Nitric Oxide

by Balligand, J. L.

• ISBN13: 9783540661221
• ISBN10: 3540661220
• Edition: 1st
• Format: Hardcover
• Copyright: 2000-06-01
• Publisher: SPRINGER

Summary

Nitric oxide (NO) has been discovered to play a fundamental role in a number of biological phenomena. This book describes various aspects of nitric oxide biology, physiology and pharmacology. It is divided into three sections. The first part deals with the basic chemistry and enzymology of NO, thus laying a molecular basis for what follows. The middle part surveys the physiological roles of NO under normal conditions. The concluding part explores the relevance of NO to disease, both as a pathogenic factor and a therapeutic target. The book thus provides detailed information on NO biology to the reader unfamiliar with the field and represents a reference work for scientists working in an NO-related field of biomedical research. Each chapter, written by experts in their fields, gives a broad introduction followed by a comprehensive review of the current knowledge and a detailed reference list.

Table of Contents

Introduction	1	(6)
S. Moncada
Section I: Chemistry
The Chemical Biology of Nitric Oxide. Balancing Nitric Oxide with Oxidative and Nitrosative Stress	7	(26)
D.A. Wink
K.M. Miranda
M.G. Espey
J.B. Mitchell
M.B. Grisham
J. Fukuto
M. Feelisch
Introduction	7	(2)
Direct Effects	9	(5)
Reactions Between NO and Metal Complexes	9	(2)
Interaction of NO with Metal-Oxygen and Metal-Oxo Complexes	11	(2)
The Reaction of NO with Radical Species	13	(1)
Indirect Effects	14	(1)
Nitrosative Stress	15	(3)
Oxidative Stress	18	(3)
NO/O2- Chemistry	21	(2)
Conclusion	23	(10)
References	24	(9)
Section II: Biochemistry and Pharmacology of NO Synthesis and Action
Enzymology of Nitric Oxide Synthases	33	(38)
D.J. Stuehr
S. Ghosh
Introduction	33	(1)
NOS Structure-Function	33	(16)
Domain Organization	33	(2)
NOS Oxygenase Domains and Mutagenesis	35	(1)
Arg-Binding Site	36	(2)
H4biopterin-Binding Site	38	(3)
N-Terminal Hairpin Loop	41	(1)
NOS Cysteines and Metal Binding	42	(1)
NOS Reductase Domains	43	(1)
General Features	43	(1)
Catalytic Properties and Response to CaM	44	(1)
Mutagenesis	45	(2)
CaM Activation of NOS	47	(1)
Mechanism of Action	47	(1)
Structural Determinants of CaM Binding	47	(1)
NOS Domain Interactions	48	(1)
Catalysis of NO Synthesis from L-Arg	49	(9)
Heme-NO Complex Formation	49	(1)
NOS Partitioning into an NO-Bound Form During Catalysis	49	(1)
Impact of NO Complex Formation on NOS Catalysis	49	(1)
The NO Complex and NOS O2 Response	50	(1)
The Active Catalytic Cycle	51	(1)
Steps involved, O2, Binding and Activation	51	(1)
NOS Heme Iron Reduction	52	(1)
Control of Heme Reduction by H4B and Arg	53	(1)
Enzyme Structural Features that may Impact on NO Synthesis	54	(2)
Roles for Heme and H4B	56	(2)
Control Mechanisms and Targeting	58	(13)
NOS Dimerization	58	(1)
Stepwise Assembly Mechanism	58	(1)
Positive and Negative Regulation	59	(1)
