Nitric Oxide Jacob Poirier, Philip Johnston, Sami Khan

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PHM142 Fall . 2017. Instructor: Dr. Jeffrey Henderson. Nitric Oxide (NO). Originally known as endothelium-derived relaxing factor, however in 1987 it was discovered to be NO. 1. Small, two-atom gaseous molecule . ID: 650171 Download Presentation

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Nitric Oxide Jacob Poirier, Philip Johnston, Sami Khan




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Presentations text content in Nitric Oxide Jacob Poirier, Philip Johnston, Sami Khan

Slide1

Nitric Oxide

Jacob Poirier, Philip Johnston, Sami Khan

PHM142 Fall

2017

Instructor: Dr. Jeffrey Henderson

Slide2

Nitric Oxide (NO)

Originally known as endothelium-derived relaxing factor, however in 1987 it was discovered to be NO

1

Small, two-atom gaseous molecule

Short half-life and highly reactive 2, 3Lipid soluble 3

Slide3

Synthesis via Dietary Nitrates

 

 

 

 

Nitrate Reductase

Facultative anaerobic bacteria

in the oral cavity

 

In the acidic stomach environment

(Nitrate)

(Nitrite)

 

Lundberg

et al.,

2008

Benjamin

et al.,

1994

Slide4

Synthesis via Nitric Oxide Synthase

L-Arginine

Intermediate

L-Citrulline

Knowles &

Moncada

, 1994

Slide5

Enzymatic Production via Nitric Oxide Synthase (NOS)

Type of NOS

Primary location

Function

Expression

Neuronal NOS

Nervous tissue

Skeletal muscle (Type II)

Long-term potentiation; excitation contraction coupling

Constitutive

Endothelial NOS

Endothelial cells

Modulation of vascular tone

Constitutive

Inducible NOS

Immune cells

Immune defence against pathogens

Inducible

Slide6

Mechanism of NO in smooth muscle relaxation

Slide7

What is Angina?

Ischemic heart disease is the leading cause of death in the United States and angina pectoris is a common symptom of this disease

10

“Angina" is used to describe clinical symptoms such as discomfort in the chest, jaw, shoulder, back, or arms that are induced by physical exertion or emotional stress

Angina is due to the mismatch between myocardial oxygen demand and supply, resulting in myocardial ischemia. Symptoms are alleviated with rest or treatment with nitroglycerin.11

Slide8

Nitroglycerin

Mechanism of Action

NO

MtALDH

XOR

Mitochondrial Matrix

MtALDH: Mitochondrial Aldehyde Dehydrogenase

XOR: Xanthine Oxidoreductase

Vascular Smooth Muscle Cell

NO activates Guanylyl Cyclase and cGMP production

cGMP activates downstream signaling to lower [Ca

2+

]

Lower [Ca

2+

] causes muscle relaxation and dilation of blood vessels

Slide9

Erectile Dysfunction

Due to lack of smooth muscle relaxation = reduced of blood flow

Most common causes include: Antidepressants such as SSRI’s, and Nicotine

12, 13

Other causes include: neurogenic disorders, cavernosal disorders, and psychological disorders such as stress/anxiety14

Slide10

Sildenafil (Viagra)

Mechanism of Action

Fazio & Brock, 2004

Slide11

Summary

Nitric oxide (NO) can be produced from dietary nitrates via a two-step process. Bacterial nitrate reductases in the oral cavity reduce nitrates to nitrites, which are then non-enzymatically reduced further from nitrite to NO in the acidic stomach.

NO can also be synthesized from L-Arginine via one of three nitric oxide synthase (NOS) isoforms: neuronal NOS (

nNOS

) which is found in nervous and skeletal tissue, inducible NOS (iNOS) used by immune cells and endothelial NOS (eNOS) used by endothelial cells. Endothelial is expressed constitutively and used by the endothelial cells primarily as a vasodilator.Newly formed NO diffuses into the adjacent smooth muscle cell to make cyclic GMP (cGMP) via activation of guanylyl cyclase. cGMP activates protein kinase G which results in muscle relaxation.Symptoms of Angina pectoris can be treated by Nitroglycerin (sublingually) which dilates the coronary arteries by first entering the smooth muscle cells and entering the mitochondrial matrix where it is converted enzymatically to 1,2-glyceryldinatrate and nitrite. The nitrite molecule is converted to NO enzymatically by Xanthine Oxidereductase which then activates guanylyl cyclase.Sildenafil and other PDE-5 inhibitors are used to treat erectile dysfunction (ED) by preventing the degradation of cyclic GMP (cGMP) in the corpus cavernosum resulting in decreased intracellular Ca2+ in the smooth muscle cell, causing relaxation.

