Adapting nitric oxide: A review of its foundation, uses in austere medical conditions, and emerging applications.

Nitric oxide was first identified as a novel and effective treatment for persistent pulmonary hypertension of the newborn (PPHN), and has since been found to be efficacious in treating acute respiratory distress syndrome (ARDS) and pulmonary hypertension. Physicians and researchers have also found it shows promise in resource-constrained settings, both within and outside of the hospital, such as in high altitude pulmonary edema (HAPE) and COVID-19. The treatment has been well tolerated in these settings, and is both efficacious and versatile when studied across a variety of clinical environments. Advancements in inhaled nitric oxide continue, and the gas is worthy of investigation as physicians contend with new respiratory and cardiovascular illnesses, as well as unforeseen logistical challenges.

Notoginsenoside R1 treatment facilitated Nrf2 nuclear translocation to suppress ferroptosis via Keap1/Nrf2 signaling pathway to alleviated high-altitude myocardial injury.

High-altitude myocardial injury (HAMI) represents a critical form of altitude illness for which effective drug therapies are generally lacking. Notoginsenoside R1, a prominent constituent derived from Panax notoginseng, has demonstrated various cardioprotective properties in models of myocardial ischemia/reperfusion injury, sepsis-induced cardiomyopathy, cardiac fibrosis, and myocardial injury. The potential utility of notoginsenoside R1 in the management of HAMI warrants prompt investigation. Following the successful construction of a HAMI model, a series of experimental analyses were conducted to assess the effects of notoginsenoside R1 at dosages of 50 mg/Kg and 100 mg/Kg. The results indicated that notoginsenoside R1 exhibited protective effects against hypoxic injury by reducing levels of CK, CK-MB, LDH, and BNP, leading to improved cardiac function and decreased incidence of arrhythmias. Furthermore, notoginsenoside R1 was found to enhance Nrf2 nuclear translocation, subsequently regulating the SLC7A11/GPX4/HO-1 pathway and iron metabolism to mitigate ferroptosis, thereby mitigating cardiac inflammation and oxidative stress induced by high-altitude conditions. In addition, the application of ML385 has confirmed the involvement of Nrf2 nuclear translocation in the therapeutic approach to HAMI. Collectively, the advantageous impacts of notoginsenoside R1 on HAMI have been linked to the suppression of ferroptosis via Nrf2 nuclear translocation signaling.

Rhodiola crenulata alleviates hypobaric hypoxia-induced brain injury by maintaining BBB integrity and balancing energy metabolism dysfunction.

BACKGROUND/PURPOSE: Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba (R. crenulate), a famous and characteristic Tibetan medicine, has been demonstrated to exert an outstanding brain protection role in the treatment of high-altitude hypoxia disease. However, the metabolic effects of R. crenulate on high-altitude hypoxic brain injury (HHBI) are still incompletely understood. Herein, the anti-hypoxic effect and associated mechanisms of R. crenulate were explored through both in vivo and in vitro experiments. STUDY DESIGN/METHODS: The mice model of HHBI was established using an animal hypobaric and hypoxic chamber. R. crenulate extract (RCE, 0.5, 1.0 and 2.0 g/kg) and salidroside (Sal, 25, 50 and 100 mg/kg) was given by gavage for 7 days. Pathological changes and neuronal apoptosis of mice hippocampus and cortex were evaluated using H&E and TUNEL staining, respectively. The effects of RCE and Sal on the permeability of blood brain barrier (BBB) were detected by Evans blue staining and NIR-II fluorescence imaging. Meanwhile, the ultrastructural BBB and cerebrovascular damages were observed using a transmission electron microscope (TEM). The levels of tight junction proteins Claudin-1, ZO-1 and occludin were detected by immunofluorescence. Additionally, the metabolites in mice serum and brain were determined using UHPLC-MS and MALDI-MSI analysis. The cell viability of Sal on hypoxic HT22 cells induced by CoCl2 was investigated by cell counting kit-8. The contents of LDH, MDA, SOD, GSH-PX and SDH were detected by using commercial biochemical kits. Meanwhile, intracellular ROS, Ca2+ and mitochondrial membrane potential were determined by corresponding specific labeled probes. The intracellular metabolites of HT22 cells were performed by the targeted metabolomics analysis of the Q300 kit. The cell apoptosis and necrosis were examined by YO-PRO-1/PI, Annexin V/PI and TUNEL staining. In addition, mitochondrial morphology was tested by Mito-tracker red with confocal microscopy and TEM. Real-time ATP production, oxygen consumption rate, and proton efflux rate were measured using a Seahorse analyzer. Subsequently, MCU, OPA1, p-Drp1ser616, p-AMPKα, p-AMPKß and Sirt1 were determined by immunofluorescent and western blot analyses. RESULTS: The results demonstrated that R. crenulate and Sal exert anti-hypoxic brain protection from inhibiting neuronal apoptosis, maintaining BBB integrity, increasing tight junction protein Claudin-1, ZO-1 and occludin and improving mitochondrial morphology and function. Mechanistically, R. crenulate and Sal alleviated HHBI by enhancing the tricarboxylic acid cycle to meet the demand of energy of brain. Additionally, experiments in vitro confirmed that Sal could ameliorate the apoptosis of HT22 cells, improve mitochondrial morphology and energy metabolism by enhancing mitochondrial respiration and glycolysis. Meanwhile, Sal-mediated MCU inhibited the activation of Drp1 and enhanced the expression of OPA1 to maintain mitochondrial homeostasis, as well as activation of AMPK and Sirt1 to enhance ATP production. CONCLUSION: Collectively, the findings suggested that RCE and Sal may afford a protective intervention in HHBI through maintaining BBB integrity and improving energy metabolism via balancing MCU-mediated mitochondrial homeostasis by activating the AMPK/Sirt1 signaling pathway.

