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Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T‐type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L‐ and T‐type calcium channel blocker (CCB)) or nifedipine (L‐type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium‐dependent vasodilator) and sodium nitroprusside (endothelium‐independent vasodilator) both with and without co‐infusion of N‐acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra‐arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co‐infusion of NAC did not affect endothelium‐dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks' inhibition of T‐ and L‐type calcium channels augments endothelium‐dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T‐type calcium channel inhibition can counteract endothelial dysfunction. What is the central question of this study?Does T‐type calcium channel inhibition prevent age‐related endothelium dysfunction in humans?What is the main finding and its importance?Eight weeks of L+T‐type calcium channel blockade (CCB) increased endothelium‐dependent vasodilatation in the leg of otherwise healthy elderly males, while 8 weeks of L‐type CCB only did not. Thus, T‐type calcium channels may be involved in endothelium dysfunction. [ABSTRACT FROM AUTHOR]

Aldosterone has been suggested to be involved in the microvascular complications observed in type 2 diabetes. We aimed to investigate the effect of mineralocorticoid receptor (MR) blockade on endothelial function in individuals with type 2 diabetes compared to healthy controls. We included 12 participants with type 2 diabetes and 14 controls. We measured leg hemodynamics at baseline and during femoral arterial infusion of acetylcholine and sodium nitroprusside before and 8 weeks into treatment with MR blockade (eplerenone). Acetylcholine infusion was repeated with concomitant n‐acetylcysteine (antioxidant) infusion. No difference in leg blood flow or vascular conductance was detected before or after the treatment with MR blockade in both groups and there was no difference between groups. Infusion of n‐acetylcysteine increased baseline blood flow and vascular conductance, but did not change the vascular response to acetylcholine before or after treatment with MR blockade. Skeletal muscle eNOS content was unaltered by MR blockade and no difference between groups was detected. In conclusion, we found no effect of MR blockade endothelial function in individuals with and without type 2 diabetes. As the individuals with type 2 diabetes did not have vascular dysfunction, these results might not apply to individuals with vascular dysfunction. [ABSTRACT FROM AUTHOR]

The effect of low blood flow at onset of moderate-intensity exercise on the rate of rise in muscle oxygen uptake was examined. Seven male subjects performed a 3.5-min one-legged knee-extensor exercise bout (24 [+ or -] 1 W, mean [+ or -] SD) without (Con) and with (double blockade; DB) arterial infusion of inhibitors of nitric oxide synthase (NG-monomethyl-L-arginine) and cyclooxygenase (indomethacin) to inhibit the synthesis of nitric oxide and prostanoids, respectively. Leg blood flow and leg oxygen delivery throughout exercise was 25-50% lower (P < 0.05) in DB compared with Con. Leg oxygen extraction (arteriovenous O2 difference) was higher (P < 0.05) in DB than in Con (5 s: 127 [+ or -] 3 vs. 56 [+ or -] 4 ml/1), and leg oxygen uptake was not different between Con and DB during exercise. The difference between leg oxygen delivery and leg oxygen uptake was smaller (P < 0.05) during exercise in DB than in Con (5 s: 59 [+ or -] 12 vs. 262 [+ or -] 39 ml/min). The present data demonstrate that muscle blood flow and oxygen delivery can be markedly reduced without affecting muscle oxygen uptake in the initial phase of moderate-intensity exercise, suggesting that blood flow does not limit muscle oxygen uptake at the onset of exercise. Additionally, prostanoids and/or nitric oxide appear to play important roles in elevating skeletal muscle blood flow in the initial phase of exercise. oxygen delivery; oxygen extraction; nitric oxide; prostanoids doi:10.1152/ajpregu.00730.2009

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 P2 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 [micro]mol/min] in 19 healthy male subjects with and without coinfusion of [N.sup.G]-monomethyl-L-arginine (L-NMMA; NO formation inhibitor; 12.3 [+ or -] 0.3 (SE) mg/min), indomethacin (INDO; prostaglandin formation blocker; 613 [+ or -] 12 [micro]g/ min), and/or theophylline (adenosine receptor blocker; 400 [+ or -] 26 mg). During control conditions, ATP infusion increased leg blood flow (LBF) from baseline conditions by 1.82 [+ or -] 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 [+ or -] 6, 15 [+ or -] 9, and 39 [+ or -] 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.sub.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.sub.2Y2] receptors of the 10 investigated [P.sub.2] receptor subtypes. Immunohistochemistry showed that [P.sub.2Y2] receptors were located in the endothelium of microvessels and smooth muscle cells, whereas [P.sub.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.sub.2Y2] and [P.sub.2x1] receptors suggest that these receptors may mediate ATP-induced vasodilation in skeletal muscle. skeletal muscle; adenosine 5'-triphosphate; purinergic receptors; nitric oxide; prostaglandins

