Article

Nitric Oxide Release Accounts for the Biological Activity of Endothelium-Derived Relaxing Factor

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Abstract

Endothelium-derived relaxing factor (EDRF) is a labile humoral agent which mediates the action of some vasodilators. Nitrovasodilators, which may act by releasing nitric oxide (NO), mimic the effect of EDRF and it has recently been suggested by Furchgott that EDRF may be NO. We have examined this suggestion by studying the release of EDRF and NO from endothelial cells in culture. No was determined as the chemiluminescent product of its reaction with ozone. The biological activity of EDRF and of NO was measured by bioassay. The relaxation of the bioassay tissues induced by EDRF was indistinguishable from that induced by NO. Both substances were equally unstable. Bradykinin caused concentration-dependent release of NO from the cells in amounts sufficient to account for the biological activity of EDRF. The relaxations induced by EDRF and NO were inhibited by haemoglobin and enhanced by superoxide dismutase to a similar degree. Thus NO released from endothelial cells is indistinguishable from EDRF in terms of biological activity, stability, and susceptibility to an inhibitor and to a potentiator. We suggest that EDRF and NO are identical.

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... All of the above compounds interact with a multitude of cellular signalling molecules and proteins in various tissues. These effects occur in the vasculature, where nitrergic signalling was first characterised [5,6], during neuroinflammatory responses [7,8], in neurovascular coupling [9,10], the olfactory, auditory and nociceptive systems (see review [11]). This review focuses predominantly on neuronal aspects of NO signalling and redox biology in physiology and disease. ...
... In particular, in vivo, under physiological conditions, neurons are exposed to low oxygen levels at about 2-4 kPa and comparisons between normoxia (in vivo-like 2-4 kPa O 2 ) and hyperoxia (in vitro-like ∼20 kPa O 2 ) conditions in various cellular models revealed fundamental differences in redox signalling, mitochondrial phenotypes, protein expressions and NO bioavailability [14][15][16][17][18]. Likewise, it is important to consider conditions of redox signalling and oxygen tension during neuronal development and Steinert and H. Amal Free Radical Biology and Medicine xxx (xxxx) [1][2][3][4][5][6][7][8][9][10][11][12][13] stem cell research [19,20]. All of the studies discussed below have to interpreted in light of the redox conditions under which the experiments have been performed. ...
... Disease-associated increased amounts of O 2 •− may result from aberrant NADPH oxidase activities as a consequence of mitochondrial dysfunction. Steinert and H. Amal Free Radical Biology and Medicine xxx (xxxx) [1][2][3][4][5][6][7][8][9][10][11][12][13] [SNAP], DEA-NONOate) modulates voltage-gated ion channels, such as the high voltage-gated potassium channels Kv3 and Kv2 in the medial nucleus of the trapezoid body (MNTB) in brain slice preparations, Kv3 channels expressed in cultured CHO cells [34][35][36][37] as well as the Mcurrent (Kv7) in cultured trigeminal ganglia neurons [38]. These modifications are the result of either direct cGMP/protein kinase G (PKG)mediated phosphorylation events or occur via cysteine S-nitrosylation and result in changes of neuronal excitabilities. ...
Article
Nitric oxide and other redox active molecules such as oxygen free radicals provide essential signalling in diverse neuronal functions, but their excess production and insufficient scavenging induces cytotoxic redox stress which is associated with numerous neurodegenerative and neurological conditions. A further component of redox signalling is mediated by a homeostatic regulation of divalent metal ions, the imbalance of which contributes to neuronal dysfunction. Additional antioxidant molecules such as glutathione and enzymes such as super oxide dismutase are involved in maintaining a physiological redox status within neurons. When cellular processes are perturbed and generation of free radicals overwhelms the antioxidants capacity of the neurons, a resulting redox damage leads to neuronal dysfunction and cell death. Cellular sources for production of redox-active molecules may include NADPH oxidases, mitochondria, cytochrome P450 and nitric oxide (NO)-generating enzymes, such as endothelial, neuronal and inducible NO synthases. Several neurodegenerative and developmental neurological conditions are associated with an imbalanced redox state as a result of neuroinflammatory processes and leading to nitrosative and oxidative stress. Ongoing research aims at understanding the causes and consequences of such imbalanced redox homeostasis and its role in neuronal dysfunction.
... Few years later, Furchgott found that the ability of rabbit thoracic aorta to relax after exposure to acetylcholine was dependent on the presence of an intact vessel intima, concluding that relaxation involved endothelial cells [3] releasing an endotheliumderived relaxation factor (EDRF). Two independents studies [4,5] in 1987 finally identified NO as this EDRF involved in vascular smooth muscle relaxation through the activation of soluble guanylyl cyclase (sGC). The significance of NO-cGMP was recognized by the 1998 Nobel Prize in Physiology and Medicine awarded to Professors Furchgott, Ignarro and Murad for their discoveries on NO as a signaling molecule in the cardiovascular system [6]. ...
... S-nitroso-albumin (1) and S-nitroso-Hb (3) serve as storage pools of NO. NO can also be oxidized into nitrite under normoxic condition (4). Combined with the dietary intake, nitrite, in turn, it serves as the storage pool and can be reduced to NO under hypoxic and acidic conditions (4). ...
Article
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Nitric oxide (NO) is implicated in numerous physiological processes, including vascular homeostasis. Reduced NO bioavailability is a hallmark of endothelial dysfunction, a prequel to many cardiovascular diseases. Biomarkers of an early NO-dependent endothelial dysfunction obtained from routine venous blood sampling would be of great interest but are currently lacking. The direct measurement of circulating NO remains a challenge due by its high reactivity and short half-life. The current techniques measure stable products from the NO signaling pathway or metabolic end products of NO that do not accurately represent its bioavailability and, therefore, endothelial function per se. In this review, we will concentrate on an original technique of low temperature electron paramagnetic resonance spectroscopy capable to directly measure the 5-α-coordinated heme nitrosyl-hemoglobin in the T (tense) state (5-α-nitrosyl-hemoglobin or HbNO) obtained from fresh venous human erythrocytes. In humans, HbNO reflects the bioavailability of NO formed in the vasculature from vascular endothelial NOS or exogenous NO donors with minor contribution from erythrocyte NOS. The HbNO signal is directly correlated with the vascular endothelial function and inversely correlated with vascular oxidative stress. Pilot studies support the validity of HbNO measurements both for the detection of endothelial dysfunction in asymptomatic subjects and for the monitoring of such dysfunction in patients with known cardiovascular disease. The impact of therapies or the severity of diseases such as COVID-19 infection involving the endothelium could also be monitored and their incumbent risk of complications better predicted through serial measurements of HbNO.
... NO exerts its effects by soluble guanylate cyclase (sGC) activation and is synthetized from L-arginine through three isoforms of nitric oxide synthase (NOS) which includes NOS1 (neuronal), NOS2 (inducible) and NOS3 (endothelial) (Fig. 2) [96]. Furthermore, NO affects cellular activity and vascular tone independently of sGC-activation by a process called S-nitrosylation. ...