Is NOS Oxygenase Domain Structure Modified by Dimerization, H4B Binding, or Both?	59	(1)
Another Type of NO Inhibition	60	(1)
Interactions Between NOS and Other Proteins	60	(1)
PDZ, PIN	60	(1)
Caveolins	61	(1)
Heat Shock Proteins	62	(1)
Kalirin	62	(1)
References	62	(9)
Regulation of Nitric Oxide Synthase Expression and Activity	71	(22)
U. Forstermann
Introduction	71	(2)
Nitric Oxide Synthase I	73	(2)
Cellular Expression of NOS-I	73	(1)
Regulation of NOS-I Expression	73	(1)
Regulation of NOS-I Activity	74	(1)
Nitric Oxide Synthase II	75	(4)
Cellular Expression of NOS-II	75	(1)
Regulation of NOS-II Expression	75	(3)
Regulation of NOS-II Activity	78	(1)
Nitric Oxide Synthase III	79	(3)
Cellular Expression of NOS-III	79	(1)
Regulation of NOS-III Expression	79	(2)
Regulation of NOS-III Activity	81	(1)
Summary and Conclusions	82	(11)
References	83	(10)
Enzymology of Soluble Guanylyl Cyclase	93	(18)
D. Koesling
A. Friebe
Introduction	93	(1)
Regulation of sGC	94	(7)
NO, the Physiological Activator of sGC	94	(2)
Mechanism of Activation of sGC by NO	96	(1)
Termination of the NO-Induced Activation	96	(2)
CO: a Physiological Activator of sGC?	98	(1)
Redox Regulation of sGC?	98	(1)
Modulators of sGC	99	(1)
ODQ: An Inhibitor of the Stimulated Activity of sGC	99	(1)
YC-1: A Novel Activator of sGC	99	(2)
Structure of sGC	101	(4)
Isoforms and Tissue Distribution	101	(1)
Primary Structure and Homology among the Subunits of sGC	102	(1)
The Regulatory Heme-Binding Domain	102	(1)
Catalytic Domain	103	(2)
Conclusions	105	(6)
References	105	(6)
Nitric Oxide Synthase Inhibitors I: Substrate Analogs and Heme Ligands	111	(26)
J.F. Parkinson
Introduction	111	(3)
Therapeutic Concepts for NOS Inhibitors	111	(1)
NOS-Knockout Mice	112	(2)
Mechanism-Based NOS Inhibitors	114	(23)
Substrate-Based NOS Inhibitors	114	(1)
Arginine Analogs	114	(5)
Amidine-Containing Inhibitors	119	(5)
Summary for Substrate Analogs	124	(1)
Heme Ligands	124	(3)
Summary for Heme Ligands	127	(1)
Towards Rational Design of NOS Inhibitors	127	(2)
References	129	(8)
Nitric-Oxide-Synthase Inhibitors II-Pterin Antagonists/Anti-Pterins	137	(22)
E.R. Werner
H.H.H.W. Schmidt
Introduction	137	(1)
H4B Dependence of the NOS Reaction	137	(3)
NOS-Associated H4B	138	(1)
Allosteric and Stabilising Effects	138	(1)
Possible Electron-Transfer Role	138	(2)
The Pterin-Binding Site	140	(1)
Pterin-Based Inhibition OF NOS	140	(14)
Manipulating Intracellular H4B Levels	140	(1)
Approaches to Pterin Antagonists	141	(1)
4-Amino-H4B	142	(1)
Effects of 4-Amino-H4B on Purified Enzymes	142	(2)
Effects of 4-Amino-H4B on Cultured Cells	144	(1)
Effects of 4-Amino-H4B in Animals	144	(1)
Further 4-Aminopteridines	145	(1)
The 4-Amino Function	145	(1)
The 2, 5 and 7 Positions	145	(2)
The C6 Side Chain and Pterin Exosite	147	(2)
Conclusion	149	(1)
4-Oxopteridines as Inhibitors of NOS	149	(2)
Specificity and the Anti-Pterin-Binding Domain	151	(1)
Type-I and -II Anti-Pterins	151	(2)
