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.

BackgroundMaximal left ventricular (LV) pressure rise (LV dP/dtmax), a classical marker of LV systolic function, requires LV catheterization, thus surrogate arterial pressure waveform measures have been proposed. We compared LV and arterial (femoral and radial) dP/dtmax to the slope of the LV end-systolic pressure-volume relationship (Ees), a load-independent measure of LV contractility, to determine the interactions between dP/dtmax and Ees as loading and LV contractility varied.MethodsWe measured LV pressure-volume data using a conductance catheter and femoral and radial arterial pressures using a fluid-filled catheter in 10 anesthetized pigs. Ees was calculated as the slope of the end-systolic pressure-volume relationship during a transient inferior vena cava occlusion. Afterload was assessed by the effective arterial elastance. The experimental protocol consisted of sequentially changing afterload (phenylephrine/nitroprusside), preload (bleeding/fluid bolus), and contractility (esmolol/dobutamine). A linear-mixed analysis was used to assess the contribution of cardiac (Ees, end-diastolic volume, effective arterial elastance, heart rate, preload-dependency) and arterial factors (total vascular resistance and arterial compliance) to LV and arterial dP/dtmax.ResultsBoth LV and arterial dP/dtmax allowed the tracking of Ees changes, especially during afterload and contractility changes, although arterial dP/dtmax was lower compared to LV dP/dtmax (bias 732 ± 539 mmHg⋅s− 1 for femoral dP/dtmax, and 625 ± 501 mmHg⋅s− 1 for radial dP/dtmax). Changes in cardiac contractility (Ees) were the main determinant of LV and arterial dP/dtmax changes.ConclusionAlthough arterial dP/dtmax is a complex function of central and peripheral arterial factors, radial and particularly femoral dP/dtmax allowed reasonably good tracking of LV contractility changes as loading and inotropic conditions varied.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2260-1) contains supplementary material, which is available to authorized users.

Background The aim of this study was to quantify the impact of different cardiovascular factors on left ventricular ejection fraction (LVEF) and test a novel LVEF calculation considering these factors. Results 10 pigs were studied. The experimental protocol consisted of sequentially changing afterload, preload and contractility. LV pressure–volume (PV) loops and peripheral arterial pressure were obtained before and after each intervention. LVEF was calculated as stroke volume (SV)/end-diastolic volume (EDV). We studied global cardiac function variables: LV end-systolic elastance (Ees), effective arterial elastance (Ea), end-diastolic volume and heart rate. Diastolic function was evaluated by means of the ventricular relaxation time ( τ ) and ventricular stiffness constant ( β ) obtained from the end-diastolic PV relationship. Ventriculo-arterial coupling (VAC), an index of cardiovascular performance, was calculated as Ea/Ees. LV mechanical efficiency (LVeff) was calculated as the ratio of stroke work to LV pressure–volume area. A linear mixed model was used to determine the impact of cardiac factors (Ees, Ea, EDV and heart rate), VAC and LVeff on LVEF during all experimental conditions. LVEF was mainly related to Ees and Ea. There was a strong relationship between LVEF and both VAC and LVeff ( r 2 = 0.69 and r 2 = 0.94, respectively). The relationship between LVEF and Ees was good ( r 2 = 0.43). Adjusting LVEF to afterload ( ) performed better for estimating Ees ( r 2 = 0.75) and improved the tracking of LV contractility changes, even when a peripheral Ea was used as surrogate (Ea = radial MAP/SV; r 2 = 0.73). Conclusions LVEF was mainly affected by contractility and afterload changes and was strongly related to VAC and LVeff. An adjustment to LVEF that considers the impact of afterload provided a better assessment of LV contractility.