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Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization (V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$), 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 V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ 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 V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ 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 V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$, and the PHEN‐induced increase in LBF (P < 0.05). Together, these data indicate that excessive α‐adrenergic vasoconstriction restrains blood flow and limits V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ 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. [ABSTRACT FROM AUTHOR]

Key points: Within skeletal muscle the greatest resistance to oxygen transport is thought to reside across the short distance at the red blood cell–myocyte interface. These structures generate a significant transmural oxygen pressure (PO2) gradient in mixed fibre‐type muscle.Increasing O2 flux across the capillary wall during exercise depends on: (i) the transmural O2 pressure gradient, which is maintained in mixed‐fibre muscle, and/or (ii) elevating diffusing properties between microvascular and interstitial compartments resulting, in part, from microvascular haemodynamics and red blood cell distribution.We evaluated the PO2 within the microvascular and interstitial spaces of muscles spanning the slow‐ to fast‐twitch fibre and high‐ to low‐oxidative capacity spectrums, at rest and during contractions, to assess the magnitude of transcapillary PO2 gradients in rats.Our findings demonstrate that, across the metabolic rest–contraction transition, the transcapillary pressure gradient for O2 flux is: (i) maintained in all muscle types, and (ii) the lowest in contracting highly oxidative fast‐twitch muscle. In mixed fibre‐type skeletal muscle transcapillary PO2 gradients (PO2mv‐PO2is; microvascular and interstitial, respectively) drive O2 flux across the blood–myocyte interface where the greatest resistance to that O2 flux resides. We assessed a broad spectrum of fibre‐type and oxidative‐capacity rat muscles across the rest‐to‐contraction (1 Hz, 120 s) transient to test the novel hypotheses that: (i) slow‐twitch PO2is would be greater than fast‐twitch, (ii) muscles with greater oxidative capacity have greater PO2is than glycolytic counterparts, and (iii) whether PO2mv‐PO2is at rest is maintained during contractions across all muscle types. PO2mv and PO2is were determined via phosphorescence quenching in soleus (SOL; 91% type I+IIa fibres and CSa: ∼21 μmol min‐1 g‐1), peroneal (PER; 33% and ∼20 μmol min‐1 g‐1), mixed (MG; 9% and ∼26 μmol min‐1 g‐1) and white gastrocnemius (WG; 0% and ∼8 μmol min‐1 g‐1) across the rest–contraction transient. PO2mv was higher than PO2is in each muscle (∼6–13 mmHg; P < 0.05). SOL PO2isarea was greater than in the fast‐twitch muscles during contractions (P < 0.05). Oxidative muscles had greater PO2isnadir (9.4 ± 0.8, 7.4 ± 0.9 and 6.4 ± 0.4; SOL, PER and MG, respectively) than WG (3.0 ± 0.3 mmHg, P < 0.05). The magnitude of PO2mv‐PO2is at rest decreased during contractions in MG only (∼11 to 7 mmHg; time × (PO2mv‐PO2is) interaction, P < 0.05). These data support the hypothesis that, since transcapillary PO2 gradients during contractions are maintained in all muscle types, increased O2 flux must occur via enhanced intracapillary diffusing conductance, which is most extreme in highly oxidative fast‐twitch muscle. Key points: Within skeletal muscle the greatest resistance to oxygen transport is thought to reside across the short distance at the red blood cell–myocyte interface. These structures generate a significant transmural oxygen pressure (PO2) gradient in mixed fibre‐type muscle.Increasing O2 flux across the capillary wall during exercise depends on: (i) the transmural O2 pressure gradient, which is maintained in mixed‐fibre muscle, and/or (ii) elevating diffusing properties between microvascular and interstitial compartments resulting, in part, from microvascular haemodynamics and red blood cell distribution.We evaluated the PO2 within the microvascular and interstitial spaces of muscles spanning the slow‐ to fast‐twitch fibre and high‐ to low‐oxidative capacity spectrums, at rest and during contractions, to assess the magnitude of transcapillary PO2 gradients in rats.Our findings demonstrate that, across the metabolic rest–contraction transition, the transcapillary pressure gradient for O2 flux is: (i) maintained in all muscle types, and (ii) the lowest in contracting highly oxidative fast‐twitch muscle. [ABSTRACT FROM AUTHOR]

