The ubiquitous role of nitric oxide in cardioprotection

Jones, Steven P.; Bolli, Roberto

doi:10.1016/j.yjmcc.2005.09.011

Cited by 389 publications

(349 citation statements)

References 81 publications

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“…Coupling these observations with the proposed critical role of NO • in IPC [16,55], and the demonstration that manipulation of experimental variables to enhance SNO stability (i.e. turning off the lights) improves recovery of perfused hearts from IR injury (Figure 6), we hypothesized that reversible S-nitrosation and inhibition of complex I may be an endogenous cardioprotective mechanism [27].…”

Section: Discussionmentioning

confidence: 79%

“…Currently a consensus exists that low levels of NO • are cardioprotective [16,[53][54][55]. However, NO • signaling is pleiotropic, such that for example NO • mediated coronary vasodilatation would be beneficial in IR, but concurrent systemic vasodilatation would decrease pre-load and after-load, thereby impeding cardiac output.…”

Section: Discussionmentioning

confidence: 99%

“…Considering several reports of reversible complex I inhibition by S-nitrosation [27,28,47,48], with the recent finding that complex I inhibition is cardioprotective [29,30], and the known importance of NO • in IPC [16], we hypothesized that complex I S-nitrosation may be an endogenous cardioprotective mechanism [27]. While ischemic conditions (acidic pH) can favor SNO formation from nitrite [21,50], and hypoxia has been proposed to enhance complex I Snitrosation [51], it is known that typical laboratory lighting conditions can degrade SNOs.…”

Section: Preservation Of Endogenous Sno Correlates With Cardioprotectionmentioning

confidence: 99%

“…Production of NO • by eNOS is elevated during IPC [15,16], leading us to hypothesize that IPC could enhance endogenous mitochondrial S-nitrosation during ischemia. Indeed, we previously showed that mitochondria isolated from hearts subjected to IPC followed by ischemia (all in the dark) contained 17 ± 3 pmol SNO per mg protein [27], whereas mitochondria isolated from hearts that underwent ischemia alone contained only 8 ± 1 pmol of SNO per mg protein (current study).…”

Section: Preservation Of Endogenous Sno Correlates With Cardioprotectionmentioning

confidence: 99%

“…Nitric oxide (NO • ) is a signaling molecule soundly implicated in the mechanism of IPC [15][16][17]. Potential sources of cardioprotective NO • include endogenous production by NO • synthases (NOSs) [15,18], or exogenous administration of various NO • precursors including S-nitrosoglutathione (GSNO) [19], nitroglycerine [20], or nitrite [21].…”

Section: Introductionmentioning

confidence: 99%

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Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

Nadtochiy

Burwell

Brookes

2007

Journal of Molecular and Cellular Cardiology

132

118

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Mitochondrial dysfunction is a key pathologic event in cardiac ischemia-reperfusion (IR) injury, and protection of mitochondrial function is a potential mechanism underlying ischemic preconditioning (IPC). Acknowledging the role of nitric oxide (NO • ) in IPC, it was hypothesized that mitochondrial protein S-nitrosation may be a cardioprotective mechanism. The reagent S-nitroso-2-mercaptopropionyl-glycine (SNO-MPG) was therefore developed to enhance mitochondrial Snitrosation and elicit cardioprotection. Within cardiomyocytes, mitochondrial proteins were effectively S-nitrosated by SNO-MPG. Consistent with the recent discovery of mitochondrial complex I as an S-nitrosation target, SNO-MPG inhibited complex I activity and cardiomyocyte respiration. The latter effect was insensitive to the NO • scavenger c-PTIO, indicating no role for NO • -mediated complex IV inhibition. A cardioprotective role for reversible complex I inhibition has been proposed, and consistent with this SNO-MPG protected cardiomyocytes from simulated IR injury. Further supporting a cardioprotective role for endogenous mitochondrial S-nitrosothiols, patterns of protein S-nitrosation were similar in mitochondria isolated from Langendorff perfused hearts subjected to IPC, and mitochondria or cells treated with SNO-MPG. The functional recovery of perfused hearts from IR injury was also improved under conditions which stabilized endogenous S-nitrosothiols (i.e. dark), or by pre-ischemic administration of SNO-MPG. Mitochondria isolated from SNO-MPG-treated hearts at the end of ischemia exhibited improved Ca 2+ handling and lower ROS generation. Overall these data suggest that mitochondrial S-nitrosation and complex I inhibition constitute a protective signaling pathway that is amenable to pharmacologic augmentation.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Preservation Of Endogenous Sno Correlates With Cardioprotectionmentioning

confidence: 99%

Section: Preservation Of Endogenous Sno Correlates With Cardioprotectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

