Nitric Oxide: What a Vascular Surgeon Needs to Know

Summary

Atherosclerosis in the form of coronary artery disease and peripheral vascular disease continues to be a major source of morbidity and mortality. Unfortunately, the procedures and materials that are currently used to alleviate these disease states are temporary at best because of the inevitable injury to the native endothelium and the subsequent impairment of NO release. Since the discovery of NO and its role in vascular biology, a main focus in vascular research has been to create novel mechanisms to use NO to combat neointimal hyperplasia. To date, numerous animal studies have restored NO production to the vasculature and have shown that this inhibits neointimal hyperplasia, improves patency rates, and is safe to the animal. Clinical studies using these novel NO-releasing compounds in humans are on the horizon.

Table 1. Comparison of Different Nitric Oxide Donor Drugs Currently Used for Clinical or Research Purposes
Drug	Mechanism of NO Release	Unique Properties
Diazeniumdiolates	Spontaneous when in contact with physiologic fluids NO release follows first-order kinetics	Stable as solids Various reliable half-lives depending on the structure of the nucleophile it is attached to
Nitrosamines can form as by-products
S-Nitrosothiols	Copper ion-mediated decomposition	Stable as a solid
Direct reaction with ascorbate	Must be protected from light
Homeolytic cleavage by light	Present in circulating blood
Potential for unlimited NO release
Sydnonimines	Requires enzymatic cleavage by liver esterases to form active metabolite	Stable as a solid Must be protected from light
Requires molecular oxygen as an electron acceptor	Requires alkaline pH Releases superoxide as a by-product, which may have negative effects
l-Arginine	Substrate for NOS genes	Stable as a solid
Ease of administration
Dependent on presence of NOS for NO production
Sodium nitroprusside	Requires a one-electron reduction to release NO	Stable as a solid
Must be protected from light
Light can induce NO release	Must be given intravenously
Releases cyanide as a by-product
Organic nitrates	Either by enzymatic cleavage or nonenzymatic bioactivation with sulfhydryl or thiol groups	Stable as a solid
Must be protected from light
Ease of administration
Development of tolerance limits efficacy
NO-releasing aspirin	Require enzymatic cleavage to break the covalent bond between the aspirin and the NO moiety	Stable as a solid
Ease of administration
Inherent benefits of aspirin also
Does not affect systemic blood pressure

Table 1. Comparison of Different Nitric Oxide Donor Drugs Currently Used for Clinical or Research Purposes

Drug

Mechanism of NO Release

Unique Properties

Diazeniumdiolates

Spontaneous when in contact with physiologic fluids

NO release follows first-order kinetics

Stable as solids

Various reliable half-lives depending on the structure of the nucleophile it is attached to

Nitrosamines can form as by-products

S-Nitrosothiols

Copper ion-mediated decomposition

Stable as a solid

Direct reaction with ascorbate

Must be protected from light

Homeolytic cleavage by light

Present in circulating blood

Potential for unlimited NO release

Sydnonimines

Requires enzymatic cleavage by liver esterases to form active metabolite

Stable as a solid

Must be protected from light

Requires molecular oxygen as an electron acceptor

Requires alkaline pH

Releases superoxide as a by-product, which may have negative effects

l-Arginine

Substrate for NOS genes

Stable as a solid

Ease of administration

Dependent on presence of NOS for NO production

Sodium nitroprusside

Requires a one-electron reduction to release NO

Stable as a solid

Must be protected from light

Light can induce NO release

Must be given intravenously

Releases cyanide as a by-product

Organic nitrates

Either by enzymatic cleavage or nonenzymatic bioactivation with sulfhydryl or thiol groups

Stable as a solid

Must be protected from light

Ease of administration

Development of tolerance limits efficacy

NO-releasing aspirin

Require enzymatic cleavage to break the covalent bond between the aspirin and the NO moiety

Stable as a solid

Ease of administration

Inherent benefits of aspirin also

Does not affect systemic blood pressure

Table 1. Comparison of Different Nitric Oxide Donor Drugs Currently Used for Clinical or Research Purposes
Drug	Mechanism of NO Release	Unique Properties
Diazeniumdiolates	Spontaneous when in contact with physiologic fluids NO release follows first-order kinetics	Stable as solids Various reliable half-lives depending on the structure of the nucleophile it is attached to
Nitrosamines can form as by-products
S-Nitrosothiols	Copper ion-mediated decomposition	Stable as a solid
Direct reaction with ascorbate	Must be protected from light
Homeolytic cleavage by light	Present in circulating blood
Potential for unlimited NO release
Sydnonimines	Requires enzymatic cleavage by liver esterases to form active metabolite	Stable as a solid Must be protected from light
Requires molecular oxygen as an electron acceptor	Requires alkaline pH Releases superoxide as a by-product, which may have negative effects
l-Arginine	Substrate for NOS genes	Stable as a solid
Ease of administration
Dependent on presence of NOS for NO production
Sodium nitroprusside	Requires a one-electron reduction to release NO	Stable as a solid
Must be protected from light
Light can induce NO release	Must be given intravenously
Releases cyanide as a by-product
Organic nitrates	Either by enzymatic cleavage or nonenzymatic bioactivation with sulfhydryl or thiol groups	Stable as a solid
Must be protected from light
Ease of administration
Development of tolerance limits efficacy
NO-releasing aspirin	Require enzymatic cleavage to break the covalent bond between the aspirin and the NO moiety	Stable as a solid
Ease of administration
Inherent benefits of aspirin also
Does not affect systemic blood pressure

