Brief Periods of Nitric Oxide Inhalation Protect against Myocardial Ischemia–Reperfusion Injury

Nagasaka, Yasuko; Fernandez, Bernadette; García-Saura, María Francisca; Petersen, Bodil; Ichinose, Fumito; Bloch, Kenneth D.; Feelisch, Martin; Zapol, Warren M.

doi:10.1097/aln.0b013e318186316e

Cited by 93 publications

(70 citation statements)

References 33 publications

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“…The prominent function of circulating NO species and transport of bioactivity in some way from the lungs to the periphery is further supported by a variety of animal and human studies using NO gas for inhalation (74,96). In concert, these investigations have clearly shown that breathing NO gas (up to 80 parts/million) for variable periods of time has not only prominent and selective pulmonary vasodilator effects but also detectable systemic effects in remote vascular beds.…”

Section: No Donorsmentioning

confidence: 71%

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Zhang¹,

Janssens

Wingler

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Zhang Y, Janssens SP, Wingler K, Schmidt HH, Moens AL. Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy. Am J Physiol Heart Circ Physiol 301: H634 -H646, 2011. First published May 27, 2011 doi:10.1152/ajpheart.01315.2010.-The pathogenesis of many cardiovascular diseases is associated with reduced nitric oxide (NO) bioavailability and/or increased endothelial NO synthase (eNOS)-dependent superoxide formation. These findings support that restoring and conserving adequate NO signaling in the heart and blood vessels is a promising therapeutic intervention. In particular, modulating eNOS, e.g., through increasing the bioavailability of its substrate and cofactors, enhancing its transcription, and interfering with other modulators of eNOS pathway, such as netrin-1, has a high potential for effective treatments of cardiovascular diseases. This review provides an overview of the possibilities for modulating eNOS and how this may be translated to the clinic in addition to describing the genetic models used to study eNOS modulation.endothelial nitric oxide synthase uncoupling; modulators; superoxide; tetrahydrobiopterin; enhancers; nitric oxide donors THE REVALENCE AND SEVERITY of incipient or overt cardiovascular diseases associated with reduced nitric oxide (NO) bioavailability has resulted in efforts to restore and conserve adequate NO signaling in the heart and blood vessels through therapeutic interventions. In the cardiovascular system, the signaling molecule NO, which is produced by the enzyme endothelial NO synthase (eNOS, NOS3), has a crucial role in maintaining normal vascular function, mediated by its vasodilating capacity and through a variety of antiatherogenic effects. eNOS is not only expressed in endothelial cells of the heart and blood vessels, in both atrial and ventricular myocytes, but also in specialized pacemaker tissue.Uncoupling of bioactive, i.e., dimeric eNOS to an inactive monomeric form (73) is caused by oxidative stress, which reduces the bioavailability of tetrahydrobiopterin (BH 4 ), an essential cofactor of eNOS. In this uncoupled state, NADPH consumption and oxygen reduction are uncoupled from L-arginine oxidation and NO formation with a subsequently decreased NO production and increased superoxide generation (157). eNOS generated superoxide, further oxidizes BH 4 , and hence enhances the uncoupling of eNOS. However, it is unclear which source of superoxide initiates eNOS uncoupling.Uncoupling of eNOS has been described in 1) situations associated with endothelial dysfunction such as atherosclerosis (3, 70), diabetes mellitus (135), ischemia-reperfusion (I/R) injury (35,138), hypertension (68), and chronic flow overload (78); 2) cardiac hypertrophy with ventricular remodeling (133); and 3) diastolic heart failure (149). eNOS also uncouples physiologically. For example, eNOS may uncouple postnatal in the lung, possibly leading to a developmental adaptation of the pulmonary vascular system to produce reactive oxygen species (ROS) (81). In addition, it ...

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Section: No Donorsmentioning

confidence: 71%

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Zhang¹,

Janssens

Wingler

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Over the ensuing decade, evidence was presented that strongly suggested that inhaled NO led to distinct extrapulmonary effects, for example, in mesenteric, renal, and cardiac vessels. Recently, there is growing evidence that iNO might be protective in reducing ischemiareperfusion injury within mesentery (Fox-Robichaud et al, 1998), and myocardium (Nagasaka et al, 2008), thus reducing tissue damage. While experimental (Rosenberg et al, 1995;Lopes Cardozo et al, 1996;Kusuda et al, 1999) and clinical (Vavilala et al, 2001) studies could not detect changes in CBF during iNO therapy, one experimental study revealed that while it did not alter cerebral perfusion, iNO was shown to possess a cerebrovascular effect (Kuebler et al, 2003).…”