Aim: Skeletal muscle convective and diffusive oxygen (O2) transport are peripheral determinants of exercise capacity in both patients with chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). We hypothesised that differences in these peripheral determinants of performance between COPD and CHF patients are revealed during small muscle mass exercise, where the cardiorespiratory limitations to exercise are diminished. Methods: Eight patients with moderate to severe COPD, eight patients with CHF (NYHA II), and eight age- and sex-matched controls were studied. We measured leg blood flow (Q'leg) by Doppler ultrasound during submaximal one legged knee-extensor exercise (KEE), while sampling arterio-venous variables across the leg. The capillary oxyhaemoglobin dissociation curve was reconstructed from paired femoral arterial-venous oxygen tensions and saturations, which enabled the estimation of O2 parameters at the microvascular level within skeletal muscle, so that skeletal muscle oxygen conductance (DSMO2) could be calculated and adjusted for flow (DSMO2/ Q'leg) to distinguish convective from diffusive oxygen transport. Results: During KEE, Q'leg increased to a similar extent in CHF (2.0 (0.4) L/min) and controls (2.3 (0.3) L/min), but less in COPD patients (1.8 (0.3) L/min) (p <0.03). There was no difference in resting DSMO2 between COPD and CHF and when adjusting for flow, the DSMO2 was higher in both groups compared to controls (COPD: 0.97 (0.23) vs. controls 0.63 (0.24) mM/kPa, p= 0.02; CHF 0.98 (0.11) mM/kPa vs. controls, p= 0.001). The Q_ -adjusted DSMO2 was not different in COPD and CHF during KEE (COPD: 1.19 (0.11) vs. CHF: 1.00 (0.18) mM/kPa; p= 0.24) but higher in COPD vs. controls: 0.87 (0.28) mM/kPa (p= 0.02), and only CHF did not increase Q_ -adjusted DSMO2 from rest (p= 0.2). Conclusion: Disease-specific factors may play a role in peripheral exercise limitation in patients with COPD compared with CHF. Thus, low convective O2 transport to contracting muscle seemed to predominate in COPD, whereas muscle diffusive O2 transport was unresponsive in CHF. [ABSTRACT FROM AUTHOR]

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]

Individuals with type 2 diabetes have an increased risk of cardiovascular disease. A correlation between plasma aldosterone and hyperinsulinemia has been demonstrated in vivo, and hyperinsulinemia and insulin resistance are independently associated with the development of cardiovascular complications. We investigated if mineralocorticoid blockade (Eplerenone) improves insulin sensitivity in individuals with type 2 diabetes compared to healthy controls. We included 13 participants with type 2 diabetes (<5 years; male/female, Caucasians) and 10 healthy control participants (male/female, Caucasians). On 2 experimental days, before and at the end of the 8 weeks of treatment with mineralocorticoid blockade, a two‐stage hyperinsulinemic‐isoglycemic clamp (20 and 50 mU∙m−2min−1) was performed for the determination of insulin sensitivity. No change in insulin sensitivity was detected at the end of the mineralocorticoid blockade in the individuals with type 2 diabetes or the healthy controls. Both before and at the end of the treatment with mineralocorticoid blockade, the individuals with type 2 diabetes had a lower insulin sensitivity compared to healthy controls. In conclusion, mineralocorticoid receptor blockade does not appear to improve insulin sensitivity in individuals with type 2 diabetes. Clinical Trial Registration: NCT03017703. https://clinicaltrials.gov/ct2/show/NCT03017703 [ABSTRACT FROM AUTHOR]

