scholarly journals Hybrids as NO Donors

2021 ◽  
Vol 22 (18) ◽  
pp. 9788
Author(s):  
Ioanna-Chrysoula Tsopka ◽  
Dimitra Hadjipavlou-Litina
Keyword(s):  
Nitric Oxide ◽  
Significant Role ◽  
Cinnamic Acid ◽  
Biological Properties ◽  
Bioactive Molecules ◽  
Biological Processes ◽  
No Donor ◽  
No Donors ◽  
Anti Inflammatory

Cinnamic acid and its derivatives have been studied for a variety of biological properties, including anti-inflammatory, antioxidant, anticancer, antihypertensive, and antibacterial. Many hybrids of cinnamic derivatives with other bioactive molecules have been synthesized and evaluated as nitric oxide (NO) donors. Since NO plays a significant role in various biological processes, including vasodilation, inflammation, and neurotransmission, NO donor groups are incorporated into the structures of already-known bioactive molecules to enhance their biological properties. In this review, we present cinnamic hybrids with NO-donating ability useful in the treatment of several diseases.

Nitric oxide stimulates the stress-activated protein kinase p38 in rat renal mesangial cells

1999 ◽  
Vol 202 (6) ◽  
pp. 655-660
Author(s):  
A. Huwiler ◽  
J. Pfeilschifter
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
Mapk Cascade ◽  
No Donor ◽  
No Donors ◽  
Mitogen Activated Protein ◽  
Rapid Activation

Nitric oxide (NO) has gained increased attention as a diffusible universal messenger that plays a crucial role in the pathogenesis of inflammatory and autoimmune diseases. Recently, we reported that exogenous NO is able to activate the stress-activated protein kinase (SAPK) cascade in mesangial cells. Here, we demonstrate that exposure of glomerular mesangial cells to compounds releasing NO, including spermine-NO and (Z)-1-?N-methyl-N-[6-(N-methylammoniohexyl)amino]diazen?-1-ium+ ++-1,2-diolate (MAHMA-NO), results in an activation of the stress-activated p38-mitogen-activated protein kinase (p38-MAPK) cascade as measured by the phosphorylation of the activator of transcription factor-2 (ATF2) in an immunocomplex kinase assay. Activation of the p38-MAPK cascade by a short stimulation (10 min) with the NO donor MAHMA-NO causes a large increase in ATF2 phosphorylation that is several times greater than that observed after stimulation with interleukin-1beta, a well-known activator of the p38-MAPK pathway. Time course studies reveal that MAHMA-NO causes rapid and maximal activation of p38-MAPK after 10 min of stimulation and that activation declines to basal levels within 60 min. The longer-lived NO donor spermine-NO causes a comparable rapid activation of the p38-MAPK pathway; however, the increased activation state of p38-MAPK was maintained for several hours before control values were reattained after 24 h of stimulation. Furthermore, the NO donors also activated the classical extracellular signal-regulated kinase (ERK) p44-MAPK cascade as shown by phosphorylation of the specific substrate cytosolic phospholipase A2 in an immunocomplex kinase reaction. Both MAHMA-NO and spermine-NO cause a rapid activation of p44-MAPK after 10 min of stimulation. Interestingly, there is a second delayed peak of p44-MAPK activation after 4–24 h of stimulation with NO donors. These results suggest that there is a differential activation pattern for stress-activated and mitogen-activated protein kinases by NO and that the integration of these signals may lead to specific cell responses.

Nitric oxide affects sarcoplasmic calcium release in skeletal myotubes

2001 ◽  
Vol 91 (5) ◽  
pp. 2117-2124 ◽  
Author(s):  
Leo M. A. Heunks ◽  
Herwin A. Machiels ◽  
P. N. Richard Dekhuijzen ◽  
Y. S. Prakash ◽  
Gary C. Sieck
Keyword(s):  
Nitric Oxide ◽  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Similar Data ◽  
Release Channel ◽  
No Donor ◽  
No Donors ◽  
Subsequent Exposure ◽  
Skeletal Myotubes ◽  
Dose Dependent