... Growing evidence has been supporting the idea of a crosstalk between H 2 S and NO not only in their biosynthesis but also in their physiological responses (Fig. 2). In this sense, it has been reported that (1) H 2 S increases eNOS expression through the regulation of miRNA-455-3p [181]; (2) H 2 S promotes eNOS activation through an Akt-dependent mechanism [182], sulfhydration in the Cys 443 residue of the eNOS [183]; meanwhile, NO reduces CBS activity when bind to the reduced heme group of this enzyme [184]; (3) H 2 S and NO raises cGMP intracellular levels by inhibiting phosphodiesterase 5 (PDE5) and activating guanylate cyclase, respectively [96,185]; and (4) H 2 S reacts with NO to form intermediates such as nitroxyl (HNO) and SNO [142,186]. Indeed, a decrease in H 2 S endogenous synthesis contributes to endothelial dysfunction suggesting an important role of this molecule in the establishment of this condition [187][188][189]. ...
Article
The systemic cardiovascular effects of major trauma, especially neurotrauma, contribute to death and permanent disability in trauma patients and treatments are needed to improve outcomes. In some trauma patients, dysfunction of the autonomic nervous system produces a state of adrenergic overstimulation, causing either a sustained elevation in catecholamines (sympathetic storm) or oscillating bursts of paroxysmal sympathetic hyperactivity. Trauma can also activate innate immune responses that release cytokines and damage-associated molecular patterns into the circulation. This combination of altered autonomic nervous system function and widespread systemic inflammation produces secondary cardiovascular injury, including hypertension, damage to cardiac tissue, vascular endothelial dysfunction, coagulopathy and multiorgan failure. The gasotransmitters gases nitric oxide (NO) and hydrogen sulfide (H2S) are small gaseous molecules with potent effects on vascular tone regulation. Exogenous NO (inhaled) has potential therapeutic benefit in cardio-cerebrovascular diseases, but limited data suggests potential efficacy in traumatic brain injury (TBI). H2S is a modulator of NO signaling and autonomic nervous system function that has also been used as a drug for cardio-cerebrovascular diseases. The inhaled gases NO and H2S are potential treatments to restore cardio-cerebrovascular function in the post-trauma period.
... Additionally, estrogen may inhibit NO degradation by inhibiting superoxide anion formation or by increasing the level of endogenous free radical scavengers (15). NO from endothelial cells diffuses to Hormonal treatment of male to female gender identity disorder smooth muscle in the arterial wall, allowing endotheliumdependent vasodilation, and into the arterial lumen where it can prevent the adherence of monocytes and platelets that are involved in the formation of the atherosclerotic lesion (16,17). ...
... These values obtained in vitro with purified SGC are not compatible with fast deactivation required for efficient NO signaling and observed experimentally. For example, studies performed on aortic rings demonstrated that relaxation of aortic rings can be re-elicited 1-2 min after previous exposure to NO [46]. This discrepancy most likely reflects the contribution of different cellular factors. ...
Article
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NO-stimulated guanylyl cyclase (SGC) is a hemoprotein that plays key roles in various physiological functions. SGC is a typical enzyme-linked receptor that combines the functions of a sensor for NO gas and cGMP generator. SGC possesses exclusive selectivity for NO and exhibits a very fast binding of NO, which allows it to function as a sensitive NO receptor. This review describes the effect of various cellular factors, such as additional NO, cell thiols, cell-derived small molecules and proteins on the function of SGC as cellular NO receptor. Due to its vital physiological function SGC is an important drug target. An increasing number of synthetic compounds that affect SGC activity via different mechanisms are discovered and brought to clinical trials and clinics. Cellular factors modifying the activity of SGC constitute an opportunity for improving the effectiveness of existing SGC-directed drugs and/or the creation of new therapeutic strategies.
... However, other biochemical substances locally released from the endothelial or smooth muscle components of the erectile tissue may also take part in this function. The premise that NO could modulate corporeal smooth muscle function concerns with its original description as an endothelium-derived relaxing factor, this substance was discovered in vasculature to derive from endothelial cells and to induce vascular smooth muscle relaxation (Palmer et al., 1987). Cholinergic agents, alpha-adrenergic antagonists, endothelium-derived relaxing factor, peptides, prostaglandins, histamine, calcium channel blocking agents, and other nonspecific vasodilators are some of the substances that induce cavernosal muscle relaxation (Anderson, 1993& Holmquist et al., 1990. ...
... The mechanism of blood vessel dilatation was explained by Palmer et al. 55 , who reported that NO is a small bioactive gas that was first identified as mediating arterial vasodilatation. The present biochemical study showed a substantial increase in NO production in the kidneys of BPA-treated rats, which might be related to blood vessel dilatation. ...
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This study aimed to determine the effect of gallic acid (GA) on ameliorating bisphenol A (BPA) nephrotoxicity in male rat kidneys. Forty rats were assigned randomly into two groups: control (ten animals) and BPA (40 mg/kg bwt) (thirty animals), the second group was divided into three subgroups: BPA alone, BPA + G50 (50 mg/kg bwt), and BPA + G200 (200 mg/kg bwt). The biochemical analysis included measurements of the contents of nitric oxide, lipid peroxidation, reactive oxygen species, and cytokines (interleukin-1α and interleukin-6) in the kidney. The antioxidant enzymes catalase and superoxide dismutase were also measured in the kidney. Kidney function was assessed by determining uric acid, urea, and creatinine levels. The morphological investigations included hematoxylin and eosin staining for assessing the general histology and determining the glomerular and corpuscular areas, the tubular cell degeneration mean area, and the mean leukocyte infiltration area. Also, collagen fiber intensity and polysaccharide content were analyzed. Furthermore, immunohistochemical, morphometric, and ultrastructural studies were carried out. The results revealed morphological, immunohistochemical, and biochemical alterations in the kidney. Most of these changes showed a satisfactory improvement of kidney damage when BPA-administered rats were treated with GA at both doses. In conclusion, GA exhibited a strong protective effect against BPA-induced nephrotoxicity.
... The mechanism of blood vessel dilatation was explained by Palmer et al. 55 , who reported that NO is a small bioactive gas that was first identified as mediating arterial vasodilatation. The present biochemical study showed a substantial increase in NO production in the kidneys of BPA-treated rats, which might be related to blood vessel dilatation. ...
Article
Full-text available
This study aimed to determine the effect of gallic acid (GA) on ameliorating bisphenol A (BPA) nephrotoxicity in male rat kidneys. Forty rats were assigned randomly into two groups: control (ten animals) and BPA (40 mg/kg bwt) (thirty animals), the second group was divided into three subgroups: BPA alone, BPA + G50 (50 mg/kg bwt), and BPA + G200 (200 mg/kg bwt). The biochemical analysis included measurements of the contents of nitric oxide, lipid peroxidation, reactive oxygen species, and cytokines (interleukin‑1α and interleukin‑6) in the kidney. The antioxidant enzymes catalase and superoxide dismutase were also measured in the kidney. Kidney function was assessed by determining uric acid, urea, and creatinine levels. The morphological investigations included hematoxylin and eosin staining for assessing the general histology and determining the glomerular and corpuscular areas, the tubular cell degeneration mean area, and the mean leukocyte infiltration area. Also, collagen f iber intensity and polysaccharide content were analyzed. Furthermore, immunohistochemical, morphometric, and ultrastructural studies were carried out. The results revealed morphological, immunohistochemical, and biochemical alterations in the kidney. Most of these changes showed a satisfactory improvement of kidney damage when BPA‑administered rats were treated with GA at both doses. In conclusion, GA exhibited a strong protective effect against BPA‑induced nephrotoxicity.
