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Breathlessness during daily activities is the primary symptom in patients with heart failure (HF). Poor correlation between the hemodynamic parameters of left ventricular performance and perceived symptoms suggests that other factors, such as skeletal muscle function, play a role in determining exercise capacity. We investigated the effect of 6 wk of high-intensity, one-legged cycling (HIC; 8 × 4 at 90% one-legged cycling max) on 1) the ability to override sympathetic vasoconstriction (arterial infusion of tyramine) during one-legged knee-extensor exercise (KEE), 2) vascular function (arterial infusion of ACh, sodium nitroprusside, tyramine, and ATP), and 3) exercise capacity in HF patients with reduced ejection fraction ( n = 8) compared with healthy individuals ( n = 6). Arterial tyramine infusion lowered leg blood flow and leg vascular conductance at rest and during KEE before the training intervention in both groups ( P < 0.05) but not during KEE after the training intervention. There was no difference between groups. The peak vasodilatory response to ATP was blunted in HF patients ( P < 0.05), whereas there was no difference in ACh- and sodium nitroprusside-induced vasodilation between HF patients and healthy individuals. ACh-induced vasodilation increased in HF patients after the training intervention ( P < 0.05). HIC improved aerobic capacity in both groups ( P < 0.05), whereas only HF patients made improvements in the 6-min walking distance ( P < 0.05). These results suggest that exercise hyperemia and functional sympatholysis are not altered in HF patients and that functional sympatholysis is improved with HIC in both HF patients and healthy individuals. Moreover, these results suggest that the peak vasodilatory response to ATP is blunted in HF. NEW & NOTEWORTHY The ability to override sympathetic vasoconstrictor activity (by arterial tyramine infusion) during exercise is not different between heart failure patients and healthy individuals and is improved by high-intensity, one-legged cycling training. The peak vasodilatory response to ATP is reduced in heart failure patients.

Aging is associated with an altered regulation of blood flow to contracting skeletal muscle; however, the precise mechanisms remain unclear. We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not young human subjects. Here we examined whether this effect of PDE5 inhibition was related to an improved ability to blunt α-adrenergic vasoconstriction (functional sympatholysis) and/or improved efficacy of local vasodilator pathways. A group of young (23 ± 1 yr) and a group of older (72 ± 1 yr) male subjects performed knee-extensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. During both conditions, exercise was performed without and with arterial tyramine infusion to evoke endogenous norepinephrine release and consequently stimulation of α1- and α2-adrenergic receptors. The level of the sympatholytic compound ATP was measured in venous plasma by use of the microdialysis technique. Sildenafil increased (P < 0.05) vascular conductance during exercise in the older group, but tyramine infusion reduced (P < 0.05) this effect by 38 ± 9%. Similarly, tyramine reduced (P < 0.05) the vasodilation induced by arterial infusion of a nitric oxide (NO) donor by 54 ± 9% in the older group, and this effect was not altered by sildenafil. Venous plasma [ATP] did not change with PDE5 inhibition in the older subjects during exercise. Collectively, PDE5 inhibition in older humans was not associated with an improved ability for functional sympatholysis. An improved efficacy of the NO system may be one mechanism underlying the effect of PDE5 inhibition on exercise hyperemia in aging., (Copyright © 2015 the American Physiological Society.)