Table 1. Comparison of Different Nitric Oxide Donor Drugs Currently Used for Clinical or Research Purposes

Drug

Mechanism of NO Release

Unique Properties

Diazeniumdiolates

Spontaneous when in contact with physiologic fluids

NO release follows first-order kinetics

Stable as solids

Various reliable half-lives depending on the structure of the nucleophile it is attached to

Nitrosamines can form as by-products

S-Nitrosothiols

Copper ion-mediated decomposition

Stable as a solid

Direct reaction with ascorbate

Must be protected from light

Homeolytic cleavage by light

Present in circulating blood

Potential for unlimited NO release

Sydnonimines

Requires enzymatic cleavage by liver esterases to form active metabolite

Stable as a solid

Must be protected from light

Requires molecular oxygen as an electron acceptor

Requires alkaline pH

Releases superoxide as a by-product, which may have negative effects

l-Arginine

Substrate for NOS genes

Stable as a solid

Ease of administration

Dependent on presence of NOS for NO production

Sodium nitroprusside

Requires a one-electron reduction to release NO

Stable as a solid

Must be protected from light

Light can induce NO release

Must be given intravenously

Releases cyanide as a by-product

Organic nitrates

Either by enzymatic cleavage or nonenzymatic bioactivation with sulfhydryl or thiol groups

Stable as a solid

Must be protected from light

Ease of administration

Development of tolerance limits efficacy

NO-releasing aspirin

Require enzymatic cleavage to break the covalent bond between the aspirin and the NO moiety

Stable as a solid

Ease of administration

Inherent benefits of aspirin also

Does not affect systemic blood pressure

Table 1. Comparison of Different Nitric Oxide Donor Drugs Currently Used for Clinical or Research Purposes
Drug	Mechanism of NO Release	Unique Properties
Diazeniumdiolates	Spontaneous when in contact with physiologic fluids NO release follows first-order kinetics	Stable as solids Various reliable half-lives depending on the structure of the nucleophile it is attached to
Nitrosamines can form as by-products
S-Nitrosothiols	Copper ion-mediated decomposition	Stable as a solid
Direct reaction with ascorbate	Must be protected from light
Homeolytic cleavage by light	Present in circulating blood
Potential for unlimited NO release
Sydnonimines	Requires enzymatic cleavage by liver esterases to form active metabolite	Stable as a solid Must be protected from light
Requires molecular oxygen as an electron acceptor	Requires alkaline pH Releases superoxide as a by-product, which may have negative effects
l-Arginine	Substrate for NOS genes	Stable as a solid
Ease of administration
Dependent on presence of NOS for NO production
Sodium nitroprusside	Requires a one-electron reduction to release NO	Stable as a solid
Must be protected from light
Light can induce NO release	Must be given intravenously
Releases cyanide as a by-product
Organic nitrates	Either by enzymatic cleavage or nonenzymatic bioactivation with sulfhydryl or thiol groups	Stable as a solid
Must be protected from light
Ease of administration
Development of tolerance limits efficacy
NO-releasing aspirin	Require enzymatic cleavage to break the covalent bond between the aspirin and the NO moiety	Stable as a solid
Ease of administration
Inherent benefits of aspirin also
Does not affect systemic blood pressure

Table 1. Comparison of Different Nitric Oxide Donor Drugs Currently Used for Clinical or Research Purposes

Drug

Mechanism of NO Release

Unique Properties

Diazeniumdiolates

Spontaneous when in contact with physiologic fluids

NO release follows first-order kinetics

Stable as solids

Various reliable half-lives depending on the structure of the nucleophile it is attached to

Nitrosamines can form as by-products

S-Nitrosothiols

Copper ion-mediated decomposition

Stable as a solid

Direct reaction with ascorbate

Must be protected from light

Homeolytic cleavage by light

Present in circulating blood

Potential for unlimited NO release

Sydnonimines

Requires enzymatic cleavage by liver esterases to form active metabolite

Stable as a solid

Must be protected from light

Requires molecular oxygen as an electron acceptor

Requires alkaline pH

Releases superoxide as a by-product, which may have negative effects

l-Arginine

Substrate for NOS genes

Stable as a solid

Ease of administration

Dependent on presence of NOS for NO production

Sodium nitroprusside

Requires a one-electron reduction to release NO

Stable as a solid

Must be protected from light

Light can induce NO release

Must be given intravenously

Releases cyanide as a by-product

Organic nitrates

Either by enzymatic cleavage or nonenzymatic bioactivation with sulfhydryl or thiol groups

Stable as a solid

Must be protected from light

Ease of administration

Development of tolerance limits efficacy

NO-releasing aspirin

Require enzymatic cleavage to break the covalent bond between the aspirin and the NO moiety

Stable as a solid

Ease of administration

Inherent benefits of aspirin also

Does not affect systemic blood pressure

Nitric Oxide: What a Vascular Surgeon Needs to Know

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