3,601,997 research outputs found
Therapeutic uses of inorganic nitrite and nitrate - from the past to the future
No full textPotential carcinogenic effects, blue baby syndrome, and occasional intoxications caused by nitrite, as well as the suspected health risks related to fertilizer overuse, contributed to the negative image that inorganic nitrite and nitrate have had for decades. Recent experimental studies related to the molecular interaction between nitrite and heme proteins in blood and tissues, the potential role of nitrite in hypoxic vasodilatation, and an unexpected protective action of nitrite against ischemia/reperfusion injury, however, paint a different picture and have led to a renewed interest in the physiological and pharmacological properties of nitrite and nitrate. The range of effects reported suggests that these simple oxyanions of nitrogen have a much richer profile of biological actions than hitherto assumed, and several efforts are currently underway to investigate possible beneficial effects in the clinical arena. We provide here a brief historical account of the medical uses of nitrite and nitrate over the centuries that may serve as a basis for a careful reassessment of the health implications of their exposure and intake and may inform investigations into their therapeutic potential in the future
Nitrated cyclic GMP as a new cellular signal
No full textNitric oxide–mediated production of cyclic guanosine 3',5'-monophosphate (cGMP) is a crucial signal transduction pathway that controls a wide array of biological functions. A new layer of complexity in mammalian cell regulation is revealed by the discovery of a redox-active nitrated cGMP derivative with the ability to post-translationally modify protein thiol residues by S-guanylation
The early role of nitric oxide in evolution
No full textNitric oxide (NO), which today serves many different purposes in regulating complex cellular functions, must have played a crucial role in the early stages of the evolution of life. The formation of NO may have been a critical defence mechanism for primitive microorganisms at a time when life faced the problem of rising atmospheric levels of ozone (03) formed upon photolysis of oxygen (Oz), which occurred shortly after the development of respiration in cyanobacteria. The production of NO by organisms would have allowed neutralization of toxic 03 by chemical reaction outside the cell, thus acting as a protective mechanism against oxidative destruction, allowing evolutionary advantage. Later, NO production might have allowed the control of reactive OZ species within cells before the development of specific electron-accepting enzymes. The pathway of NO formation was then consequently developed further to serve other useful functions. Although mammalian cells produce NO from L-arginine, the origin of this ability might have arisen from the essential process of either nitrification or denitrification in prokaryotic cells
The key role of nitric oxide in hypoxia: hypoxic vasodilation and energy supply-demand matching
No full textSignificance: a mismatch between energy supply and demand induces tissue hypoxia with the potential to cause cell death and organ failure. Whenever arterial oxygen concentration is reduced, increases in blood flow - 'hypoxic vasodilation' - occur in an attempt to restore oxygen supply. Nitric oxide is a major signalling and effector molecule mediating the body's response to hypoxia, given its unique characteristics of vasodilation (improving blood flow and oxygen supply) and modulation of energetic metabolism (reducing oxygen consumption and promoting utilization of alternative pathways). Recent advances: this review covers the role of oxygen in metabolism and responses to hypoxia, the hemodynamic and metabolic effects of nitric oxide, and mechanisms underlying the involvement of nitric oxide in hypoxic vasodilation. Recent insights into nitric oxide metabolism will be discussed, including the role for dietary intake of nitrate, endogenous nitrite reductases, and release of nitric oxide from storage pools. The processes through which nitric oxide levels are elevated during hypoxia are presented, namely (i) increased synthesis from nitric oxide synthases, increased reduction of nitrite to nitric oxide by heme- or pterin-based enzymes and increased release from nitric oxide stores, and (ii) reduced deactivation by mitochondrial cytochrome c oxidase. Critical issues: several reviews covered modulation of energetic metabolism by nitric oxide, while here we highlight the crucial role NO plays in achieving cardiocirculatory homeostasis during acute hypoxia through both vasodilation and metabolic suppression Future directions: we identify a key position for nitric oxide in the body's adaptation to an acute energy supply-demand mismatc
Nitroxyl gets to the heart of the matter
No full textComment on: Paolocci, N., et al. (2003) Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: independence from beta-adrenergic signaling. [Proc Natl Acad Sci USA. 100(9):5537-42
The use of nitric oxide donors in pharmacological studies
