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Zaobornyj T, Valdez LB, Iglesias DE, Gasco M, Gonzales GF, Boveris A. Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil, L-NAME, and L-arginine treatments. Am J Physiol Heart Circ Physiol 296: H1741-H1747, 2009. First published April 3, 2009 doi:10.1152/ajpheart.00422.2008.-Rats submitted to high altitude (Cerro de Pasco, Perú, 4,340 m, PO2 ϭ 12.2 kPa) for up to 84 days showed a physiological adaptive response with decreased body weight gain (15%), increased right ventricle weight (100%), and increased hematocrit (40%) compared with sea level animals. These classical parameters of adaptation to high altitude were accompanied by an increase in heart mitochondrial enzymes: complexes I-III activity by 34% and mitochondrial nitric oxide synthase (mtNOS) activity and expression by Ͼ75%. The hyperbolic increase for mtNOS activity during adaptation to high altitude was similar to the observed pattern for hematocrit. Hematocrit and mtNOS activity mean values correlated linearly (r 2 ϭ 0.75, P Յ 0.05). Chronic treatment for 28 days with sildenafil (50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) decreased the response of mtNOS to high altitude by 25%. Conversely, N Gnitro-L-arginine methyl ester treatment (8.3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) increased such response by 40%, whereas L-arginine treatment (106 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) had no effect. Nitric oxide (NO) production by mtNOS accounts for ϳ49% of total cellular NO production in sea level rats and for ϳ54% in rats exposed to high altitude for 84 days. It is concluded that mtNOS is a substantial source of cardiac NO, a factor in the adaptive response to sustained heart hypoxia that is susceptible to be modified by pharmacological treatments. mitochondrial nitric oxide synthase activity; mitochondrial nitric oxide synthase expression; mitochondrial respiratory complexes; hematocrit; nitro-L-arginine methyl ester HIGH ALTITUDE IS A MULTIFACTORIAL source of stress in which hypobaric hypoxia is the most important component. The O 2 gradient between atmospheric air and cells decreases from 105 mmHg at sea level to 49 mmHg at high altitude (20). There are a number of adaptive responses that are triggered by this situation, such as increased ventilation (28), pulmonary hypertension (40), erythropoiesis (39), and heart work load. The adaptation to high altitude constitutes a situation that has both advantageous and disadvantageous consequences for human health. The main long term effects are decreased physical activity and life span. Among the beneficial effects, there is a recognized cardioprotection with improvement of the myocardial tolerance to ischemic episodes. A number of studies involving exposure to natural (22) or simulated (29) hypobaric hypoxia reported that this adaptation is associated to lower incidence and smaller size of myocardial infarction (30).Although the mechanism by which adaptation to hypoxia has cardioprotective effects remains not elucidated, nitric oxide (NO) has been extensively proposed as one of the molecular messengers inv...

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Obesity has major adverse consequences on human health contributing to the development of, among others, insulin resistance and type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, altered behavior and cognition, and cancer. Changes in dietary habits and lifestyle could contribute to mitigate the development and/or progression of these pathologies. This review will discuss current evidence on the beneficial actions of the flavan-3-ol (−)-epicatechin (EC) on obesity-associated comorbidities. These benefits can be in part explained through EC's capacity to mitigate several common events underlying the development of these pathologies, including: i) high circulating levels of glucose, lipids and endotoxins; ii) chronic systemic inflammation; iii) tissue endoplasmic reticulum and oxidative stress; iv) insulin resistance; v) mitochondria dysfunction and vi) dysbiosis. The currently known underlying mechanisms and cellular targets of EC's beneficial effects are discussed. While, there is limited evidence from human studies supplementing with pure EC, other studies involving cocoa supplementation in humans, pure EC in rodents and in vitro studies, support a potential beneficial action of EC on obesity-associated comorbidities. This evidence also stresses the need of further research in the field, which would contribute to the development of human dietary strategies to mitigate the adverse consequences of obesity. Alarmingly, the prevalence of obesity was almost three times higher in 2016 compared to 1975. Numerous comorbidities and an increased risk of mortality are associated to obesity [3-5]. Among those comorbidities, obesity can increase the risk to develop: i) insulin resistance and type 2 diabetes (T2D); ii) hypertension and cardiovascular disease (CVD); iii) dyslipidemia; iv) non-alcoholic fatty liver disease (NAFLD); v) altered behavior and cognition; vi) cancer, and vii) alterations in the gastrointestinal, musculoskeletal, renal, respiratory and immune systems.

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