Background: An elevated intramuscular pressure during a single forearm isometric muscle contraction may restrict muscle hyperemia. However, during repeated isometric exercise, it is unclear to what extent mechanical compression and muscle vasodilatation contribute to the magnitude and time course of beat-to-beat limb hemodynamics, due to alterations in leg vascular conductance (LVC)., Methods: In eight healthy male subjects, the time course of both beat-to-beat leg blood flow (LBF) and LVC in the femoral artery was determined between repeated 10-s isometric thigh muscle contractions and 10-s muscle relaxation (a duty cycle of 20 s) for steady-state 120 s at five target workloads (10, 30, 50, 70, and 90% of maximum voluntary contraction (MVC)). The ratio of restricted LBF due to mechanical compression across workloads was determined by the formula (relaxation LBF--contraction LBF)/relaxation LBF (%)., Results: The exercise protocol was performed completely by all subjects (≤ 50% MVC), seven subjects (≤ 70% MVC), and two subjects (≤ 90% MVC). During a 10-s isometric muscle contraction, the time course in both beat-to-beat LBF and LVC displayed a fitting curve with an exponential increase (P < 0.001, r (2) ≥ 0.956) at each workload but no significant difference in mean LBF across workloads and pre-exercise. During a 10-s muscle relaxation, the time course in both beat-to-beat LBF and LVC increased as a function of workload, followed by a linear decline (P < 0.001, r (2) ≥ 0.889), that was workload-dependent, resulting in mean LBF increasing linearly across workloads (P < 0.01, r (2) = 0.984). The ratio of restricted LBF can be described as a single exponential decay with an increase in workload, which has inflection point distinctions between 30 and 50% MVC., Conclusions: In a 20-s duty cycle of steady-state repeated isometric muscle contractions, the post-contraction hyperemia (magnitude of both LBF and LVC) during muscle relaxation was in proportion to the workload, which is in agreement with previous findings. Furthermore, time-dependent beat-to-beat muscle vasodilatation was seen, but not restricted, during isometric muscle contractions through all target workloads. Additionally, the relative contribution of mechanical obstruction and vasodilatation to the hyperemia observed in the repeated isometric exercise protocol was non-linear with regard to workload. In combination with repeated isometric exercise, the findings could potentially prove to be useful indicators of circulatory adjustment by mechanical compression for muscle-related disease.

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; 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 approximately 0.3 to approximately 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.

Plasma ATP is thought to contribute to the local regulation of skeletal muscle blood flow. Intravascular ATP infusion can induce profound limb muscle vasodilatation, but the purinergic receptors and downstream signals involved in this response remain unclear. This study investigated: 1) the role of nitric oxide (NO), prostaglandins, and adenosine as mediators of ATP-induced limb vasodilation and 2) the expression and distribution of purinergic P(2) receptors in human skeletal muscle. Systemic and leg hemodynamics were measured before and during 5-7 min of femoral intra-arterial infusion of ATP [0.45-2.45 micromol/min] in 19 healthy male subjects with and without coinfusion of N(G)-monomethyl-l-arginine (l-NMMA; NO formation inhibitor; 12.3 +/- 0.3 (SE) mg/min), indomethacin (INDO; prostaglandin formation blocker; 613 +/- 12 microg/min), and/or theophylline (adenosine receptor blocker; 400 +/- 26 mg). During control conditions, ATP infusion increased leg blood flow (LBF) from baseline conditions by 1.82 +/- 0.14 l/min. When ATP was coinfused with either l-NMMA, INDO, or l-NMMA + INDO combined, the increase in LBF was reduced by 14 +/- 6, 15 +/- 9, and 39 +/- 8%, respectively (all P < 0.05), and was associated with a parallel lowering in leg vascular conductance and cardiac output and a compensatory increase in leg O(2) extraction. Infusion of theophylline did not alter the ATP-induced leg hyperemia or systemic variables. Real-time PCR analysis of the mRNA content from the vastus lateralis muscle of eight subjects showed the highest expression of P(2Y2) receptors of the 10 investigated P(2) receptor subtypes. Immunohistochemistry showed that P(2Y2) receptors were located in the endothelium of microvessels and smooth muscle cells, whereas P(2X1) receptors were located in the endothelium and the sacrolemma. Collectively, these results indicate that NO and prostaglandins, but not adenosine, play a role in ATP-induced vasodilation in human skeletal muscle. The expression and localization of the nucleotide selective P(2Y2) and P(2X1) receptors suggest that these receptors may mediate ATP-induced vasodilation in skeletal muscle.