In the present study, we used real-time confocal microscopy to examine the effects of two nitric oxide (NO) donors on acetylcholine (ACh; 10 μM)- and caffeine (10 mM)-induced intracellular calcium concentration ([Ca2+]i) responses in C2C12 mouse skeletal myotubes. We hypothesized that NO reduces [Ca2+]i in activated skeletal myotubes through oxidation of thiols associated with the sarcoplasmic reticulum Ca2+-release channel. Exposure to diethylamine NONOate (DEA-NO) reversibly increased resting [Ca2+]i level and resulted in a dose-dependent reduction in the amplitude of ACh-induced [Ca2+]i responses (25 ± 7% reduction with 10 μM DEA-NO and 78 ± 14% reduction with 100 μM DEA-NO). These effects of DEA-NO were partly reversible after subsequent exposure to dithiothreitol (10 mM). Preexposure to DEA-NO (1, 10, and 50 μM) also reduced the amplitude of the caffeine-induced [Ca2+]i response. Similar data were obtained by using the chemically distinct NO donor S-nitroso- N-acetyl-penicillamine (100 μM). These results indicate that NO reduces sarcoplasmic reticulum Ca2+ release in skeletal myotubes, probably by a modification of hyperreactive thiols present on the ryanodine receptor channel.

Sodium Nitrite Increases Regional Blood Flow in Patients with Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2328-2328
Author(s):  
A. Kyle Mack ◽  
Roberto F. Machado ◽  
Vandana Sachdev ◽  
Mark T. Gladwin ◽  
Gregory J. Kato
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Forearm Blood Flow ◽  
Regional Blood Flow ◽  
Cell Disease ◽  
No Donor ◽  
No Donors ◽  
Before And After

Abstract Patients with sickle cell disease have decreased nitric oxide bioavailability, and studies from several groups have confirmed a blunted response to various NO donors in humans and mice with sickle cell disease. Recently published studies show that nitrite induces vasodilation in humans, apparently mediated by conversion of nitrite to NO. This study is designed to determine the potential therapeutic effect of intra-arterial nitrite infusion to restore nitric oxide dependent blood flow in the forearms of patients with sickle cell disease. Venous occlusion strain gauge plethysmography is used to measure the change of forearm blood flow in patients with sickle cell disease, before and after sequential brachial artery infusions of increasing doses of sodium nitrite. In addition, NO responsiveness before and after nitrite infusion is measured by test doses of the NO donor sodium nitroprusside (SNP). Six patients have completed the study and enrollment is continuing. These data indicate that nitrite promotes regional blood flow in patients with sickle cell disease, albeit with a blunted response compared to our healthy control subjects, in whom we previously have found increased blood flow up to 187% with comparable dosing. The significant but blunted response is consistent with the state of nitric oxide resistance to NO donors that has been seen by several groups in patients and mice with SCD. Additionally, we find in these patients that nitrite partially restores SNP responsiveness, with baseline maximal SNP responses more than doubling on average following nitrite infusion, although this finding is preliminary. No adverse effects of nitrite were seen in these six patients. Our early results support a role for nitrite as an NO donor effective in restoring NO-dependent blood flow in patients with sickle cell disease. Additional translational studies are warranted to evaluate the therapeutic effects of systemic nitrite dosing. Table 1. Forearm Blood Flow Response to Nitrite Infusion Nitrite Dose (micromole/min) Sickle Cell Disease Historical Controls P< .0001 (ANOVA) 0.4 5 +/−7.2% N=6 22 +/−3.2% N=10 4 15 +/− 11% N=6 Not infused 40 49 +/− 8.9% N=6 187 +/− 16%N=18 Table 2. Nitrite Effect on Nitroprusside Responsiveness SNP Dose (micrograms/min) Pre-Nitrite Post-Nitrite P= .02 (RM-ANOVA) N=6 0.8 +21 +/− 5.6% +33 +/− 8.3% 1.6 +15 +/− 5.9% +62 +/− 15.1% 3.2 +29 +/− 6.3% +67 +/− 11.5%

Hypoxia enhances a cGMP-independent nitric oxide relaxing mechanism in pulmonary arteries