Section: Inhaled Nitric Oxide Donorsmentioning

confidence: 99%

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Terpolilli¹,

Moskowitz

Plesnila³

2012

J Cereb Blood Flow Metab

129

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Some 40 years ago it was recognized by Furchgott and colleagues that the endothelium releases a vasodilator, endothelium-derived relaxing factor (EDRF). Later on, several groups identified EDRF to be a gas, nitric oxide (NO). Since then, NO was identified as one of the most versatile and unique molecules in animal and human biology. Nitric oxide mediates a plethora of physiological functions, for example, maintenance of vascular tone and inflammation. Apart from these physiological functions, NO is also involved in the pathophysiology of various disorders, specifically those in which regulation of blood flow and inflammation has a key role. The aim of the current review is to summarize the role of NO in cerebral ischemia, the most common cause of stroke.

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“…Опосредованное NO-угнетение адренергической стимуляции и сократимости с сохране-нием эндотелий-зависимой вазодилатации и снижением кальциевой перегрузки клеток ведет к уменьшению фе-номена no-reflow. В исследовании у грызунов установ-лено, что ингаляция оксида азота приводит к быстрому накоплению метаболитов NO в крови и тканях, способс- твуя кардиопротекции при ишемически-реперфузион-ном повреждении и уменьшению ЗИ/ОР на 31% [20,21]. Полученные нами данные также свидетельствуют о кардиопротективных свойствах NO при его подаче в кон-тур экстракорпоральной циркуляции при моделировании ишемически-реперфузионного повреждения миокарда.…”

Section: Discussionunclassified

Myocardium protection against ischemic-reperfusion injury by nitric oxide supplied to the extracorporeal circulation line during cardiopulmonary bypass (experimental study)

Каменщиков¹,

Mandel²,

Подоксенов³

et al. 2017

PKiK

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Aim. The study was designed to assess the efficiency of exogenous nitric oxide supply to the extracorporeal circulation line for myocardial protection against ischemic-reperfusion injury in acute myocardial infarction simulation during cardiopulmonary bypass (CPB) in the experiment. Methods. Acute ischemia was simulated in rabbits (n = 20) with subsequent myocardial reperfusion. All animals were anesthetized and mechanically ventilated through a nasotracheal tube. The experiment included occlusion of the left coronary artery by its clamping with a ligature for 45 min with subsequent reperfusion for 120 min during CPB. All animals were divided into 2 equal groups: 10 rabbits received nitric oxide supply to the extracorporeal circulation line in a dose of 40 ppm throughout the entire CPB period (the main group); 10 rabbits made up the control group. The ratio of the infarction area to the risk area was determined, and the quantity and nature of ventricular arrhythmias were accessed. Results. It was established that nitric oxide supply through the extracorporeal circulation line during CPB had a pronounced infarct-limiting effect, the infarct area to the risk area ratio decreased by 15% as compared to the control group, р = 0.0002. There was also a significant antiarrhythmic effect. A lesser quantity of polytopic and polymorphic ventricular extrasystoles were observed in the main group during periods of ischemia and reperfusion (p = 0.003 and p = 0.012). A statistically significant decrease in the venoarterial gradient of the partial pressure of carbon dioxide in the main group was associated with an increase in the urine flow rate amounting to 1.4 [1.3; 1.5] ml/kg/h in the main group and 1.15 [1; 1.3] ml/kg/h in the control group, p = 0.013. Conclusion. The data obtained during the experiment demonstrate the presence of cardioprotective properties of nitric oxide delivered to the extracorporeal circulation line when simulating myocardial ischemic-reperfusion injury. These properties manifest themselves as a 15% decrease of the infarction zone-risk area ratio, a fewer number of arrhythmias and improvement of tissue perfusion during CPB. Intraoperative myocardial protection by nitric oxide in patients operated with CPB should be the object of further clinical research.Received 19 June 2017. Revised 9 October 2017. Accepted 15 October 2017.Funding: The study did not have sponsorship.Conflict of interest: Authors declare no conflict of interest.Author contributions: All the authors comply with 4 ICMJE authorship criteria and contributed equally at every stage of the study.Acknowledgement: The authors express their gratitude to Ekaterina S. Tokareva and Aleksandra A. Nenakhova for support in preparation of the article.

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Brief Periods of Nitric Oxide Inhalation Protect against Myocardial Ischemia–Reperfusion Injury

Cited by 93 publications

References 33 publications

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Myocardium protection against ischemic-reperfusion injury by nitric oxide supplied to the extracorporeal circulation line during cardiopulmonary bypass (experimental study)

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