4-Oxo Anti-Pterins in Intact Cells	153	(1)
Conclusions	153	(1)
Outlook	154	(5)
References	155	(4)
Mechanisms of Cellular Resistance Against Nitric Oxide	159	(20)
B. Brune
Andreas von Knethen
K. Sandau
Introduction	159	(2)
Cell Death: Apoptosis Versus Necrosis	159	(2)
NO: Formation and Signaling	161	(1)
Cytotoxicity of Nitric Oxide	161	(3)
NO-Mediated Cytotoxicity/Apoptosis	161	(1)
Apoptotic-Signal Transduction: p53 Accumulation and Caspase Activation	162	(2)
Resistance Against NO-Mediated Toxicity	164	(5)
Antagonism by Bcl-2-Family Members	164	(1)
Protection by NO and O2-Co-Generation	164	(2)
Protective Protein Expression	166	(1)
cGMP Formation and Protein Thiol Modification	167	(2)
Conclusions	169	(10)
References	171	(8)
Section III: Physiological Functions of NO
Nitric Oxide and Regulation of Vascular Tone	179	(28)
R. Busse
I. Fleming
Regulation of Vascular Tone	179	(1)
Endothelial Nitric Oxide Synthase	180	(7)
Ca2+-Dependent eNOS Activation	181	(1)
The Interaction of eNOS with CaM	181	(1)
The Interaction of eNOS with Caveolin-1	182	(1)
Other Modulators of eNOS Activity	183	(1)
Endothelial NOS-Associated Protein-1	183	(1)
Hsp90	183	(1)
Phosphorylation	184	(1)
Ca2+-Independent eNOS Activation	185	(1)
The Link Between Fluid Shear Stress and NO Production	186	(1)
Mechanisms of Action of NO on Vascular Smooth Muscle	187	(6)
Effects of NO on [Ca2+]i	187	(2)
Effects of NO on Cyclic Nucleotide Phosphodiesterase III	189	(1)
Effects of NO on Other Systems Involved in the Control of Vascular Tone	190	(1)
Endothelin-1	190	(1)
Noradrenaline	190	(1)
NO and Iron-Containing Proteins	191	(1)
NO and Mitochondrial Respiration	191	(1)
Dinitrosyl Iron Complexes, Nitrosothiol-Containing Proteins and Vascular Tone	192	(1)
NO and the Control of Blood Flow	193	(14)
Interaction between NO and O2	195	(2)
NO and 20-HETE	197	(1)
References	198	(9)
Regulation of Cardiac Function by Nitric Oxide	207	(28)
J.-L. Balligand
Introduction	207	(1)
Specifics on Cardiac NOS Biology	207	(7)
Which Isoform(s)?	207	(2)
How are they Regulated?	209	(1)
Endothelial Nitric Oxide Synthase	209	(1)
Expressional Control	209	(1)
Acute Regulation of Activity	210	(1)
Mechanical Forces	210	(1)
Beating Rate	210	(1)
β-Adrenergic Agonists	211	(1)
Muscarinic Cholinergic Agonists	211	(1)
Acute Effect of Cytokines	212	(1)
Inducible Nitric Oxide Synthase	213	(1)
Expressional Control	213	(1)
Acute Regulation of Activity	213	(1)
Intracellular Mechanisms of Action of NO in Cardiac Muscle Cells	214	(5)
Cyclic GMP-Dependent Mechanisms	214	(1)
Contraction-Enhancing Mechanisms	214	(3)
Contraction-Decreasing Mechanisms	217	(1)
Cyclic GMP-Independent Mechanisms	218	(1)
Contraction-Enhancing Mechanisms	218	(1)
Contraction-Decreasing Mechanisms	218	(1)
Regulation of Cardiac Function by eNOS	219	(3)
Basal Systolic and Diastolic Function	219	(1)
Regulation of β-Adrenergic Response	220	(1)
Regulation of Muscarinic Cholinergic Response	221	(1)