2003 ◽  
Vol 285 (2) ◽  
pp. L296-L304 ◽  
Author(s):  
Christopher J. Mingone ◽  
Sachin A. Gupte ◽  
Takafumi Iesaki ◽  
Michael S. Wolin
Keyword(s):  
Nitric Oxide ◽  
Sarcoplasmic Reticulum ◽  
Myosin Light Chain ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Cyclopiazonic Acid ◽  
No Donor ◽  
No Donors ◽  
Hypoxic Conditions ◽  
Guanylate Cyclase Activation

Nitric oxide (NO) donors generally relax vascular preparations through cGMP-mediated mechanisms. Relaxation of endothelium-denuded bovine pulmonary arteries (BPA) and coronary arteries to the NO donor S-nitroso- N-acetyl-penicillamine (SNAP) is almost eliminated by inhibition of soluble guanylate cyclase activation with 10 μM 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), whereas only a modest inhibition of relaxation is observed under hypoxia (PO2 = 8–10 Torr). This effect of hypoxia is independent of the contractile agent used and is also observed with NO gas. ODQ eliminated SNAP-induced increases in cGMP under hypoxia in BPA. cGMP-independent relaxation of BPA to SNAP was not attenuated by inhibition of K+ channels (10 mM tetraethylammonium), myosin light chain phosphatase (0.5 μM microcystin-LR), or adenylate cyclase (4 μM 2′,5′-dideoxyadenosine). SNAP relaxed BPA contracted with serotonin under Ca2+-free conditions in the presence of hypoxia and ODQ, and contraction to Ca2+ readdition was also attenuated. The sarcoplasmic reticulum Ca2+-reuptake inhibitor cyclopiazonic acid (0.2 mM) attenuated SNAP-mediated relaxation of BPA in the presence of ODQ. Thus hypoxic conditions appear to promote a cGMP-independent relaxation of BPA to NO by enhancing sarcoplasmic reticulum Ca2+ reuptake.

Accumulation of HIF-1α under the influence of nitric oxide

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 1009-1015 ◽  
Author(s):  
Katrin Britta Sandau ◽  
Joachim Fandrey ◽  
Bernhard Brüne
Keyword(s):  
Nitric Oxide ◽  
Close Correlation ◽  
No Synthase ◽  
Protein Stabilization ◽  
Time Dependent ◽  
Target Cells ◽  
Dependent Manner ◽  
No Donor ◽  
No Donors ◽  
The Impact

Abstract The key player for adaptation to reduced oxygen availability is the transcription factor hypoxia-inducible factor 1 (HIF-1), composed of the redox-sensitive HIF-1α and the constitutively expressed HIF-1β subunits. Under normoxic conditions, HIF-1α is rapidly degraded, whereas hypoxia, CoCl2, or desferroxamine promote protein stabilization, thus evoking its transcriptional activity. Because HIF-1 is regulated by reactive oxygen species, investigation of the impact of reactive nitrogen species was intended. By using different nitric oxide (NO) donors, dose- and time-dependent HIF-1α accumulation in close correlation with the release of NO from chemically distinct NO donors was established. Intriguingly, small NO concentrations induced a faster but transient HIF-1α accumulation than higher doses of the same NO donor. In contrast, NO attenuated up-regulation of HIF-1α evoked by CoCl2 in a concentration- and time-dependent manner, whereas the desferroxamine-elicited HIF-1α signal remained unaltered. To demonstrate an autocrine or paracrine signaling function of NO, we overexpressed the inducible NO synthase and used a coculture system of activated macrophages and tubular cells. Expression of the NO synthase induced HIF-1α accumulation, which underscored the role of NO as an intracellular activator for HIF-1. In addition, macrophage-derived NO triggered HIF-1α up-regulation in LLC-PK1 target cells, which points to intercellular signaling properties of NO in achieving HIF-1 accumulation. Our results show that NO does not only modulate the HIF-1 response under hypoxic conditions, but it also functions as a HIF-1 inducer. We conclude that accumulation of HIF-1 occurs during hypoxia but also under inflammatory conditions that are characterized by sustained NO formation.

scholarly journals Sildenafil-nitric oxide donor combination promotes ventricular tachyarrhythmias in the swine right ventricle