Context: Individuals with type 2 diabetes have an increased risk of endothelial dysfunction and cardiovascular disease. Plasma aldosterone could contribute by reactive oxygen species-dependent mechanisms by inducing a shift in the balance between a vasoconstrictor and vasodilator response to aldosterone.Objective: We aimed to investigate the acute vascular effects of aldosterone in individuals with type 2 diabetes compared with healthy controls and if infusion of an antioxidant (n-acetylcysteine [NAC]) would alter the vascular response.Methods: In a case-control design, 12 participants with type 2 diabetes and 14 healthy controls, recruited from the general community, were studied. Leg hemodynamics were measured before and during aldosterone infusion (0.2 and 5 ng min-1 [L leg volume]-1) for 10 minutes into the femoral artery with and without coinfusion of NAC (125 mg kg-1 hour-1 followed by 25 mg kg-1 hour-1). Leg blood flow and arterial blood pressure was measured, and femoral arterial and venous blood samples were collected.Results: Compared with the control group, leg blood flow and vascular conductance decreased during infusion of aldosterone at the high dose in individuals with type 2 diabetes, whereas coinfusion of NAC attenuated this response. Plasma aldosterone increased in both groups during aldosterone infusion and there was no difference between groups at baseline or during the infusions.Conclusion: These results suggests that type 2 diabetes is associated with a vasoconstrictor response to physiological levels of infused aldosterone and that the antioxidant NAC diminishes this response. [ABSTRACT FROM AUTHOR]

This study compared the effects of moderate intensity endurance training and high-intensity interval training on fiber type-specific subcellular volumetric content and morphology of lipid droplets and mitochondria in skeletal muscles of type 2 diabetic patients. Sixteen sedentary type 2 diabetic patients (57 7 yr old) were randomized to complete 11 wk of either 40-min cycling at 50% peak workload (Endurance, n 8) or 10 1-min cycling intervals at 95% peak workload separated by 1 min of recovery (High-Intensity Interval, n 8), three times per week. Assessments for cardiorespiratory fitness, body composition, glycemic control, together with muscle biopsies were performed before and after the intervention. Morphometric analyses of lipid droplets and mitochondria were conducted in the subcellular fractions of biopsied muscle fibers using quantitative electron microscopy. The training intervention increased cardiorespiratory fitness, lowered fat mass, and improved non-fasting glycemic control (P<0.05), with no difference between training modalities. In the subsarcolemmal space, training decreased lipid droplet volume (P=0.003), and high-intensity interval, but not endurance, training reduced the size of lipid droplets, specifically in type 2 fibers (P <0.001). No training-induced change in intermyofibrillar lipid droplets was observed in both fiber types. Subsarcolemmal mitochondrial volume was increased by high-intensity interval (P = 0.02), but not endurance, training (P=0.79). Along with improvement in glycemic control, low-volume high-intensity interval training is an alternative time-saving training modality that affects subcellular morphology and volumetric content of lipid droplets in skeletal muscle of type 2 diabetic patients. [ABSTRACT FROM AUTHOR]

Aim: To evaluate whether high‐intensity interval training (HIIT) with a lower time commitment can be as effective as endurance training (END) on glycaemic control, physical fitness and body composition in individuals with type 2 diabetes. Materials and Methods: A total of 29 individuals with type 2 diabetes were allocated to control (CON; no training), END or HIIT groups. Training groups received 3 training sessions per week consisting of either 40 minutes of cycling at 50% of peak workload (END) or 10 1‐minute intervals at 95% of peak workload interspersed with 1 minute of active recovery (HIIT). Glycaemic control (HbA1c, oral glucose tolerance test, 3‐hour mixed meal tolerance test with double tracer technique and continuous glucose monitoring [CGM]), lipolysis, VO2peak and body composition were evaluated before and after 11 weeks of intervention. Results: Exercise training increased VO2peak more in the HIIT group (20% ± 20%) compared with the END group (8% ± 9%) despite lower total energy expenditure and time usage during the training sessions. HIIT decreased whole body and android fat mass compared with the CON group. In addition, visceral fat mass, HbA1c, fasting glucose, postprandial glucose, glycaemic variability and HOMA‐IR decreased after HIIT. The reduced postprandial glucose in the HIIT group was driven primarily by a lower rate of exogenous glucose appearance. In the CON group, postprandial lipolysis was augmented over the 11‐week control period. Conclusions: Despite a ~45% lower training volume, HIIT resulted in similar or even better improvements in physical fitness, body composition and glycemic control compared to END. HIIT therefore appears to be an important time‐efficient treatment for individuals with type 2 diabetes. [ABSTRACT FROM AUTHOR]