Regulation of Cardiac Function by iNOS	222	(3)
Basal Contractile Function	223	(1)
Regulation of β-Adrenergic Response	224	(1)
iNOS and Cardiomyocyte Biology	224	(1)
Conclusion and Perspectives	225	(10)
References	226	(9)
Regulation of Platelet Function	235	(24)
L. McNaughton
A. Radomski
G. Sawicki
M. W. Radomski
Introduction	235	(1)
Platelet Rheology	235	(1)
Platelet Control	235	(1)
Nitric Oxide	236	(5)
NO in Platelets: the Quest	236	(1)
Molecular Biology of Platelet NOS	236	(1)
Regulation of NO Generation in Platelet Microenvironment	237	(1)
Cell Activation	237	(1)
Role of Substrate	238	(1)
Role of Co-Factors	238	(1)
Rheology	238	(1)
Physiological Effects of NO on Platelets	238	(1)
Effects of NO on Platelet Function In Vitro	238	(1)
Effects of NO on Platelet Function In Vivo	239	(1)
NO in Synergistic Regulation of Platelet Function	239	(1)
The Mechanisms of NO Action on Platelets	239	(2)
The Role of NO in the Pathogenesis of Vascular Disorders Associated with Platelet Activation	241	(3)
Pathomechanism	241	(1)
Atherosclerosis, Thrombosis and Hypertension	242	(1)
Diabetes Mellitus and Stress	242	(1)
Pre-Eclampsia	243	(1)
Septicaemia	243	(1)
Uraemia	244	(1)
Cancer	244	(1)
Pharmacological Modulation of Formation and Action of NO on Platelets	244	(5)
L-Arginine	244	(1)
Stimulators of NOS	245	(1)
Inhibitors of NOS and NO Scavengers	245	(1)
NO Gas	246	(1)
NO Donors	246	(2)
Novel NO Donors	248	(1)
NO-Independent Activators of GC-S	249	(1)
E. Conclusions	249	(10)
References	249	(10)
The Physiological Roles of Nitric Oxide in the Central Nervous System	259	(18)
J. Garthwaite
Introduction	259	(2)
Acute Actions of NO	261	(5)
Synaptic Transmission	261	(2)
Gap Junctions	263	(1)
Local Cerebral Blood Flow	264	(1)
Glial Cells	265	(1)
NO and Synaptic Plasticity	266	(2)
Short-Term Plasticity	266	(1)
Long-Term Potentiation	267	(1)
Long-Term Depression	268	(1)
NO and Developmental Plasticity	268	(2)
Concluding Remarks	270	(7)
References	270	(7)
The Role of Nitric Oxide in the Peripheral Nervous System	277	(38)
W. Martin
Introduction	277	(4)
Nomenclature	277	(1)
Historical Perspective	277	(1)
The Concept of Non-Adrenergic, Non-Cholinergic Neurotransmission	278	(1)
The Concept of Nitrergic Nerves	279	(2)
Properties of Nitrergic Nerves	281	(3)
Properties of nNOS	281	(1)
Localisation of nNOS in Nitrergic Nerves	281	(1)
Anatomical Distribution and Physiological Functions of Nitrergic Nerves	282	(1)
Unitary Transmission, Dual Transmission and Co-Transmission	283	(1)
Nature of the Nitrergic Neurotransmitter	284	(5)
Predicted Differences in the Effects of Drugs on Nerve-Derived and Bath-Applied NO	285	(1)
Evidence that the Nitrergic Neurotransmitter is a NO-Like or NO-Releasing Molecule	285	(2)
Evidence that NO is the Nitrergic Neurotransmitter and is Protected from Inactivation	287	(2)
Pre-Junctional Mechanisms	289	(4)
Activation of Nitrergic Nerves	289	(1)
Role of Ca2+ in Activation of Nitrergic Nerves	289	(1)
