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ATP‐sensitive K+ channels (KATP) have been implicated in the regulation of resting vascular smooth muscle membrane potential and tone. However, whether KATP channels modulate skeletal muscle microvascular hemodynamics at the capillary level (the primary site for blood‐myocyte O2 exchange) remains unknown. We tested the hypothesis that KATP channel inhibition would reduce the proportion of capillaries supporting continuous red blood cell (RBC) flow and impair RBC hemodynamics and distribution in perfused capillaries within resting skeletal muscle. RBC flux (fRBC), velocity (VRBC), and capillary tube hematocrit (Hctcap) were assessed via intravital microscopy of the rat spinotrapezius muscle (n = 6) under control (CON) and glibenclamide (GLI; KATP channel antagonist; 10 µM) superfusion conditions. There were no differences in mean arterial pressure (CON:120 ± 5, GLI:124 ± 5 mmHg; p > 0.05) or heart rate (CON:322 ± 32, GLI:337 ± 33 beats/min; p > 0.05) between conditions. The %RBC‐flowing capillaries were not altered between conditions (CON:87 ± 2, GLI:85 ± 1%; p > 0.05). In RBC‐perfused capillaries, GLI reduced fRBC (CON:20.1 ± 1.8, GLI:14.6 ± 1.3 cells/s; p < 0.05) and VRBC (CON:240 ± 17, GLI:182 ± 17 µm/s; p < 0.05) but not Hctcap (CON:0.26 ± 0.01, GLI:0.26 ± 0.01; p > 0.05). The absence of GLI effects on the %RBC‐flowing capillaries and Hctcap indicates preserved muscle O2 diffusing capacity (DO2m). In contrast, GLI lowered both fRBC and VRBC thus impairing perfusive microvascular O2 transport (Q̇m) and lengthening RBC capillary transit times, respectively. Given the interdependence between diffusive and perfusive O2 conductances (i.e., %O2 extraction∝DO2m/Q̇m), such GLI alterations are expected to elevate muscle %O2 extraction to sustain a given metabolic rate. These results support that KATP channels regulate capillary hemodynamics and, therefore, microvascular gas exchange in resting skeletal muscle. [ABSTRACT FROM AUTHOR]

Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite nitric oxide synthase (NOS) inhibition. Therefore, in nine young healthy men (25 ± 4 yr), this investigation aimed to determine whether the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement), when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P-450 (CYP450) by L-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF [area under the curve (LBFAUC)] response to both PLM (control: 456 ± 194, L-NMMA: 168±127 mL, P < 0.01) and sPLM (control: 185 ± 171, L-NMMA: 62 ±31 mL, P = 0.03). The combined inhibition of NOS, COX, and CYP450 (i.e., l-NMMA + KET + FLUC) did not further attenuate the hyperemic responses to PLM (LBFAUC: 271±97 mL, P > 0.05) or sPLM (LBFAUC: 72± 45 mL, P > 0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests. [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]

The oxygen partial pressure in the interstitial space (PO2 is) drives O2 into the myocyte via diffusion, thus supporting oxidative phosphorylation. Although crucial for metabolic recovery and the capacity to perform repetitive tasks, the time course of skeletal muscle PO2 is during recovery from contractions remains unknown. We tested the hypothesis that PO2 is would recover to resting values and display considerable on-off asymmetry (fast on-, slow off-kinetics), reflective of asymmetric capillary hemodynamics. Microvascular PO2 (PO2 mv) was also evaluated to test the hypothesis that a significant transcapillary gradient (ΔPO2 = PO2 mv -- PO2 is) would be sustained during recovery. PO2 mv and PO2 is (expressed in mmHg) were determined via phosphorescence quenching in the exposed rat spinotrapezius muscle during and after submaximal twitch contractions (n = 12). PO2 is rose exponentially (P < 0.05) from end-contraction (11.1 ± 5.1), such that the end-recovery value (17.9 ± 7.9) was not different from resting PO2 is (18.5 ± 8.1; P > 0.05). PO2 is off-kinetics were slower than on-kinetics (mean response time: 53.1 ± 38.3 versus 18.5 ± 7.3 s; P < 0.05). A significant transcapillary ΔPO2 observed at end-contraction (16.6 ± 7.4) was maintained throughout recovery (end-recovery: 18.8 ± 9.6; P > 0.05). Consistent with our hypotheses, muscle PO2 is recovered to resting values with slower off-kinetics compared with the on-transient in line with the on-off asymmetry for capillary hemodynamics. Maintenance of a substantial transcapillary ΔPO2 during recovery supports that the microvascular-interstitium interface provides considerable resistance to O2 transport. As dictated by Fick's law (VO2 = DO2 x ΔPO2), modulation of O2 flux (VO2) during recovery must be achieved via corresponding changes in effective diffusing capacity (DO2; mainly capillary red blood cell hemodynamics and distribution) in the face of unaltered ΔPO2. NEW & NOTEWORTHY Capillary blood-myocyte O2 flux (VO2) is determined by effective diffusing capacity (DO2; mainly erythrocyte hemodynamics and distribution) and microvascular-interstitial PO2 gradients (ΔPO2 = PO2 mv -- PO2 is). We show that PO2 is demonstrates on-off asymmetry consistent with PO2 mv and erythrocyte kinetics during metabolic transitions. A substantial transcapillary ΔPO2 was preserved during recovery from contractions, indicative of considerable resistance to O2 diffusion at the microvascular-interstitium interface. This reveals that effective DO2 declines in step with VO2 during recovery, as per Fick's law. [ABSTRACT FROM AUTHOR]