α-Adrenergic regulation of skeletal muscle blood flow during exercise in patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization ( V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ), possibly associated with disease-related changes in sympathetic (α-adrenergic) signaling. Thus, in seven patients with HFpEF (70 ± 6 years, 3 female/4 male) and seven controls (CON) (66 ± 3 years, 3 female/4 male), we examined changes (%Δ) in leg blood flow (LBF, Doppler ultrasound) and leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ to intra-arterial infusion of phentolamine (PHEN, α-adrenergic antagonist) or phenylephrine (PE, α1-adrenergic agonist) at rest and during single-leg knee-extension exercise (0, 5 and 10 W). At rest, the PHEN-induced increase in LBF was not different between groups, but PE-induced reductions in LBF were lower in HFpEF (-16% ± 4% vs. -26% ± 5%, HFpEF vs. CON; P < 0.05). During exercise, the PHEN-induced increase in LBF was greater in HFpEF at 10 W (16% ± 8% vs. 8% ± 5%; P < 0.05). PHEN increased leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ in HFpEF (10% ± 3%, 11% ± 6%, 15% ± 7% at 0, 5 and 10 W; P < 0.05) but not in controls (-1% ± 9%, -4% ± 2%, -1% ± 5%; P = 0.24). The 'magnitude of sympatholysis' (PE-induced %Δ LBF at rest - PE-induced %Δ LBF during exercise) was lower in patients with HFpEF (-6% ± 4%, -6% ± 6%, -7% ± 5% vs. -13% ± 6%, -17% ± 5%, -20% ± 5% at 0, 5 and 10 W; P < 0.05) and was positively related to LBF, leg oxygen delivery, leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ , and the PHEN-induced increase in LBF (P < 0.05). Together, these data indicate that excessive α-adrenergic vasoconstriction restrains blood flow and limits V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ of the exercising leg in patients with HFpEF, and is related to impaired functional sympatholysis in this patient group. KEY POINTS: Sympathetic (α-adrenergic)-mediated vasoconstriction is exaggerated during exercise in patients with heart failure with preserved ejection fraction (HFpEF), which may contribute to limitations of blood flow, oxygen delivery and oxygen utilization in the exercising muscle. The ability to adequately attenuate α1-adrenergic vasoconstriction (i.e. functional sympatholysis) within the vasculature of the exercising muscle is impaired in patients with HFpEF. These observations extend our current understanding of HFpEF pathophysiology by implicating excessive α-adrenergic restraint and impaired functional sympatholysis as important contributors to disease-related impairments in exercising muscle blood flow and oxygen utilization in these patients.

Increased skeletal muscle mitochondrial free radical production in peripheral arterial disease despite preserved mitochondrial respiratory capacity.

NEW FINDINGS: What is the central question of this study? What is the degree to which skeletal muscle mitochondria-derived reactive oxygen species (ROS) production is linked to impaired skeletal muscle function in patients with early-stage peripheral arterial disease (PAD) and what is the impact on mitochondrial respiratory capacity? What is the main finding and its importance? This is the first study to document increased mitochondria-derived reactive oxygen species production associated with elevated intramuscular oxidative stress, despite preserved mitochondrial respiratory function, in patients with PAD. Furthermore, systemic inflammation, mitochondria-derived ROS production and skeletal muscle oxidative stress were strongly correlated to disease severity, as indicated by ankle-brachial index, in patients with PAD. ABSTRACT: Skeletal muscle mitochondrial dysfunction, which is not fully explained by disease-related arterial occlusion, has been implicated in the pathophysiology of peripheral arterial disease (PAD). Therefore, this study comprehensively assessed mitochondrial respiratory function in biopsies from the gastrocnemius of 10 patients with PAD (Fontaine Stage II) and 12 healthy controls (HC). Intramuscular and systemic inflammation, mitochondria-derived reactive oxygen species (ROS) production, and oxidative stress were also assessed to better understand the mechanisms responsible for the proposed PAD-induced mitochondrial dysfunction. Interestingly, mitochondrial respiratory capacity, assessed as complex I (CI) and complex II (CII)-driven State 3 respiration, measured separately and in combination (State 3 CI+II), revealed no difference between the patients with PAD and the HC. However, mitochondria-derived ROS production was significantly elevated in PAD (HC: 1.0 ± 0.9; PAD: 4.3 ± 1.0 AU (mg tissue)-1 ). Furthermore, patients with PAD exhibited significantly greater concentrations of the pro-inflammatory markers tumour necrosis factor α in plasma (HC: 0.9 ± 0.4; PAD: 2.0 ± 0.3 pg ml-1 ) and interleukin 6 in both plasma (HC: 2.3 ± 0.4; PAD: 4.3 ± 0.5 pg ml-1 ) and muscle (∼75% greater). Intramuscular oxidative stress, assessed by protein carbonyls and 4-hydroxynonenal, was significantly greater in PAD compared to HC. Ankle brachial index was significantly correlated with intramuscular inflammation, oxidative stress and mitochondria-derived ROS production. Thus, elevated intramuscular inflammation, oxidative stress and mitochondria-derived ROS production are likely to contribute to the pathophysiology of the skeletal muscle dysfunction associated with PAD, even in the presence of preserved mitochondrial respiratory function in this population.