Skeletal muscle insulin resistance is a hallmark of individuals with type 2 diabetes mellitus (T2D). In healthy individuals insulin stimulates vasodilation, which is markedly blunted in T2D; however, the mechanism(s) remain incompletely understood. Investigations in rodents indicate augmented endothelin-1 (ET-1) action as a major contributor. Human studies have been limited to young obese participants and focused exclusively on the ET-1 A (ETA) receptor. Herein, we have hypothesized that ETA receptor antagonism would improve insulin-stimulated vasodilation and glucose uptake in T2D, with further improvements observed during concurrent ETA + ET-1 B (ETB) antagonism. Arterial pressure (arterial line), leg blood flow (LBF; Doppler), and leg glucose uptake (LGU) were measured at rest, during hyperinsulinemia alone, and hyperinsulinemia with (1) femoral artery infusion of BQ-123, the selective ETA receptor antagonist (n = 10 control, n = 9 T2D) and then (2) addition of BQ-788 (selective ETB antagonist) for blockade of ETA and ETB receptors (n = 7 each). The LBF responses to hyperinsulinemia alone tended to be lower in T2D (controls: ∆161 ± 160 mL/minute; T2D: ∆58 ± 43 mL/minute, P  = .08). BQ-123 during hyperinsulinemia augmented LBF to a greater extent in T2D (% change: controls: 14 ± 23%; T2D: 38 ± 21%, P  = .029). LGU following BQ-123 increased similarly between groups (P  = .85). Concurrent ETA + ETB antagonism did not further increase LBF or LGU in either group. Collectively, these findings suggest that during hyperinsulinemia ETA receptor activation restrains vasodilation more in T2D than controls while limiting glucose uptake similarly in both groups, with no further effect of ETB receptors (NCT04907838). [ABSTRACT FROM AUTHOR]

Aging is associated with progressive loss of cardiovascular and skeletal muscle function. The impairment in physical capacity with advancing age could be related to an insufficient peripheral O2 delivery to the exercising muscles. Furthermore, the mechanisms underlying an impaired blood flow regulation remain unresolved. Cyclic guanosine monophosphate ( cGMP) is one of the main second messengers that mediate smooth muscle vasodilation and alterations in cGMP signaling could, therefore, be one mechanism by which skeletal muscle perfusion is impaired with advancing age. The current study aimed to evaluate the effect of inhibiting the main enzyme involved in cGMP degradation, phosphodiesterase 5 ( PDE5), on blood flow and O2 delivery in contracting skeletal muscle of young and older humans. A group of young (23 ± 1 years) and a group of older (72 ± 2 years) male human subjects performed submaximal knee-extensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. Sildenafil increased leg O2 delivery (6-9%) and leg O2 uptake (10-12%) at all three exercise intensities in older but not young subjects. The increase in leg O2 delivery with sildenafil in the older subjects correlated with the increase in leg O2 uptake ( r2 = 0.843). These findings suggest an insufficient O2 delivery to the contracting skeletal muscle of aged individuals and that reduced cGMP availability is a novel mechanism underlying impaired skeletal muscle perfusion with advancing age. [ABSTRACT FROM AUTHOR]

Key points 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., Abstract Passive leg movement is associated with a ∼3-fold increase in blood flow to the leg but the underlying mechanisms remain unknown. The objective of the present study was to examine the role of nitric oxide (NO) for the hyperaemia observed during passive leg movement. Leg haemodynamics and metabolites of NO production (nitrite and nitrate; NOx) were measured in plasma and muscle interstitial fluid at rest and during passive leg movement with and without inhibition of NO formation in healthy young males. The hyperaemic response to passive leg movement and to ACh was also assessed in elderly subjects and patients with peripheral artery disease. Passive leg movement (60 r.p.m.) increased leg blood flow from 0.3 ± 0.1 to 0.9 ± 0.1 litre min−1 at 20 s and 0.5 ± 0.1 litre min−1 at 3 min ( P < 0.05). Mean arterial pressure remained unchanged during the trial. When passive leg movement was performed during inhibition of NO formation ( NG-mono-methyl- l-arginine; 29-52 mg min−1), leg blood flow and vascular conductance were increased after 20 s ( P < 0.05) and then returned to baseline levels, despite an increase in arterial pressure ( P < 0.05). Passive leg movement increased the femoral venous NOx levels from 35 ± 5 at baseline to 62 ± 11 μmol l−1 during passive leg movement ( P < 0.05), whereas muscle interstitial NOx levels remained unchanged. The hyperaemic response to passive leg movement were correlated with the vasodilatation induced by ACh ( r2= 0.704, P < 0.001) and with age ( r2= 0.612, P < 0.001). Leg blood flow did not increase during passive leg movement in individuals with peripheral arterial disease. These results suggest that the hypaeremia induced by passive leg movement is NO dependent and that the source of NO is likely to be the endothelium. Passive leg movement could therefore be used as a non-invasive tool to evaluate NO dependent endothelial function of the lower limb. [ABSTRACT FROM AUTHOR]

