Nitric oxide: mediator, murderer, and medicine

doi:10.1016/S0140-6736(94)92405-8

The Lancet

Volume 343, Issue 8907, 14 May 1994, Pages 1199-1206

https://doi.org/10.1016/S0140-6736(94)92405-8 Get rights and content

Abstract

In the past ten years several research fields have converged to show that the tiny molecule nitric oxide (NO), a reactive gas, functions both as a signalling molecule in endothelial and nerve cells and as a killer molecule by activated immune cells—and it can be used as a new medicine by inhalation. This article reviews the biology of this remarkable molecule and discusses the implications for clinical medicine.

References (61)

Hh Mitchell et al.
The origin of nitrate in the urine
J Biol Chem
(1916)
Rmj Palmer et al.
L-arginine is the physiological precursor for the formation of nitric oxide in endothelium dependent relaxation
Biochem Biophys Res Comm
(1988)
H. Drexler et al.
Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine
Lancet
(1991)
Tp Misko et al.
Selective inhibition of the inducible nitric oxide synthase by aminoguanidine
Eur J Pharmacol
(1993)
Mg Persson et al.
Single-breath measurements of nitric oxide: increased concentration in asthmatics, and reduction in smokers
Lancet
(1994)
Sa Kharitonov et al.
Endogenous nitric oxide is increased in the exhaled air of asthmatic patients
Lancet
(1994)
J. Garthwaite
Glutamate, nitric oxide and cell-cell signalling in the nervous system
Trends Neurosci
(1991)
Cf Zorumski et al.
Nitric oxide and hippocampal synaptic plasticity
Biochem Pharmacol
(1993)
Rf Furchgott et al.
Endothelium derived relaxing and contractor factors
FASEB J
(1989)
LJ. Ignarro
Endothelium-derived nitric oxide: actions and properties
FASEB J
(1989)

S. Moncada et al.

The 1-arginine-nitric oxide pathway

N Engl J Med

(1993)

C. Nathan

Nitric oxide as a secretory product of mammalian cells

FASEB J

(1992)

Cj Lowenstein et al.

Nitric oxide, a physiologic messenger

Ann Intern Med

(1994)

H. Calver et al.

Nitric oxide and cardiovascular control

Exp Physiol

(1993)

Cl Wright et al.

Protective and pathophysiological roles of nitric oxide in endotoxin shock

Cardiovasc Res

(1992)

MJ. Rand

NANC transmission: nitric oxide as a mediator of non-adrenergic, non-cholinergic neuro-effector transmission

Clin Exp Pharmacol Physiol

(1992)

Km Sanders et al.

Nitric oxide as a mediator of non-adrenergic non-cholinergic neurotransmission

Am J Physiol

(1992)

SH. Snyder

Nitric oxide: first in a new class of neurotransmitters?

Science

(1992)

Ak Nussler et al.

Inflammation, immunoregulation and inducible nitric oxide synthase

J Biol Chem

(1993)

Lc Green et al.

Nitrate biosynthesis in man

Proc Natl Acad Sci USA

(1981)

R. Ivengar et al.

Macrophage synthesis of nitrite, nitrate and N-nitroso-amines: precursors and role of the respiratory burst

Proc Natl Acad Sci USA

(1987)

Ma Marletta et al.

Macrophage oxidation of 1-arginine to nitrite and nitrate: nitric oxide is an intermediate

Biochemistry

(1988)

Jb Hibbs et al.

Nitric oxide: a cytostatic activated macrophage effector molecule

Biochem Biophys Res Comm

(1989)

Rf Furchgott et al.

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

Nature

(1980)

Rmj Palmer et al.

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

Nature

(1987)

P. Needleman et al.

Organic nitrate metabolism

Annu Rev Pharmacol Toxicol

(1976)

Lj Ignarro et al.

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

J Pharmacol Exp Ther

(1981)

M. Hecker et al.

The metabolism of 1-arginine and its significance for the biosynthesis of endothelium derived relaxing factors: cultured endothelial cells recycle 1-citrulline to 1-arginine

Proc Natl Acad Sci

(1990)

L. Buscona et al.

Endothelial nitric oxide synthase: N-terminal determines subcellular localisation

J Biol Chem

(1993)

Wc Sessa et al.

Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression

Circ Res

(1994)

Cited by (778)

Advances in nitric oxide-releasing hydrogels for biomedical applications
2023, Current Opinion in Colloid and Interface Science
Hydrogels provide a plethora of advantages to biomedical treatments due to their highly hydrophilic nature and tissue-like mechanical properties. Additionally, the numerous and widespread endogenous roles of nitric oxide have led to an eruption in research developing biomimetic solutions to the many challenges the biomedical world faces. Though many design factors and fabrication details must be considered, utilizing hydrogels as nitric oxide delivery vehicles provides promising materials in several applications. Such applications include cardiovascular therapy, vasodilation and angiogenesis, antimicrobial treatments, wound dressings, and stem cell research. Herein, a recent update on the progress of NO-releasing hydrogels is presented in depth. In addition, considerations for the design and fabrication of hydrogels and specific biomedical applications of nitric oxide-releasing hydrogels are discussed.
Biomimetic gasotransmitter-releasing alginate beads for biocompatible antimicrobial therapy
2022, Journal of Colloid and Interface Science
Hypothesis: Alginate is widely used in biomedical applications due to its high biocompatibility as well as structural and mechanical similarities to human tissue. Further, simple ionic crosslinking of alginate allows for the formation of alginate beads capable of drug delivery. S-nitrosoglutathione is a water-soluble molecule that releases nitric oxide in physiological conditions, where it acts as a potent antimicrobial gas, among other functions. As macrophages and endothelial cells endogenously produce nitric oxide, incorporating nitric oxide donors into polymers and hydrogels introduces a biomimetic approach to mitigate clinical infections, including those caused by antibiotic-resistant microorganisms. The incorporation of S-nitrosoglutathione into macro-scale spherical alginate beads is reported for the first time and shows exciting potential for biomedical applications.
Experiments: Herein, nitric oxide-releasing crosslinked alginate beads were fabricated and characterized for surface and cross-sectional morphology, water uptake, size distribution, and storage stability. In addition, the NO release was quantified by chemiluminescence and its biological effects against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus were investigated. The biocompatibility of the alginate beads was tested against 3T3 mouse fibroblast cells.
Findings: Overall, nitric oxide-releasing alginate beads demonstrate biologically relevant activities without eliciting a cytotoxic response, revealing their potential use as an antimicrobial material with multiple mechanisms of bacterial killing.
Characterization of a nitric oxide (NO) donor molecule and cerium oxide nanoparticle (CNP) interactions and their synergistic antimicrobial potential for biomedical applications
2021, Journal of Colloid and Interface Science
Broad-spectrum antimicrobials are needed to mitigate the complicated nature of antibiotic-resistant infections. It is imperative to formulate new antimicrobials by combining agents with different mechanisms and broader microbial targets. A combined antimicrobial solution could be a highly critical step towards developing a strategy to prevent polymicrobial infections. Herein, we have investigated the interaction and antimicrobial potential of a solution that contains cerium oxide nanoparticles (CNP) and a nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine (SNAP). It is hypothesized that these two agents induce synergistic effects and would provide broad antimicrobial effects since CNP is known to be an effective antifungal agent while NO released by SNAP is known to be a potent bactericidal agent.
Different concentrations of SNAP and CNP were combined in a solution and tested for colloidal stability, NO release, mammalian cell cytotoxicity, and antimicrobial efficacy against Staphylococcus aureus, Escherichia coli, and Candida albicans, accounting for Gram-positive bacteria, Gram-negative bacteria, and fungi, respectively.
SNAP and CNP combined in equimolar solution of 3 mM were found to be highly virulent for all microbes tested compared to higher amounts of the treatments required individually. These results hold a promising outlook toward the development of broad-spectrum antimicrobial coatings and films with the potential to prevent polymicrobial infections and further enhance biomedical device usage and applications.
Pharmacotherapeutic properties of Strelitzia nicolai aril extract containing bilirubin
2021, South African Journal of Botany
Citation Excerpt :
Both these groups offered a more effective nitric oxide radical scavenging potential as compared to ascorbic acid (IC50 518.4 µg/mL). Nitric oxide has fundamentally binary action in the human body, where low optimum levels standardize numerous biological progressions, while, overproduction of nitric oxide revenues a part in the pathogenesis of various illnesses (Anggard, 1994). Several clinical studies verified that low serum concentrations of bilirubin are associated with a greater danger of developing atherosclerosis (Schwertner et al., 1994).
The surprising discovery of an animal pigment bilirubin found in the plant Strelitzia nicolai, has led us to investigate the biological properties of bilirubin in human physiology. Classically, it is a well-known toxic metabolite in the degradation of hemoglobin, however at slightly elevated levels could be beneficial. Reports suggest that bilirubin could be involved in scavenging of reactive oxygen species (ROS), anti-inflammatory actions and cellular signaling. This study aimed to investigate the possible therapeutic effects of the seed aril extract of S. nicolai and bilirubin. High Performance Liquid Chromatography (HPLC) and Attenuated Total reflectance-Fourier transform Infrared (ATR-FTIR) analysis were used to confirm the organic functional groups present in the aril extracts. Subsequently, the antioxidant potential was established using the hydrogen peroxide and nitric oxide scavenging activity. In vitro anti-bacterial, anti-inflammatory, anti-hypertensive and glucose metabolism assays were conducted. This was also supplemented by in silico binding affinity of bilirubin to the metabolic enzymes. The antioxidant activity of the aril extract using the nitric oxide inhibition showed increased activity when compared with the bilirubin isolate. Conversely, the bilirubin isolate proved to be a potent hydrogen peroxide inhibitor. The S. nicolai aril extract showed greater glucose metabolising potential over bilirubin. Both the bilirubin and aril extract did not possess any antibacterial activity. This study reveals new insights into the presence of the only animal pigment found in the plant species and the potential advantages of bilirubin found in a plant. This study proposes that the constricted view of bilirubin as a toxic compound needs to be revisited. Furthermore, this extract containing bilirubin might be a suitable candidate for the therapeutic intervention for oxidative stress related diseases.
Modulation of Nitric Oxide Bioavailability Attenuates Ischemia-Reperfusion Injury in Type II Diabetes
2021, Journal of Plastic, Reconstructive and Aesthetic Surgery
Diabetes mellitus increases the susceptibility of free tissue transplantations to ischemia-reperfusion injury. The aim of this study was to enhance nitric oxide (NO) bioavailability through exogenous NO synthase and the substrate L-arginine to attenuate ischemia reperfusion-induced alterations in a type 2 diabetes rodent model.
Sixty-four Wistar rats were divided into 8 experimental groups. Type 2 diabetes was established over 3 months with a combination of a high-fat diet and streptozotocin. A vascular pedicle isolated rat skin flap model that underwent 3 h of ischemia was used. At 30 min before ischemia, normal saline, endothelial NOSs (eNOSs), inducible NOSs, neuronal NOSs (1 and 2 IU), and L-arginine (50 mg/kg body weight) were administered by intravenous infusion alone or in combination. Ischemia-reperfusion-induced alterations were measured 5 days after the operation.
The three isoforms of NOS significantly increased the flap vitality rate (VR) between 20% and 28% as compared to the control group (3%). Sole L-arginine administration increased the VR to 33%. The combination of L-arginine with NOS resulted in a further increase in flap VRs (39%-50%). Best results were achieved with the combination of eNOS and L-arginine (50%). An increase in enzyme dosage led to decreased VRs in all NOS isoforms alone and even in combination with L-arginine.
Modulation of NO bioavailability through the exogenous application of NOSs and L-arginine significantly attenuated ischemia-reperfusion-induced alterations in a type 2 diabetic skin flap rat model. The combination of enzyme and substrate result in the highest VRs. Higher enzyme dosage seems to be less effective. This pharmacological preconditioning could be an easy and effective interventional strategy to support the conversion of L-arginine to NO in ischemic and in type 2 diabetic conditions.
Novel surface biochemical modifications of urinary catheters to prevent catheter-associated urinary tract infections
2024, Journal of Biomedical Materials Research - Part B Applied Biomaterials