Oral antioxidants improve leg blood flow during exercise in patients with chronic obstructive pulmonary disease.

The consequence of elevated oxidative stress on exercising skeletal muscle blood flow as well as the transport and utilization of O2 in patients with chronic obstructive pulmonary disease (COPD) is not well understood. The present study examined the impact of an oral antioxidant cocktail (AOC) on leg blood flow (LBF) and O2 consumption during dynamic exercise in 16 patients with COPD and 16 healthy subjects. Subjects performed submaximal (3, 6, and 9 W) single-leg knee extensor exercise while LBF (Doppler ultrasound), mean arterial blood pressure, leg vascular conductance, arterial O2 saturation, leg arterial-venous O2 difference, and leg O2 consumption (direct Fick) were evaluated under control conditions and after AOC administration. AOC administration increased LBF (3 W: 1,604 ± 100 vs. 1,798 ± 128 ml/min, 6 W: 1,832 ± 109 vs. 1,992 ± 120 ml/min, and 9W: 2,035 ± 114 vs. 2,187 ± 136 ml/min, P < 0.05, control vs. AOC, respectively), leg vascular conductance, and leg O2 consumption (3 W: 173 ± 12 vs. 210 ± 15 ml O2/min, 6 W: 217 ± 14 vs. 237 ± 15 ml O2/min, and 9 W: 244 ± 16 vs 260 ± 18 ml O2/min, P < 0.05, control vs. AOC, respectively) during exercise in COPD, whereas no effect was observed in healthy subjects. In addition, the AOC afforded a small, but significant, improvement in arterial O2 saturation only in patients with COPD. Thus, these data demonstrate a novel beneficial role of AOC administration on exercising LBF, O2 consumption, and arterial O2 saturation in patients with COPD, implicating oxidative stress as a potential therapeutic target for impaired exercise capacity in this population.

Dietary nitrate supplementation and small muscle mass exercise hemodynamics in patients with essential hypertension.