2002 ◽  
Vol 282 (5) ◽  
pp. H1787-H1792 ◽  
Author(s):  
Moshe Swissa ◽  
Toshihiko Ohara ◽  
Moon-Hyoung Lee ◽  
Sanjay Kaul ◽  
Prediman K. Shah ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Donor ◽  
Tyrode Solution ◽  
No Donor ◽  
Maximum Slope ◽  
No Donors ◽  
Restitution Curve ◽  
Rapid Pacing ◽  
Drug Free ◽  
Endocardial Activation

We tested the hypothesis that sildenafil, singly or in combination with nitric oxide (NO) donors, promotes ventricular tachycardia (VT) and ventricular fibrillation (VF). Vulnerability to VT/VF was tested by rapid pacing in eight isolated normal swine right ventricles (RV). The endocardial activation was optically mapped, and the dynamic action potential duration (APD) restitution curves were constructed with metal microelectrodes. At baseline, no VT/VF could be induced. Sildenafil (0.2 μg/ml) or NO donor singly or in combination did not alter VT/VF vulnerability. However, when 2 μg/ml sildenafil was combined with NO donors, the incidence of VT and VF rose significantly ( P < 0.01). VT with a single periodic wavefront was induced in five of eight RVs, and VF with multiple wavefronts was induced in all eight RVs. The sildenafil-NO donor pro-VT/VF combination significantly increased the maximum slope of the APD restitution curve and the amplitude of the APD alternans. The pro-VT/VF effects of sildenafil were reversible after drug-free Tyrode solution perfusion. We conclude that a sildenafil (2 μg/ml) and NO donor combination increases VT/VF vulnerability in the normal RV by a mechanism compatible with the restitution hypothesis.

scholarly journals Nitric Oxide Inhibition of Tobacco Catalase and Ascorbate Peroxidase

2000 ◽  
Vol 13 (12) ◽  
pp. 1380-1384 ◽  
Author(s):  
Daniel Clark ◽  
Jörg Durner ◽  
Duroy A. Navarre ◽  
Daniel F. Klessig
Keyword(s):  
Nitric Oxide ◽  
Enzymatic Activity ◽  
Ascorbate Peroxidase ◽  
Plant Cells ◽  
Defense Responses ◽  
No Donor ◽  
No Donors ◽  
Nitric Oxide Inhibition ◽  
Scavenging Enzymes ◽  
Oxide Inhibition

We used a variety of nitric oxide (NO) donors to demonstrate that NO inhibits the activities of tobacco catalase and ascorbate peroxidase (APX). This inhibition appears to be reversible because removal of the NO donor led to a significant recovery of enzymatic activity. In contrast, APX and catalase were irreversibly inhibited by peroxynitrite. The ability of NO and peroxynitrite to inhibit the two major H2O2-scavenging enzymes in plant cells suggests that NO may participate in redox signaling during the activation of defense responses following pathogen attack.

scholarly journals Nitric oxide signalling in plant nanobiology: current status and perspectives

2020 ◽  
Author(s):  
Zsuzsanna Kolbert ◽  
Réka Szőllősi ◽  
Gábor Feigl ◽  
Zoltán Kónya ◽  
Andrea Rónavári
Keyword(s):  
Nitric Oxide ◽  
Basic Research ◽  
Scientific Basis ◽  
Research Field ◽  
Current Status ◽  
Signal Molecules ◽  
No Production ◽  
No Donor ◽  
No Donors ◽  
Agricultural Use

Abstract Plant nanobiology as a novel research field provides a scientific basis for the agricultural use of nanoparticles (NPs). Plants respond to the presence of nanomaterials by synthesizing signal molecules, such as the multifunctional gaseous nitric oxide (NO). Several reports have described the effects of different nanomaterials (primarily chitosan NPs, metal oxide NPs, and carbon nanotubes) on endogenous NO synthesis and signalling in different plant species. Other works have demonstrated the ameliorating effect of exogenous NO donor (primarily sodium nitroprusside) treatments on NP-induced stress. NO-releasing NPs are preferred alternatives to chemical NO donors, and evaluating their effects on plants has recently begun. Previous studies clearly indicate that endogenous NO production in the presence of nanomaterials or NO levels increased by exogenous treatments (NO-releasing NPs or chemical NO donors) exerts growth-promoting and stress-ameliorating effects in plants. Furthermore, an NP-based nanosensor for NO detection in plants has been developed, providing a new and excellent perspective for basic research and also for the evaluation of plants’ health status in agriculture.

