Michael Nyberg

Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men

•  In rodents, resveratrol has been shown to enhance training‐induced changes in cardiovascular function, exercise performance and the retardation of atherosclerosis. We examined the effect of 8 weeks of exercise training with and without concomitant resveratrol supplementation in aged men. •  Exercise training potently improved blood pressure, blood cholesterol, maximal oxygen uptake and the plasma lipid profile. •  Resveratrol supplementation reduced the positive effect of exercise training on blood pressure, blood cholesterol and maximal oxygen uptake and did not affect the retardation of atherosclerosis. •  Whereas exercise training improved formation of the vasodilator prostacyclin, concomitant resveratrol supplementation caused a shift in vasoactive systems favouring vasoconstriction. •  The present study is the first to demonstrate negative effects of resveratrol on training‐induced improvements in cardiovascular health parameters in humans and adds to the growing body of evidence questioning the positive effects of resveratrol supplementation in humans.

Vasodilator interactions in skeletal muscle blood flow regulation

Abstract  During exercise, oxygen delivery to skeletal muscle is elevated to meet the increased oxygen demand. The increase in blood flow to skeletal muscle is achieved by vasodilators formed locally in the muscle tissue, either on the intraluminal or on the extraluminal side of the blood vessels. A number of vasodilators have been shown to bring about this increase in blood flow and, importantly, interactions between these compounds seem to be essential for the precise regulation of blood flow. Two compounds stand out as central in these vasodilator interactions: nitric oxide (NO) and prostacyclin. These two vasodilators are both stimulated by several compounds, e.g. adenosine, ATP, acetylcholine and bradykinin, and are affected by mechanically induced signals, such as shear stress. NO and prostacyclin have also been shown to interact in a redundant manner where one system can take over when formation of the other is compromised. Although numerous studies have examined the role of single and multiple pharmacological inhibition of different vasodilator systems, and important vasodilators and interactions have been identified, a large part of the exercise hyperaemic response remains unexplained. It is plausible that this remaining hyperaemia may be explained by cAMP‐ and cGMP‐independent smooth muscle relaxation, such as effects of endothelial derived hyperpolarization factors (EDHFs) or through metabolic modulation of sympathetic effects. The nature and role of EDHF as well as potential novel mechanisms in muscle blood flow regulation remain to be further explored to fully elucidate the regulation of exercise hyperaemia.

Adenosine Contributes to Blood Flow Regulation in the Exercising Human Leg by Increasing Prostaglandin and Nitric Oxide Formation

Adenosine can induce vasodilation in skeletal muscle, but to what extent adenosine exerts its effect via formation of other vasodilators and whether there is redundancy between adenosine and other vasodilators remain unclear. We tested the hypothesis that adenosine, prostaglandins, and NO act in synergy to regulate skeletal muscle hyperemia by determining the following: (1) the effect of adenosine receptor blockade on skeletal muscle exercise hyperemia with and without simultaneous inhibition of prostaglandins (indomethacin; 0.8 to 1.8 mg/min) and NO (NG-mono-methyl-l-arginine; 29 to 52 mg/min); (2) whether adenosine-induced vasodilation is mediated via formation of prostaglandins and/or NO; and (3) the femoral arterial and venous plasma adenosine concentrations during leg exercise with the microdialysis technique in a total of 24 healthy, male subjects. Inhibition of adenosine receptors (theophylline; 399±9 mg, mean ± SEM) or combined inhibition of prostaglandins and NO formation inhibited the exercise-induced increase in leg blood flow by 14±1% and 29±2% (P<0.05), respectively, but combined inhibition of prostaglandins, NO, and adenosine receptors did not result in an additive reduction of leg blood flow (31±5%). Femoral arterial infusion of adenosine increased leg blood flow from ≈0.3 to ≈2.5 L/min. Inhibition of prostaglandins or NO, or prostaglandins and NO combined, inhibited the adenosine-induced increase in leg blood flow by 51±3%, 39±8%, and 66±8%, respectively (P<0.05). Arterial and venous plasma adenosine concentrations were similar at rest and during exercise. These results suggest that adenosine contributes to the regulation of skeletal muscle blood flow by stimulating prostaglandin and NO synthesis.

Local release of ATP into the arterial inflow and venous drainage of human skeletal muscle: insight from ATP determination with the intravascular microdialysis technique

Non‐technical summary  ATP has been proposed to contribute to the local regulation of skeletal muscle blood flow by inducing local vasodilatation. ATP is continuously released, degraded and taken up by cells and the physiological levels are therefore difficult to determine. In the present investigation, we used a novel technique involving microdialysis probes to determine plasma ATP levels in blood vessels supplying and draining resting and contracting human skeletal muscle and to investigate the stimuli for ATP release. The results show a local release of ATP into arterial and venous blood. In addition, we found that thigh compression is a stimulus for ATP release. Furthermore, we find that the half‐life of ATP in arterial blood is <1 s.