Key points: Exercise in patients with hypertension can be accompanied by an abnormal cardiovascular response that includes attenuated blood flow and an augmented pressor response.Endothelin‐1, a very potent vasoconstrictor, is a key modulator of blood flow and pressure during in health and has been implicated as a potential cause of the dysfunction in hypertension.We assessed the role of endothelin‐1, acting through endothelin A (ETA) receptors, in modulating the central and peripheral cardiovascular responses to exercise in patients with hypertension via local antagonism of these receptors during exercise.ETA receptor antagonism markedly increased leg blood flow, vascular conductance, oxygen delivery, and oxygen consumption during exercise; interestingly, these changes occurred in the presence of reduced leg perfusion pressure, indicating that these augmentations were driven by changes in vascular resistance.These data indicate that ETA receptor antagonism could be a viable therapeutic approach to improve blood flow during exercise in hypertension. Patients with hypertension can exhibit impaired muscle blood flow and exaggerated increases in blood pressure during exercise. While endothelin (ET)‐1 plays a role in regulating blood flow and pressure during exercise in health, little is known about the role of ET‐1 in the cardiovascular response to exercise in hypertension. Therefore, eight volunteers diagnosed with hypertension were studied during exercise with either saline or BQ‐123 (ETA receptor antagonist) infusion following a 2‐week withdrawal of anti‐hypertensive medications. The common femoral artery and vein were catheterized for drug infusion, blood collection and blood pressure measurements, and leg blood flow was measured by Doppler ultrasound. Patients exercised at both absolute (0, 5, 10, 15 W) and relative (40, 60, 80% peak power) intensities. BQ‐123 increased blood flow at rest (79 ± 87 ml/min; P = 0.03) and augmented the exercise‐induced hyperaemia at most intensities (80% saline: Δ3818±1222 vs. BQ‐123: Δ4812±1469 ml/min; P = 0.001). BQ‐123 reduced leg MAP at rest (−8 ± 4 mmHg; P < 0.001) and lower intensities (0–10 W; P < 0.05). Systemic diastolic blood pressure was reduced (0 W, 40%; P < 0.05), but systemic MAP was defended by an increased cardiac output. The exercise pressor response (ΔMAP) did not differ between conditions (80% saline: 25 ± 10, BQ‐123: 30 ± 7 mmHg; P = 0.17). Thus, ET‐1, acting through the ETA receptors, contributes to the control of blood pressure at rest and lower intensity exercise in these patients. Furthermore, the finding that ET‐1 constrains the blood flow response to exercise suggests that ETA receptor antagonism could be a therapeutic approach to improve blood flow during exercise in hypertension. Key points: Exercise in patients with hypertension can be accompanied by an abnormal cardiovascular response that includes attenuated blood flow and an augmented pressor response.Endothelin‐1, a very potent vasoconstrictor, is a key modulator of blood flow and pressure during in health and has been implicated as a potential cause of the dysfunction in hypertension.We assessed the role of endothelin‐1, acting through endothelin A (ETA) receptors, in modulating the central and peripheral cardiovascular responses to exercise in patients with hypertension via local antagonism of these receptors during exercise.ETA receptor antagonism markedly increased leg blood flow, vascular conductance, oxygen delivery, and oxygen consumption during exercise; interestingly, these changes occurred in the presence of reduced leg perfusion pressure, indicating that these augmentations were driven by changes in vascular resistance.These data indicate that ETA receptor antagonism could be a viable therapeutic approach to improve blood flow during exercise in hypertension. [ABSTRACT FROM AUTHOR]

Key points: Oxygen pressure gradients across the microvascular walls are essential for oxygen diffusion from blood to tissue cells. At any given flux, the magnitude of these transmural gradients is proportional to the local resistance. The greatest resistance to oxygen transport into skeletal muscle is considered to reside in the short distance between red blood cells and myocytes. Although crucial to oxygen transport, little is known about transmural pressure gradients within skeletal muscle during contractions. We evaluated oxygen pressures within both the skeletal muscle microvascular and interstitial spaces to determine transmural gradients during the rest–contraction transient in anaesthetized rats. The significant transmural gradient observed at rest was sustained during submaximal muscle contractions. Our findings support that the blood–myocyte interface provides substantial resistance to oxygen diffusion at rest and during contractions and suggest that modulations in microvascular haemodynamics and red blood cell distribution constitute primary mechanisms driving increased transmural oxygen flux with contractions. Abstract: Oxygen pressure ( P O 2) gradients across the blood–myocyte interface are required for diffusive O2 transport, thereby supporting oxidative metabolism. The greatest resistance to O2 flux into skeletal muscle is considered to reside between the erythrocyte surface and adjacent sarcolemma, although this has not been measured during contractions. We tested the hypothesis that O2 gradients between skeletal muscle microvascular ( P O 2 mv ) and interstitial ( P O 2 is ) spaces would be present at rest and maintained or increased during contractions. P O 2 mv and P O 2 is   were determined via phosphorescence quenching (Oxyphor probes G2 and G4, respectively) in the exposed rat spinotrapezius during the rest–contraction transient (1 Hz, 6 V; n = 8). P O 2 mv was higher than P O 2 is in all instances from rest (34.9 ± 6.0 versus 15.7 ± 6.4) to contractions (28.4 ± 5.3 versus 10.6 ± 5.2 mmHg, respectively) such that the mean P O 2 gradient throughout the transient was 16.9 ± 6.6 mmHg (P < 0.05 for all). No differences in the amplitude of P O 2 fall with contractions were observed between the microvasculature and interstitium (10.9 ± 2.3 versus 9.0 ± 3.5 mmHg, respectively; P > 0.05). However, the speed of the P O 2 is fall during contractions was slower than that of P O 2 mv (time constant: 12.8 ± 4.7 versus 9.0 ± 5.1 s, respectively; P < 0.05). Consistent with our hypothesis, a significant transmural gradient was sustained (but not increased) from rest to contractions. This supports that the blood–myocyte interface is the site of a substantial P O 2 gradient driving O2 diffusion during metabolic transients. Based on Fick's law, elevated O2 flux with contractions must thus rely primarily on modulations in effective diffusing capacity (mainly erythrocyte haemodynamics and distribution) as the P O 2 gradient is not increased. [ABSTRACT FROM AUTHOR]