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.

Pharmacological modulation of adrenergic tone alters the vasodilatory response to passive leg movement in young but not in old adults.

The age-related increase in α-adrenergic tone may contribute to decreased leg vascular conductance (LVC) both at rest and during exercise in the old. However, the effect on passive leg movement (PLM)-induced LVC, a measure of vascular function, which is markedly attenuated in this population, is unknown. Thus, in eight young (25 ± 5 yr) and seven old (65 ± 7 yr) subjects, this investigation examined the impact of systemic ß-adrenergic blockade (propanalol, PROP) alone, and PROP combined with either α1-adrenergic stimulation (phenylephrine, PE) or α-adrenergic inhibition (phentolamine, PHEN), on PLM-induced vasodilation. LVC, calculated from femoral artery blood flow and pressure, was determined and PLM-induced Δ peak (LVCΔpeak) and total vasodilation (LVCAUC, area under curve) were documented. PROP decreased LVCΔpeak (PROP: 4.8 ± 1.8, Saline: 7.7 ± 2.7 mL·mmHg-1, P < 0.001) and LVCAUC (PROP: 1.1 ± 0.7, Saline: 2.4 ± 1.6 mL·mmHg-1, P = 0.002) in the young, but not in the old (LVCΔpeak, P = 0.931; LVCAUC, P = 0.999). PE reduced baseline LVC (PE: 1.6 ± 0.4, PROP: 2.3 ± 0.4 mL·min-1·mmHg-1, P < 0.01), LVCΔpeak (PE: 3.2 ± 1.3, PROP: 4.8 ± 1.8 mL·min-1·mmHg-1, P = 0.004), and LVCAUC (PE: 0.5 ± 0.4, PROP: 1.1 ± 0.7 mL·mmHg-1, P = 0.011) in the young, but not in the old (baseline LVC, P = 0.199; LVCΔpeak, P = 0.904; LVCAUC, P = 0.823). PHEN increased LVC at rest and throughout PLM in both groups (drug effect: P < 0.05), however LVCΔpeak was only improved in the young (PHEN: 6.4 ± 3.1, PROP: 4.4 ± 1.5 mL·min-1·mmHg-1, P = 0.004), and not in the old (P = 0.904). Furthermore, the magnitude of α-adrenergic modulation (PHEN - PE) of LVCΔpeak was greater in the young compared with the old (Young: 3.35 ± 2.32, Old: 0.40 ± 1.59 mL·min-1·mmHg-1, P = 0.019). Therefore, elevated α-adrenergic tone does not appear to contribute to the attenuated vascular function with age identified by PLM.NEW & NOTEWORTHY Stimulation of α1-adrenergic receptors eliminated age-related differences in passive leg movement (PLM) by decreasing PLM-induced vasodilation in the young. Systemic ß-blockade attenuated the central hemodynamic component of the PLM response in young individuals. Inhibition of α-adrenergic receptors did not improve the PLM response in older individuals, though withdrawal of α-adrenergic modulation augmented baseline and maximal vasodilation in both groups. Accordingly, α-adrenergic signaling plays a role in modulating the PLM vasodilatory response in young but not in old adults, and elevated α-adrenergic tone does not appear to contribute to the attenuated vascular function with age identified by PLM.

Combined use of a Total Control Introducer and a hyperangulated video laryngoscope to place a left-sided double lumen endotracheal tube in a patient with a history of difficult laryngoscopy.

We describe the use of a Total Control Introducer (TCI) in combination with video laryngoscopy (VL) to place a left-sided double-lumen endotracheal tube (DLT) in a patient with a history of difficult laryngoscopy undergoing video-assisted thoracoscopic surgery (VATS). VL was used to obtain visualisation of the glottis and a TCI articulating introducer was used to dynamically navigate the airway and access the trachea. A 39 French DLT was subsequently passed over the TCI shaft and into the trachea under indirect visualisation. The TCI shaft was removed and the DLT was gently guided into the left main bronchus. Successful endobronchial intubation was confirmed with capnography, auscultation and fibreoptic bronchoscopy. We propose that the combined use of VL and a TCI can facilitate placement of a DLT in a patient with a known difficult airway who may otherwise be limited to a bronchial blocker placement for lung isolation during VATS.