... NO is a free radical that reacts with biological molecules with unpaired orbital electrons, including transition metal ions such as the heme iron [11]. The interest in these reactions has greatly increased since NO was identified as the previously elusive endothelium-derived relaxing factor (EDRF), a vertebrate biological messenger that plays a role in various biological processes [12]. The discovery that NO, CO, and H 2 S are essential in signaling pathways is a relatively recent development [13]. ...
Article
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Heme proteins are a diverse group that includes several unrelated families. Their biological function is mainly associated with the reactivity of the heme group, which—among several other reactions—can bind to and react with nitric oxide (NO) and other nitrogen compounds for their production, scavenging, and transport. The S-nitrosylation of cysteine residues, which also results from the reaction with NO and other nitrogen compounds, is a post-translational modification regulating protein activity, with direct effects on a variety of signaling pathways. Heme proteins are unique in exhibiting this dual reactivity toward NO, with reported examples of cross-reactivity between the heme and cysteine residues within the same protein. In this work, we review the literature on this interplay, with particular emphasis on heme proteins in which heme-dependent nitrosylation has been reported and those for which both heme nitrosylation and S-nitrosylation have been associated with biological functions.
... Ferid Murad was awarded the Nobel Prize in Physiology or Medicine in 1998 for his finding on cyclic guanosine monophosphate (GMP) dependence.In his early findings, NO was shown to activate the cytoplasmic isoform of guanylyl cyclase, which catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (GMP). In these circumstances, the increase of GMP level will lead to a series of phosphorylation processes, thereby causing the dilation of blood vessels and the change of blood flow velocity (15). This pathway is known as the GMP-dependent pathway. ...
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Thyroid carcinoma is the most common endocrine cancer in the world, and its incidence has been steadily increasing in recent years. Despite its relatively good prognosis, therapies have not improved greatly in recent years. Therefore, exploring new therapies for thyroid carcinoma represents an unmet need. Nitric oxide (NO) is a short-term endogenous signaling molecule that plays a vital role in various physiological and pathological processes and is synthesized by nitric oxide synthase (NOS). Many studies have been conducted over the past decades to explain its correlation to cancer. NO exerts a wide range of effects on cancer, involving angiogenesis, apoptosis, cell cycle, invasion, and metastasis. It also serves a dual function by promoting and halting tumor development simultaneously. The relationship between NO and thyroid carcinoma has been intensively studied and discussed. This paper reviews the role and molecular mechanism of NO in thyroid carcinoma and discusses potentials of prevention and treatment of thyroid carcinoma.
... 32 The proinflammatory chemokine IL-8, a critical index of inflammatory response determining the degree of gastric mucosal inflammation, can induce neutrophils to accumulate in the gastric mucosa, leading to severe gastric mucosal damage. 33 In the present study, we found that indicators related to inflammatory response were significantly affected by the excessive intake of alcohol. However, tea saponin treatment downregulated the expression of TNF-α, IL-1β, and IL-8 in the stomachs of alcohol-induced mice ( Figures 5 and 6). ...
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Excessive alcohol consumption harms the human body, particularly the digestive system, by causing damage to the gastric mucosa. Tea saponin is a natural active substance extracted from tea tree seeds that has gastroprotective potential against alcohol-induced mucosal damage. However, the protective mechanism of tea saponins is not fully understood. The current study aimed to explore the protective mechanism of tea saponins against alcohol-induced gastric mucosal injury in mice. Histopathological changes, immunohistochemistry, immunoblotting, and gastric mucosa-related cytokine levels were analyzed in three groups of male mice: model, control, and tea saponin-treated. Compared to the model group, the tea saponin group prominently ameliorated alcohol-induced gastric mucosal injury by improving cell necrosis, inflammatory cell infiltration, and edema. Downregulation of inflammation-related factors cluster of differentiation 68 (CD68), myeloperoxidase (MPO), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) was also found in the tea saponin group. These results suggest that tea saponins have a protective effect against alcohol-induced gastric mucosal damage in mice. Therefore, tea saponin may serve as a food additive for gastric mucosal protection.
... It is metabolized by nitric oxide synthase to NO, citrulline, or ornithine/urea by arginase [24]. Several studies have identified arginine as a biological precursor to identify activated macrophages based on their nitrite and nitrate release patterns [25]. After calcium supplementation of M 2 macrophages, it acts as an anti-inflammatory agent via the diversion of arginine. ...
Article
Innate immune cells play a pivotal role in controlling tissue repair and rejection after biomaterial implantation. Calcium supplementation regulates cellular responses and alter the pathophysiology of various diseases. A series of macrophage activations through differential plasticity has been observed after cell-to-material interactions. We investigated the role of calcium supplementation in controlling macrophage phenotypes in pro-inflammatory and pre-reparative states. Oxidative defence and mitochondria involvement in cellular plasticity and the sequential M0 to M1 and M1 to M2 transitions were observed after calcium supplementation. This study describes the molecular mechanism of reactive oxygen species and drives the interconnected cellular plasticity of macrophages in the presence of calcium. Gene expression, and immunostaining, revealed a relationship between MHC class II maturation and cellular plasticity. This study elucidated the role of controlled calcium supplementation under various conditions. These findings underscore the molecular mechanism of calcium-mediated immune induction and its favourable use in different calcium-containing biomaterials., essential for tissue regeneration.
... NO is synthesized by nitric oxide synthase, and NOS-positive nerve fibers are widely distributed in bladder and urethra tissues. Through the NO-cGMP signaling pathway, NO can effectively relax the lower urinary smooth muscle and reduce urethral pressure during normal urination, which is of great significance for maintaining normal urinary bladder storage and urination functions [49]. It is well established that reduced NO synthesis is closely associated with increased detrusor excitability due to a variety of causes [50]. ...
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Overactive bladder syndrome (OAB) has made increasing progress in mechanism and treatment research. Traditional Chinese medicine (TCM) is a common complementary therapy for OAB, and it has been found to be effective. However, the intervention mechanism of TCM in the treatment of OAB is still unclear. The aim of this review is to consolidate the current knowledge about the mechanism of TCM: acupuncture, moxibustion, herbs in treating OAB, and the animal models of OAB commonly used in TCM. Finally, we put forward the dilemma of TCM treatment of OAB and discussed the insufficiency and future direction of TCM treatment of OAB.
... I still remember the incredulous astonishment within the scientific community when it became clear that the so-called endothelium-derived relaxation factor (EDRF) was nothing more than nitric oxide (NO). 4 That the endothelium would release a dissolved gas towards the adjacent vascular smooth muscle layer to induce vascular relaxation was difficult to reconcile with current concepts of the time. Robert Furchgott shared the Nobel Price for the discovery of this new cellular signal with Louis Ignarro and Ferid Murad in 1998. ...
... NO exerts its physiological functions through the cGMP-independent pathway and the cGMP-dependent pathway that is mediated by activation of sGC [28]. Catalysis of sCG induces an increase in the intracellular concentrations of cGMP and its downstream effector PKG, which underlies their diverse biological functions, such as mediation of vascular smooth muscle cell relaxation, inhibition of platelet aggregation, and participation in neurotransmission [34,35]. ...
... The identification of nitric oxide (NO) as endothelium-derived relaxing factor (Ignarro et al., 1987;Palmer et al., 1987) ushered in the modern era of vascular biology; yet, the medical promise of NO in cardiovascular disease, the most common cause of death in the developed world, remains largely unrealized. While NO bioactivity reduces cardiovascular risk through combined effects on endothelial function, blood pressure, and diabetes (Huang et al., 1995;Johnstone et al., 1993;Kauser et al., 2000;Knowles et al., 2000;Kuhlencordt et al., 2001;Shankar et al., 2000), NO has seemingly little impact on the serum lipoproteins that are primary drivers of the atherogenic process and of disease progression (Knowles et al., 2000;Kuhlencordt et al., 2001;Ozaki et al., 2002). ...
