Retraction: The contribution of N2O3 to the cytotoxicity of the nitric oxide donor DETA/NO: an emerging role for S-nitrosylation.

In the vasculature it is well established that cGMP is involved in the relaxant response to nitric oxide (NO) and NO donors. However, there is an increasing evidence that alternative/additional pathways that are cGMP-independent may also exist. A key criterion for a response to NO or a NO donor drug to be classified as cGMP-independent is lack of (or incomplete) inhibition by the selective inhibitor of soluble guanylate cyclase, ODQ (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one). In many blood vessels cGMP-independent mechanisms contribute to the vasorelaxation, and in certain vascular beds cGMP-independent relaxation may be the predominant mechanism of action of NO and NO donors. NO donor drugs that generate NO "spontaneously", like authentic NO (i.e. solutions of NO gas), appear to exhibit a larger component of cGMP-independent vasorelaxation than do those drugs that require bioactivation in the tissue. The long lasting inhibition of responses to vasoconstrictors by S-nitrosothiols, persisting after removal of these NO donors, may be a cGMP-independent process, at least in some vessels. The mechanisms involved in the inhibition of vascular growth by NO and NO donors are predominantly cGMP-independent, as are the mechanisms responsible for the effects of NO donors on apoptosis in vascular smooth muscle and endothelial cells. The ability of NO and NO donors to inhibit platelet aggregation has a significant cGMP-independent component. cGMP-independent pathways are most often, though not exclusively, seen at high concentrations (microM - mM) of NO and NO donors. Hence, in relation to the actions of endogenous NO, these pathways may be particularly important in settings when the inducible isoform of NO-synthase is expressed. Furthermore, cGMP-independent pathways are enhanced in animal models of atherosclerosis and ischaemia. This suggests that it may be possible to target cGMP-independent mechanisms with selected NO donors in disease states.

Cervical priming before first-trimester surgical abortion is recommended in certain groups of women. Nitric oxide (NO) donors induce cervical ripening without uterine contractions, but the efficacy and side effects are of concern. To evaluate NO donors for cervical ripening before first-trimester surgical abortion, in terms of efficacy, side effects, and reduction of complications. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and POPLINE. We also searched reference lists of retrieved papers. We contacted experts in the field for information on both published and unpublished trials. Randomised controlled trials comparing NO donors alone or in combination with other methods for cervical ripening in first-trimester surgical abortion. Two review authors independently selected and extracted the data onto a data extraction form. We processed the data using Review Manager (RevMan 5) software. We included 9 studies involving 766 participants. There were no serious complications (infection requiring antibiotic treatment, blood transfusion, complications requiring unintended operation, cervical injury, uterine perforation, death or serious morbidity) in the included trials.NO donors were more effective in cervical ripening when compared with placebo or no treatment. Baseline cervical dilatation before the procedure was higher in NO donors group (mean difference (MD) 0.30, 95% confidence interval (CI) 0.01 to 0.58) The cumulative force required to dilate the cervix to 8 mm (MD -4.29, 95% CI -9.92 to 1.35), headache (risk ratio (RR) 1.73, 95% CI 0.86 to 3.46), abdominal pain (RR 0.87, 95% CI 0.50 to 1.50), or patient satisfaction (RR 0.95, 95% CI 0.84 to 1.07) were not different. More nausea and vomiting occurred in the women who received a NO donor (RR 2.62, 95% CI 1.07 to 6.45).NO donors were inferior to prostaglandins for cervical ripening. The cumulative force required to dilate the cervix to 8 mm to 9 mm was higher (MD 13.12, 95% CI 9.72 to 16.52), and baseline cervical dilatation was less (MD -0.73, 95% CI -1.01 to -0.45) in the NO donor group. However, the probability of dilation greater than 8 mm at three hours was higher in the NO donor group (RR 6.67, 95% CI 2.21 to 20.09). Side effects including headache (RR 5.13, 95% CI 3.29 to 8.00), palpitation (RR 3.43, 95% CI 1.64 to 7.15), dizziness (RR 3.29, 95% CI 1.46 to 7.41), and intraoperative blood loss (MD 33.59 ml, 95% CI 24.50 to 42.67) were also higher. However, abdominal pain (RR 0.33, 95% CI 0.25 to 0.44) and vaginal bleeding (RR 0.14, 95% CI 0.07 to 0.27) were less in the NO donor group. No difference for nausea/vomiting in both groups(RR 1.17, 95% CI 0.94 to 1.46). Patient satisfaction was not different.One trial compared a NO donor with a NO donor plus prostaglandin. The cumulative force required to dilate the cervix to 8 mm was higher (MD 14.50, 95% CI 0.50 to 28.50) in the NO donor group. There was no difference in headache (RR 0.88, 95% CI 0.38 to 2.00), abdominal pain (RR 0.14, 95% CI 0.02 to 1.07), or intraoperative blood loss (MD -50, 95% CI -164.19 to 64.19). NO donors are superior to placebo or no treatment, but inferior to prostaglandins for first-trimester cervical ripening, and associated with more side effects.

