17th November 2016 Endocrinology Second Messengers: NO and cGMP Nitric Oxide (NO) NO is a free radical gas This is the first gas 'second messenger' that you have been introduced to! Gas second messengers can diffuse through both the cytosol and the plasma membrane. This makes them excellent paracrine and autocrine signalling molecules, as they have the ability to activate small discrete region of cells. Cells in the body can produce small amounts of gases that are important as signalling molecules. Lipid soluble molecule, thus it can diffuse through membranes; cover a wide area It has enough water solubility also, therefore it can have wide spread effects up to a point, because NO is very chemically reactive (free radical) and very quickly breaks down. Small concentration of a reactive substance that reacts locally NO can damage and kill cells that it is produce or activates Physiological relevance of NO NO mediates a plethora of functions in the body, including: · Relaxation of vascular and gastrointestinal smooth muscle · Inhibition of platelet aggregation · Reduction of cardiac hypertrophy · Protection against ischemia/reperfusion damage of the heart · Improvement in cognitive (brain) functions NO is a mediator in the relaxation of smooth muscle EDRF - is NO and is made by the endothelial cells lining the blood vesicle cells; NO is a good thing in the cardiovascular system. NO can help protect and recover the tissue when oxygen returns NO is important as a neurotransmitter
17th November 2016 Endocrinology Toxicity of NO NO is a free radical; it can react with the superoxide anion to give peroxoynitrite and then hydoxyl radicals. The latter are very reactive and toxic. This occurs in macrophages. It can also bind to non-haem iron in proteins irreversibly, leading to destruction of these proteins. Many of these are in the mitochondria, leading to cell death. This is because NO is a free radical and it will grab any electron to produce a stable electron pair. Macrophages produce large quantities of NO in the respiratory burst of the pathogen. NO reacts with mitochondria NO has to be produced in the right place at the right time other wise it will kill cells! Biosynthesis of NO Nitric Oxide Synthase (NOS) enzymes are responsible for the formation of NO as they catalyse the production of NO (and citrulline) from L-arginine. Arginine NOS1 / nNOS NADPH NOS2 / iNOS NOS3 / eNOS O2 NO synthase isozymes Isoform Abbreviation Neuronal NOS nNOS Endothelial NOS eNOS nitric oxide nNOS- nerve cells iNOS - immune system cells eNOS - endothelial cells NADP Citrulline They are all regulated differently Location Nervous system and Skeletal muscles (type II) Endothelium (also present in cardiac myocytes, renal mesangial cells, osteoblasts and osteoclasts) General Function Cell communication Vasodilation Inducible NOS iNOS Immune system and Cardiovascular system Immune defence nNOS and eNOS are called 'constitutive' enzymes and generate relatively small amounts of NO
17th November 2016 Endocrinology In contrast, iNOS activity is approximately 1,000 fold higher (predominately viewed as a mechanism