View all citing articles on Scopus

View full text

Review articleNitric oxide: mediator, murderer, and medicine

Abstract

J Biol Chem

Biochem Biophys Res Comm

Lancet

Eur J Pharmacol

Lancet

Lancet

Trends Neurosci

Biochem Pharmacol

Endothelium derived relaxing and contractor factors

FASEB J

Endothelium-derived nitric oxide: actions and properties

FASEB J

The 1-arginine-nitric oxide pathway

N Engl J Med

Nitric oxide as a secretory product of mammalian cells

FASEB J

Nitric oxide, a physiologic messenger

Ann Intern Med

Nitric oxide and cardiovascular control

Exp Physiol

Protective and pathophysiological roles of nitric oxide in endotoxin shock

Cardiovasc Res

NANC transmission: nitric oxide as a mediator of non-adrenergic, non-cholinergic neuro-effector transmission

Clin Exp Pharmacol Physiol

Nitric oxide as a mediator of non-adrenergic non-cholinergic neurotransmission

Am J Physiol

Nitric oxide: first in a new class of neurotransmitters?

Science

Inflammation, immunoregulation and inducible nitric oxide synthase

J Biol Chem

Nitrate biosynthesis in man

Proc Natl Acad Sci USA

Macrophage synthesis of nitrite, nitrate and N-nitroso-amines: precursors and role of the respiratory burst

Proc Natl Acad Sci USA

Macrophage oxidation of 1-arginine to nitrite and nitrate: nitric oxide is an intermediate

Biochemistry

Nitric oxide: a cytostatic activated macrophage effector molecule

Biochem Biophys Res Comm

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

Nature

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

Nature

Organic nitrate metabolism

Annu Rev Pharmacol Toxicol

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

J Pharmacol Exp Ther

The metabolism of 1-arginine and its significance for the biosynthesis of endothelium derived relaxing factors: cultured endothelial cells recycle 1-citrulline to 1-arginine

Proc Natl Acad Sci

Endothelial nitric oxide synthase: N-terminal determines subcellular localisation

J Biol Chem

Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression

Circ Res

Review article
Nitric oxide: mediator, murderer, and medicine