Cervical priming before first-trimester surgical abortion is recommended in certain groups of women. Nitric oxide (NO) donors induce cervical ripening without uterine contractions, but the efficacy and side effects are of concern. To evaluate efficacy, side effects and complications of NO donors for cervical ripening before first-trimester surgical abortion. We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE and Popline. We also searched reference lists of retrieved papers. We contacted experts in the field for information on both published and unpublished trials. Randomised controlled trials comparing NO donors alone or in combination with other methods for cervical ripening in first-trimester surgical abortion. Two reviewers independently selected and extracted the data onto a data extraction form. We processed the data using Review Manager (RevMan5) software. We included eight studies involving 718 participants. There were no serious complications (infection requiring antibiotic treatment, blood transfusion, complications requiring unintended operation, cervical injury, uterine perforation, death or serious morbidity) in the trials included.NO donors were ineffective in cervical ripening comparing with placebo or no treatment. The cumulative force required to dilate the cervix to 8 mm (mean difference -4.29, 95% CI -9.92, 1.35), baseline cervical dilatation before the procedure (mean difference 0.21, 95% CI -0.12, 0.53), headache (RR 1.73, 95% CI 0.86, 3.46), abdominal pain (RR 0.87, 95% CI 0.51, 1.50) or patient satisfaction (RR 0.95, 95% CI 0.84, 1.07) were not different. More nausea and vomiting occurred in the women who received a NO donor (RR 2.62, 95% CI 1.07, 6.75).NO donors were inferior to prostaglandins for cervical ripening. The cumulative force required to dilate the cervix to 8-9 mm was higher (mean difference 13.12, 95% CI 9.72, 16.52) and baseline cervical dilatation was less (mean difference -0.73, 95% CI -1.01, -0. 45) in the NO donor group. Side effects including headache (RR 5.13, 95% CI 3.29, 8.00), palpitation (RR 3.43, 95% CI 1.64, 7.15), dizziness (RR 3.29, 95% CI 1.46, 7.41) and intraoperative blood loss (mean difference 33.59 ml, 95% CI 24.50, 42.67) were also higher. However, abdominal pain (RR 0.33, 95% CI 0.25, 0.44) and vaginal bleeding (RR 0.14, 95% CI 0.07, 0.27) was less in the NO donor group. Patient satisfaction was not different.One trial compared a NO donor with a NO donor plus prostaglandin. The cumulative force required to dilate the cervix to 8 mm was higher (mean difference 14.50, 95% CI 0.50, 28.50) in the NO donor group. There was no difference in headache (RR 0.88, 95% CI 0.38, 2.00), abdominal pain (RR 0.14, 95% CI 0.02, 1.07) or intraoperative blood loss (mean difference -50, 95% CI -164.19, 64.19). NO donors are inferior to prostaglandins for first-trimester cervical ripening, and associated with more side effects. NO donors are comparable to placebo and no treatment for cervical ripening.