New ibuprofen derivatives as H2S and NO donors as safer anti-inflammatory agents

2019 ◽  
Vol 11 (23) ◽  
pp. 3029-3045
Author(s):  
Ghaneya S Hassan ◽  
Gehan H Hegazy ◽  
Noha M Ibrahim ◽  
Samar H Fahim
Keyword(s):  
Docking Studies ◽  
Inflammatory Activity ◽  
Ulcer Index ◽  
No Donor ◽  
No Donors ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Edema Inhibition ◽  
Cox 1 ◽  
Gastrointestinal Ulceration

Aim: Nonsteroidal anti-inflammatory drugs are expansively used worldwide. However, their prolonged administration is associated with serious side effects, especially gastrointestinal ulceration. Materials & methods: New ibuprofen derivatives hybridized with H2S- or NO-donating moieties were synthesized and evaluated for their anti-inflammatory activity and ulcerogenic effect. COX-1/COX-2 isozymes selectivity test for the most promising derivatives was performed. Molecular docking studies were performed. Results: Most of the compounds showed promising anti-inflammatory activity comparable to that of ibuprofen (% edema inhibition = 76.6 and ulcer index = 21.26) with much better gastrointestinal tract tolerance (ulcer indices ranging from 0 to 14.67), especially compound 2 -H2S donor- (% edema inhibition = 75.5 and ulcer index = 11.75) and compound 16 -NO donor- (% edema inhibition = 65.4 and ulcer index = 8.66).

Effect of in vivo nitrate tolerance on hypersensitivity to NO donors after NO-synthase blockade

2002 ◽  
Vol 80 (11) ◽  
pp. 1106-1118 ◽  
Author(s):  
Jodan D Ratz ◽  
Michael A Adams ◽  
Brian M Bennett
Keyword(s):  
Nitric Oxide ◽  
Glyceryl Trinitrate ◽  
Nitrate Tolerance ◽  
Metabolite Formation ◽  
No Donor ◽  
No Donors ◽  
Nos Inhibitors ◽  
Pressure Lowering ◽  
Oxide Synthase

Animals treated with nitric oxide synthase (NOS) inhibitors exhibit marked hypersensitivity to the blood pressure lowering effects of exogenous nitric oxide (NO) donors. We used this model as a sensitive index to evaluate the relative importance of reduced biotransformation of glyceryl trinitrate (GTN) to NO in the development of nitrate tolerance. NOS-blockade hypertension using NG-nitro-L-arginine methyl ester (L-NAME) caused a marked enhancement of the mean arterial pressure (MAP) decrease mediated by GTN in nontolerant rats. However, even large doses of GTN were unable to change the MAP in GTN-tolerant, NOS-blockade hypertensive animals. In contrast, the MAP responses to the spontaneous NO donor sodium nitroprusside (SNP) were completely unaltered in either tolerant rats or tolerant NOS-blockade hypertensive animals, indicating that NO-dependent vasodilatory mechanisms remain intact despite the development of GTN tolerance. The MAP-lowering effects of GTN in NOS-blockade hypertensive animals were restored 48 h after cessation of chronic GTN exposure. These alterations in the pharmacodynamic response to GTN during tolerance development and reversal were associated with parallel changes in the pattern of GTN metabolite formation, suggesting that the activity of one or more enzymes involved in nitrate metabolism was altered as a consequence of chronic GTN exposure. These findings suggest that the vasodilation resulting from the vascular biotransformation of GTN to NO (or a closely related species) is severely compromised in nitrate-tolerant animals, and that although other mechanisms may contribute to the vascular changes observed following the development of GTN tolerance, decreased GTN bioactivation is likely the most important.Key words: biotransformation, glyceryl trinitrate, hypertension, nitric oxide, tolerance.

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