Despite increases in muscle sympathetic vasoconstrictor activity, skeletal muscle blood flow and O 2 delivery increase during exercise in humans in proportion to the local metabolic demand, a phenomenon coupled to local reductions in the oxygenation state of haemoglobin and concomitant increases in circulating ATP. We tested the hypothesis that circulating ATP contributes to local blood flow and O 2 delivery regulation by both inducing vasodilatation and blunting the augmented sympathetic vasoconstrictor activity. In eight healthy subjects, we first measured leg blood flow (LBF) and mean arterial pressure (MAP) during three hyperaemic conditions: (1) intrafemoral artery adenosine infusion (vasodilator control), (2) intrafemoral artery ATP infusion (vasodilator), and (3) mild knee-extensor exercise (∼20 W), and then compared the responses with the combined infusion of the vasoconstrictor drug tyramine, which evokes endogenous release of noradrenaline from sympathetic nerve endings. In all three hyperaemic conditions, LBF equally increased from ∼0.5 ± 0.1 l min −1 at rest to ∼3.6 ± 0.3 l min −1 , with no change in MAP. Tyramine caused significant leg vasoconstriction during adenosine infusion (53 ± 5 and 56 ± 5% lower LBF and leg vascular conductance, respectively, P < 0.05), which was completely abolished by both ATP infusion and exercise. In six additional subjects resting in the sitting position, intrafemoral artery infusion of ATP increased LBF and leg vascular conductance 27 ± 3-fold, despite concomitant increases in venous noradrenaline and muscle sympathetic nerve activity of 2.5 ± 0.2-and 2.4 ± 0.1-fold, respectively. Maximal ATP-induced vasodilatation at rest accounted for 78% of the peak LBF during maximal bicycling exercise. Our findings in humans demonstrate that circulating ATP is capable of regulating local skeletal muscle blood flow and O 2 delivery by causing substantial vasodilatation and negating the effects of increased sympathetic vasoconstrictor activity.

Highlights d Exercise reduces visceral adipose tissue mass d Loss of visceral adipose tissue mass following exercise is dependent on IL-6 d IL-6 receptor blockade increases total cholesterol and is not influenced by exercise d Improvements in cardiorespiratory fitness following exercise are not IL-6 dependent

Sympathetic vasoconstriction is blunted in the vascular beds of contracting skeletal muscles. We sought to determine whether this blunted vasoconstriction is specific for post-junctional alpha1- or alpha2-adrenergic receptors. We measured forearm blood flow (Doppler ultrasound) and calculated the vascular conductance (FVC) responses to brachial artery infusions of tyramine (which evokes endogenous noradrenaline release), phenylephrine (an alpha1 agonist) and clonidine (an alpha2 agonist) in 10 healthy men during rhythmic handgrip exercise (10-15 % of maximum) and during a control non-exercise vasodilator condition (intra-arterial adenosine). Steady-state FVC during exercise and adenosine was similar in all trials (range: 243-272 and 234-263 ml min-1 (100 mmHg)-1, respectively; P > 0.5). During exercise the percentage reductions in FVC in response to tyramine (-24 +/- 7 vs. -55 +/- 6 %), phenylephrine (-12 +/- 8 vs. -37 +/- 8 %) and clonidine (-17 +/- 6 vs. -49 +/- 4 %) were significantly less compared with adenosine (all P < 0.05). The magnitude of the blunted vasoconstrictor responses was similar for both receptor subtypes. These findings are in contrast to those from studies in animals demonstrating that alpha2-adrenergic receptor-mediated vasoconstrictor responses are much more sensitive to contraction-induced inhibition than alpha1-mediated responses. We conclude that vasoconstrictor responses mediated via both post-junctional alpha1- and alpha2-adrenergic receptors are blunted in contracting human skeletal muscles.