Article
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Accumulating evidence suggests that protein S-nitrosylation is enzymatically regulated and that specificity in S-nitrosylation derives from dedicated S-nitrosylases and denitrosylases that conjugate and remove S-nitrosothiols, respectively. Here, we report that mice deficient in the protein denitrosylase SCoR2 (S-nitroso-Coenzyme A Reductase 2; AKR1A1) exhibit marked reductions in serum cholesterol due to reduced secretion of the cholesterol-regulating protein PCSK9. SCoR2 associates with endoplasmic reticulum (ER) secretory machinery to control an S-nitrosylation cascade involving ER cargo-selection proteins SAR1 and SURF4, which moonlight as S-nitrosylases. SAR1 acts as a SURF4 nitrosylase and SURF4 as a PCSK9 nitrosylase to inhibit PCSK9 secretion, while SCoR2 counteracts nitrosylase activity by promoting PCSK9 denitrosylation. Inhibition of PCSK9 by an NO-based drug requires nitrosylase activity, and small-molecule inhibition of SCoR2 phenocopies the PCSK9-mediated reductions in cholesterol observed in SCoR2-deficient mice. Our results reveal enzymatic machinery controlling cholesterol levels through S-nitrosylation and suggest a distinct treatment paradigm for cardiovascular disease.
... En 1980, Furchgott y Zawadzki descubrieron un factor relajante derivado del endotelio, que posteriormente se identificó como NO (44,45). Existen diferentes NO sintasas (NOS), dos constitutivas y una inducible. ...
Article
Hypertension and obesity are major health problems worldwide with significant consequences on morbidity and mortality. In fact, both hypertension and obesity are important risk factors for the development of cardiovascular diseases. Endothelial dysfunction, vascular remodeling, and alterations in vascular mechanics are common aspects of vascular damage in hypertension, obesity, and aneurysms. During the last decades, the importance of low-grade inflammation in vascular damage associated with cardiovascular diseases has been demonstrated. This inflammation is characterized by the accumulation of inflammatory cells in the vasculature, as well as by the increase of local and circulating pro-inflammatory cytokines. Therefore, the identification of new inflammatory mediators involved in this damage has become a very important area of research. Interferón-γ (IFNγ) or tumor necrosis tumoral-α (TNFα) are important cytokines involved in the vascular damage associated with hypertension. Furthermore, it is accepted that TNFα is a key mediator involved in insulin resistance and vascular damage observed in obesity. Both cytokines induce the expression of interferon-stimulated gene 15 (ISG15), a protein similar to ubiquitin that induces a reversible post-translational modification (ISGylation) and that can also be secreted as a free form. The functions of ISG15 are mainly related to the immune response against infections, however, it could also be an interesting new target for cardiovascular damage.
... 09 Filimonova et al. 10.3389/fphar.2022.995272 Discussion Since the discovery of the NOS/sGC/cGMP pathway of vascular relaxation in the 1980's (Furchgott and Zawadzki, 1980;Palmer et al., 1987;Rees et al., 1989), our understanding of the physiological and pathophysiological role of NO and various NOS isoforms in regulation of vascular tone and hemodynamics are constantly refined and expanded. Nevertheless, since that time, the vasoconstrictive, vasopressor ability of effective eNOS and iNOS inhibitors blocking the vascular relaxation pathway has been perceived rather as a natural property. ...
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The ongoing COVID-19 pandemic has been a daunting challenge for healthcare systems worldwide. The World Health Organization has recommended various measures to reduce or limit the spread of the virus, one of which includes the use of face masks. This increase in their demand has provided a unique opportunity to improve the technology by offering, in addition to their inherent protection, therapeutic benefits. One such benefit involves inhaled nitric oxide (iNO) therapy. iNO has proven to be a beneficial therapeutic in patients with acute, hypoxemic respiratory failure and lung injury. Specifically, its potential application stems from its ability to rapidly increase oxygen partial pressure in arterial blood. However, iNO treatments generally require pressurized gas cylinders which are coupled with high costs and lack of portability. A face mask which can deliver therapeutic NO is developed using humidity-triggered NO-releasing nanoparticles. This platform can deliver a low dose of 2.1–2.5 ppm NO for 90 min in a sustained manner. Moreover, it can be stored for extended periods of time and can be easily transported due to its light weight. This NO mask has the potential to alleviate the strain that affects financially limited healthcare systems in developing regions.
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The toxicity profiles of nanoparticles (NPs) used in appliances nowadays remain unknown. In this study, we investigated the toxicological implications of cerium oxide (CeO 2 ) and zinc oxide (ZnO) NPs given singly or in combination on the integrity of liver and kidney of male Wistar rats. Twenty rats were assigned equally into four groups and treated as: Control (normal saline), CeO 2 NPs (50µg/kg), ZnONPs (80µg/kg) and [CeO 2 NPs (50µg/kg) + ZnONPs (80µg/kg)]. The NPs were administered intraperitoneally thrice weekly for four consecutive weeks. Results showed that administration of CeO 2 and ZnO NPs (Singly) increased serum AST and ALT by 29% & 57%; 41% & 18%, and co-administration by 53% and 23%, respectively. CeO 2 and ZnO NPs increased hepatic and renal malondialdehyde (MDA) by 33% and 30%; 38% and 67%, respectively, while co-administration increased hepatic and renal MDA by 43% and 40%, respectivelyThe combined NPs increased hepatic NO by 28%. Also, CeO 2 and ZnO NPs, and combined increased BAX, interleukin-1β and TNF-α by 45, 38, 52%; 47, 23, 82% and 41, 83, 70%, respectively. Histology revealed hepatic necrosis and renal haemorrhagic parenchymal in NPs-treated rats. Overall, NPs elicited oxidative stress and inflammation in the liver and kidney of the rats.
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Objective: Angina pectoris (AP), affecting over 523 million people, can be alleviated by corydalis rhizome (CR), usually combined with chuanxiong rhizome (CXR), angelica dahuricae radix (ADR), or astragali radix (AR) to enhance the effect. This study aims to distinguish the different mechanisms among 3 drug pairs to treat AP. Methods: The drug pair-disease intersection targets, compound targets, protein–protein interaction (PPI), and herb-compound-target-pathway network were obtained by Cytoscape, STRING, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses ( http://www.kegg.jp/ or http://www.genome.jp/kegg/ ). Importantly, with principal component analysis (PCA), the key point of KEGG and GO were explored and supported, while by meta-analysis, the different mechanisms of the drug pairs on AP were discovered. Results: JUN, SRC, PIK3CA, and MAPK1 as PPI core network of CR-AP, (CR-CXR)-AP, (CR-ADR)-AP, and (CR-AR)-AP. (highest confidence > 0.9). 10, 45, 35, and 21 key compounds, and 68, 123, 117, and 97 core targets were obtained from CR-AP, (CR-CXR)-AP, (CR-ADR)-AP, and (CR-AR)-AP based on more than 2-fold median value for degree and betweenness centrality, more than the median of closeness centrality. The core pathways of (CR-CXR)-AP and (CR-AR)-AP cover “fluid shear stress and atherosclerosis” and the “pathways in cancer”, while (CR-ADR)-AP was found as the “pathways in cancer” by PCA and KEGG ( P < .01). The core biological processes of (BP) (CR-CXR)-AP, (CR-ADR)-AP, and (CR-AR)-AP were all enriched in the “circulatory system process” by PCA and GO ( P < .01). Moreover, meta-analysis indicated the significant differences ( P < .05) of the 3 drug pairs. Conclusion: CR-CXR, CR-ADR, or CR-AR outperformed CR-AP in AP mitigation. Furthermore, meta-analysis revealed, CR-CXR was superior to alleviating AP by affecting “circulatory system process” and “fluid shear stress and atherosclerosis”, particularly the targets PTGS1, PTGS2, ADRB2, ADRA2C, and NOS, when compared with the drug pair of CR-ADR and the CR-AR.
