Abstract-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 (N G -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; 399Ϯ9 mg, mean Ϯ SEM) or combined inhibition of prostaglandins and NO formation inhibited the exercise-induced increase in leg blood flow by 14Ϯ1% and 29Ϯ2% (PϽ0.05), respectively, but combined inhibition of prostaglandins, NO, and adenosine receptors did not result in an additive reduction of leg blood flow (31Ϯ5%). Femoral arterial infusion of adenosine increased leg blood flow from Ϸ0.3 to Ϸ2.5 L/min. Inhibition of prostaglandins or NO, or prostaglandins and NO combined, inhibited the adenosine-induced increase in leg blood flow by 51Ϯ3%, 39Ϯ8%, and 66Ϯ8%, respectively (PϽ0.05). 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.

Key points• 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. AbstractWe examined the role of nitric oxide (NO) and prostanoids in the regulation of leg blood flow and systemic blood pressure before and after 8 weeks of aerobic high-intensity training in individuals with essential hypertension (n = 10) and matched healthy control subjects (n = 11). Hypertensive subjects were found to have a lower (P < 0.05) blood flow to the exercising leg than normotensive subjects (30 W: 2.92 ± 0.16 vs. 3.39 ± 0.37 l min −1 ). Despite the lower exercise hyperaemia, pharmacological inhibition of the NO and prostanoid systems reduced leg blood flow to a similar extent during exercise in the two groups and vascular relaxation to the NO-dependent vasodilator acetylcholine was also similar between groups. High-intensity aerobic training lowered (P < 0.05) resting systolic (∼9 mmHg) and diastolic (∼12 mmHg) blood pressure in subjects with essential hypertension, but this effect of training was abolished when the NO and prostanoid systems were inhibited. Skeletal muscle vascular endothelial NO synthase uncoupling, expression and phosphorylation status were similar in the two groups before and after training. These data demonstrate that a reduction in exercise hyperaemia in hypertensive subjects is not associated with a reduced capacity of the NO and prostanoid systems to induce vasodilatation or with altered acetylcholine-induced response. However, our data suggest that the observed reduction in blood pressure is related to a training-induced change in the tonic effect of NO and/or prostanoids on vascular tone.

Key pointsr Essential hypertension is linked to an increased sympathetic vasoconstrictor activity and reduced tissue perfusion.r Exercise training can improve the ability to override sympathetic vasoconstrictor activity. r Here we show that 8 weeks of exercise training reduces the vasoconstrictor response to sympathetic nerve activity (induced by tyramine) and improves the ability to override sympathetic vasoconstrictor activity.r We found no difference in the ability to override sympathetic vasoconstrictor activity during exercise, the reduction in blood flow in response to increases in sympathetic nerve activity or the hyperaemic response to infused ATP between normo-and hypertensive subjects.r These results help us to better understand how exercise training can reduce blood pressure and improve tissue perfusion.Abstract Essential hypertension is linked to an increased sympathetic vasoconstrictor activity and reduced tissue perfusion. We investigated the role of exercise training on functional sympatholysis and postjunctional α-adrenergic responsiveness in individuals with essential hypertension. Leg haemodynamics were measured before and after 8 weeks of aerobic training (3-4 times per week) in eight hypertensive (47 ± 2 years) and eight normotensive untrained individuals (46 ± 1 years) during arterial tyramine infusion, arterial ATP infusion and/or one-legged knee extensions. Before training, exercise hyperaemia and leg vascular conductance (LVC) were lower in the hypertensive individuals (P < 0.05) and tyramine lowered exercise hyperaemia and LVC in both groups (P < 0.05). Training lowered blood pressure in the hypertensive individuals (P < 0.05) and exercise hyperaemia was similar to the normotensive individuals in the trained state. After training, tyramine did not reduce exercise hyperaemia or LVC in either group. When tyramine was infused at rest, the reduction in blood flow and LVC was similar between groups, but exercise training lowered the magnitude of the reduction in blood flow and LVC (P < 0.05). There was no difference in the vasodilatory response to infused ATP or in muscle P2Y 2 receptor content between the groups before and after training. However, training lowered the vasodilatory response to ATP and increased skeletal muscle P2Y 2 receptor content in both groups (P < 0.05). These results demonstrate that exercise training improves functional sympatholysis and reduces postjunctional α-adrenergic responsiveness in both normo-and hypertensive individuals. The ability for functional sympatholysis and the vasodilator and sympatholytic effect of intravascular ATP appear not to be altered in essential hypertension.

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.Abstract Intraluminal ATP could play an important role in the local regulation of skeletal muscle blood flow, but the stimuli that cause ATP release and the levels of plasma ATP in vessels supplying and draining human skeletal muscle remain unclear. To gain insight into the mechanisms by which ATP is released into plasma, we measured plasma [ATP] with the intravascular microdialysis technique at rest and during dynamic exercise (normoxia and hypoxia), passive exercise, thigh compressions and arterial ATP, tyramine and ACh infusion in a total of 16 healthy young men. Femoral arterial and venous [ATP] values were 109 ± 34 and 147 ± 45 nmol l −1 at rest and increased to 363 ± 83 and 560 ± 111 nmol l −1 , respectively, during exercise (P < 0.05), whereas these values did not increase when exercise was performed with the other leg. Hypoxia increased venous plasma [ATP] at rest compared to normoxia (P < 0.05), but not during exercise. Arterial ATP infusion (≤1.8 μmol min −1 ) increased arterial plasma [ATP] from 74 ± 17 to 486 ± 82 nmol l −1 (P < 0.05), whereas it remained unchanged in the femoral vein at ∼150 nmol l −1 . Both arterial and venous plasma [ATP] decreased during acetylcholine infusion (P < 0.05). Rhythmic thigh compressions increased arterial and venous plasma [ATP] compared to baseline conditions, whereas these values did not change during passive exercise or tyramine infusion. These results demonstrate that ATP is released locally into arterial and venous plasma during exercise and during hypoxia at rest. Compression of the vascular system could contribute to the increase during exercise whereas there appears to be little ATP release in response to increased blood flow, vascular stretch or sympathetic ATP release. Furthermore, the half-life of arterially infused ATP is <1 s.