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Drugs Modulating the L-Arginine:NO:Cgmp Pathway – Current Use in Therapy Magdalena Polakowska1, Jolanta Orzelska-Gorka2*, Sylwia Talarek2

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Drugs Modulating the L-Arginine:NO:Cgmp Pathway – Current Use in Therapy Magdalena Polakowska1, Jolanta Orzelska-Gorka2*, Sylwia Talarek2 DOI: 10.1515/cipms-2016-0004 Curr. Issues Pharm. Med. Sci., Vol. 29, No. 1, Pages 14-20 Current Issues in Pharmacy and Medical Sciences Formerly ANNALES UNIVERSITATIS MARIAE CURIE-SKLODOWSKA, SECTIO DDD, PHARMACIA journal homepage: http://www.curipms.umlub.pl/ Drugs modulating the L-arginine:NO:cGMP pathway – current use in therapy Magdalena Polakowska1, Jolanta Orzelska-Gorka2*, Sylwia Talarek2 1 Student Research Group at the Chair and Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodzki 4A, 20-093 Lublin, Poland 2 Chair and Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodzki 4A, 20-093 Lublin, Poland ARTICLE INFO ABSTRACT Received 13 November 2015 Nitric oxide (NO) is a relatively novel messenger that plays a significant role in a wide Accepted 26 November 2015 range of physiological processes. Currently, it is known that, both, lack and excess Keywords: of NO can cause diseases, thus a lot of substances have been discovered and utilized nitric oxide, which can change the concentration of this molecule within the organism. The aim of vasodilators, the present work is to provide an overview of currently used agents modulating the nebivolol, L-arginine:NO:cGMP pathway, as well as to summarize current understanding of their sildenafil, statins, pharmacological profiles. Nowadays, most of these agents are employed particularly in L-arginine. the treatment of cardiovascular diseases. Further studies can hold promise for enhancing the therapeutic equipment for a variety of other impairments, such as osteoporosis, and also in treatments of the central nervous system. INTRODUCTION Nitric oxide (nitrogen monoxide, NO) is a relatively reason, it is quickly converted into nitrates and nitrites by novel messenger that plays a significant role in a wide range oxygen and water [24]. It is also a free radical that through a of physiological processes. In 1978, Feride Murad showed binding of the 8-electron atom of oxygen with the 7-electron that nitroglycerine is a substrate for NO and increases the atom of nitrogen, has 1 unpaired electron [6]. This molecule level of cyclic guanosine-3’,5’-monophosphate (cGMP) in plays a meaningful role in various physiological processes in tissues. In 1980, Robert F. Furchgott indicated that the endo- the body. These are mainly associated with the cardiovascu- thelium released an agent that brought about the relaxation lar, immune and nervous systems, but also can be engaged in of the central smooth muscles. This he called “endothelium- certain pathological responses, e.g. in hypertension, estab- derived relaxing factor” (EDRF). Louis J. Ignarro found lished ischemic heart disease (lack of NO) and septic shock later that EDRF was, in fact, NO [6]. Their discoveries have or inflammation (NO in excess) [35]. shown the importance of NO as a signaling molecule in the NO is generated by a family of NO synthases (NOS) that cardiovascular system. In 1998, the Nobel Prize in Physiol- convert L-arginine as the substrate, to NO and L – citrul- ogy or Medicine was awarded to these three scientists “for line, in the presence of molecular oxygen and reduced their discoveries concerning the nitric oxide as a signaling nicotinamide-adenine-dinucleotide phosphate as co-sub- molecule in the cardiovascular system” [48]. This was the strates. Flavin adenine dinucleotide, flavin mononucleo- beginning of precious studies on the role of NO as a bio- tide, and (6R-)5,6,7,8-tetrahydrobiopterin are cofactors logical mediator. Currently, it is known that, both, lack and of all NOS/isoenzymes [15, Fig.1]. NO is synthesized excess of NO can induce a variety of diseases, thus, work by three genetically different synthases: endothelial NOS has been undertaken in discovering a lot of substances which (eNOS), neuronal NOS (nNOS) (which are constitutively bring about changes in the concentration of this molecule expressed) and inducible NOS (iNOS). These are synthe- within the organism. sized following induction by pro-inflammatory cytokines NO is an important gaseous chemical messenger which or endotoxin [51]. The presence of nNOS was found in is extremely labile, and has a very short half-life. For this blood platelets, neurons, synaptic spines, cardiac, skeletal and smooth muscles, while eNOS is mainly located in the * Corresponding author endothelial cells. Those constitutive isoforms are dependent e-mail: [email protected] on calmoduline and factors increasing Ca2+ concentration. In tel. 81 448 72 56 contrast, iNOS is mainly found in the microglia, astrocytes, © 2016 Medical University of Lublin. This is an open