Bawei Chenxiang Wan ameliorates right ventricular hypertrophy in rats with high altitude heart disease by SIRT3-HIF1α-PDK/PDH signaling pathway improving fatty acid and glucose metabolism.

BACKGROUND: Bawei Chenxiang Wan (BCW) is among the most effective and widely used therapies for coronary heart disease and angina pectoris in Tibet. However, whether it confers protection through a right-ventricle (RV) myocardial metabolic mechanism is unknown. METHODS: Male Sprague-Dawley rats were orally administrated with BCW, which was injected concurrently with a bolus of Sugen5416, and subjected to hypoxia exposure (SuHx; 5000 m altitude) for 4 weeks. Right ventricular hypertrophy (RVH) in high-altitude heart disease (HAHD) was assessed using Fulton's index (FI; ratio of RV to left ventricle + septum weights) and heart-weight-to-body-weight ratio (HW/BW). The effect of therapeutic administration of BCW on the RVH hemodynamics was assessed through catheterization (mean right ventricular pressure and mean pulmonary artery pressure (mRVP and mPAP, respectively)). Tissue samples were used to perform histological staining, and confirmatory analyses of mRNA and protein levels were conducted to detect alterations in the mechanisms of RVH in HAHD. The protective mechanism of BCW was further verified via cell culture. RESULTS: BCW considerably reduced SuHx-associated RVH, as indicated by macro morphology, HW/BW ratio, FI, mPAP, mRVP, hypertrophy markers, heart function, pathological structure, and myocardial enzymes. Moreover, BCW can alleviate the disorder of glucose and fatty acid metabolism through upregulation of carnitine palmitoyltransferase1ɑ, citrate synthase, and acetyl-CoA and downregulation of glucose transport-4, phosphofructokinase, and pyruvate, which resulted in the reduced levels of free fatty acid and lactic acid and increased aerobic oxidation. This process may be mediated via the regulation of sirtuin 3 (SIRT3)-hypoxia-inducible factor 1α (HIF1α)-pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase (PDH) signaling pathway. Subsequently, the inhibition of SIRT3 expression by 3-TYP (a selective inhibitor of SIRT3) can reverse substantially the anti-RVH effect of BCW in HAHD, as indicated by hypertrophy marker and serum myocardial enzyme levels. CONCLUSIONS: BCW prevented SuHx-induced RVH in HAHD via the SIRT3-HIF1ɑ-PDK/PDH signaling pathway to alleviate the disturbance in fatty acid and glucose metabolism. Therefore, BCW can be used as an alternative drug for the treatment of RVH in HAHD.

Acetazolamide to Prevent Adverse Altitude Effects in COPD and Healthy Adults.