Influence of nitrate supplementation on VO2 kinetics and endurance of elite cyclists

The present study examined if an elevated nitrate intake would improve VO2 kinetics, endurance, and repeated sprint capacity in elite endurance athletes.

Lifelong physical activity preserves functional sympatholysis and purinergic signalling in the ageing human leg

•  Ageing is associated with a reduced exercise hyperaemia and impaired ability to override sympathetic vasoconstrictor activity (functional sympatholysis). •  We find that sedentary elderly have a lower vasodilator response to ACh and ATP in the leg compared to young, but also that this age‐related reduction is partially (ACh) or completely (ATP) offset in lifelong physically active elderly subjects. •  An increase in sympathetic vasoconstrictor activity induced by tyramine reduces exercise hyperaemia in sedentary elderly, but not active elderly and young subjects. •  Interstitial ATP levels during exercise and P2Y2 receptor content are more related to the physical activity level than age. •  Physical activity can prevent the age‐related impairment in functional sympatholysis and maintain a sufficient O2 delivery during moderate intensity exercise despite a loss of endothelial function.

Lifelong physical activity prevents an age-related reduction in arterial and skeletal muscle nitric oxide bioavailability in humans

•  Ageing has been proposed to be associated with increased levels of reactive oxygen species (ROS) that scavenge nitric oxide (NO), thereby decreasing the bioavailability of this potent vasodilator. •  Here we show that NO bioavailability is compromised in the systemic circulation and in skeletal muscle of sedentary older humans as evidenced by an increase in NO metabolites after antioxidant infusion. •  Lifelong physical activity opposes this effect within the trained musculature and in the arterial circulation. •  The reduced blood flow to contracting leg muscles with ageing does not appear to be related to changes in NO bioavailability. •  These findings expand our understanding of the mechanisms underlying the age‐related changes in vascular function and highlight the beneficial effect of exercise training throughout the lifespan.

Interstitial and plasma adenosine stimulate nitric oxide and prostacyclin formation in human skeletal muscle.

One major unresolved issue in muscle blood flow regulation is that of the role of circulating versus interstitial vasodilatory compounds. The present study determined adenosine-induced formation of NO and prostacyclin in the human muscle interstitium versus in femoral venous plasma to elucidate the interaction and importance of these vasodilators in the 2 compartments. To this end, we performed experiments on humans using microdialysis technique in skeletal muscle tissue, as well as the femoral vein, combined with experiments on cultures of microvascular endothelial versus skeletal muscle cells. In young healthy humans, microdialysate was collected at rest, during arterial infusion of adenosine, and during interstitial infusion of adenosine through microdialysis probes inserted into musculus vastus lateralis. Muscle interstitial NO and prostacyclin increased with arterial and interstitial infusion of adenosine. The addition of adenosine to skeletal muscle cells increased NO formation (fluorochrome 4-amino-5-methylamino-2′,7-difluorescein fluorescence), whereas prostacyclin levels remained unchanged. The addition of adenosine to microvascular endothelial cells induced an increase in NO and prostacyclin levels. These findings provide novel insight into the role of adenosine in skeletal muscle blood flow regulation and vascular function by revealing that both interstitial and plasma adenosine have a stimulatory effect on NO and prostacyclin formation. In addition, both skeletal muscle and microvascular endothelial cells are potential mediators of adenosine-induced formation of NO in vivo, whereas only endothelial cells appear to play a role in adenosine-induced formation of prostacyclin.

Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high‐intensity aerobic training

•  Nitric oxide and prostanoids are substances that dilate the blood vessels. We examined the role of these vasodilators in the regulation of blood flow to contracting muscle and systemic blood pressure before and after a training intervention in subjects with essential hypertension and in healthy controls. •  We show that blood flow to the exercising leg is lower in essential hypertension. •  Surprisingly, this effect on blood flow is not the result of a reduced capacity of the nitric oxide and prostanoid systems to dilate the blood vessels; however, these systems do appear to play a role in the training induced reduction in blood pressure. •  These findings advance our understanding of vascular dysfunction associated with essential hypertension and the mechanisms underlying the blood pressure reducing effect of exercise.

The hyperaemic response to passive leg movement is dependent on nitric oxide: a new tool to evaluate endothelial nitric oxide function

Passive leg movement is associated with a ∼3‐fold increase in blood flow to the leg, but the underlying mechanisms remain unknown. Passive leg movement increased venous levels of metabolites of nitric oxide (NO) in young subjects, whereas they remained unaltered in the muscle interstitial space. Inhibition of NO synthesis lowered the vasodilatory response to passive leg movement by ∼90%. The increase in leg blood flow was lower in elderly subjects compared to young subjects and leg blood flow did not increase when passive leg movement was performed by elderly with peripheral artery disease. The results suggest that the hyperaemia induced by passive leg movement is NO dependent. The hyperaemic response to passive leg movement and to ACh was also assessed in elderly subjects and patients with peripheral artery disease.