Article
Background Heart transplantation with a donation after circulatory death (DCD) heart is complicated by substantial organ ischemia and ischemia–reperfusion injury. Exenatide, a glucagon‐like peptide−1 receptor agonist, manifests protection against cardiac ischemia–reperfusion injury in other settings. Here we evaluate the effects of exenatide on DCD hearts in juvenile pigs. Methods and Results DCD hearts with 15‐minutes of global warm ischemia after circulatory arrest were reperfused ex vivo and switched to working mode. Treatment with concentration 5‐nmol exenatide was given during reperfusion. DCD hearts treated with exenatide showed higher myocardial oxygen consumption (exenatide [n=7] versus controls [n=7], over 60–120 minutes of reperfusion, P <0.001) and lower cardiac troponin‐I release (27.94±11.17 versus 42.25±11.80 mmol/L, P =0.04) during reperfusion compared with controls. In working mode, exenatide‐treated hearts showed better diastolic function (dp/dt min: −3644±620 versus −2193±610 mm Hg/s, P <0.001; Tau: 15.62±1.78 versus 24.59±7.35 milliseconds, P =0.02; lateral e ′ velocity: 11.27 ± 1.46 versus 7.19±2.96, P =0.01), as well as lower venous lactate levels (3.17±0.75 versus 5.17±1.44 mmol/L, P =0.01) compared with controls. Higher levels of activated endothelial nitric oxide synthase (phosphorylated to total endothelial nitric oxide synthase levels: 2.71±1.16 versus 1.37±0.35, P =0.02) with less histological evidence of endothelial damage (von Willebrand factor expression: 0.024±0.007 versus 0.331±0.302, pixel/μm, P =0.04) was also observed with exenatide treatment versus controls. Conclusions Acute treatment of DCD hearts with exenatide limits myocardial and endothelial injury and improves donor cardiac function.
Article
Significance: Coronary artery disease (CAD) is commonly treated using percutaneous coronary interventions (PCI). However, PCI with stent placement damages the endothelium, and failure to restore endothelial function may result in PCI failure with poor patient outcomes. Recent Advances: Oxidative signalling is central to maintaining endothelial function. Potentiation of oxidant production, as observed post-PCI, results in endothelial dysfunction. This review delves into our current understanding of the physiological role that endothelial-derived oxidants play within the vasculature and the effects of altered redox signalling during dysfunction. We then examine the impact of PCI and intra-coronary stent placement on oxidant production in the endothelium, which can culminate in stent failure. Finally, we explore how recent advances in PCI and stent technologies aim to mitigate PCI-induced oxidative damage and improve clinical outcomes. Critical issues: Current PCI technologies exacerbate cellular oxidant levels, driving endothelial dysfunction. If left uncontrolled, oxidative signalling leads to increased intravascular inflammation, restenosis, and neoatherosclerosis. Future Directions: Through the development of novel biomaterials and therapeutics, we can limit PCI-induced oxidant production, allowing for the restoration of a healthy endothelium and preventing CAD recurrence.
Article
Endothelial cells (ECs) maintain the health of blood vessels and prevent the development of cardiovascular disease (CVD). Free saturated fatty acids (FAs) induce EC damage and increase the risk of CVD by promoting arteriosclerosis. Conversely, polyunsaturated FAs (PUFAs), such as docosahexaenoic acid, are thought to suppress EC damage induced during the early stages of CVD. This review describes the effects of multiple dietary FAs on EC disorders involved in the development of CVD. The roles of FAs in atherosclerosis and CVD were analyzed by evaluating articles published in PubMed, Science Direct, and Web of Science. Saturated FAs were found to induce EC damage by reducing the production and action of EC-derived nitric oxide. Oxidative stress, inflammation, and the renin-angiotensin system were found to be involved in EC disorder. Furthermore, n-3 PUFAs were found to reduce EC dysfunction and prevent the development of EC disorder. These results indicate that FAs may affect EC failure induced during the early stages of CVD and reduce the risk of developing the disease.
Article
Nitric oxide (NO or endothelium-derived relaxing factor) has many of biologic actions, including the maintenance of blood pressure, inhibition of platelet aggregation, and cytotoxicity by phagocytic cells. Several cell types produce NO from L-arginine. Given recent emphasis on mast cell (MC)-dependent TNF-alpha-mediated cytotoxicity, we investigated the role of NO in rat peritoneal MC (PMC)-and intestinal mucosal mast cell-mediated cytotoxicity. MC cytotoxicity against the TNF alpha-sensitive target, WEHI-164, was potentiated by L-arginine. The NO competitive inhibitors, N omega-nitro-L-arginine and NG-methyl-L-arginine, diminished the cytotoxicity of rat PMC by 27 and 17%, respectively. However, hemoglobin, which binds to NO, inhibited the cytotoxic activity of PMC by 49% in the presence of 1 mM L-arginine and by 24% in L-arginine-free medium. The latter suggests that PMC use intracellular stores of L-arginine to produce NO. Neither hemoglobin nor NO metabolites affected human rTNF-alpha cytotoxicity. Furthermore, sodium nitroprusside, with its free radical NO group, restored PMC cytotoxicity in L-arginine-free medium to the level observed in 1 mM L-arginine medium. Studies with a platelet aggregation bioassay and various NO inhibitors confirmed that PMC produce NO. In addition, increased levels of NO2- were observed in medium of A23187, TNF-alpha, or WEHI-164-stimulated PMC.