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 x 4 at 90% one-legged cycling max) on 1) the ability to override sympathetic vasoconstriction (arterial infusion of tyramine) during onelegged 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 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. [ABSTRACT FROM AUTHOR]

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 kneeextensor 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. [ABSTRACT FROM AUTHOR]

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, r² ≥ 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, r² ≥ 0.889), that was workload-dependent, resulting in mean LBF increasing linearly across workloads (P < 0.01, r² = 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. [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]

The objective of this study was to assess the insulin-independent effects of incretin hormones on glucose and glycerol metabolism and hemodynamics under euglycemic and hyperglycemic conditions. Young, healthy men (n = 10) underwent three trials in a randomized, controlled, crossover study. Each trial consisted of a two-stage (euglycemia and hyperglycemia) pancreatic clamp (using somatostatin to prevent endogenous insulin secretion). Glucose and lipid metabolism was measured via infusion of stable glucose and glycerol isotopic tracers. Hemodynamic variables (femoral, brachial, and common carotid artery blood flow and flow-mediated dilation of the brachial artery) were also measured. The three trials differed as follows: 1) saline [control (CON)], 2) glucagon-like peptide (GLP-1, 0.5 pmol•kg-1•min-1), and 3) glucose-dependent insulinotropic polypeptide (GIP, 1.5 pmol•kg-1•min-1). No between-trial differences in glucose infusion rates (GIR) or glucose or glycerol kinetics were seen during euglycemia, whereas hyperglycemia resulted in increased GIR and glucose rate of disappearance during GLP-1 compared with CON and GIP (P < 0.01 for all). However, when normalized to insulin levels, no differences between trials were seen for GIR or glucose rate of disappearance. Besides a higher femoral blood flow during hyperglycemia with GIP (vs. CON and GLP-1, P < 0.001), no between-trial differences were seen for the hemodynamic variables. In conclusion, GLP-1 and GIP have no direct effect on whole body glucose metabolism or hemodynamics during euglycemia. On the contrary, during hyperglycemia, GIP increases femoral artery blood flow with no effect on glucose metabolism, whereas GLP-1 increases glucose disposal, potentially due to increased insulin levels. [ABSTRACT FROM AUTHOR]

The present study examined whether a marked reduction in oxygen delivery, unlike findings in moderate-intensity exercise, would slow leg oxygen uptake (...O2) kinetics during intense exercise (86 ± 3% of incremental test peak power). Seven healthy males (26 ± 1 years, means ± SE) performed one-legged knee-extensor exercise (60 ± 3W) for 4 min in a control setting (CON) and with arterial infusion of NG-monomethyl- L-arginine and indomethacin in the working leg to reduce blood flow by inhibiting formation of nitric oxide and prostanoids (double blockade; DB). In DB leg blood flow (LBF) and oxygen delivery during the first minute of exercise were 25-50% lower (P < 0.01) compared with CON (LBF after 10 s: 1.1 ± 0.2 vs. 2.5 ± 0.3 l/min and 45 s: 2.7 ± 0.2 vs. 3.8 ± 0.4 l/min) and 15% lower (P < 0.05) after 2 min of exercise. Leg ...O2 in DB was attenuated (P < 0.05) during the first 2 min of exercise (10 s: 161 ± 26 vs. 288 ± 34 ml/min and 45 s: 459 ± 48 vs. 566 ± 81 ml/min) despite a higher (P < 0.01) oxygen extraction in DB. Net leg lactate release was the same in DB and CON. The present study shows tŖhat a marked reduction in oxygen delivery can limit the rise in ...O2 during the initial part of intense exercise. This is in contrast to previous observations during moderate-intensity exercise using the same DB procedure, which suggests that fast-twitch muscle fibers are more sensitive to a reduction in oxygen delivery than slow-twitch fibers. [ABSTRACT FROM AUTHOR]

