LECTURE-8 - Outline Nitric Oxide The Good, the Bad, and the...

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Nitric Oxide The Good, the Bad, and the Ugly Dr. Christiaan Leeuwenburgh Outline • Sources and Types of Nitric Oxide • Chemistry of Nitric Oxide • Nitric Oxide and Aging • Nitric Oxide, Endothelial Dysfunction, and Atheriosclerosis Chemical Properties of NOS -Homodimer, MW = 135-150kD/monomer -Each monomer has two domains for activity 1) reductase domain and 2) oxygenase domain -Prosthetic groups: FAD, FMN, and Heme -Cofactors: BH 4 and Ca-calmodulin tetrahydrobiopterin (cofactor) Nitric oxide synthase isoenzymes NOS neuronal ( nNOS nNOS , NOS -I) I) NOS inducible ( iNOS , NOS , NOS -II) II) NOS endothelial ( eNOS , NOS -III) III) NOS mitochondrial ( mNOS mNOS )
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1. Modulation of Vascular Tone 2. Memory Formation 3. Penile Erection 4. Inflammation (Macrophage-dependent killing) 5. Lack of may cause “Violent Behavior”?
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Protein Nitration Protein Chlorination NO reacts very rapidly with the free O 2 •- to form ONOO - . N=O + O-O: - O=N-O-O: - .. .. .. .. .. .. .. .. .. .. . . . . . . .. .. .. .. .. .. . . . . .. .. .. ..
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Nitration CHEMICAL SUMMARY
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SUMMARY SUMMARY Endothelial Dysfunction General Background Normal Arterial Wall Tunica adventitia Tunica media Tunica intima Endothelium Subendothelial connective tissue Internal elastic membrane Smooth muscle cells Elastin/collagen fibers External elastic membrane Physiology of Nitric Oxide • Endothelial nitric oxide synthase (eNOS) catalyzes the synthesis of NO from L- arginine. L-arginine + NADPH + O 2 eNOS L-citrulline + NADP + + H 2 O + NO
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Endothelial Function • The endothelium is actively involved in the control of vascular tone and homeostasis. • In response to various stimuli endothelial cells release both vasodilating and vasoconstricting substances. Physiology of Nitric Oxide Physiology of Nitric Oxide NOS Acetylcholine Bradykinin Ca 2+ [Ca 2+ ] L-Arg NO + + + + Shear stress + GTP cGMP sGC Smooth Muscle Endothelium Relaxation Adapted from Moncada & Higgs, NEJM 1993 + Endothelial Function Vasodilators • Nitric Oxide (NO ) • Prostacyclin • Endothelial derived hyperpolarizing factor (EDHF) Vasoconstrictors • Endothelin-1 • Thromboxane Functions of Nitric Oxide • Vasodilation • Inhibit platelet adhesion • Inhibit leukocyte adhesion Endothelial Dysfunction • Endothelial dysfunction is characterized by an impaired bioactivity of endothelial derived NO .
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NO reacts very rapidly with the free O 2 •- to form ONOO - . This may deplete NO N=O + O-O: - O=N-O-O: - .. ..
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This note was uploaded on 05/19/2011 for the course BCH 3218 taught by Professor Johnsteward during the Fall '08 term at University of Florida.

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LECTURE-8 - Outline Nitric Oxide The Good, the Bad, and the...

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