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Background Benign prostatic hyperplasia (BPH) is a major health concern in men associated with lower urinary tract symptoms and sexual dysfunction. Recurrent inflammation, decreased apoptotic rate and oxidative stress are some of the theories that explain the pathophysiology of BPH. Common salt, a food additive, is known to cause systemic inflammation and redox imbalance, and may serve as potential risk factors for BPH development or progression. This study examined the effect of common salt intake on the pathophysiology of testosterone-induced BPH. Methods Forty male Wistar rats were randomly divided into four groups (10 in each group): the control group and three salt diet groups-low salt diet (LSD), standard salt diet (SSD) and high salt diet (HSD). The rats were castrated, allowed to recuperate and placed on salt free diet (control), 0.25% salt diet (LSD), 0.5% salt diet (SSD) and 1.25% salt diet (HSD) for 60 days ad libitum. On day 33, BPH was induced in all the rats with daily injection of testosterone propionate (Testost®) for 28 days. The rats had overnight (12 hours) on day 60 and euthanized the following day in order to collect blood and prostate samples for biochemical, molecular and immunohistochemistry (IHC) analyses. Mean ± SD values were calculated and compared for significant difference with t-test (control and salt diet groups) and one-way ANOVA (in between salt diet groups) at p < 0.05. Results There was a significant rise in prostatic levels of IL-6, IL-8 and COX-2 in salt diet groups and moderate IHC staining of COX-2 in HSD group. The prostatic level of IL-17, IL-1β, PGE2, relative prostate weight and serum PSA levels were not statistically different. The concentrations of IGF-1, TGF-β were similar in all the groups but there was fold increase in Bcl-2 expression in salt diet groups-LSD (13.2), SSD (9.5) and HSD (7.9) and fold decrease in VEGF expression in LSD (-6.3), SSD (-5.1) and HSD (-14.1). Activity of SOD and concentration of nitric oxide increased in LSD and SSD groups, and SSD and HSD groups respectively. Activities of glutathione peroxidase and catalase, and concentration of NADPH and hydrogen peroxide were not significantly different. IHC result showed positive immunostaining for iNOS expression in all the groups whereas histopathology revealed moderate to severe prostate hyperplasia in salt diet groups. Conclusions There is a relationship between dietary salt intake and risk testosterone-induced BPH in Wistar rats, possibly, by promoting inflammation, oxidative stress, and suppressing apoptosis. These results reveal that intake of dietary salt at low, standard and high quantity aggravated the pathophysiology of testosterone-induced BPH in Wistar rats by promoting inflammation, oxidative stress, and suppressing apoptosis.
Article
In this work, we assemble amphiphilic iron(III) corroles at air‐water interfaces into well‐defined quasi‐two‐dimensional molecular monolayers and theirs stacks for sensing of nitric oxide (NO). For this purpose, we use the Langmuir‐Blodgett (LB) technique, which allows varying the packing density of iron(III) corroles anchored to the aqueous subphase via one molecular side. The stacks of ten down to three molecular monolayers on the front and back sides of the substrates are sufficiently optically dense to detect NO binding to the layers photometrically. This sensing with few layers demonstrates the potential for electronic detection, where very thin surface functionalizations enable efficient electronic communication between the layer and the (semi)conductor. Despite increasing optical densities, the spectral responses to NO exposure become smaller with increasing packing density until the collapse point of the monolayers is reached. This demonstrates that the highest molecular efficiency for binding and detection of NO is achieved at the smallest packing densities. This finding is relevant to all molecular sensor films with axial binding of analytes to the sensor molecules and demonstrates the advantage of sensor molecule assembly into monolayers on water‐air interfaces using the LB technique.
Article
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Amyotrophic lateral sclerosis (ALS) is a rare, cumulative neurological deteriorating disease that disturbs the neurons (nerve cells) that control voluntary muscle movement (those muscles we choose to move). Currently, the Food and Drug Administration (FDA) approved drugs such as Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta to treat ALS. Given the wide range of pharmaceutical applications of heterocyclic compounds, especially those containing the nitrogen ring systems such as pyridine, pyrimidine, and indole. These molecular frameworks have piqued the interest of medicinal chemists for further investigation in a variety of diseases. We have found several review works done on this research topic. Until now, no reviews published on the nitrogen heterocycles for treating ALS. This review examines the major causes of ALS, a brief history of medications that have been used to treat it so far, and the most recent breakthroughs in nitrogen ring systems for treating ALS. The novelty of this study provides insights on several effective synthetic techniques for nitrogen-based heterocyclic medications that operate as potent anti-inflammatory treatments and guard against ALS. KEY POINTS: • Pharmacological activity of heterocyclic compounds. • Neurodegenerative diseases and their drawbacks are discussed in detail. • Recent survey of nitrogen heterocycles in treating ALS disease are highlighted.
Chapter
Guanosine 3′5′ cyclic monophosphate (cGMP) is synthesized by soluble guanylyl cyclase (sGC) when vascular smooth muscle is stimulated with nitric oxide (NO) and nitrovasodilators and by particulate guanylate cyclase (pGC) when stimulated with natriuretic peptides. The intracellular cGMP levels are determined by the balance of the synthesis of this cyclic nucleotide by sGC and pGC and its hydrolysis mainly by the type 5 phosphodiesterase. cGMP exerts its action predominantly through the activation of cGMP-dependent protein kinase (PKG) resulting in reduced cytosolic Ca2+ and decreased Ca2+ sensitivity of the myofilaments and consequently vasodilation. In these processes, the activation of the large conductance Ca2+-activated K+ channel, phosphorylation of IP3R-associated cGMP kinase substrate, phosphorylation of myosin phosphatase target subunit 1, and the counteraction on Rho A/Rho kinase activity may serve as the major mechanisms for the cGMP/PKG signaling.KeywordsSoluble guanylyl cyclaseParticulate guanylate cyclasescGMPcIMPPhosphodiesterasePKGIRAGMLCPMYPT1ROCK
Article
Background and aim The leaves of Garcinia cowa (G. cowa) are used in Thai traditional medicine to improve blood circulation. However, there is no scientific evidence to confirm this therapeutic claim. Here, we investigated the vasorelaxing effect and its underlying mechanisms of an aqueous extract of G. cowa leaves in rat thoracic aortic rings. Materials and methods Dried leaves of G. cowa were extracted with water, followed by phytochemical analysis. Vascular reactivity experiments were performed in isolated rat thoracic aortic rings using an organ bath system. The results were recorded using the data acquisition system Power Lab. Results Phytochemical analysis showed that the leaves of G. cowa are rich in polyphenols and flavonoids, especially kaempferol, vitexin, and isovitexin. The G. cowa leaf extract caused a concentration-dependent relaxation of aortic rings. This effect was attenuated by denudation of the endothelium, or by pre-treatment of the aortic rings with l-NAME, ODQ, indomethacin, or glibenclamide, but not with TEA. Conclusion This study indicates that G. cowa leaf extract induces vasorelaxation through both endothelium-dependent and endothelium-independent manners. Its mechanism of action mainly involves the production of nitric oxide and prostanoids, as well as opening ATP-sensitive K⁺ channels. The vasorelaxing effect of G. cowa leaf extract is probable promoted by the action of flavonoids.
