Key points• Inorganic nitrate (NO 3 − ) supplementation with beetroot juice (BR) in humans lowers blood pressure and the O 2 cost of exercise and may improve exercise tolerance following its reduction to nitrite (NO 2 − ) and nitric oxide (NO).• The effect of inorganic NO 3 − supplementation with BR on skeletal muscle blood flow (BF) and vascular conductance (VC) within and among locomotory muscles during exercise is unknown.• Inorganic NO 3 − supplementation with BR in rats resulted in lower exercising mean arterial pressure, lower blood [lactate], and higher total skeletal muscle hindlimb BF and VC during submaximal treadmill running.• The greater BF and VC was found in muscles and muscle parts containing primarily type IIb + d/x muscle fibres.• These data demonstrate that inorganic NO 3 − supplementation improves vascular control and elevates skeletal muscle O 2 delivery during exercise predominantly in fast-twitch type II muscles, and provide a potential mechanism by which NO 3 − supplementation improves metabolic control. Abstract Dietary nitrate (NO 3− ) supplementation, via its reduction to nitrite (NO 2 − ) and subsequent conversion to nitric oxide (NO) and other reactive nitrogen intermediates, reduces blood pressure and the O 2 cost of submaximal exercise in humans. Despite these observations, the effects of dietary NO 3 − supplementation on skeletal muscle vascular control during locomotory exercise remain unknown. We tested the hypotheses that dietary NO 3 − supplementation via beetroot juice (BR) would reduce mean arterial pressure (MAP) and increase hindlimb muscle blood flow in the exercising rat. Male Sprague-Dawley rats (3-6 months) were administered either NO 3 − (via beetroot juice; 1 mmol kg −1 day −1 , BR n = 8) or untreated (control, n = 11) tap water for 5 days. MAP and hindlimb skeletal muscle blood flow and vascular conductance (radiolabelled microsphere infusions) were measured during submaximal treadmill running (20 m min −1 , 5% grade). BR resulted in significantly lower exercising MAP (control: 137 ± 3, BR: 127 ± 4 mmHg, P < 0.05) and blood [lactate] (control: 2.6 ± 0.3, BR: 1.9 ± 0.2 mM, P < 0.05) compared to control. Total exercising hindlimb skeletal muscle blood flow (control: 108 ± 8, BR: 150 ± 11 ml min −1 (100 g) −1 , P < 0.05) and vascular conductance (control: 0.78 ± 0.05, BR: 1.16 ± 0.10 ml min −1 (100 g) −1 mmHg −1 , P < 0.05) were greater in rats that received BR compared to control. The relative differences in blood flow and vascular conductance for the 28 individual hindlimb muscles and muscle parts correlated positively with their percentage type IIb + d/x muscle fibres (blood flow: r = 0.74, vascular conductance: r = 0.71, P < 0.01 for both). These data support the hypothesis that NO 3 − supplementation improves vascular control and elevates skeletal muscle O 2 delivery during exercise predominantly in fast-twitch type II muscles, and provide a potential mechanism by which NO 3 − supplementation improves metabolic control.

The defining characteristic of chronic heart failure (CHF) is an exercise intolerance that is inextricably linked to structural and functional aberrations in the O(2) transport pathway. CHF reduces muscle O(2) supply while simultaneously increasing O(2) demands. CHF severity varies from moderate to severe and is assessed commonly in terms of the maximum O(2) uptake, which relates closely to patient morbidity and mortality in CHF and forms the basis for Weber and colleagues' (167) classifications of heart failure, speed of the O(2) uptake kinetics following exercise onset and during recovery, and the capacity to perform submaximal exercise. As the heart fails, cardiovascular regulation shifts from controlling cardiac output as a means for supplying the oxidative energetic needs of exercising skeletal muscle and other organs to preventing catastrophic swings in blood pressure. This shift is mediated by a complex array of events that include altered reflex and humoral control of the circulation, required to prevent the skeletal muscle "sleeping giant" from outstripping the pathologically limited cardiac output and secondarily impacts lung (and respiratory muscle), vascular, and locomotory muscle function. Recently, interest has also focused on the dysregulation of inflammatory mediators including tumor necrosis factor-α and interleukin-1β as well as reactive oxygen species as mediators of systemic and muscle dysfunction. This brief review focuses on skeletal muscle to address the mechanistic bases for the reduced maximum O(2) uptake, slowed O(2) uptake kinetics, and exercise intolerance in CHF. Experimental evidence in humans and animal models of CHF unveils the microvascular cause(s) and consequences of the O(2) supply (decreased)/O(2) demand (increased) imbalance emblematic of CHF. Therapeutic strategies to improve muscle microvascular and oxidative function (e.g., exercise training and anti-inflammatory, antioxidant strategies, in particular) and hence patient exercise tolerance and quality of life are presented within their appropriate context of the O(2) transport pathway.

Hirai DM, Musch TI, Poole DC. Exercise training in chronic heart failure: improving skeletal muscle O 2 transport and utilization. Am J Physiol Heart Circ Physiol 309: H1419 -H1439, 2015. First published August 28, 2015; doi:10.1152/ajpheart.00469.2015.-Chronic heart failure (CHF) impairs critical structural and functional components of the O 2 transport pathway resulting in exercise intolerance and, consequently, reduced quality of life. In contrast, exercise training is capable of combating many of the CHF-induced impairments and enhancing the matching between skeletal muscle O 2 delivery and utilization (Q mO 2 and V mO 2 , respectively). The Q mO 2 /V mO 2 ratio determines the microvascular O2 partial pressure (PmvO 2 ), which represents the ultimate force driving blood-myocyte O 2 flux (see Fig. 1). Improvements in perfusive and diffusive O2 conductances are essential to support faster rates of oxidative phosphorylation (reflected as faster V mO 2 kinetics during transitions in metabolic demand) and reduce the reliance on anaerobic glycolysis and utilization of finite energy sources (thus lowering the magnitude of the O 2 deficit) in trained CHF muscle. These adaptations contribute to attenuated muscle metabolic perturbations (e.g., changes in [PCr], [Cr], [ADP], and pH) and improved physical capacity (i.e., elevated critical power and maximal V mO 2 ). Preservation of such plasticity in response to exercise training is crucial considering the dominant role of skeletal muscle dysfunction in the pathophysiology and increased morbidity/mortality of the CHF patient. This brief review focuses on the mechanistic bases for improved Q mO 2 /V mO 2 matching (and enhanced PmvO 2 ) with exercise training in CHF with both preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). Specifically, O 2 convection within the skeletal muscle microcirculation, O 2 diffusion from the red blood cell to the mitochondria, and muscle metabolic control are particularly susceptive to exercise training adaptations in CHF. Alternatives to traditional whole body endurance exercise training programs such as small muscle mass and inspiratory muscle training, pharmacological treatment (e.g., sildenafil and pentoxifylline), and dietary nitrate supplementation are also presented in light of their therapeutic potential. Adaptations within the skeletal muscle O 2 transport and utilization system underlie improvements in physical capacity and quality of life in CHF and thus take center stage in the therapeutic management of these patients.