Nadtochiy

Burwell

Brookes

2007

Journal of Molecular and Cellular Cardiology

132

118

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Effect of Out-of-Hospital Sodium Nitrite on Survival to Hospital Admission After Cardiac Arrest

Kim

Maynard

Dezfulian

et al. 2021

JAMA

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IMPORTANCE Therapeutic delivery of sodium nitrite during resuscitation improved survival in animal models of cardiac arrest, but efficacy has not been evaluated in clinical trials in humans.OBJECTIVE To determine whether parenteral administration of sodium nitrite given by paramedics during resuscitation for out-of-hospital cardiac arrest improved survival to hospital admission. DESIGN, SETTING, AND PARTICIPANTS Double-blind, placebo-controlled, phase 2 randomized clinical trial including 1502 adults in King County, Washington, with out-of-hospital cardiac arrest from ventricular fibrillation or nonventricular fibrillation. Patients underwent resuscitation by paramedics and were enrolled between February 8, 2018, and August 19, 2019; follow-up and data abstraction were completed by December 31, 2019.INTERVENTIONS Eligible patients with out-of-hospital cardiac arrest were randomized (1:1:1) to receive 45 mg of sodium nitrite (n = 500), 60 mg of sodium nitrite (n = 498), or placebo (n = 499), which was given via bolus injection by the paramedics as soon as possible during active resuscitation. MAIN OUTCOMES AND MEASURESThe primary outcome was survival to hospital admission and was evaluated with 1-sided hypothesis testing. The secondary outcomes included out-of-hospital variables (rate of return of spontaneous circulation, rate of rearrest, and use of norepinephrine to support blood pressure) and in-hospital variables (survival to hospital discharge; neurological outcomes at hospital discharge; cumulative survival to 24 hours, 48 hours, and 72 hours; and number of days in the intensive care unit). RESULTS Among 1502 patients with out-of-hospital cardiac arrest who were randomized (mean age, 64 years [SD, 17 years]; 34% were women), 99% completed the trial. Overall, 205 patients (41%) in the 45 mg of sodium nitrite group and 212 patients (43%) in the 60 mg of sodium nitrite group compared with 218 patients (44%) in the placebo group survived to hospital admission; the mean difference for the 45-mg dose vs placebo was −2.9% (1-sided 95% CI, −8.0% to ϱ; P = .82) and the mean difference for the 60-mg dose vs placebo was −1.3% (1-sided 95% CI, −6.5% to ϱ; P = .66). None of the 7 prespecified secondary outcomes were significantly different, including survival to hospital discharge for 66 patients (13.2%) in the 45 mg of sodium nitrite group and 72 patients (14.5%) in the 60 mg of sodium nitrite group compared with 74 patients (14.9%) in the placebo group; the mean difference for the 45-mg dose vs placebo was −1.7% (2-sided 95% CI, −6.0% to 2.6%; P = .44) and the mean difference for the 60-mg dose vs placebo was −0.4% (2-sided 95% CI, −4.9% to 4.0%; P = .85).CONCLUSIONS AND RELEVANCE Among patients with out-of-hospital cardiac arrest, administration of sodium nitrite, compared with placebo, did not significantly improve survival to hospital admission. These findings do not support the use of sodium nitrite during resuscitation from out-of-hospital cardiac arrest.

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Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery

Schlapbach

Gibbons

Horton

et al. 2022

JAMA

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IMPORTANCEIn children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation).OBJECTIVE To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease.DESIGN, SETTING, AND PARTICIPANTS Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021. INTERVENTIONS Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685). MAIN OUTCOMES AND MEASURESThe primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels. RESULTS Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of −0.01 days (95% CI, −0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups. CONCLUSIONS AND RELEVANCEIn children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery.

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The ubiquitous role of nitric oxide in cardioprotection

Cited by 389 publications

References 81 publications

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

Effect of Out-of-Hospital Sodium Nitrite on Survival to Hospital Admission After Cardiac Arrest

Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery

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