BACKGROUND: We evaluated the efficacy of acetazolamide in preventing adverse altitude effects in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and in healthy lowlanders 40 years of age or older. METHODS: Trial 1 was a randomized, double-blind, parallel-design trial in which 176 patients with COPD were treated with acetazolamide capsules (375 mg/day) or placebo, starting 24 hours before staying for 2 days at 3100 m. The mean (±SD) age of participants was 57±9 years, and 34% were women. At 760 m, COPD patients had oxygen saturation measured by pulse oximetry of 92% or greater, arterial partial pressure of carbon dioxide less than 45 mm Hg, and mean forced expiratory volume in 1 second of 63±11% of predicted. The primary outcome in trial 1 was the incidence of the composite end point of altitude-related adverse health effects (ARAHE) at 3100 m. Criteria for ARAHE included acute mountain sickness (AMS) and symptoms or findings relevant to well-being and safety, such as severe hypoxemia, requiring intervention. Trial 2 comprised 345 healthy lowlanders. Their mean age was 53±7 years, and 69% were women. The participants in trial 2 underwent the same protocol as did the patients with COPD in trial 1. The primary outcome in trial 2 was the incidence of AMS assessed at 3100 m by the Lake Louise questionnaire score (the scale of self-assessed symptoms ranges from 0 to 15 points, indicating absent to severe, with 3 or more points including headache, indicating AMS). RESULTS: In trial 1 of patients with COPD, 68 of 90 (76%) receiving placebo and 42 of 86 (49%) receiving acetazolamide experienced ARAHE (hazard ratio, 0.54; 95% confidence interval [CI], 0.37 to 0.79; P<0.001). The number needed to treat (NNT) to prevent one case of ARAHE was 4 (95% CI, 3 to 8). In trial 2 of healthy individuals, 54 of 170 (32%) receiving placebo and 38 of 175 (22%) receiving acetazolamide experienced AMS (hazard ratio, 0.48; 95% CI, 0.29 to 0.80; chi-square statistic P=0.035). The NNT to prevent one case of AMS was 10 (95% CI, 5 to 141). No serious adverse events occurred in these trials. CONCLUSIONS: Preventive treatment with acetazolamide reduced the incidence of adverse altitude effects requiring an intervention in patients with COPD and the incidence of AMS in healthy lowlanders 40 years of age or older during a high-altitude sojourn. (Funded by the Swiss National Science Foundation [Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung], Lunge Zürich, and the Swiss Lung Foundation; ClinicalTrials.gov numbers, NCT03156231 and NCT03561675.)

Mal agudo de montaña: pasado, presente y futuro / Acute mountain sickness: past, present and future

Evidencias en textos históricos Chinos de los años 403 AC y de la Conquista Española en 1590, muestran de las condiciones singulares que afectaban tanto a hombres como a animales al ascender por sectores montañosos por sobre 4000 m., y que ahora reconocemos como mal agudo de montaña. Ya desde el siglo XIX, se ha reconocido que es la falta de oxígeno (hipoxia) el factor determinante de la respuesta aclimatatoria como de la desaclimatización a la hipoxia de altura. El objetivo de la actual revisión fue una puesta al día de definiciones, factores que inciden en una mayor incidencia de mal agudo de montaña, mecanismo fisiológico propuesto, el desarrollo de estrategias farmacológicas para la prevención y/o tratamiento y por último, se ha revisado respecto de las distintas estrategias que se han desarrollado para la evaluación de la susceptibilidad individual, conocido comúnmente como test de hipoxia.

Some Chinese historical text from 403 BC and the Spanish Conquest in 1590 indicates unique conditions that affected both men and animals when climbing mountainous areas over 4000 m. and that is currently known as Acute Mountain Sickness (MAM). Since the XIX century, the lack of oxygen (hypoxia), has been recognized as the main factor of the acclimatization and declimatization to the high altitude hypoxia. The aim of the current revision is an update of definitions, factors that contribute the Acute Mountain Sickness, the proposed physiological mechanism, the development of pharmacological strategies for the prevention and/or treatment, and finally, we reviewed the different strategies developed for the individual susceptibility assessment, generally known as hypoxia test.

Acetazolamida como tratamiento del mal agudo de montaña / Acetazolamide for the treatment of acute mountain sickness

INTRODUCCIÓN El mal agudo de montaña es la patología más prevalente relacionada con la exposición aguda a la altura, secundaria a los efectos de la hipoxia hipobárica en nuestro organismo. La acetazolamida se ha utilizado tradicionalmente para su prevención y tratamiento, sin embargo, aún existe controversia respecto al grado de utilidad que tiene este medicamento como monoterapia. MÉTODOS Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un meta análisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES Identificamos una revisión sistemática que incluyó dos estudios primarios, ambos correspondientes a ensayos aleatorizados. Concluimos que no es posible establecer con claridad si el tratamiento con acetazolamida disminuye los síntomas del mal agudo de montaña ni si aumenta el riesgo de efectos adversos, debido a que la certeza de la evidencia existente ha sido evaluada como muy baja.

INTRODUCTION Acute mountain sickness is the most prevalent illness related to acute exposure to high altitude, secondary to the hypobaric hypoxia effects in our body. Acetazolamide has been traditionally used for its prevention and treatment, however, there is still controversy regarding the degree of usefulness of this medication as monotherapy. METHODS We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS We identified a systematic review that included two primary studies, both corresponding to randomized trials. We conclude that it is not possible to establish clearly whether treatment with acetazolamide reduces the symptoms of acute mountain disease or increases the risk of adverse effects, because the certainty of the existing evidence has been evaluated as very low.