Cervical priming before first-trimester surgical abortion is recommended in certain groups of women. Nitric oxide (NO) donors induce cervical ripening without uterine contractions, but the efficacy and side effects are of concern. To evaluate efficacy, side effects and complications of NO donors for cervical ripening before first-trimester surgical abortion. We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE and POPLINE. We also searched reference lists of retrieved papers. We contacted experts in the field for information on both published and unpublished trials. Randomised controlled trials comparing NO donors alone or in combination with other methods for cervical ripening in first-trimester surgical abortion. Two reviewers independently selected and extracted the data onto a data extraction form. We processed the data using Review Manager (RevMan5) software. We included nine studies involving 766 participants. There were no serious complications (infection requiring antibiotic treatment, blood transfusion, complications requiring unintended operation, cervical injury, uterine perforation, death or serious morbidity) in the trials included.NO donors were more effective in cervical ripening comparing with placebo or no treatment. Baseline cervical dilatation before the procedure was higher in NO donors group (mean difference 0.30, 95% CI 0.01, 0.58) The cumulative force required to dilate the cervix to 8 mm (mean difference -4.29, 95% CI -9.92, 1.35), headache (RR 1.73, 95% CI 0.86, 3.46), abdominal pain (RR 0.87, 95% CI 0.50, 1.50) or patient satisfaction (RR 0.95, 95% CI 0.84, 1.07) were not different. More nausea and vomiting occurred in the women who received a NO donor (RR 2.62, 95% CI 1.07, 6.45).NO donors were inferior to prostaglandins for cervical ripening. The cumulative force required to dilate the cervix to 8-9 mm was higher (mean difference 13.12, 95% CI 9.72, 16.52) and baseline cervical dilatation was less (mean difference -0.73, 95% CI -1.01, -0.45) in the NO donor group. Side effects including headache (RR 5.13, 95% CI 3.29, 8.00), palpitation (RR 3.43, 95% CI 1.64, 7.15), dizziness (RR 3.29, 95% CI 1.46, 7.41) and intraoperative blood loss (mean difference 33.59 ml, 95% CI 24.50, 42.67) were also higher. However, abdominal pain (RR 0.33, 95% CI 0.25, 0.44) and vaginal bleeding (RR 0.14, 95% CI 0.07, 0.27) was less in the NO donor group. Patient satisfaction was not different.One trial compared a NO donor with a NO donor plus prostaglandin.The cumulative force required to dilate the cervix to 8 mm was higher (mean difference 14.50, 95% CI 0.50, 28.50) in the NO donor group. There was no difference in headache (RR 0.88, 95% CI 0.38, 2.00), abdominal pain (RR 0.14, 95% CI 0.02, 1.07) or intraoperative blood loss (mean difference -50, 95% CI -164.19, 64.19). NO donors are superior to placebo or no treatment, but inferior to prostaglandins for first-trimester cervical ripening, and associated with more side effects.

Direct measurement of actual levels of nitric oxide (NO) in cell culture conditions using soluble NO donors

Comparison of the mechanisms underlying the relaxation induced by two nitric oxide donors: Sodium nitroprusside and a new ruthenium complex

Photoactive ruthenium nitrosyls: Effects of light and potential application as NO donors

The positive contractile effect of nitric oxide (NO) donors was studied on isolated rat ventricular cardiomyocytes within a range of a positive force/frequency relationship. We determined whether the observed effect depended on cGMP. The NO donors S-nitroso-acetyl-D,L-penicillamine (SNAP) and N-[4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]butyl]-1,3-propanediamine (spermine-NONO) increased contractile responsiveness transiently in a concentration- and frequency-dependent manner. The influence of NO donors on cGMP levels was enhanced under beating conditions. The positive contractile effect of NO donors was inhibited by adenosine 3',5'-cyclic monophosphothioate Rp diastereomer (Rp-cAMPS), but not by bisindolylmaleimide. Inhibition of the soluble guanylyl cyclase (sGC) by 1 H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ) inhibited the positive contractile effect of NO donors. Direct activation of sGC by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC1) or addition of 8-bromo cGMP increased cell contractility comparably to NO donors. Inhibition of G(alphas) proteins by NF441 inhibited the positive contractile effect of NO donors. In contrast, NO donors did not potentiate the positive contractile effect of forskolin. These results demonstrate that the positive contractile effect of NO donors on rat ventricular cardiomyocytes working in a range of a positive force/frequency relationships is enhanced. It is mediated by NO-dependent stimulation of the sGC interacting with G(alphas) proteins.

