , T. Wielkoszyski 3 , B. Adamek 2 , G. Cielar 1 , A.Wiczkowski 2 and A. Siero 1 1 Department of Internal Diseases, Angiology and Physical Medicine, Medical University of Silesia, Bytom, 2 Department of General Biology, Medical University of Silesia, Zabrze and 3 Department of Chemistry, Medical University of Silesia, Zabrze, Poland Abstract: In this paper the physiological role of NO and isoforms of NOS in the gastrointestinal tract and the involvement of NO in pathological processes of digestive tract as well as the perspective of therapeutic use of NO-donating drugs and selective inhibitors of phosphodiesterase in the treatment of gastric diseases were presented. Key Words: Nitric oxide, constitutive nitric oxide synthase, inducible nitric oxide synthase, gastrointestinal tract, inflammatory process, malignant transformations, NO-donor drugs, phosphodiesterase inhibitors. INTRODUCTION Studies of the role of nitric oxide (NO) have been carried out for over twenty years. In 1992, NO was named the mole- cule of the year by the Science journal. Six years later, the Nobel prize for Medicine was awarded to Robert Furchgott, Louis Ignarro and Ferid Murad for the identification of NO as an important signaling molecule in the cardiovascular system [1]. Nowadays in clinical chemistry many different methods for determining NO or its metabolites are used in- cluding: “real time” NO • determination, determination of stable end-products nitric/nitrate, incorporation of stable heavy nitrogen isotopes into nitrite and nitrate, determination of nitric oxide synthase activity as well as spectroscopy: electron paramagnetic resonance and near-infrared [2]. Nitric oxide is a gaseous small molecule generated by nitric oxide synthase (E.C. 1.14.13.39, NOS) which oxidizes the terminal nitrogen atom of L-arginine, leading to produc- tion of L-citrulline and NO as presented in Fig. (1). NOS requires the following cofactors to exert its action: flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), calmodulin (CaM), tetrathydrobiopterin (BH 4 ) and heme [3,4]. There are three isoforms of NOS [3,5,6]:  two forms constitutively expressed nitric oxide synthase (cNOS): neuronal (nNOS or type I NOS) and endothelial (eNOS or type III NOS) nitric oxide synthase; Ca 2+ - dependent  inducible nitric oxide synthase (iNOS or type II NOS); Ca 2+ -independent *Address correspondence to this author at the Department of Internal Dis- eases, Angiology and Physical Medicine, Medical University of Silesia, Batorego St. 15, PL-41902 Bytom, Poland, Tel./Fax: +48 32 7861630; E- mail: agatastanek@mediclub.pl Both isoforms of cNOS generates NO in an intermittent way over seconds or minutes in small amounts (pmol/l). nNOS is located in the neurons of central and peripheral nervous system (non adrenergic non cholinergic fibres). In the gastrointestinal tract the main role of nNOS-derived NO is the control of the smooth muscles’ relaxation. eNOS is mainly localized in platelets and endothelial cells. It is in- volved in the maintenance of gastrointestinal mucosa integ- rity via modulation of gastric mucosal blood flow, epithelial secretion and barrier function. It also plays a role in inhibi- tion of leukocytes, platelets and mast cells adhesion [1,7-9]. Based on these data, it is thought that both eNOS and nNOS are involved in homeostasis. Main activator of NOS is change in cellular calcium lev- els. The constitutive isoforms of NOS: eNOS and nNOS show an increased activity following increase in calcium and therefore calmodulin concentration in the cell as well as fol- lowing increased activity of phosphorylation. Especially activity of eNOS could be regulated by a number of different kinases and phosphatases with special role of the protein kinase Akt. On the other hand iNOS activity is mostly regu- lated at the transcriptional level and through its intracellular distribution [9]. The activity of NOS is also regulated by endogenously produced competitive inhibitors present in the plasma and cells, that inhibit (in some cases irreversibly) both the consti- tutive and the inducible NOS [10]. Some inhibitors of NOS are shown in Fig (2). The iNOS isoform expression may be induced by certain immunological factors such as cytokines, which may lead to continuous (over hours or days) NO production resulting in cellular concentration if this compound of nmols/l. iNOS isoform is localised in endothelial cells, smooth vascular muscle, neutrophils, macrophages and hepatocytes. Large amounts of NO synthesized from the inducible isoform have