Nitric oxide: An overview

doi:10.1016/S0002-9610(05)80017-0

The American Journal of Surgery

Volume 170, Issue 3, September 1995, Pages 292-303

https://doi.org/10.1016/S0002-9610(05)80017-0 Get rights and content

Nitric oxide (NO), a paracrine-acting gas enzymatically synthesized from l-arginine, is a unique biologic mediator that has been implicated in a myriad of physiologic and pathophysiologic states. It is an important regulator of vascular tone and may be the mediator of the hemodynamic changes involved in sepsis and cirrhosis. In addition, there is increasing evidence that NO is involved in coagulation, immune function, inhibitory innervation of the gastrointestinal tract, protection of gastrointestinal mucosa, and the hepatotoxicity of cirrhosis. It has already been speculated that NO may represent a point of control or intervention in a number of disease states. The purpose of this paper is to provide the surgeon with a broad overview of the scientific and clinical aspects of this important molecule.

References (174)

PalmerRMJ et al.
l-arginine is the physiologic precursor for the formation of nitric oxide in endothelium dependent relaxation
Biochem Biophys Res Commun
(1988)
LeoneAM et al.
Constitutive and inducible nitric oxide synthases incorporate molecular oxygen into both nitric oxide and citrulline
J Biol Chem
(1991)
BredtDS et al.
Nitric oxide, a novel neuronal messenger
Neuron
(1992)
FukutoJM et al.
Chemical oxidation of N-hydroxyguanidine compounds
Biochem Pharmacol
(1992)
MoncadaS et al.
Endothelium derived relaxing factor: identification as nitric oxide and role in the control of vascular tone and platelet function
Biochem Pharmacol
(1988)
VallanceP et al.
Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man
Lancet
(1989)
WaldmanSA et al.
Desensitization to nitroglycerin in vascular smooth muscle from rat and human
Biochem Pharmacol
(1986)
MellionBT et al.
Evidence for the inhibitory role of guanosine 3-,5-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators
Blood
(1981)
AlheidU et al.
Human endothelial cells inhibit platelet aggregation by separately stimulating platelet cyclic AMP and cyclic GMP
Eur J Pharmacol
(1989)
RadomskiMW et al.
The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium
Biochem Biophys Res Commun
(1987)

MacDonaldPB et al.

Synergistic inhibition of platelet aggregation by endothelium-derived relaxing factor and prostacyclin

Thromb Res

(1988)

KorbutR et al.

Prolongation of fibrinolytic activity of tissue plasminogen activator by nitrovasodilators

Lancet

(1990)

KwonNS et al.

Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages

J Biol Chem

(1989)

LyonsCR et al.

Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line

J Biol Chem

(1992)

NathanCF et al.

Role of nitric oxide synthesis in macrophage antimicrobial activity

Curr Opin Immunol

(1991)

LancasterJR et al.

EPR detection of heme and nonheme iron-containing protein nitrosylation by nitric oxide during rejection of rat heart allograft

J Biol Chem

(1992)

MoncadaS et al.

Endogenous nitric oxide: physiology, pathology and clinical relevance

Eur J Clin Invest.

(1991)

FurchgottRF et al.

The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine

Nature

(1980)

ÄnggårdEE

Endogenous and exogenous nitrates

Acta Anaesthesiol Scand

(1992)

MikiW et al.

Activation of cerebral guanylate cyclase by nitric oxide

Biochem Biophys Res Commun

(1977)

KatsukiS et al.

Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine

J Cyclic Nucleotide Res

(1977)

HolzmannS

Endothelium-induced relaxation by acetylcholine associated with larger rises in cyclic GMP in coronary arterial strips

J Cyclic Nucleotide Res

(1982)

RapoportRM et al.

Agonist-induced endothelium-dependent relaxation in rat thoracic aorta may be mediated through cGMP

Circ Res

(1983)

MuradF

Cyclic guanosine monophosphate as a mediator of vasodilation

J Clin Invest

(1986)

IgnarroLJ et al.

Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide

PalmerRMJ et al.

Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor

Nature

(1987)

FlavahanNA et al.

G proteins and endothelial responses

Blood Vessels

(1990)

PohlU et al.

Pulsartile perfusion stimulates the release of endothelial autocoids

J Appl Cardiol

(1986)

RubanyiGM et al.

Flow induced release of endothelium derived relaxing factor

Am J Physiol

(1986)

IgnarroLJ et al.

Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates

J Pharmacol Exp Ther

(1981)

StamlerJS et al.

S-Nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds

RosenblumWI

Endothelium-derived relaxing factor in brain blood vessels is not nitric oxide

Stroke

(1992)

PalmerRMJ

The discovery of nitric oxide in the vessel wall

Arch Surg

(1993)

KeelySL et al.

Interaction of acetylcholine and epinephrine on heart cyclic AMP-dependent protein kinases

Am J Physiol

(1978)

FujinoA et al.

Effects of nitroglycerin on ATP-induced Ca⁺⁺-mobilization, Ca⁺⁺-activated K channels and contraction of cultured smooth muscle cells of porcine coronary artery

J Pharmacol Exp Ther

(1991)

FurchgottRF et al.

Endothelium-derived relaxing and contracting factors

FASEB J

(1989)

IgnarroLJ

Biosynthesis and metabolism of endothelium-derived nitric oxide

Annu Rev Pharmacol Toxicol

(1990)

GryglewskiRJ et al.

Mediators produced by the endothelium

Hypertension

(1988)

BathPMW et al.

Nitric oxide and prostacyclin: divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro

Arterioscler Thromb

(1991)

ReesDD et al.