Exaggerated blood pressure and diminished limb hemodynamics during exercise in patients with hypertension often are not resolved by antihypertensive medications. We hypothesized that, independent of antihypertensive medication status, dietary nitrate supplementation would increase limb blood flow, decrease mean arterial pressure (MAP), and increase limb vascular conductance during exercise in patients with hypertension. Patients with hypertension either abstained from (n = 14, Off-Meds) or continued (n = 12, On-Meds) antihypertensive medications. Within each group, patients consumed (crossover design) nitrate-rich or nitrate-depleted (placebo) beetroot juice for 3 days before performing handgrip (HG) and knee-extensor exercise (KE). Blood flow and MAP were measured using Doppler ultrasound and an automated monitor, respectively. Dietary nitrate increased plasma-[nitrite] Off-Meds and On-Meds. There were no significant effects of dietary nitrate on blood flow, MAP, or vascular conductance during HG in Off-Meds or On-Meds. For KE, dietary nitrate decreased MAP (means ± SD across all 3 exercise intensities, 118 ± 14 vs. 122 ± 14 mmHg, P = 0.024) and increased vascular conductance (26.2 ± 6.1 vs. 24.7 ± 7.0 mL/min/mmHg, P = 0.024), but did not affect blood flow for Off-Meds, with no effects On-Meds. Dietary nitrate-induced changes in blood flow (r = -0.67, P < 0.001), MAP (r = -0.43, P = 0.009), and vascular conductance (r = -0.64, P < 0.001) during KE, but only vascular conductance (r = -0.35, P = 0.039) during HG, were significantly related to the magnitude of placebo values, with no differentiation between groups. Thus, the effects of dietary nitrate on limb hemodynamics and MAP during exercise in patients with hypertension are dependent on the values at baseline, independent of antihypertensive medication status, and dependent on whether exercise was performed by the forearm or quadriceps.NEW & NOTEWORTHY Adverse hemodynamic responses to exercise in patients with hypertension, despite antihypertensive medication, indicate a sustained cardiovascular risk. The efficacy of dietary nitrate to improve limb vascular conductance during exercise was inversely dependent on the magnitude of exercising limb vascular conductance at baseline, rather than antihypertensive medication status. The effects of dietary nitrate on hemodynamics during exercise in patients with hypertension are dependent on the values at baseline and independent of antihypertensive medication status.

On the contribution of group III and IV muscle afferents to the circulatory response to rhythmic exercise in humans.

We investigated the role of skeletal muscle afferent feedback in circulatory control during rhythmic exercise in humans. Nine healthy males performed single leg knee-extensor exercise (15/30/45 watts, 3 min each) under both control conditions (Ctrl) and with lumbar intrathecal fentanyl impairing µ-opioid receptor-sensitive muscle afferents. Cardiac output and femoral blood flow were determined, and femoral arterial/venous blood samples were collected during the final minute of each workload. To rule out cephalad migration of fentanyl to the brainstem,we documented unchanged resting ventilatory responses to different levels of hypercapnia. There were no haemodynamic differences between conditions at rest. However, during exercise cardiac output was -2 % lower with fentanyl blockade compared to control (P < 0.05), secondary to a 6% and 13% reduction in heart rate and stroke volume, respectively. Throughout exercise mean arterial pressure (MAP) was reduced by 7% (P < 0.01) which is likely to have contributed to the 15% fall in femoral blood flow. However, MAP was not completely responsible for this peripheral haemodynamic change as vascular conductance was also attenuated (-9%). Evidence of increasing noradrenaline spillover (P = 0.09) implicated an elevation in sympathetic outflow in this response. The attenuated femoral blood flow during exercise with fentanyl was associated with a 17%reduction in leg O2 delivery (P < 0.01) and a concomitant rise in the arteriovenous O2 difference (4­9%), but leg O2 consumption remained 7­13% lower than control (P < 0.05). Our findings reveal an essential contribution of continuous muscle afferent feedback to ensure the appropriate haemodynamic and ultimately metabolic response to rhythmic exercise in humans

Ascorbate attenuates cycling exercise-induced neuromuscular fatigue but fails to improve exertional dyspnea and exercise tolerance in COPD.

