role of no in the cv

Role of Nitric Oxide in the Cardiovascular system : 

ST Oh HANALL Pharmaceutical. Role of Nitric Oxide in the Cardiovascular system

What is Nitric Oxide? : 

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

The structure and nature of Nitric Oxide : 

Nitric oxide is a diatomic free radical consisting of one atom of nitrogen and one atom of oxygen Short lived, usually degraded or reacted within a few seconds The natural form is a colorless gas. Water soluble The structure and nature of Nitric Oxide

Synthesis of Nitric Oxide : 

Nitric oxide is synthesized from L-arginine This reaction is catalyzed by nitric oxide synthase Synthesis of Nitric Oxide

Synthesis and action of Nitric oxide : 

Synthesis and action of Nitric oxide

Activation of NOS : 

Ca++ channels open causing Ca influx into cell Activation of calmodulin, which activates NOS Mechanism for start of synthesis dependent on body system NO synthesis takes place in endothelial cells, lung cells, and neuronal cells Activation of NOS

Types of NOS : 

nNOS (Neuronal type: constitutive) Central and peripheral neuronal cells Ca+2 dependent, used for neuronal communication eNOS (Endothelial type : constitutive) Vascular endothelial cells Ca+2 dependent Vascular regulation mNOS (Macrophage-type : inducible) Most nucleated cells, particularly macrophages Independent of intracellular Ca+2 Inducible in presence of inflammatory cytokines Types of NOS

What is the role of Nitric Oxide in the human body? : 

Nitric Oxide in the human body has many uses which are best summarized under five categories. NO in the nervous system NO in the cardiovascular system NO in the muscular system NO in the immune system NO in the digestive system What is the role of Nitric Oxide in the human body?

Nitric Oxide in the Nervous System : 

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

Nitric Oxide in the Cardiovascular System : 

Regulation of vascular tone Regulation of myocardial contractility Regulation of antithrombotic properties of the endothelium Regulation of endothelial-leukocyte interactions and vascular permeability Regulation of cell proliferation Aids of gas exchange between hemoglobin and cells Nitric Oxide in the Cardiovascular System

Nitric Oxide in the Cardiovascular System : 

Regulation of vascular tone NO is continuously produced by vascular endothelial cells this basal release of NO appears to regulate vascular tone It is involved in blood pressure regulation (L-NMMA , a specific inhibitor of NOS cause increase in systolic blood pressure) It is involved in auto-regulation of blood flow NO and PDGF-B are involved in a negative feedback loop Nitric Oxide in the Cardiovascular System

Nitric Oxide in the Cardiovascular System : 

Regulation of myocardial contractility Endothelial –derived NO and sod nitropruside cause a substantial reduction in cardiac myocyte contraction via a cGMP dependent mechanism Regulation of antithrombotic properties of the endothelium NO is a potent inhibitor of platelet function NO also inhibits platelet adhesion to the vascular endothelium Nitric Oxide in the Cardiovascular System

Nitric Oxide in the Cardiovascular System : 

Regulation of endothelial-leukocyte interactions and vascular permeability NO inhibits neutrophil aggregation NO inhibition promoted leukocyte adhesion and emigration NO inhibition causes a rapid increase in microvascular permeability and vascular protein leakage. Features characteristic of an acute inflammatory response (P. Kubes) However, this effect is caused by imbalance of superoxide and NO, thus, this response is considered to be caused by superoxide. Nitric Oxide in the Cardiovascular System

Nitric Oxide in the Cardiovascular System : 

Regulation of cell proliferation NO can inhibit cell proliferation by a variety of mechanism Inhibition of ribonucleotide reductase Inhibition of electron transport Impairment of glycolysis Impairment of endothelial-leukocyte interactions Inhibition of platelet adhesion, secretion and aggregation Increase of intracellular cGMP Aids of gas exchange between hemoglobin and cells Nitric Oxide in the Cardiovascular System

Nitric Oxide in the Muscular System : 

NO signals inhibition of smooth muscle contraction Ca+2 is released from the vascular lumen activating NOS NO is synthesized from NOS III in vascular endothelial cells This causes guanylyl cyclase to produce cGMP A rise in cGMP causes Ca+2 pumps to be activated, thus reducing Ca+2 concentration in the cell This causes muscle relaxation Nitric Oxide in the Muscular System

Slide 16: 

Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-11.htm

Nitric Oxide in the Immune System : 

mNOS catalyzes synthesis of NO used in host defense reactions Activation of mNOS is independent of Ca+2 in the cell Synthesis of NO happens in most nucleated cells, particularly macrophages NO is a potent inhibitor of viral replication NO is a bactericidal agent NO is created from the nitrates extracted from food near the gums This kills bacteria in the mouth that may be harmful to the body Nitric Oxide in the Immune System

Nitric Oxide in the Digestive System : 

NO is used in adaptive relaxation NO promotes the stretching of the stomach in response to filling. When the stomach gets full, stretch receptors trigger smooth muscle relaxation through NO releasing neurons NO has cytoprotective properties in the stomach (preventing inhibition of cyclooxygenase 1) Nitric Oxide in the Digestive System

References : 

Marieb, Elaine N. Human Anatomy and Physiology. (1998) 4th ed. California, Benjamin/Cummings Science Publishing. 391, 826-27, 533, 859 Stryer Lubert. Biochemistry. (1996) 4th ed. New York, W. H. Freeman and Company. 732 Keefer, Larry K. “Nitric oxide-releasing compounds: From basic research to promising drugs.” Modern Drug Discovery. November/December 1998. 20-29. Joseph Loscalzo and George Welch. “Nitric oxide and its role in the cardiovasculr system” Progress in Cardiovascular Disease / 1995 : pp87-104 References

References : 

Louis J. Ignarro, Claudio Napoli and Joseph Loscalzo “ Nitric oxide donor and Cardiovascular agents Modulating the bioactivity of nitric oxide : An overview ” Journal of the american hear association, July 21, 2008 A.C. Quinn, A.J. Petros and P. Vallance “Nitric oxide : an endogeneous gas” British Journal of Anaesthesia, 1995 :74 References