Phytochemistry and Biological Activities of Werneria and Xenophyllum species / Fitoquímica y actividades biológicas de especies de Werneria y Xenophyllum

Plants of the genera Werneria (Asteraceae) and Xenophyllum (genus extracted from Werneria) are used in traditional medicine of Latin America for the treatment of mountain sickness, hypertension and gastrointestinal disorders. Only a small number of species of these genera have been studied, leading to the isolation of compounds belonging to the classes of benzofurans, chromenes, acetophenones, coumarates, diterpenes and pyrrolizidine alkaloids. Some of the plant extracts and/or compounds have shown antimicrobial, anti-HIV, hypotensive and photoprotective activities.

Las plantas de los géneros Werneria (Asteraceae) y Xenophyllum (género extraido de Werneria) son usadas en la medicina tradicional de América Latina para el tratamiento del mal de montaña, hipertensión y desórdenes gastrointestinales. Solo un pequeño número de especies de estos géneros ha sido investigado, lográndose aislar compuestos que pertenecen a las clases de benzofuranos, cromenos, acetofenonas, cumaratos, diterpenos y alcaloides pirrolizidínicos. Algunos de los extractos y/o compuestos de dichas plantas han mostrado actividades antimicrobianas, anti-HIV, hipotensoras y fotoprotectoras.

Edema pulmonar de altura: Modelo de estudio de la fisiopatología del edema pulmonar y de la hipertensión pulmonar hipóxica en humanos / High altitude pulmonary edema. An experiment of Nature to study the underlying mechanisms of hypoxic pulmonary hypertension and pulmonary edema in humans

La altura, fascinante laboratorio natural de investigación médica, provee resultados con importantes implicancias para la comprensión de enfermedades que afectan a millones de personas que viven en ella, asi como para el tratamiento de enfermedades ligadas a la hipoxemia en pacientes que viven en baja altitud. El edema pulmonar de altura (EPA) es una entidad que pone en peligro la vida y que ocurre en sujetos predispuestos pero sanos. Esto permite estudiar los mecanismos subyacentes del edema pulmonar en humanos, sin la presencia de factores que presten a la confusión como enfermedades concomitantes. El EPA resulta de la conjunción de dos defectos mayores: acumulación de líquido en el espacio alveolar debido a una hipertensión pulmonar hipóxica exagerada, y alteración en la eliminación del mismo por un defecto en el transporte transepitelial alveolar de sodio. En esta revisión, describimos brevemente las características clínicas y revisaremos este novedoso concepto. Proveemos evidencia experimental de como la síntesis alterada de óxido nítrico y/o la disminución de su biodisponibilidad representan el defecto central que predispone a la vasoconstricción pulmonar hipóxica exagerada y a la acumulación de líquido en el espacio alveolar. Mostramos que la hipertensión pulmonar hipóxica exagerada, per se, no es suficiente para producir un EPA, y que una alteración en la eliminación del fluido del espacio alveolar representa un segundo mecanismo fisiopatológico importante. Finalmente, describimos cómo los nuevos aportes obtenidos de los estudios del EPA pueden ser trasladados al manejo de otros estados patológicos ligados a la hipoxemia.

High altitude constitutes an exciting natural laboratory for medical research. Over the past decade, it has become clear that the results of high-altitude research may have important implications not only for the understanding of diseases in the millions of people living permanently at high altitude, but also for the treatment of hypoxemia-related disease states in patients living at low altitude. High-altitude pulmonary edema (HAPE) is a life-threatening condition occurring in predisposed, but otherwise healthy subjects, and, therefore, allows to study underlying mechanisms of pulmonary edema in humans, in the absence of confounding factors. Over the past decade, evidence has accumulated that HAPE results from the conjunction of two major defects, augmented alveolar fluid flooding resulting from exaggerated hypoxic pulmonary hypertension, and impaired alveolar fluid clearance related to defective respiratory transepithelial sodium transport. Here, after a brief presentation of the clinical features of HAPE, we review this novel concept. We provide experimental evidence for the novel concept that impaired pulmonary endothelial and epithelial nitric oxide synthesis and/or bioavailability may represent the central underlying defect predisposing to exaggerated hypoxic pulmonary vasoconstriction and alveolar fluid flooding. We demonstrate that exaggerated pulmonary hypertension, while possibly a condition sine qua non, may not be sufficient to cause HAPE, and how defective alveolar fluid clearance may represent a second important pathogenic mechanism. Finally, we outline how this insight gained from studies in HAPE may be translated into the management of hypoxemia related disease states in general.