We examined the effect of intravenous ascorbate (VitC) administration on exercise-induced redox balance, inflammation, exertional dyspnea, neuromuscular fatigue, and exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). Eight COPD patients completed constant-load cycling (∼80% of peak power output, 83 ± 10 W) to task failure after intravenous VitC (2 g) or saline (placebo, PL) infusion. All participants repeated the shorter of the two exercise trials (isotime) with the other infusate. Quadriceps fatigue was determined by pre- to postexercise changes in quadriceps twitch torque (ΔQtw, electrical femoral nerve stimulation). Corticospinal excitability before, during, and after exercise was assessed by changes in motor evoked potentials triggered by transcranial magnetic stimulation. VitC increased superoxide dismutase (marker for endogenous antioxidant capacity) by 129% and mitigated C-reactive protein (marker for inflammation) in the plasma during exercise but failed to alter the exercise-induced increase in lipid peroxidation (malondialdehyde) and free radicals [electron paramagnetic resonance (EPR)-spectroscopy]. Although VitC did, indeed, decrease neuromuscular fatigue (ΔQtw: PL -29 ± 5%, VitC -23 ± 6%, P < 0.05), there was no impact on corticospinal excitability and time to task failure (∼8 min, P = 0.8). Interestingly, in terms of pulmonary limitations to exercise, VitC had no effect on perceived exertional dyspnea (∼8.5/10) and its determinants, including oxygen saturation ([Formula: see text]) (∼92%) and respiratory muscle work (∼650 cmH2O·s·min-1) (P > 0.3). Thus, although VitC facilitated indicators for antioxidant capacity, diminished inflammatory markers, and improved neuromuscular fatigue resistance, it failed to improve exertional dyspnea and cycling exercise tolerance in patients with COPD. As dyspnea is recognized to limit exercise tolerance in COPD, the otherwise beneficial effects of VitC may have been impacted by this unaltered sensation.NEW & NOTEWORTHY We investigated the effect of intravenous vitamin C on redox balance, exertional dyspnea, neuromuscular fatigue, and exercise tolerance in chronic obstructive pulmonary disease (COPD) patients. Acute vitamin C administration increased superoxide dismutase (marker of antioxidant capacity) and attenuated fatigue development but failed to improve exertional dyspnea and exercise tolerance. These findings suggest that a compromised redox balance plays a critical role in the development of fatigue in COPD but also highlight the significance of exertional dyspnea as an important symptom limiting the patients' exercise tolerance.

Influence of dietary inorganic nitrate on blood pressure and vascular function in hypertension: prospective implications for adjunctive treatment.

Dietary inorganic nitrate (nitrate) is a promising adjunctive treatment to reduce blood pressure and improve vascular function in hypertension. However, it remains unknown if the efficacy of nitrate is dependent upon an elevated blood pressure or altered by medication in patients with hypertension. Therefore, blood pressure and vascular function, measured by passive leg movement (PLM) and flow-mediated dilation (FMD), were assessed following 3 days of placebo (nitrate-free beetroot juice) and nitrate (nitrate-rich beetroot juice) administration in 13 patients (age: 53 ± 12 yr) with hypertension taking antihypertensive medications (study 1) and in 14 patients (49 ± 13 yr) with hypertension not taking antihypertensive medications (study 2). In study 1, plasma nitrite concentration was greater for nitrate than placebo (341 ± 118 vs. 308 ± 123 nmol/L, P < 0.05), yet blood pressure and vascular function were unaltered. In study 2, plasma nitrite concentration was greater for nitrate than placebo (340 ± 102 vs. 295 ± 93 nmol/L, P < 0.01). Systolic (136 ± 16 vs. 141 ± 19 mmHg), diastolic (84 ± 13 vs. 88 ± 12 mmHg), and mean (101 ± 12 vs. 106 ± 13 mmHg) blood pressures were lower (P < 0.05), whereas the PLM change in leg vascular conductance (6.0 ± 3.0 vs. 5.1 ± 2.6 mL·min-1·mmHg-1) and FMD (6.1 ± 2.4% vs. 4.1 ± 2.7%) were greater (P < 0.05) for nitrate than placebo. The changes in systolic blood pressure (r = -0.60) and FMD (r = -0.48) induced by nitrate were inversely correlated (P < 0.05) to the respective baseline values obtained in the placebo condition. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive medication status, per se.NEW & NOTEWORTHY Dietary nitrate (nitrate) is a promising intervention to improve blood pressure and vascular function in hypertension. We demonstrate that these beneficial effects of nitrate are inversely related to the baseline value in a continuous manner with no distinction between antihypertensive medication status. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive mediation status.