Role of endothelium-derived nitric oxide in the regulation of blood pressure

GardinerSM et al.

Control of regional blood flow by endothelium-derived nitric oxide

Hypertension

(1990)

EkelundU et al.

Role of endothelium-derived nitric oxide in the regulation of tonus in large-bore arterial resistance vessels, arterioles and veins in cat skeletal muscle

Acta Physiol Scand

(1990)

KukovetzWR et al.

Mechanism of nitrate induced vasodilatation and tolerance

Z Kardiol

(1983)

AxellssonKL et al.

Tolerance towards nitroglycerin induced in vivo is correlated to a reduced cGMP response and an alteration in cGMP turnover

Eur J Pharmacol

(1983)

AmezcuaJL et al.

Nitric oxide synthesized from l-arginine regulates vascular tone in the coronary circulation of the rabbit

Br J Pharmacol

(1989)

TolinsJP et al.

Role of endothelium-derived relaxing factor (EDRF) in regulation of renal hemodynamic responses

Am J Physiol

(1990)

PerssonMG et al.

Endogenous nitric oxide as a probable modulator of pulmonary circulation and hypoxic pressor response in vivo

Acta Physiol Scand

(1990)

VilaJ et al.

N^G-Monomethyl-l-arginine and N^G-nitro-l-arginine inhibit endothelium-dependent relaxations in human isolated omental arteries

J Pharm Pharmacol

(1991)

SalomMG et al.

Blockade of pressure natriuresis induced by inhibition of renal synthesis of nitric oxide in dogs

Am J Physiol

(1991)

PanzaJA et al.

Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension

NEJM

(1990)

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^*: Supported by Shriners of North America Research Fellowship and Surgical Infection Society Research Fellowship.

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ReviewNitric oxide: An overview*

Biochem Biophys Res Commun

J Biol Chem

Neuron

Biochem Pharmacol

Biochem Pharmacol

Lancet

Biochem Pharmacol

Blood

Eur J Pharmacol

Biochem Biophys Res Commun

Thromb Res

Lancet

J Biol Chem

J Biol Chem

Curr Opin Immunol

EPR detection of heme and nonheme iron-containing protein nitrosylation by nitric oxide during rejection of rat heart allograft

J Biol Chem

Endogenous nitric oxide: physiology, pathology and clinical relevance

Eur J Clin Invest.

The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine

Nature

Endogenous and exogenous nitrates

Acta Anaesthesiol Scand

Activation of cerebral guanylate cyclase by nitric oxide

Biochem Biophys Res Commun

Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine

J Cyclic Nucleotide Res

Endothelium-induced relaxation by acetylcholine associated with larger rises in cyclic GMP in coronary arterial strips

J Cyclic Nucleotide Res

Agonist-induced endothelium-dependent relaxation in rat thoracic aorta may be mediated through cGMP

Circ Res

Cyclic guanosine monophosphate as a mediator of vasodilation

J Clin Invest

Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide

Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor

Nature

G proteins and endothelial responses

Blood Vessels

Pulsartile perfusion stimulates the release of endothelial autocoids

J Appl Cardiol

Flow induced release of endothelium derived relaxing factor

Am J Physiol

Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates

J Pharmacol Exp Ther

S-Nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds

Endothelium-derived relaxing factor in brain blood vessels is not nitric oxide

Stroke

The discovery of nitric oxide in the vessel wall

Arch Surg

Interaction of acetylcholine and epinephrine on heart cyclic AMP-dependent protein kinases

Am J Physiol

Effects of nitroglycerin on ATP-induced Ca++-mobilization, Ca++-activated K channels and contraction of cultured smooth muscle cells of porcine coronary artery

J Pharmacol Exp Ther

Endothelium-derived relaxing and contracting factors

FASEB J

Biosynthesis and metabolism of endothelium-derived nitric oxide

Annu Rev Pharmacol Toxicol

Mediators produced by the endothelium

Hypertension

Nitric oxide and prostacyclin: divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro

Arterioscler Thromb

Role of endothelium-derived nitric oxide in the regulation of blood pressure

Control of regional blood flow by endothelium-derived nitric oxide

Hypertension

Role of endothelium-derived nitric oxide in the regulation of tonus in large-bore arterial resistance vessels, arterioles and veins in cat skeletal muscle

Acta Physiol Scand

Mechanism of nitrate induced vasodilatation and tolerance

Z Kardiol

Tolerance towards nitroglycerin induced in vivo is correlated to a reduced cGMP response and an alteration in cGMP turnover

Eur J Pharmacol

Nitric oxide synthesized from l-arginine regulates vascular tone in the coronary circulation of the rabbit

Br J Pharmacol

Role of endothelium-derived relaxing factor (EDRF) in regulation of renal hemodynamic responses

Am J Physiol

Endogenous nitric oxide as a probable modulator of pulmonary circulation and hypoxic pressor response in vivo

Acta Physiol Scand

NG-Monomethyl-l-arginine and NG-nitro-l-arginine inhibit endothelium-dependent relaxations in human isolated omental arteries

J Pharm Pharmacol

Blockade of pressure natriuresis induced by inhibition of renal synthesis of nitric oxide in dogs

Review
Nitric oxide: An overview*

Effects of nitroglycerin on ATP-induced Ca⁺⁺-mobilization, Ca⁺⁺-activated K channels and contraction of cultured smooth muscle cells of porcine coronary artery

N^G-Monomethyl-l-arginine and N^G-nitro-l-arginine inhibit endothelium-dependent relaxations in human isolated omental arteries