access article distributed under the Creative Commons 14 Attribution-NonComercial-No Derivs licence (http://creativecommons.org/licenses/by-nc-nd/3.0/) Drugs modulating the L-arginine:NO:cGMP pathway - current use in therapy Magdalena Polakowska, Jolanta Orzelska-Gorka, Sylwia Talarek Magdalena Polakowska, Jolanta Orzelska-Gorka, Sylwia Talarek macrophages and neutrofiles. It is not Ca2+ – calmoduline of mastocytes [35]. In high concentrations, NO inhibits the – dependent, but its long activity defines the concentration proliferation of smooth muscle cells [36]. Furthermore, it is of cytokines, as well as inflammatory and immunological involved in the reaction between the body’s white blood cells stimulation [16,17]. and the membranes of blood vessel walls. These findings established NO as a homeostatic regulator in the cardiovas- cular system. In addition, NO plays a role in a number of physiological conditions and pathological states with regard to the system. Among these are atherosclerosis, hypertension and vasoconstriction [35]. Therefore, endothelial dysfunc- tion results in NO deficiency and the uncoupling of NOS generating free radicals [24]. CVD are a group of disorders that include congestive heart failure (CHF) and ischemic heart disease. Such disor- ders can subsequently lead to angina pectoris or even acute myocardial infarction, and are characterized by vasocon- striction. Ischemic myocardium appears when the supply Figure 1. Biosynthesis of NO (nicotinamide-adenine-dinucleotide of oxygenated blood through the coronary arteries becomes phosphate (NADPH); flavin adenine dinucleotide (FAD), flavin inadequate to meet the demands of the cardiac muscle, mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin leading to myocardial hypoxia [39]. Acute and chronic isch- (BH4) [4] aemia results in the destruction of the endothelium. This NO functions as a neurotransmitter in the peripheral may restrict vasodilation or promote vasoconstriction. The and central nervous system (CNS), however, it is not like cause of CVD is found to be a shortage of NO, and this situ- the typical neurotransmitter stored in the synaptic vesicles, ation can confine the NO-dependent signal pathways [9,39]. but after its synthesis, it is quickly released to the synaptic In CVD therapy, substances with vasorelaxant properties, cleft. NO diffuses out between neurons, whereas a typical as well as other cardiovascular agents modulating endog- neurotransmitter is released in the process of exocytosis enous NO bioactivity, are used [24]. Such nitrovasodilators [40]. In addition, it does not interact with the receptors on consist of metabolic donors (organic nitrates and nitrites, the neural membranes, but directly binds to soluble guanyl nicorandil) and direct donors (sodium nitroprusside (SNP), cyclase (sGC) – one of the most specific targets for NO [7]. NO gas and molsidomine) [49]. Moreover, NO may also NO interacts with the haem iron at the active site of sGC, interfere with β-blockers and with the renin-angiotensin- and, during this process, induces a modification of confor- aldosterone system (RAAS) [34,41]. mation in the haem structure. The result of this binding is Nitrates and nitrites the increase in quantity of cGMP. This, in turn, activates cGMP-dependent protein kinases, ion channels and phos- Organic nitrates and nitrites have similar properties, phodiesterases (PDE), and, subsequently, gets up to protein but they have different mechanisms of action and different phosphorylation. The cGMP compound plays a central enzymatic requirements for NO generation. Glyceryl trini- role in NO signaling and in the regulation of physiologic trate (nitroglycerine), isosorbide dinitrate, and isosorbide- responses. Furthermore, the L-arginine:NO:cGMP signaling 5-mononitrate – the most commonly used organic nitrates pathway takes part in blood pressure regulation, synaptic – are effective in reducing ventricular preload, by increas- plasticity, atypical neurotransmission, penile erection in the ing peripheral venous capacity [39]. In the vascular smooth presence of nNOS; non-specific immune defense, mediation muscle cells, they are metabolized to 1,2-glyceryl dinitrate of inflammation and septic shock in the presence of iNOS; and nitrite, via mitochondrial aldehyde dehydrogenase-2, as well as vasodilation, vasoprotection and prevention of and then to NO and S-nitrosothiols [26]. Current indications atherosclerosis in the presence of eNOS [7,15]. for the need to undergo nitrate therapy include chronic stable The aim of the present work is to provide an overview angina pectoris, unstable angina pectoris, acute coronary of currently used agents modulating L-arginine:NO:cGMP syndrome, stable coronary artery disease and acute or pathway, and to summarize current understanding of their chronic CHF [37]. Nitroglycerine is a very popular drug pharmacological profiles. used
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