No full textA growing appreciation of the involvement of nitric oxide (NO) in numerous bioregulatory pathways has not only opened up new therapeutic avenues for organic nitrates and other NO donors but also led to an increased use of such compounds in pharmacological studies. By definition, all NO donors produce NO-related activity when applied to biological systems and are thus principally suited to either mimic an endogenous NO-related response or substitute for an endogenous NO deficiency. However, the pathways leading to enzymatic and/or non-enzymatic formation of NO differ greatly among individual compound classes, as do their chemical reactivities and kinetics of NO release. Moreover, since the reaction of NO with oxygen is a function of its concentration, the same absolute amounts of NO generated over different periods of time may lead to substantially different rates of NOx formation and, consequently, to varying extents of side reactions, such as nitration and/or nitrosation of biomolecules. Matters are further complicated by compound-specific formation of by-products, which may arise during decomposition or metabolism, sometimes in amounts far exceeding those of NO. The term "NO donor" implies that the compound releases the active mediator, NO. Ultimately, this may be true for many different chemical classes of compound, since the principal NO-related species generated may be converted to NO, if not directly released as such. However, in a biological system, the redox form of nitrogen monoxide (NO+, NO. or NO-) that is actually released makes a substantial difference to the NO donor's reactivity towards other biomolecules, the profile of by-products, and the bioresponse. Such considerations are likely to account for much of the discrepancy in experimental results obtained using the same cell or tissue preparation but different NO mimetics. Thus, compound selection is not a trivial issue and the investigator should be aware of the key properties and differences between various NO donor classes in order to avoid misinterpretation of experimental results
The chemical biology of nitric oxide - an outsider's reflections about its role in osteoarthritis
No full textExcess formation of nitric oxide (NO) has been invoked in the development of osteoarthritis and blamed for triggering chondrocyte apoptosis and matrix destruction. Much of the evidence for a deleterious role of NO in disease progression has been obtained indirectly and inferred from the measurement of nitrite/nitrate and nitrotyrosine concentrations as well as iNOS expression in biopsy specimen, cartilage explants and cytokine-stimulated cells in culture. While these results clearly indicate an involvement of NO and suggest additional contributions from oxidative stress-related components they do not necessarily establish a cause/effect relationship. Many NO metabolites are not mere dosimeters of local NO production but elicit potent down-stream effects in their own right. Moreover, oxygen tension and other experimental conditions typical of many in vitro studies would seem to be at odds with the particular situation in the joint. Recent insight into the chemical biology of NO, in particular with regard to cellular redox-regulation, mitochondrial signaling and nitration reactions, attest to a much richer network of chemical transformations and interactions with biological targets than hitherto assumed. In conjunction with the emerging biology of nitrite and nitrate this information challenges the validity of the long-held view that "too much NO" is contributing to disease progression. Instead, it suggests that part of the problem is a shift from NO to superoxide-dominated chemistries triggering changes in thiol-dependent redox signaling, hypoxia-induced gene expression and mitochondrial function. This essay aims to provide a glimpse into research areas that may hold promise for future investigations into the underlying causes of osteoarthritis
Nitric oxide (NO) formation from nitrovasodilators occurs independently of hemoglobin or non-heme iron
No full textThe aim of the present study was to exclude a potential role of hemoglobin in the formation of nitric oxide (NO) from several nitrovasodilators. NO was measured with a chemiluminescence technique after purging with argon from the aqueous solution. Nitric oxide generation occurred in the absence of hemoglobin or non-heme iron. Sodium nitroprusside and SIN-1 released NO spontaneously. Nitroglycerin produced NO only in the presence of those thiols which are effective co-stimulators of guanylate cyclase. All other thiols degraded nitroglycerin only into nitrite ions without formation of NO. Our results support the role of nitric oxide as terminal activator of guanylate cyclase stimulation by nitrovasodilators
How to beet hypertension in pregnancy: is there more to beetroot juice than nitrate?
No full textPregnancy is associated with a number of structural and functional cardiovascular adaptations that ensure the fetus is adequately supplied with nutrients throughout all phases of growth and development. Failure to meet the increased metabolic demands can lead to significant maternal and fetal morbidity. Maternal hypertension, either pre-existing or developing during pregnancy, is complicated by the limitations of our current anti-hypertensive medication. The mainstays of anti-hypertensive treatment, such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor antagonists/blockers (ARBs/Sartans) and thiazide diuretics are associated with an increased risk of congenital abnormalities to the developing fetus (NICE, 2019). As such, there remains a need to increase the available options for treatment of hypertension in pregnancy
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