Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo.

Endothelial nitric oxide synthase (eNOS) is associated with a number of physiological functions involved in the regulation of metabolism; however, the functional role of eNOS is poorly understood. We tested the hypothesis that eNOS is critical to muscle cell signaling and fuel usage during exercise in vivo, using 16-wk-old catheterized (carotid artery and jugular vein) C57BL/6J mice with wild-type (WT), partial (+/-), or no expression (-/-) of eNOS. Quantitative reductions in eNOS expression ( approximately 40%) elicited many of the phenotypic effects observed in enos(-/-) mice under fasted, sedentary conditions, with expression of oxidative phosphorylation complexes I to V and ATP levels being decreased, and total NOS activity and Ca(2+)/CaM kinase II Thr(286) phosphorylation being increased in skeletal muscle. Despite these alterations, exercise tolerance was markedly impaired in enos(-/-) mice during an acute 30-min bout of exercise. An eNOS-dependent effect was observed with regard to AMP-activated protein kinase signaling and muscle perfusion. Muscle glucose and long-chain fatty acid uptake, and hepatic and skeletal muscle glycogenolysis during the exercise bout was markedly accelerated in enos(-/-) mice compared with enos(+/-) and WT mice. Correspondingly, enos(-/-) mice exhibited hypoglycemia during exercise. Thus, the ablation of eNOS alters a number of physiological processes that result in impaired exercise capacity in vivo. The finding that a partial reduction in eNOS expression is sufficient to induce many of the changes associated with ablation of eNOS has implications for chronic metabolic diseases, such as obesity and insulin resistance, which are associated with reduced eNOS expression.

Abnormal shock index exposure and clinical outcomes among critically ill patients: A retrospective cohort analysis.

PURPOSE: To assess the predictive value of a single abnormal shock index reading (SI ≥0.9; heart rate/systolic blood pressure [SBP]) for mortality, and association between cumulative abnormal SI exposure and mortality/morbidity. MATERIALS AND METHODS: Cohort comprised of adult patients with an intensive care unit (ICU) stay ≥24-h (years 2010-2018). SI ≥0.9 exposure was evaluated via cumulative minutes or time-weighted average; SBP ≤100-mmHg was analyzed. Outcomes were in-hospital mortality, acute kidney injury (AKI), and myocardial injury. RESULTS: 18,197 patients from 82 hospitals were analyzed. Any single SI ≥0.9 within the ICU predicted mortality with 90.8% sensitivity and 36.8% specificity. Every 0.1-unit increase in maximum-SI during the first 24-h increased the odds of mortality by 4.8% [95%CI; 2.6-7.0%; p < .001]. Every 4-h exposure to SI ≥0.9 increased the odds of death by 5.8% [95%CI; 4.6-7.0%; p < .001], AKI by 4.3% [95%CI; 3.7-4.9%; p < .001] and myocardial injury by 2.1% [95%CI; 1.2-3.1%; p < .001]. ≥2-h exposure to SBP ≤100-mmHg was significantly associated with mortality. CONCLUSIONS: A single SI reading ≥0.9 is a poor predictor of mortality; cumulative SI exposure is associated with greater risk of mortality/morbidity. The associations with in-hospital mortality were comparable for SI ≥0.9 or SBP ≤100-mmHg exposure. Dynamic interactions between hemodynamic variables need further evaluation among critically ill patients.