ATP has been proposed to play multiple roles in local skeletal muscle blood flow regulation by inducing vasodilation and modulating sympathetic vasoconstrictor activity, but the mechanisms remain unclear. Here we evaluated the effects of arterial ATP infusion and exercise on leg muscle interstitial ATP and norepinephrine (NE) concentrations to gain insight into the interstitial and intravascular mechanisms by which ATP causes muscle vasodilation and sympatholysis. Leg hemodynamics and muscle interstitial nucleotide and NE concentrations were measured during 1) femoral arterial ATP infusion (0.42 ± 0.04 and 2.26 ± 0.52 μmol/min; mean ± SE) and 2) one-leg knee-extensor exercise (18 ± 0 and 37 ± 2 W) in 10 healthy men. Arterial ATP infusion and exercise increased leg blood flow (LBF) in the experimental leg from ∼0.3 l/min at baseline to 4.2 ± 0.3 and 4.6 ± 0.5 l/min, respectively, whereas it was reduced or unchanged in the control leg. During arterial ATP infusion, muscle interstitial ATP, ADP, AMP, and adenosine concentrations remained unchanged in both legs, but muscle interstitial NE increased from ∼5.9 nmol/l at baseline to 8.3 ± 1.2 and 8.7 ± 0.7 nmol/l in the experimental and control leg, respectively (P < 0.05), in parallel to a reduction in arterial pressure (P < 0.05). During exercise, however, interstitial ATP, ADP, AMP, and adenosine concentrations increased in the contracting muscle (P < 0.05), but not in inactive muscle, whereas interstitial NE concentrations increased similarly in both active and inactive muscles. These results suggest that the vasodilatory and sympatholytic effects of intraluminal ATP are mainly mediated via endothelial purinergic receptors. Intraluminal ATP and muscle contractions appear to modulate sympathetic nerve activity by inhibiting the effect of NE rather than blunting its local concentration. [ABSTRACT FROM AUTHOR]

Adenosine-5′-triphosphate (ATP) can bind to P2y-purinergicreceptors and induce vasodilation in skeletal muscle, but the precise mechanisms by which this occurs remain unclear. To investigate whether ATP induced vasodilation is mediated by the action of nitric oxide (NO), prostaglandins and/or endothelial-derived hyperpolarizing factors (EDHFs), we measured leg hemodynamics before and during 5 min of intra-arterial infusion of ATP (0.41±0.04µmol min-1; mean±SEM) in 8 healthy, male subjects (24±2 years, 76±3 kg) with and without co-infusion of indomethacin (INDO; 621±17 µg min-1), NG-mono-methyl-L-arginine (L-NMMA; 12.4±0.3 mg min-1), tetraethylammonium chloride (TEA; 12.4±0.3 mg min-1) or INDO + L-NMMA + TEA. Basal leg blood flow (LBF) was 0.46±0.06 1 min-1, but was lower with either L-NMMA (0.32±0.03) or all three inhibitors (0.28±0.06)(P<0.05), whereas infusion of either TEA or INDO had no effect on basal flow. ATP infusion increased LBF to 2.4±0.21 min-1, but with co-infusion of either INDO or L-NMMA alone, or all three inhibitors combined, it was 13±8, 22±8 and 39±5 % lower, respectively, than with ATP infusion alone. Infusion of TEA did not alter the ATP induced hyperemia. The lower LBF with ATP combined with INDO, L-NMMA and triple blockade was associated with a 8-12% higher blood pressure and a 15-45 % lower vascular conductance, while heart rate and leg VO2 remained similar. These results indicate that both NO and prostaglandins play an important role in ATP mediated vasodilatation, whereas EDHFs appear to be less important. [ABSTRACT FROM AUTHOR]