Slide12

Summary

NO

MtALDH

XOR

Mitochondrial Matrix

MtALDH

: Mitochondrial Aldehyde Dehydrogenase

XOR: Xanthine Oxidoreductase

Vascular Smooth Muscle Cell

NO activates Guanylyl Cyclase and cGMP production

cGMP activates downstream signaling to lower [Ca

2+

]

Lower [Ca

2+

] causes muscle relaxation and dilation of blood vessels

Slide13

References

Villanueva, C., &

Giulivi

, C. (2010). Subcellular and cellular locations of nitric-oxide synthase isoforms as determinants of health and disease. 

Free Radical Biology & Medicine, 49(3), 307–316. http://doi.org/10.1016/j.freeradbiomed.2010.04.004Beckman JS. The physiological and pathological chemistry of nitric oxide. In: Lancaster JR Jr, editor. Nitric oxide. Principles and actions. San Diego: Academic Press; 1996. pp. 1–82.Martin N. Hughes, Chapter One - Chemistry of Nitric Oxide and Related Species, Editor(s): Robert K. Poole, In Methods in Enzymology, Academic Press, Volume 436, 2008, Pages 3-19, ISSN 0076-6879, ISBN 9780123742773, https://doi.org/10.1016/S0076-6879(08)36001-7.Lundberg, J. O., Weitzberg, E., & Gladwin, M. T. (2008). The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov

, 7

(2), 156-167. doi:10.1038/nrd2466

Benjamin, N., O'Driscoll, F.,

Dougall

, H., Duncan, C., Smith, L., Golden, M., & McKenzie, H. (1994). Stomach NO synthesis. 

Nature, 368

(6471), 502. doi:10.1038/368502a0

Knowles, R. G., &

Moncada

, S. (1994). Nitric oxide synthases in mammals. Biochemical Journal, 298(Pt 2), 249–258.Förstermann, U., &

Sessa, W. C. (2012). Nitric oxide synthases: regulation and function. European Heart Journal, 33(7), 829–837.

http://doi.org/10.1093/eurheartj/ehr304Kapur S, Bédard S, Marcotte B, Côté H, Marette A. (1997). Expression of Nitric Oxide Synthase in Skeletal Muscle: A Novel Role for Nitric Oxide as a Modulator of Insulin Action. Diabetes. 46 (11) 1691-1700; DOI: 10.2337/diab.46.11.1691

Stamler JS, Gerhard M. (2001). Physiology of Nitric Oxide in Skeletal Muscle. Physiological Reviews

. 81(1) 209-237.Zamora, R., Vodovotz, Y., & Billiar, T. R. (2000). Inducible nitric oxide synthase and inflammatory diseases. Molecular Medicine

, 6(5), 347–373.Lloyd-Jones D, Adams R, Carnethon M, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee [published correction appears in Circulation. 2009;119(3):e182] 

Circulation 2009;119(3):480-486

Cassar, A., Holmes, D. R., Rihal, C. S., & Gersh, B. J. (2009). Chronic Coronary Artery Disease: Diagnosis and Management. Mayo Clinic Proceedings, 84

(12), 1130–1146. http://doi.org/10.4065/mcp.2009.0391Delgado PL, Brannan SK, Mallinckrodt CH, Tran PV, McNamara RK, Wang F, Watkin JG, Detke MJ (2005). "Sexual functioning assessed in 4 double-blind placebo- and paroxetine-controlled trials of duloxetine for major depressive disorder". The Journal of Clinical Psychiatry

. 66 (6): 686–92. 

PMID 15960560. doi:

10.4088/JCP.v66n0603.Harte, C. B., & Meston, C. M. (2008). Acute Effects of Nicotine on Physiological and Subjective Sexual Arousal in Nonsmoking Men: A Randomized, Double-Blind, Placebo-Controlled Trial. The Journal of Sexual Medicine, 5

(1), 110–121. http://doi.org/10.1111/j.1743-6109.2007.00637.xHedon F. (2003). Anxiety and erectile dysfuntion: a global approach to ED enhances results and quality of life. Nature 15(2), S16-S19. doi:10.1038/sj.ijir.3900994

Fazio L., & Brock G. (2004). Erectile dysfunction: management update.

Canadian Medical Association Journal

, 170(9), 1429-1437. doi: 10.1503/cmaj.1020049

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