Pre-Junctional Augmentation of Nitrergic Transmission	290	(1)
Blockade of Nitrergic Transmission by Inhibition of NOS	291	(2)
Nerve-Nerve Interactions	293	(2)
Nitrergic-Adrenergic Interactions	293	(1)
Nitrergic-Cholinergic Interactions	293	(1)
Nitrergic-NANC Interactions	294	(1)
Junctional and Post-Junctional Mechanisms	295	(2)
Scavengers of NO	295	(1)
Blockade of Soluble Guanylate Cyclase	295	(1)
Post-Junctional Potentiation of Nitrergic Transmission	296	(1)
Post-Junctional Transduction Pathway	297	(2)
Role of Cyclic GMP	297	(1)
Inhibition of Calcium Mobilisation	297	(1)
Role of Membrane Hyperpolarisation	298	(1)
Concluding Remarks	299	(16)
References	299	(16)
Nitric Oxide and Neuroendocrine Function	315	(14)
P. Navarra
A. Costa
A. Grossman
Introduction	315	(1)
NO Biosynthesis in the Hypothalamus: Relationship Between Localization and Function	315	(2)
Physiology of Hypothalamic NO	317	(12)
Vasopressin and Oxytocin	317	(1)
Corticotrophin-Releasing Hormone and the Hypothalamo-Pituitary-Adrenal Axis	318	(2)
Hypothalamo-Pituitary-Gonadal Axis	320	(2)
Other Hormonal Systems	322	(1)
References	323	(6)
The Role of Nitric Oxide in Kidney Function	329	(36)
E. Hackenthal
Introduction	329	(1)
Nitric Oxide Synthase Isoforms in the Kidney	329	(1)
Distribution of NOS in the Kidney	330	(3)
Distribution of NOS in the Renal Vasculature	330	(1)
Distribution of NOS in Renal Tubules	331	(2)
Distribution of NOS in Renal Nerves	333	(1)
Physiological Roles of NO	333	(9)
Role of NO in the Regulation of Renal Blood Flow	333	(1)
Endogenous Mediators of NO Release	333	(1)
Inhibitors of NOS	334	(1)
Role of NO in Glomerular Circulation	335	(1)
Role of NO in Renal Autoregulation	336	(2)
The Myogenic Response and NO	338	(1)
NO and Tubuloglomerular Feedback	338	(3)
Role of NO in the Control of Medullary Blood Flow and Pressure Natriuresis	341	(1)
Tubular Functions of NO	342	(1)
NO, Renin Secretion and Renin Synthesis	343	(9)
NO as a Stimulator of Renin Secretion	344	(1)
NO and Pressure Control of Renin Release	344	(3)
NO, Renal Nerves and Renin Release	347	(1)
NO and Macula-Densa-Mediated Renin Secretion	348	(2)
NO, Prostaglandins and Renin Synthesis	350	(2)
Concluding Remarks	352	(13)
References	353	(12)
Section IV: The Role of Pharmacological Action of NO in Human Disease
Therapeutic Importance of Nitrovasodilators	365	(20)
G. Kojda
Introduction	365	(2)
Mechanisms of Action	367	(1)
Hemodynamic Actions	368	(4)
Preferential Venodilation	368	(1)
Vessel-Size-Selective Coronary Vasodilation	369	(1)
Effects on Blood Pressure	370	(1)
Other Effects on Hemodynamics	371	(1)
Effects on Platelets	371	(1)
Pharmacokinetics	372	(1)
Clinical Use	373	(4)
Effects in Stable Angina	373	(1)
Treatment and Short-Term Prevention of Anginal Attacks	374	(1)
Long-Term Management of Chronic Stable Angina	374	(1)
Effects in Unstable Angina	374	(1)
Effects in Acute Myocardial Infarction	375	(1)
Effects in Heart Failure	375	(1)
