Assessment of continuous low-dose and high-dose burst of inhaled nitric oxide in spontaneously breathing COVID-19 patients: A randomized controlled trial.

BACKGROUND: Inhaled nitric oxide (iNO) showed to improve oxygenation at low doses by reducing intrapulmonary shunt and to display antiviral properties at high doses. To assess the safety and potential benefits, we designed an exploratory clinical trial comparing low-dose with intermittent high-dose iNO to only intermittent high-dose iNO in hypoxemic COVID-19 patients. METHODS: In this single-center interventional non-inferiority randomized trial (ClinicalTrials.gov, NCT04476992), twenty oxygen-dependent COVID-19 patients were randomly assigned to the high-dose (200 ppm for 30 min) + continuous low-dose (20 ppm) iNO group (iNO200/20) or the high-dose iNO group (iNO200). Methemoglobinemia (MetHb) assessed 48 h after iNO initiation was the primary endpoint. Reverse-transcription polymerase chain reaction for SARS-CoV-2, inflammatory markers during hospitalization, and heart ultrasounds during the iNO200 treatments were evaluated. RESULTS: MetHb difference between iNO groups remained within the non-inferiority limit of 3 %, indicating comparable treatments despite being statistically different (p-value<0.01). Both groups presented similar SpO2/FiO2 ratio at 48 h (iNO200 vs. iNO200/20 341[334-356] vs. 359 [331-380], respectively, p-value = 0.436). Both groups showed the same time to SARS-CoV-2 negativization, hospital length of stay, and recovery time. iNO-treated patients showed quicker SARS-CoV-2 negativization compared to a similar group of non-iNO patients (HR 2.57, 95%CI 1.04-6.33). During the 228 treatments, iNO200 and iNO200/20 groups were comparable for safety, hemodynamic stability, and respiratory function improvement. CONCLUSIONS: iNO200/20 and iNO200 are equally safe in non-intubated patients with COVID-19-induced respiratory failure with regards to MetHb and NO2. Larger studies should investigate whether iNO200/20 leads to better outcomes compared to non-iNO treated patients.

The Nephroprotective Effect of Nitric Oxide during Extracorporeal Circulation: An Experimental Study.

This study aims to determine the effectiveness of administering 80 ppm nitric oxide in reducing kidney injury, mitochondrial dysfunction and regulated cell death in kidneys during experimental perfusion. Twenty-four sheep were randomized into four groups: two groups received 80 ppm NO conditioning with 90 min of cardiopulmonary bypass (CPB + NO) or 90 min of CPB and hypothermic circulatory arrest (CPB + CA + NO), while two groups received sham protocols (CPB and CPB + CA). Kidney injury was assessed using laboratory (neutrophil gelatinase-associated lipocalin, an acute kidney injury biomarker) and morphological methods (morphometric histological changes in kidney biopsy specimens). A kidney biopsy was performed 60 min after weaning from mechanical perfusion. NO did not increase the concentrations of inhaled NO2 and methemoglobin significantly. The NO-conditioning groups showed less severe kidney injury and mitochondrial dysfunction, with statistical significance in the CPB + NO group and reduced tumor necrosis factor-α expression as a trigger of apoptosis and necroptosis in renal tissue in the CPB + CA + NO group compared to the CPB + CA group. The severity of mitochondrial dysfunction in renal tissue was insignificantly lower in the NO-conditioning groups. We conclude that NO administration is safe and effective at reducing kidney injury, mitochondrial dysfunction and regulated cell death in kidneys during experimental CPB.

Potential Mechanisms for Organoprotective Effects of Exogenous Nitric Oxide in an Experimental Study.

Performing cardiac surgery under cardiopulmonary bypass (CPB) and circulatory arrest (CA) provokes the development of complications caused by tissue metabolism, microcirculatory disorders, and endogenous nitric oxide (NO) deficiency. This study aimed to investigate the potential mechanisms for systemic organoprotective effects of exogenous NO during CPB and CA based on the assessment of dynamic changes in glycocalyx degradation markers, deformation properties of erythrocytes, and tissue metabolism in the experiment. A single-center prospective randomized controlled study was conducted on sheep, n = 24, comprising four groups of six in each. In two groups, NO was delivered at a dose of 80 ppm during CPB ("CPB + NO" group) or CPB and CA ("CPB + CA + NO"). In the "CPB" and "CPB + CA" groups, NO supply was not carried out. NO therapy prevented the deterioration of erythrocyte deformability. It was associated with improved tissue metabolism, lower lactate levels, and higher ATP levels in myocardial and lung tissues. The degree of glycocalyx degradation and endothelial dysfunction, assessed by the concentration of heparan sulfate proteoglycan and asymmetric dimethylarginine, did not change when exogenous NO was supplied. Intraoperative delivery of NO provides systemic organoprotection, which results in reducing the damaging effects of CPB on erythrocyte deformability and maintaining normal functioning of tissue metabolism.

