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Nitric Oxide By Steven Knapp Chemistry 412 4-12-99.

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1 Nitric Oxide By Steven Knapp Chemistry 412 4-12-99

2 What is Nitric Oxide? zFirst described in 1979 as a potent relaxant of peripheral vascular smooth muscle. zUsed by the body as a signaling molecule. zServes different functions depending on body system. i.e. neurotransmitter, vasodilator, bactericide. zEnvironmental Pollutant zFirst gas known to act as a biological messenger

3 The structure and nature of Nitric Oxide zNitric oxide is a diatomic free radical consisting of one atom of nitrogen and one atom of oxygen zLipid soluble and very small for easy passage between cell membranes zShort lived, usually degraded or reacted within a few seconds zThe natural form is a gas NO

4 Synthesis of Nitric Oxide zNitric oxide is synthesized from L-arginine zThis reaction is catalyzed by nitric oxide synthase, a 1,294 aa enzyme COO- C (CH2)3 NH C H2N H NH2+ +H3N Arginine NOS NADPH + O2 NAD+ COO- C (CH2)3 NH C H+H3N N + H2N H OH N-w-Hydroxyarginine COO- C (CH2)3 NH H+H3N + NO NOS C ONH2 Citrulline

5 Activation of NOS zGlutamate neurotransmitter binds to NMDA receptors zCa++ channels open causing Ca influx into cell zActivation of calmodulin, which activates NOS zMechanism for start of synthesis dependent on body system zNO synthesis takes place in endothelial cells, lung cells, and neuronal cells

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7 Types of NOS zNOS I yCentral and peripheral neuronal cells yCa+2 dependent, used for neuronal communication zNOS II yMost nucleated cells, particularly macrophages yIndependent of intracellular Ca+2 yInducible in presence of inflammatory cytokines zNOS III yVascular endothelial cells yCa+2 dependent yVascular regulation

8 What is the role of Nitric Oxide in the human body? zNitric Oxide in the human body has many uses which are best summarized under five categories. yNO in the nervous system yNO in the circulatory system yNO in the muscular system yNO in the immune system yNO in the digestive system

9 Nitric Oxide in the Nervous System zNitric oxide as a neurotransmitter yNO is a signaling molecule, but not necessarily a neurotransmitter yNO signals inhibition of smooth muscle contraction, adaptive relaxation, and localized vasodilation zNitric oxide believed to play a role in long term memory yMemory mechanism proposed is a retrograde messenger that facilitates long term potentiation of neurons (memory) ySynthesis mechanism involving Ca/Calmodulin activates NOS-I yNO travels from postsynaptic neuron back to presynaptic neuron which activates guanylyl cyclase, the enzyme that catalyzes cGMP production yThis starts a cycle of nerve action potentials driven by NO

10 Is Nitric Oxide a “neurotransmitter?” zNO serves in the body as a neurotransmitter, but there are definite differences between other neurotransmitters used commonly in the body yNO is synthesized on demand vs. constant synthesis yNO diffuses out of the cells making it vs. storage in vesicles and release by exocytosis yNO does not bind to surface receptors, but instead exits cytoplasm, enters the target cell, and binds with intracellular guanylyl cyclase z Similarities to normal NTs yPresent in presynaptic terminal yNatural removal from synaptic junction

11 Nitric Oxide in the Circulatory System zNO serves as a vasodilator yReleased in response to high blood flow rate and signaling molecules (Ach and bradykinin) yHighly localized and effects are brief yIf NO synthesis is inhibited, blood pressure skyrockets y(Diagram of vasodilation mechanism after muscular system) zNO aids in gas exchange between hemoglobin and cells yHemoglobin is a vasoconstrictor, Fe scavenges NO yNO is protected by cysteine group when O2 binds to hemoglobin yDuring O2 delivery, NO locally dilates blood vessels to aid in gas exchange yExcess NO is picked up by HGB with CO2

12 Nitric Oxide in the Muscular System zNO was orginally called EDRF (endothelium derived relaxation factor) zNO signals inhibition of smooth muscle contraction yCa+2 is released from the vascular lumen activating NOS yNO is synthesized from NOS III in vascular endothelial cells yThis causes guanylyl cyclase to produce cGMP yA rise in cGMP causes Ca+2 pumps to be activated, thus reducing Ca+2 concentration in the cell yThis causes muscle relaxation

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14 Nitric Oxide in the Immune System zNOS II catalyzes synthesis of NO used in host defense reactions yActivation of NOS II is independent of Ca+2 in the cell ySynthesis of NO happens in most nucleated cells, particularly macrophages yNO is a potent inhibitor of viral replication zNO is a bactericidal agent yNO is created from the nitrates extracted from food near the gums yThis kills bacteria in the mouth that may be harmful to the body

15 Nitric Oxide in the Digestive System zNO is used in adaptive relaxation yNO promotes the stretching of the stomach in response to filling. yWhen the stomach gets full, stretch receptors trigger smooth muscle relaxation through NO releasing neurons

16 New research ideas involving Nitric Oxide zThe role NO might play in neuronal development zThe mechanism of NO inhibiting the different forms of NOS zDiazeniumdiolates as NO releasing drugs zExcessive NO release as the cause of most brain damage after stroke

17 References zMarieb, Elaine N. Human Anatomy and Physiology. (1998) 4 th ed. California, Benjamin/Cummings Science Publishing. 391, 826-27, 533, 859 zStryer Lubert. Biochemistry. (1996) 4 th ed. New York, W. H. Freeman and Company. 732 zKeefer, Larry K. “Nitric oxide-releasing compounds: From basic research to promising drugs.” Modern Drug Discovery. November/December 1998. 20-29.

18 Sources on the World Wide Web z z 20).htm (01-20) stands for 20 distinct sites. 20).htm z z z zThe following are all Omim sources written by McKusick, Victor A. zNOS II II zNOS IIA IIA zNOS I I zNOS Chon Chon zNOS IIC IIC zNOS IIB IIB

19 Any Questions????

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