Effects in Gastrointestinal Disorders	376	(1)
Effects on the Uterus	376	(1)
Nitrate Tolerance	377	(1)
Side Effects and Contraindications	378	(7)
References	378	(7)
Therapeutic Potential of NOS Inhibitors in Septic Shock	385	(14)
P. Vallance
D. Rees
S. Moncada
Introduction	385	(1)
Clinical Features of Sepsis	385	(2)
Cardiovascular Changes	386	(1)
Tissue Oxygenation	386	(1)
Tissue and Organ Damage	386	(1)
NO in Experimental Models of Shock	387	(3)
Cardiovascular Changes	388	(1)
Tissue Oxygenation	388	(1)
Tissue and Organ Damage	389	(1)
NO in Clinical Sepsis	390	(4)
iNOS Induction in Humans	391	(1)
Cardiovascular Changes	391	(2)
Tissue Oxygenation	393	(1)
Tissue and Organ Damage	393	(1)
Outcome Studies	394	(1)
Conclusions	394	(5)
References	395	(4)
Inhalation Therapy with Nitric Oxide Gas	399	(44)
D. Keh
H. Gerlach
K. Falke
Introduction	399	(1)
Therapy with NO Gas	400	(17)
NO Inhalation in ARDS Patients	400	(1)
Introduction	400	(1)
Acute Effects of NO Inhalation in Patients with ARDS	401	(3)
NO INhalation and Non-Cardiogenic Pulmonary Edema	404	(1)
Dose-Response Relationship of NO Inhalation	404	(4)
Effects of NO Inhalation on Right Heart Function	408	(1)
NO Non-Responders	409	(1)
NO Dependency	409	(1)
Recent Studies of NO Inhalation in ARDS	410	(2)
NO Inhalation in PPHN	412	(2)
NO Inhalation in Other Diseases	414	(1)
NO Autoinhalation	415	(2)
NO Metabolism, Toxicology, and Adverse Effects	417	(7)
NO Uptake and Clearance	417	(1)
NO and Nitrogen Dioxide	417	(2)
NO, Superoxide, and Peroxynitrite	419	(3)
NO and S-Nitrosothiols	422	(1)
Methemoglobin	422	(2)
NO Administration	424	(19)
The NO/Nitrogen Gas Mixture	424	(1)
Delivery of NO	425	(4)
Monitoring of NO Inhalation	429	(1)
Chemiluminescence	429	(1)
Electrochemical Anlyzers	430	(2)
References	432	(11)
The Function of Nitric Oxide in the Immune System	443	(50)
C. Bogdan
Introduction	443	(1)
Type-2 NOS (NOS-II, iNOS) and the Immune System	444	(23)
Cell Types	444	(1)
Induction and Regulation	444	(1)
Overview	444	(3)
Transcriptional Regulation	447	(2)
Positive and Negative Regulation of NOS-II by Cytokines, Ligand-Receptor Interactions, and Microbial Products	449	(1)
Cytokines	449	(2)
Cross-Linking of Cell-Surface Receptors	451	(1)
Microbial Products	451	(2)
Functions	453	(1)
Overview	453	(1)
Antimicrobial Functions	453	(1)
Resuts from Host-Cell-Free Experiments and Studies in Rodents	453	(3)
NO as an Antimicrobial Molecule in Humans	456	(1)
Interaction Between NO and Other Antimicrobial Effector Pathways	457	(2)
Anti-Tumor Function	459	(1)
Autotoxic Functions	460	(1)
Regulatory Functions	461	(1)
Regulation of Proliferation, Apoptosis and Survival, and Cytotoxic Activity of Lymphcytes	462	(1)
Modulation of Cytokine Responses	463	(2)
NO and IL-12	465	(1)
Leukocyte Chemotaxis and Adhesion	466	(1)
Immune (T-Helper Cell) Deviation	466	(1)
Other NOS Isoforms and Perspective	467	(26)
References	468	(25)
Nitric Oxide: A True Inflammatory Mediator	493	(32)
R. Zamora