Angiotensin 1-7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart-The signaling mechanism.

BACKGROUND: The high mortality rate of patients with acute myocardial infarction (AMI) remains the most pressing issue of modern cardiology. Over the past 10 years, there has been no significant reduction in mortality among patients with AMI. It is quite obvious that there is an urgent need to develop fundamentally new drugs for the treatment of AMI. Angiotensin 1-7 has some promise in this regard. OBJECTIVE: The objective of this article is analysis of published data on the cardioprotective properties of angiotensin 1-7. METHODS: PubMed, Scopus, Science Direct, and Google Scholar were used to search articles for this study. RESULTS: Angiotensin 1-7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart. Angiotensin 1-7 can prevent not only ischemic but also reperfusion cardiac injury. The activation of the Mas receptor plays a key role in these effects of angiotensin 1-7. Angiotensin 1-7 alleviates Ca2+ overload of cardiomyocytes and reactive oxygen species production in ischemia/reperfusion (I/R) of the myocardium. It is possible that both effects are involved in angiotensin 1-7-triggered cardiac tolerance to I/R. Furthermore, angiotensin 1-7 inhibits apoptosis of cardiomyocytes and stimulates autophagy of cells. There is also indirect evidence suggesting that angiotensin 1-7 inhibits ferroptosis in cardiomyocytes. Moreover, angiotensin 1-7 possesses anti-inflammatory properties, possibly achieved through NF-kB activity inhibition. Phosphoinositide 3-kinase, Akt, and NO synthase are involved in the infarct-reducing effect of angiotensin 1-7. However, the specific end-effector of the cardioprotective impact of angiotensin 1-7 remains unknown. CONCLUSION: The molecular nature of the end-effector of the infarct-limiting effect of angiotensin 1-7 has not been elucidated. Perhaps, this end-effector is the sarcolemmal KATP channel or the mitochondrial KATP channel.

δ-Opioid Receptor as a Molecular Target for Increasing Cardiac Resistance to Reperfusion in Drug Development.

An analysis of published data and the results of our own studies reveal that the activation of a peripheral δ2-opioid receptor (δ2-OR) increases the cardiac tolerance to reperfusion. It has been found that this δ2-OR is localized in cardiomyocytes. Endogenous opioids are not involved in the regulation of cardiac resistance to reperfusion. The infarct-limiting effect of the δ2-OR agonist deltorphin II depends on the activation of several protein kinases, including PKCδ, ERK1/2, PI3K, and PKG. Hypothetical end-effectors of the cardioprotective effect of deltorphin II are the sarcolemmal KATP channels and the MPT pore.

Influence of Hypoxic and Hyperoxic Preconditioning on Endothelial Function in a Model of Myocardial Ischemia-Reperfusion Injury with Cardiopulmonary Bypass (Experimental Study).

The aim of the experiment was to evaluate the effect of preconditioning based on changes in inspiratory oxygen fraction on endothelial function in the model of ischemia-reperfusion injury of the myocardium in the condition of cardiopulmonary bypass. The prospective randomized study included 32 rabbits divided into four groups: hypoxic preconditioning, hyperoxic preconditioning, hypoxic-hyperoxic preconditioning, and control group. All animals were anesthetized and mechanically ventilated. We provided preconditioning, then started cardiopulmonary bypass, followed by induced acute myocardial infarction (ischemia 45 min, reperfusion 120 min). We investigated endothelin-1, nitric oxide metabolites, asymmetric dimethylarginine during cardiopulmonary bypass: before ischemia, after ischemia, and after reperfusion. We performed light microscopy of myocardium, kidney, lungs, and gut mucosa. The endothelin-1 level was much higher in the control group than in all preconditioning groups after ischemia. The endothelin-1 even further increased after reperfusion. The total concentration of nitric oxide metabolites was significantly higher after all types of preconditioning compared with the control group. The light microscopy of the myocardium and other organs revealed a diminished damage extent in the hypoxic-hyperoxic preconditioning group as compared to the control group. Hypoxic-hyperoxic preconditioning helps to maintain the balance of nitric oxide metabolites, reduces endothelin-1 hyperproduction, and enforces organ protection.