During skeletal muscle contractions, the concentration of ATP increases in muscle interstitial fluid as measured by microdialysis probes. This increase is associated with the magnitude of blood flow, suggesting that interstitial ATP may be important for contraction-induced vasodilation. However, interstitial ATP has solely been described to induce vasoconstriction in skeletal muscle. To examine whether interstitial ATP induces vasodilation in skeletal muscle and to what extent this vasoactive effect is mediated by formation of nitric oxide (NO) and prostanoids, three different experimental models were studied. The rat gluteus maximus skeletal muscle model was used to study changes in local skeletal muscle hemodynamics. Superfused ATP at concentrations found during muscle contractions (1-10 µM) increased blood flow by up to 400%. In this model, the underlying mechanism was also examined by inhibition of NO and prostanoid formation. Inhibition of these systems abolished the vasodilator effect of ATP. Cellculture experiments verified ATP-induced formation of NO and prostacyclin in rat skeletal muscle microvascular endothelial cells, and ATP-induced formation of NO in rat skeletal muscle cells. To confirm these findings in humans, ATP was infused into skeletal muscle interstitium of healthy subjects via microdialysis probes and found to increase muscle interstitial concentrations of NO and prostacyclin by ~60% and ~40%, respectively. Collectively, these data suggest that a physiologically relevant elevation in interstitial ATP concentrations increases muscle blood flow, indicating that the contraction-induced increase in skeletal muscle interstitial [ATP] is important for exercise hyperemia. The vasodilator effect of ATP application is mediated by NO and prostanoid formation. [ABSTRACT FROM AUTHOR]

Endurance training lowers heart rate and blood pressure responses to exercise, but the mechanisms and consequences remain unclear. To determine the role of skeletal muscle for the cardioventilatory response to exercise, 8 healthy young men were studied before and after 5 weeks of 1-legged knee-extensor training and 2 weeks of deconditioning of the other leg (leg cast). Hemodynamics and muscle interstitial nucleotides were determined during exercise with the (1) deconditioned leg, (2) trained leg, and (3) trained leg with atrial pacing to the heart rate obtained with the deconditioned leg. Heart rate was ≈ 15 bpm lower during exercise with the trained leg (P<0.05), but stroke volume was higher (P<0.05) and cardiac output was similar. Arterial and central venous pressures, rate-pressure product, and ventilation were lower during exercise with the trained leg (P<0.05), whereas pulmonary capillary wedge pressure was similar. When heart rate was controlled by atrial pacing, stroke volume decreased (P<0.05), but cardiac output, peripheral blood flow, arterial pressures, and pulmonary capillary wedge pressure remained unchanged. Circulating [norepinephrine], [lactate] and [K(+)] were lower and interstitial [ATP] and pH were higher in the trained leg (P<0.05). The lower cardioventilatory response to exercise with the trained leg is partly coupled to a reduced signaling from skeletal muscle likely mediated by K(+), lactate, or pH, whereas the lower cardiac afterload increases stroke volume. These results demonstrate that skeletal muscle training reduces the cardioventilatory response to exercise without compromising O2 delivery, and it can therefore be used to reduce the load on the heart during physical activity. [ABSTRACT FROM AUTHOR]

In response to hypoxic breathing most studies report slower pulmonary oxygen uptake (VO2) kinetics at the onset of exercise, but it is not known if this relates to an actual slowing of the VO2 in the active muscles. The aim of the present study was to evaluate whether thigh VO2 is slowed at the onset of intense exercise during acute exposure to hypoxia. Six healthy male subjects (25.8 ± 1.4 yr, 79.8 ± 4.0 kg, means ± SE) performed intense (100 ± 6 watts) two-legged knee-extensor exercise for 2 min in normoxia (NOR) and hypoxia [fractional inspired oxygen concentration (FIO2) = 0.13; HYP]. Thigh VO2 was measured by frequent arterial and venous blood sampling and blood flow measurements. In arterial blood, oxygen content was reduced (P < 0.05) from 191 ± 5 ml O2/l in NOR to 180 ± 5 ml O2/l in HYP, and oxygen pressure was reduced (P < 0.001) from 111 ± 4 mmHg in NOR to 63 ± 4 mmHg in HYP. Thigh blood flow was the same in NOR and HYP, and thigh oxygen delivery was consequently reduced (P < 0.05) in HYP, but femoral arterial-venous oxygen difference and thigh VO2 were similar in NOR and HYP. In addition, muscle lactate release was the same in NOR and HYP, and muscle lactate accumulation during the first 25 s of exercise determined from muscle biopsy sampling was also similar (0.35 ± 0.07 and 0.36 ± 0.07 mmol kg dry wt-1 s-1 in NOR and HYP). Thus the increase in thigh VO2 was not attenuated at the onset of intense knee-extensor exercise despite a reduction in oxygen delivery and pressure. [ABSTRACT FROM AUTHOR]

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. [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]