T.R. Billiar
Introduction	493	(1)
Biosynthesis of NO	493	(1)
NO and Inflammation	494	(8)
The Chemical Mediators of the Vascular Response	495	(1)
NO and the Vascular Response to Injury	496	(2)
NO in Acute Inflammatory Responses	498	(1)
NO and Inflammatory Cytokines	499	(2)
NO and Arachidonic Acid Metabolites	501	(1)
NO in Immunity and Chronically Inflammatory Diseases	502	(8)
NO and the Immune Response	502	(4)
NO and Chronic Inflammatory Processes	506	(2)
Induced NO in Antimicrobial Defense Mechanisms	508	(2)
Conclusions	510	(15)
References	511	(14)
Nitric Oxide in the Immunopathogenesis of Type 1 Diabetes	525	(20)
V. Burkart
H. Kolb
Introduction	525	(1)
Type 1 Diabetes	525	(3)
Clinical Characteristics	525	(1)
Studies on the Immunopathogenesis of Type 1 Diabetes	526	(1)
Cellular Immune Reactions Against Pancreatic Islet Cells	527	(1)
NO as a Major Pathogenetic Factor in Immune-Mediated Diabetes	528	(5)
Cellular Sources of β-Cell-Damaging NO	528	(1)
Macrophages	528	(1)
Endothelial Cells	529	(1)
β Cells	529	(1)
Primary Target Structures of NO in the β Cell	530	(1)
Mitochondria	530	(1)
Nuclear DNA	530	(1)
Pathways of NO-Induced β-Cell Death	531	(1)
Mitochondrial Damage	531	(1)
Apoptotic Pathway	531	(1)
Poly(Adenosine Diphosphate-Ribose)Polymerase-Dependent Pathway	532	(1)
Open Issues	533	(1)
Strategies to Protect Islet Cells from NO-Induced Damage	534	(3)
Suppression of NO Formation	534	(1)
Improvement of β-Cell Defense Mechanisms	535	(1)
Inhibition of the PARP-Dependent Pathway	536	(1)
Regulation of Th1/Th2 Balance in Islet Inflammation	536	(1)
Concluding Remarks	537	(8)
References	538	(7)
The Role of Nitric Oxide in Cardiac Ischaemia-Reperfusion	545	(26)
P.A. MacCarthy
A.M. Shah
Introduction	545	(1)
Consequences of Myocardial Ischaemia-Reperfusion	546	(1)
Interaction Between NO and ROS	547	(1)
Potential Ways in Which NO and ONOO- May Influence Myocardial Ischaemia-Reperfusion	547	(4)
Changes in Coronary Blood Flow and Vessel-Blood Cell Interactions	550	(1)
Direct Effects of NO and ONOO- on Myocardium	550	(1)
Experimental Studies	551	(10)
Post-Ischaemic Endothelial Dysfunction	551	(1)
Myocardial Function	552	(1)
NO as a Beneficial Agent	552	(1)
Post-Ischaemic Contractile Function	552	(4)
Buffer-Perfused Preparations	556	(1)
Blood/Neutrophil-Perfused Preparations	557	(1)
Myocardial Infarction	557	(1)
Reperfusion-Induced Arrhythmia	558	(1)
NO as a Deleterious Agent	559	(2)
Reasons for Conflicting Experimental Results	561	(1)
NO and Ischaemic Preconditioning	562	(1)
Summary and Conclusions	563	(8)
References	564	(7)
Nitric Oxide and Atherosclerosis	571	(48)
H. Bult
K.E. Mathys
M.M. Kockx
Introduction	571	(1)
Stages of Intimal Thickening and Atherosclerosis	571	(2)
The Physiological Intima: the Soil for Atherosclerosis	571	(1)
Successive Stages of Atherosclerosis	572	(1)
Accelerated Atherosclerosis	572	(1)
Pathogenic Mechanisms	573	(2)
The Initiation of Atherosclerosis	573	(1)
Remodeling of the Artery	574	(1)