Thesis
Les plaquettes sanguines circulent dans le sang au repos, cet état inactivé étant maintenu par la production de prostacycline et de monoxyde d'azote par l'endothélium vasculaire. Ces deux agents activent respectivement les voies des nucléotides cycliques : AMPc et GMPc. La prostacycline (ou prostaglandine I2), après liaison au récepteur IP, active l'adénylate cyclase (AC) via une protéine Gs. L'AC activée est responsable de la formation d'AMPc intraplaquettaire qui conduit à une inhibition de l'activation plaquettaire. Afin de permettre l'activation plaquettaire, le taux d'AMPc est réprimé i) par l'action des phosphodiestérases (PDE), qui le dégradent, ii) l'ADP, qui en se fixant sur P2Y12 active une Gi inhibitrice de l'AC, iii) par son efflux du cytosol via notamment la protéine d'efflux MRP4 (ABCC4), et iv) par une compartimentation subcellulaire de la voie de l'AMPc, mécanisme très peu documenté dans les plaquettes. Outre son rôle dans l'homéostasie de l'AMPc, de récentes études suggèrent que MRP4 serait également associée à des états de résistance plaquettaire à l'aspirine. En effet, un traitement par aspirine au long cours induirait une surexpression de MRP4 dans les plaquettes et cette surexpression serait par la suite responsable de l'efflux de l'aspirine hors des plaquettes, diminuant alors son efficacité. Les travaux présentés dans cette thèse ont eu pour objectif d'étudier la régulation de la voie de l'AMPc sous forme de microdomaines et l'impact d'un traitement par l'aspirine in vivo sur l'expression de MRP4 et sa répercussion sur l'homéostasie de l'AMPc. L'étude de la répartition des acteurs de la voie de l'AMPc révèlent une répartition non homogène au sein des membranes. En effet, une partie des acteurs sont présents hors des radeaux lipidiques membranaires bien qu'une fraction de PKA ainsi que de Gi soient présents dans les radeaux lipidiques. Cette répartition suggère diverses voies de régulation de la voie de l'AMPc. En effet, la présence d'acteurs hors des radeaux lipidiques est compatible avec le modèle d'organisation sous forme de microdomaines à AMPc comprenant la voie de synthèse (Gs, ACIII), l'effecteur PKA mais également la voie de régulation par les PDEs 2A et 3A. Ces microdomaines pourraient alors réguler localement la réponse plaquettaire. Par ailleurs, la présence d'acteurs de la voie de l'AMPc dans les radeaux lipidiques est compatible avec le modèle d'organisation ayant pour rôle de produire de l'AMPc qui diffuse plus facilement dans le cytoplasme (absence de PDE à proximité) pour exercer son effet inhibiteur, tout en maintenant un niveau d'inhibition contraint comme en témoigne l'augmentation de l'effet inhibiteur d'un activateur de la voie de l'AMPc lors de destruction des radeaux lipidiques. Ainsi l'organisation de la voie de l'AMPc sous différentes formes, en microdomaines AMPc ou non, pourrait impliquer des degrés différents d'inhibition plaquettaire par l'AMPc. Pour le second objectif, l'étude de différentes voies d'administration de l'aspirine chez deux souches de souris nous a permis de définir la voie orale comme étant la voie la plus appropriée pour l'étude de l'effet anti plaquettaire de l'aspirine. Son effet est mesurable 30 min après administration et reste mesurable à 3 heures avec une meilleure reproductibilité chez la souche C56/BL6. La dose de 100 mg/Kg induit une augmentation du temps de saignement et inhibe l'activité plaquettaire comme le montre une inhibition de 50 % de l'agrégation au collagène et la baisse de 85 % de la production de thromboxane B2. L'administration de l'aspirine durant 4 jours permet d'induire une augmentation de l'expression plaquettaire de MRP4 d'un facteur 2,5. Ce travail a permis de mieux caractériser le rôle de MRP4 dans la voie de l'AMPc et de définir le modèle préclinique d'administration de l'aspirine afin d'étudier le rôle de MRP4 dans la résistance au traitement.
Chapter
Type 2 diabetes (T2D) is a complex metabolic disorder characterized by impaired glucose metabolism and pancreatic β-cell dysfunction. No effective treatments are available for T2D, although there have been many developments in the therapeutic arena. Nitric oxide (NO) is an endocrine agent with multiple and important biological roles in most mammalian tissues. NO has emerged as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in T2D. Several of the pharmaceuticals used in T2D affect the NO system and perhaps even more so by the drugs we use to treat diabetic cardiovascular complications. Experimental works in animal models of T2D show promising results with interventions aimed to increase NO signaling. However, translation into human studies has so far been less successful, but more large-scale prolonged studies are clearly needed to understand its role. This book is a collection of reviews that deal with the role of nitric oxide in type 2 diabetes, providing a unique overview of NO signaling, and pointing out key areas for more detailed research. The book includes contributions about the pathophysiology of T2D, a brief history of discovery and timeline of NO research, a comprehensive overview of impaired NO metabolism in T2D, precursors of NO (i.e., L-arginine, L-citrulline, nitrate, nitrites, and NO donors), NO and T2D from genetic points of view, NO and diabetic wound healing, NO and osteoporosis, NO and hyperuricemia, NO and Alzheimer’s Disease, therapeutic applications of NO and NO donors in T2D. The compilation is of great value to anyone interested in the biochemistry of NO and its relationship to diabetes.
Article
Nitric oxide (NO) accounts for the major effects of endothelium-derived relaxing factor. We investigated whether NO, added to the inspired gas, could exert a bronchodilatory action similar to the pulmonary vasodilation described when administering NO during lung vascular constriction. New Zealand White rabbits were intubated and mechanically-ventilated with 30% oxygen during neuroleptanaesthesia. Methacholine (MCh) was nebulized at increasing concentrations from 0.5 to 4.0 mg.ml-1, with or without inhalation of 80 parts per million (ppm) NO. The technique of rapid airway occlusion during constant-flow inflation was used for measuring respiratory mechanics, i.e. resistance and compliance of the respiratory system. Methacholine nebulization without NO inhalation raised the resistance from 51 +/- 6 (mean +/- 95% confidence interval) to 107 +/- 52 cmH2O.l-1.s at Mch 4 mg.ml-1. During NO inhalation, nebulization of MCh showed no significant increase in resistance. Arterial oxygen tension (PaO2) and compliance fell to the same extent during methacholine challenge, whether NO was inhaled or not. Closure of small airways may be a mechanism that causes the decrease in PaO2 and compliance observed. This suggests that 80 ppm NO added to the inspired gas modulates the response in central airway tone to nebulized MCh in this rabbit model. However, it appears to have less effect on peripheral airways.
Article
Purpose of review: Upper airway nitric oxide (NO) is physiologically important in airway regulation and defense, and can be modulated by various airway inflammatory conditions, including allergic rhinitis and chronic rhinosinusitis - with and without polyposis. Paranasal sinuses serve as a NO 'reservoir', with concentrations typically exceeding those measured in lower airway (fractional exhaled NO or FeNO) by a few orders of magnitude. However, the dynamics of NO flux between the paranasal sinuses and main nasal airway, which are critical to respiratory NO emission, are poorly understood. Recent findings: Historically, NO emissions were thought to be contributed mostly by the maxillary sinuses (the largest sinuses) and active air movement (convection). However, recent anatomically-accurate computational modeling studies based on patients', CT scans showed that the ethmoid sinuses and diffusive transport dominate the process. Summary: These new findings may have a substantial impact on our view of nasal NO emission mechanisms and sinus physiopathology in general.
Article
Neurodegenerative diseases are a set of diseases in which slow and progressive neuronal loss occurs. Nitric oxide (NO) as a neurotransmitter performs key roles in the stimulation and blockade of various inflammatory processes. Although physiological NO is necessary for protection against a variety of pathogens, reactive oxygen species-mediated oxidative stress induces inflammatory cascades and apoptosis. Activation of glial cells particularly astrocytes and microglia induce overproduction of NO, resulting in neuroinflammation and neurodegenerative disorders. Hence, inhibiting the overproduction of NO is a beneficial therapeutic approach for numerous neuroinflammatory conditions. Several compounds have been explored for the management of neurodegenerative disorders, but they have minor symptomatic benefits and several adverse effects. Phytochemicals have currently gained more consideration owing to their ability to reduce the overproduction of NO in neurodegenerative disorders. Furthermore, phytochemicals are generally considered to be safe and beneficial. The mechanisms of NO generation and their implications in neurodegenerative disorders are explored in this review article, as well as several newly discovered phytochemicals that might have NO inhibitory activity. The current review could aid in the discovery of new anti-neuroinflammatory drugs that can suppress NO generation, particularly during neuroinflammatory and neurodegenerative conditions.