Nitric oxide (NO) donors are a potent inducer of heme oxygenase-1 (HO-1). However, it is unclear whether or not HO-1 expression induced by NO donors is a direct consequence of NO released by NO donors. Here, we investigated the effects of NO donors on the expression of HO-1 in primary rat articular chondrocytes. NO donors (SIN-1, SNAP, and SNP) significantly induced the accumulation of HO-1 protein accompanied by an increase in HO-1 mRNA. NO donor-induced HO-1 expression exerted cytoprotection against NO and/or superoxide-induced cell death. Guanylate cyclase signaling was not associated with Nrf2 and HO-1 expression in NO donor-treated chondrocytes. Interestingly, NO scavenger carboxy-PTIO and SOD mimetic TEMPOL markedly inhibited NO donor-induced HO-1 expression in chondrocytes. In addition, NO donor-induced HO-1 expression was completely abrogated by the peroxynitrite scavenger MnTBAP. Since peroxynitrite can be physiologcally formed in the cell through reaction of NO with superoxide, we analyzed whether or not peroxynitrite could directly induce HO-1 expression in chondrocytes. Peroxynitrite treatment in chondrocytes evoked dose-and time-dependent Nrf2 and HO-1 expression. These results indicate that HO-1 expression induced by NO donors in rat articular chondrocytes is due to NO-mediated peroxynitrite rather than NO.

EFFECT OF INTRAVESICAL NITRIC OXIDE THERAPY ON CYCLOPHOSPHAMIDE-INDUCED CYSTITIS

With real-time confocal microscopy, the effect of three nitric oxide (NO) donors, S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione, and diethylamine NO adduct, on the dynamic intracellular Ca2+ concentration ([Ca2+]i) response of porcine tracheal smooth muscle (TSM) cells to acetylcholine (ACh) was examined. ACh initiated propagating [Ca2+]i oscillations in TSM cells, which were inhibited by NO donors. 8-Bromoguanosine 3',5'-cyclic monophosphate slowed the frequency of [Ca2+]i oscillations but did not completely inhibit oscillations, suggesting that the effects of NO donors are only partially mediated via guanosine 3',5'-cyclic monophosphate-dependent mechanisms. After preexposure to NO donors, ACh induced a small biphasic [Ca2+]i response that was blocked by nifedipine, suggesting a lack of effect on Ca2+ influx through voltage-gated channels. In addition, NO donors did not inhibit Ca2+ influx induced by BAY K 8644. The [Ca2+]i response to caffeine was inhibited by NO donors, indicating inhibition of sarcoplasmic reticulum (SR) Ca2+ release. When Ca2+ influx and SR Ca2+ reuptake were blocked, basal [Ca2+]i increased, and this was inhibited by NO donors, suggesting enhanced Ca2+ efflux. These results indicate that NO donors inhibit [Ca2+]i oscillations by blocking SR Ca2+ release and enhancing Ca2+ extrusion.

Chapter 2 - Biomedical applications of polymeric nitric oxide (NO) donors

Four nitric oxide (NO) donors, S-nitrosoglutathione (GSNO), S-nitrosocysteine (CySNO), S-nitroso-N-acetylcysteine (SNAC), and 2-(2-S-nitroso propionamide) acetic acid (GAS) were prepared and their physicochemical characteristics were analyzed. Besides, the antibacterial properties of NO donors were investigated against Escherichia coli and Staphylococcus aureus. UV-visible absorption spectrum and Fourier transform infrared spectrum verified the successful preparation of RSNOs. All NO donors (10mmol l-1) could release NO continuously, and the amount of NO release was from 80.22 μmol l-1 to 706.63 μmol l-1, in which the release of NO from SNAC was the highest, and the release of NO from NaNO2 was the least. The inhibition zone indicated that all NO donors showed stronger antibacterial activity against E. coli and S. aureus, and the antibacterial ability was in the order of SNAC>GSNO>CySNO>GAS>NaNO2 for both E. coli and S. aureus (P<0.05). Scanning electron microscopy(SEM) showed that all NO donors could result in varying degrees of damage to cell wall and membrane of both E. coli and S. aureus and the damage of E. coli was more severe. Four alternative NO donors were successfully synthesized. All alternative NO donors showed better antibacterial properties against E. coli and S. aureus than NaNO2.