Plaque Stability	575	(1)
Dysfunction of eNOS Signaling in Atherosclerosis	575	(2)
Impaired Relaxation in Isolated Arteries	575	(1)
In vivo Studies of the eNOS Defect in Atherosclerotic Arteries	576	(1)
The Systemic Nature of the Defective eNOS Signaling	576	(1)
Explanations for the Defective eNOS-Signaling Pathway	577	(7)
Endothelial Receptor Dysfunction	577	(1)
Expression of eNOS mRNA and Protein	578	(1)
THB Deficiency	579	(1)
Arginine Availability	579	(1)
Conduit Arteries with Atherosclerosis	579	(1)
Conduit Arteries Without Overt Atherosclerosis	580	(1)
Arterioles Without Overt Atherosclerosis	580	(1)
Possible Explanations for the Arginine Paradox	580	(1)
Endogenous NOS Antagonists	581	(1)
Negative Feedback by NO Derived from iNOS	582	(1)
Superoxide Anion Inactivates NO	582	(2)
Expression of iNOS	584	(1)
iNOS Expression in Atherosclerosis	584	(1)
Mechanical Injury and iNOS Expression	585	(1)
NO: a Radical with Anti-Atherogenic Properties	585	(8)
In Vitro Studies	585	(1)
Interference with Oxidative Processes	585	(2)
Maintenance of Endothelial Barrier Function	587	(1)
Interference with Leukocyte Recruitment	587	(1)
Antiproliferative Action of NO	587	(1)
Antiplatelet Effects of NO	588	(1)
In Vivo Studies	588	(1)
Inhibition of Experimental Atherosclerosis	588	(2)
Inhibition of Intimal Thickening by NO	590	(1)
Neointima Formation after Balloon Denudation	590	(1)
Intimal Hyperplasia Due to Perivascular Manipulation	591	(1)
Inhibition of Intimal Hyperplasia in Vein Grafts	592	(1)
Inhibition of Intimal Hyperplasia Induced by Balloon Angioplasty	592	(1)
Stimulation of Compensatory Remodeling	592	(1)
NO: a Radical Promoter of Atherosclerosis	593	(5)
Peroxynitrite Formation	593	(1)
LDL Oxidation	594	(1)
Oxidative Cell Injury	594	(1)
NO and Apoptosis	595	(1)
NO as an Inhibitor of Apoptosis in the Normal Arterial Wall	595	(1)
NO as an Inducer of Apoptosis	596	(1)
PARP- and NO-Induced DNA Repair and Apoptosis	596	(1)
p53/p21 and NO-Induced DNA Repair and Apoptosis	596	(1)
NO, Apoptosis and Plaque Stability	597	(1)
Matrix Breakdown	598	(1)
Summary	598	(21)
References	599	(20)
Nitric Oxide in Brain Ischemia/Reperfusion Injury	619	(20)
M. Sasaki
T.M. Dawson
V.L. Dawson
Introduction	619	(1)
Neuronal NOS	619	(4)
Endothelial NOS	623	(3)
Immunologic NOS	626	(1)
The Role of NO in Focal Ischemic Brain Damage	627	(2)
Targets of NO	629	(2)
Summary	631	(8)
References	631	(8)
Therapeutic Potential of Nitric Oxide Synthase Gene Manipulation	639	(16)
H.E. von der Leyen
V.J. Dzau
General Principles of Gene Therapy	639	(1)
Gain of Function	640	(6)
Overexpression of the NOS Gene	640	(1)
Overexpression of Endothelial Constitutive NOS	641	(3)
Overexpression of Inducible NOS	644	(2)
Loss of Function	646	(1)
Inhibition of NOS by Antisense Technology	646	(1)
Transgenic Animals with Disrupted NOS Gene	647	(2)
Potential Therapeutic Applications of NOS Gene Transfer	649	(6)
References	649	(6)
Subject Index	655