Article
There is currently no effective treatment for dementia, of which Alzheimer's disease (AD) is the most common form. It is, therefore, imperative to focus on evidence-based preventive strategies to combat this extremely debilitating chronic disease. Nitric oxide (NO) is a key signalling molecule in the cardiovascular, cerebrovascular, and central nervous systems. Vegetables rich in nitrate, such as spinach and beetroot, are an important source of NO, with beneficial effects on validated markers of cardiovascular health and an association with a lower risk of cardiovascular disease. Given the link between cardiovascular disease risk factors and dementia, together with the important role of NO in vascular health and cognition, it is important to determine whether dietary nitrate could also improve cognitive function, markers of brain health, and lower risk of dementia. This review presents an overview of NO's role in the cardiovascular, cerebrovascular, and central nervous systems; an overview of the available evidence that nitrate, through effects on NO, improves cardiovascular health; and evaluates the current evidence regarding dietary nitrate's potential role in cerebrovascular health, cognitive function, and brain health assessed via biomarkers.
Article
Nitric oxide (NO), playing crucial roles as a cellular messenger and as a toxic ROS, is highly related to the physiological and pathological states of living systems. The very wide but very uneven distribution of this radical gas in the inhomogeneous biological microenvironment imposes big challenges for specifically detecting its local level in certain subcellular areas, which calls for a long list of NO probes for each target. In order to simplify the syntheses and designs of these probes, herein it is proposed to construct a versatile NO-sensing toolbox based on a bio-orthogonal concept, i.e., inverse electron demand Diels-Alder click reaction between tetrazine and strained alkyne BCN. On the one hand, rhodamine-o-phenylenediamine as the NO-responsive scaffold is coupled with a tetrazine unit to generate a general probe TMR-Tz-NO, which, to our knowledge, is the first case of the tetrazine-coupled analyte-responsive probe. On the other hand, the BCN moiety is connected to different targeting groups, such as TPP, morpholine, and Ac4ManN, targeting to mitochondria, lysosomes, and membranes, respectively. It works well to use TMR-Tz-NO to match with any targetable BCN counterpart in this toolbox to achieve the imaging of NO in the corresponding subcellular area. For example, through metabolism, Ac4ManN-BCN is effectively taken and grows on the cell membranes. The bio-orthogonal reaction between TMR-Tz-NO and Ac4ManN-BCN makes the NO probe anchored to the membrane surface permanently. The zebrafish experiment revealed that this bio-orthogonal pair can track and image the NO produced during inflammation in vivo.
Article
Long-term consumption of beetroot juice on efficacy of converting dietary nitrate to plasma nitrate and nitrite was investigated. Adults were randomized to consume either beetroot juice with 380 mg of nitrate (BR) or a beetroot juice placebo (PL) for 12-weeks. Plasma nitrate and nitrite were measured before and 90-minutes after consuming their intervention beverage. Percent change in nitrite across the 90 min was greater in BR (273.2 ± 39.9%) vs. PL (4.9 ± 36.9%). Long-term consumption of nitrate containing beetroot juice increased fasting nitrate and nitrite plasma levels compared to baseline.
Chapter
In recent years our understanding of molecular mechanisms of drug action and interindividual variability in drug response has grown enormously. Meanwhile, the practice of anesthesiology has expanded to the preoperative environment and numerous locations outside the OR. Anesthetic Pharmacology: Basic Principles and Clinical Practice, 2nd edition, is an outstanding therapeutic resource in anesthesia and critical care: Section 1 introduces the principles of drug action, Section 2 presents the molecular, cellular and integrated physiology of the target organ/functional system and Section 3 reviews the pharmacology and toxicology of anesthetic drugs. The new Section 4, Therapeutics of Clinical Practice, provides integrated and comparative pharmacology and the practical application of drugs in daily clinical practice. Edited by three highly acclaimed academic anesthetic pharmacologists, with contributions from an international team of experts, and illustrated in full colour, this is a sophisticated, user-friendly resource for all practitioners providing care in the perioperative period.
Article
Peroxynitrite, one of the most active reactive oxygen (ROS) and reactive nitrogen (RON) species, has been of wide interest because of its high oxidizing and nitrifying properties. As a vital physiological activator and signaling molecule, peroxynitrite (ONOO–) excess can damage proteins, nucleic acids, and amino acids in cells, thus causing inflammation and other serious diseases in living organisms. Fluorescence sensing and fluorescence imaging can label and track a wide range of biological activities and living molecules with excellent temporal and spatial resolution. As a result, many small molecule fluorescent probes have been developed for the detection and treatment of peroxynitrite. However, this interesting and cutting-edge topic has not been systematically summarized so far. Therefore, this review highlights the design strategies, reaction mechanisms, and imaging applications of organic fluorescent probes used for peroxynitrite detection in recent years. In particular, a detailed summary and description of the recognition sites for peroxynitrite (ONOO–) are provided, which can facilitate fresh ideas and inspiration for future research efforts. More meaningfully, we hope that the future developments of fluorescent probes for detecting ONOO– can overcome the current problems, such as limited water solubility, high biological toxicity, etc., and create a superior and safer fluorescent sensing technology.
Article
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The mechanism of the inhibitory action of phenidone, 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW 755C), dithiothreitol, hydroquinone, and pyrogallol on the vascular relaxation induced by endothelium-derived relaxing factor (EDRF) was investigated. EDRF was released from porcine aortic endothelial cells in culture and bioassayed on a cascade of superfused rabbit aortic strips. These compounds inhibited EDRF-induced relaxation of vascular strips, without affecting the relaxation induced by glyceryl trinitrate, and their inhibitory potency was markedly attenuated (by more than 1 order of magnitude) by the addition of superoxide dismutase (5-15 units/ml) or oxidized cytochrome c (20-40 microM) but not by catalase (30 units/ml) or heat-inactivated superoxide dismutase. These data indicate that the above five inhibitors inactivate EDRF through the formation of superoxide ions, which have recently been shown to destroy EDRF. The inhibition of EDRF by these compounds is therefore attributable to their redox properties rather than to any specific biological action.
Article
A method has been devised for the determination of N-nitrososarcosine, representative of the group of non-volatile nitrosamines of physiological origin, whereby the nitrosamine is denitrosated with hydrogen bromide to form the volatile nitrosyl bromide. After dehalogenation in a heated converter, the nitrosamine can be determined as nitric oxide by using a chemiluminescence analyser, the response being linear up to at least 200 µg. The limit of detection is below 6 ng, and is therefore much lower than that for the determination of N-nitrososarcosine as inorganic nitrite in solution after denitrosation. A response is also obtained from inorganic nitrite but this can be differentiated from that of N-nitrososarcosine by the use of acetic acid alone, prior to denitrosation with hydrogen bromide in the same solvent.
Article
The existence of endothelium-derived vascular relaxant factor (EDRF) was postulated by Furchgott and colleagues when they observed that acetylcholine paradoxically relaxed preconstricted aortic strip preparations by an endothelium-dependent mechanism. This phenomenon has since been demonstrated in different blood vessels and mammalian species and it can be elicited by several other agents. EDRF has been thought to be a humoral agent, a lipoxygenase derivative and possibly a free radical. In the study reported here, by using aortic preparations from the rabbit, alone and in cascade experiments with isolated perfused coronary preparations, we demonstrate definitively that EDRF is a humoral agent. It is released from unstimulated aortic preparations containing endothelium, its release can be stimulated for prolonged periods by acetylcholine, and it is not a lipoxygenase derivative or free radical but an unstable compound with a carbonyl group at or near its active site.