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NITRIC OXIDE:Basic Science & Role in

Endothelial Disease

Valentino Piacentino III, MD/PhD

Vascular Surgery Basic Science Conference

July 2013


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1. History

2. Role in Vascular Physiology

3. Role in Vascular Pathophysiologyand Hypertension

OUTLINE


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Furchgott & Zawadzki, 1980

DISCOVERY OF EDRF

a.k.a. NITRIC OXIDE (NO)


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DISCOVERY OF EDRF (NO)

Pivotal Experiment Implicating the Role of Intact

Endothelium in Pharmacological Cascade

Furchgott et al., 1981


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Pivotal Experiment Implicating the Role of Intact

Endothelium in Pharmacological Cascade


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Experiment Identifying the Relationship of

cGMP Abundance to Vessel Relaxation


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For their work in EDRF and Nitric Oxide,

-Robert F. Furchgott, PhD-Louis J. Ignarro, PhD

-Ferid Murad, MD, PhD

received the 1998 Nobel Prize for

Physiology and Medicine on

December 10, 1998 in Stockholm, Sweden


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DISCOVERY OF EDRFPivotal Experiment Implicating the Role of Inhibition of

Platelet Aggregation

Radomski et al., 1987


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NO CELL SIGNALING


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NOS I

Central and peripheral neuronal cells

Ca2+ dependent, used for neuronal communication

NOS II Most nucleated cells, particularly macrophages

Independent of intracellular Ca2+

Inducible in presence of inflammatory cytokines

NOS III Vascular endothelial cells

Ca2+ dependent

Vascular regulation

NOS Isoforms


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NO aids in gas exchange between hemoglobin and

cells

Hemoglobin is a vasoconstrictor, Fe scavenges NO

NO is protected by cysteine group when O2 binds

to hemoglobin

During O2 delivery, NO locally dilates blood

vessels to aid in gas exchange Excess NO is picked up by HgB with CO2

Additional Role of NO in theVascular System


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Normal vessels dilate in response to exercise or acetylcholine(ACH)

This response is dependent on endothelial production of NO

Atherosclerotic vessels are characterized by having endothelialdysfunction and constrict in response to exercise or ACH

This is explained by either a loss of endothelial cells or loss ofeNOS expression and NO production

Some theorize that proliferation of smooth muscles cellswith altered or less endothelial lining decreased thesensitivity of vascular tone control.

Cai H, Harrison DG. Circ Res. 2000;87:840-844.Bonetti PO et al. ATVB. 2003;23:168-175.

Endothelial DysfunctionDisrupted NO Signaling


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Abnormalities of endothelial cells change thevascular resistance and vessel physiology andthus, the arterial pressure.

With Hypertension, morphological vascular

alteration affecting the following occur: Endothelium

Intima

Vascular smooth muscle

Damaged endothelium disrupts vasodilation and isprocoagulant: O2- (free radicals)

Thromboxane A2

Endothelin-1 Peptide vasoconstrictor

NO and Hypertension

f


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Mitogenic activation described in hypertension is inducedby : Increased shear stress

Increase in sympathetic activity

Release of vasoactive agents such as endothelin, Ang II,

Endothelin plasma concentrations alters NO signaling andactivates cell proliferation.

Basal formation of NO decreased in hypertension.

Hypertension alters the balance of NO and O2 (super oxideanion). Patient with hypertension have elevated levels super oxide anion, H2O2,

lipid peroxides, endothelin with simultaneous decrease in eNO, SOD, Vit Eand LCPUFAs.

Endothelial DysfunctionDisrupted NO Signaling


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Pivotal to regulating vasculature tone

Helps to relax smooth muscle and minimize

platelet aggregation

Disruption in normal signaling occur with NOSalterations and contributions of free radicals.

As the VascularSurgeryMantra decrees,

NITRIC OXIDE

PROTECT THE ENDOTHELIUM!


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XXXXX

History


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History


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Documents

72013 Vas Ular Conf No