Background: Contrast-induced nephropathy (CIN) is associated with increased mortality and morbidity in patients undergoing coronary angiography (CAG) and percutaneous coronary intervention (PCI). We aimed to assess the latest evidence on the preventive effects of nitric oxide (NO) donors in CIN in patients undergoing CAG/PCI. Methods: We conducted a systematic review and meta-analysis of RCTs from PubMed, Web of Science, Scopus, Embase, and Cochrane searches until May 5th, 2024. Dichotomous data were pooled using risk ratio (RR), and continuous data were pooled using mean difference (MD), both with a 95% confidence interval (CI), using (R version 4.3). Results: Our analysis included 13 RCTs encompassing 3,550 patients. NO donors were significantly associated with a decreased incidence of CIN compared to placebo either as an oral administration (RR: 0.33 with 95% CI [0.26, 0.42], P&lt; 0.01) or IV infusions (RR: 0.56 with 95% CI [0.40, 0.78], P&lt; 0.01). Moreover, NO donors were significantly associated with decreased serum creatinine levels compared to placebo either as an oral administration (MD: -0.07 with 95% CI [-0.10, -0.04], P&lt; 0.01) or IV infusions (MD: -0.07 with 95% CI [-0.09, -0.04], P&lt; 0.01). In terms of safety, NO donors were significantly associated with a decreased incidence of MACE compared to placebo as an oral administration (RR: 0.64 with 95% CI [0.45, 0.89], P&lt; 0.01). However, there was no significant difference between NO donors as IV infusions and placebo in MACE (RR: 0.68 with 95% CI [0.38, 1.21], P= 0.18). Finally, NO donors were significantly associated with a decreased incidence of all-cause mortality compared to placebo as an oral administration (RR: 0.58 with 95% CI [0.36, 0.94], P= 0.03). However, there was no significant difference between NO donors as IV infusions and placebo in all-cause mortality (RR: 1.84 with 95% CI [0.40, 8.52], P= 0.44). Conclusion: NO donors as an adjunct therapy are associated with reduced incidence of CIN, and decreased serum creatinine levels either as an oral or IV administration. Also, it was associated with decreased incidence of MACE and all-cause mortality as an oral administration which make this simple low-cost intervention an important therapeutic option in patients undergoing CAG/PCI.

Contrast-induced nephropathy (CIN) is associated with increased mortality and morbidity in patients undergoing coronary angiography (CAG) and percutaneous coronary intervention (PCI). We aimed to assess the latest evidence on the preventive effects of nitric oxide (NO) donors in CIN patients undergoing CAG/PCI. We conducted a comprehensive systematic review and meta-analysis of RCTs from PubMed, Web of Science, Scopus, Embase, and Cochrane searches until May 5th, 2024. Dichotomous data were pooled using risk ratio (RR), and continuous data were pooled using mean difference (MD), both with a 95% confidence interval (CI), using (R version 4.3). Our analysis included 13 RCTs encompassing 3,550 patients. NO donors were significantly associated with a decreased incidence of CIN compared to placebo either as an oral administration (RR: 0.33 with 95% CI [0.26, 0.42], P < 0.01) or IV infusions (RR: 0.56 with 95% CI [0.40, 0.78], P < 0.01). Moreover, NO donors were significantly associated with decreased serum creatinine levels compared to placebo either as an oral administration (MD: - 0.07 with 95% CI [- 0.10, - 0.04], P < 0.01) or IV infusions (MD: - 0.07 with 95% CI [- 0.09, - 0.04], P < 0.01). In terms of safety, NO donors were significantly associated with a decreased incidence of major adverse cardiac events (MACE) compared to placebo as an oral administration (RR: 0.64 with 95% CI [0.45, 0.89], P < 0.01). However, there was no significant difference between NO donors as IV infusions and placebo in MACE (RR: 0.68 with 95% CI [0.38, 1.21], P = 0.18). Finally, NO donors were significantly associated with a decreased incidence of all-cause mortality compared to placebo as an oral administration (RR: 0.58 with 95% CI [0.36, 0.94], P = 0.03). Nevertheless, there was no statistically significant difference in all-cause mortality between IV infusions of NO donors and placebo (RR: 1.84 with 95% CI [0.40, 8.52], P = 0.44). NO donors as adjunct therapy are associated with reduced incidence of CIN and decreased serum creatinine levels, either as an oral or IV administration. They were also associated with reduced incidence of MACE, all-cause mortality, and recurrent myocardial infarction as an oral administration, which makes this simple, low-cost intervention an important therapeutic option in patients undergoing CAG/PCI.