Nitric Oxide Signaling PDF

Nitric oxide signalling Stuart Cruickshank Nitric oxide is a free radical gas (NO). Formed in atmosphere during electrical storms. ALSO formed in an enzyme catalysed reaction between molecular oxygen and L-arginine. NO is a key signalling molecule in cardiovascular and nervous systems. L-argin...

Nitric oxide signalling Stuart Cruickshank Nitric oxide is a free radical gas (NO). Formed in atmosphere during electrical storms. ALSO formed in an enzyme catalysed reaction between molecular oxygen and L-arginine. NO is a key signalling molecule in cardiovascular and nervous systems. L-arginine is a protein amino acid. Present in the proteins of all life forms. Classified as a semi-essential or conditionally essential amino acid. Means: that under normal circumstances the body can synthesize sufficient L-arginine to meet physiological demands. Dietary sources include animal and plant proteins. Biosynthesis of NO under control of NO synthase. 3 forms. 1) Inducible NOS (iNOS) (present in vascular smooth muscle, endothelial cells, neutrophils fibroblasts) 2) Two remaining forms: eNOS in the endothelium and nNOS present in neurons. eNOS also found in cardiac myocytes, platelets, osteoclasts. iNOS produces ~ 1000 X more NO than eNOS/nNOS. Control of Vascular Tone by the Endothelium Blood flow Platelets ET cells EDR F’s EDCF’s Contraction Relaxation VSM cells Relaxation  Endothelium-derived Vasoactive Substances EDR F’s EDCF’s – Nitric Oxide (NO) – Endothelin (ET-1) – Prostacyclin (PGI2) – Thromboxane A2 (TxA2) – Hyperpolarising factor Synthesis and Release of NO from the Endothelium NOS L-arginine + O2 NO + L-citrulline NOS activity is controlled by intracellular calcium/calmodulin Important stimuli for NO synthesis likely to be mechanical (shear stress, pulsatile flow) Agonist-induced (e.g. Ach, BK, ADP) NO release mediated by [Ca2+]i NO diffuses out of the cell and onto smooth muscle cells to exert its effects Ach bradykinin Shear stress [Ca2+] calmodulin Ca-calmodulin active inactive NOS NOS L-citrulline L-arginine + NO  NO guanylate guanylate cyclase - cyclase - basal activated cGMP GTP Protein kinase G smooth muscle relaxation  Mechanism of Action of NO NO exerts its effects by activating guanylate cyclase GC GTP cGMP  [Ca2+]i Relaxation NO not only affect blood vessels. NO modulates: 1) Skeletal muscle 2) Myocardial contractility 3) Metabolism 4) Intimately linked with insulin signalling. 5) Neuronal function Acts as 6) Anti-oxidant 7) Anti-thrombotic 8) Anti-inflammatory