The role of the endothelium in the hyperemic response to passive leg movement: looking beyond nitric oxide.

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.NEW & NOTEWORTHY Passive leg movement (PLM) evokes a highly nitric oxide (NO)-mediated hyperemic response and may provide a novel evaluation of vascular function. The contributions of endothelium-dependent vasodilatory pathways, beyond NO and including prostaglandins and endothelium-derived hyperpolarizing factor, to the PLM-induced hyperemic response to PLM have not been evaluated. With intra-arterial drug infusion, the combined inhibition of nitric oxide synthase (NOS), cyclooxygenase, and cytochrome P-450 (CYP450) pathways did not further diminish the hyperemic response to PLM compared with NOS inhibition alone.

Nitric oxide synthase inhibition with N(G)-monomethyl-l-arginine: Determining the window of effect in the human vasculature.

Nitric oxide synthase (NOS) inhibition with N(G)-monomethyl-l-arginine (L-NMMA) is often used to assess the role of NO in human cardiovascular function. However, the window of effect for L-NMMA on human vascular function is unknown, which is critical for designing and interpreting human-based studies. This study utilized the passive leg movement (PLM) assessment of vascular function, which is predominantly NO-mediated, in 7 young male subjects under control conditions, immediately following intra-arterial L-NMMA infusion (0.24 mg⋅dl-1⋅min-1), and at 45-60 and 90-105 min post L-NMMA infusion. The leg blood flow (LBF) and leg vascular conductance (LVC) responses to PLM, measured with Doppler ultrasound and expressed as the change from baseline to peak (ΔLBFpeak and ΔLVCpeak) and area under the curve (LBFAUC and LVCACU), were assessed. PLM-induced robust control ΔLBFpeak (1135 ± 324 ml⋅min-1) and ΔLVCpeak (10.7 ± 3.6 ml⋅min-1⋅mmHg-1) responses that were significantly attenuated (704 ± 196 ml⋅min-1 and 6.7 ± 2 ml⋅min-1⋅mmHg-1) immediately following L-NMMA infusion. Likewise, control condition PLM ΔLBFAUC (455 ± 202 ml) and ΔLVCAUC (4.0 ± 1.4 ml⋅mmHg-1) were significantly attenuated (141 ± 130 ml and 1.3 ± 1.2 ml⋅mmHg-1) immediately following L-NMMA infusion. However, by 45-60 min post L-NMMA infusion all PLM variables were not significantly different from control, and this was still the case at 90-105 min post L-NMMA infusion. These findings reveal that the potent reduction in NO bioavailability afforded by NOS inhibition with L-NMMA has a window of effect of less than 45-60 min in the human vasculature. These data are particularly important for the commonly employed approach of pharmacologically inhibiting NOS with L-NMMA in the human vasculature.

The role of endothelin A receptors in peripheral vascular control at rest and during exercise in patients with 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: 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.

Transesophageal echocardiography identification of aortic dissection during cardiac arrest and cessation of ECMO initiation.

Cardiac arrest is a challenging clinical presentation that emergency medicine providers often encounter. Aortic dissection is an uncommon etiology in all-comers presenting in cardiac arrest. The use of bedside point of care echocardiography to aid in resuscitative efforts is expanding, particularly with the increasing use of transesophageal echocardiography (TEE) by emergency medicine providers. Additionally, emergency department initiation of extracorporeal membrane oxygenation (ECMO) is a relatively newer development in emergency department practice. We report the case of a 64-year old male presenting to the emergency department in cardiac arrest with TEE identification of aortic dissection as the etiology resulting in discontinuation of ECMO initiation attempts.

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

Patients suffering from heart failure with reduced ejection fraction (HFrEF) experience impaired limb blood flow during exercise, which may be due to a disease-related increase in α-adrenergic receptor vasoconstriction. Thus, in eight patients with HFrEF (63 ± 4 yr) and eight well-matched controls (63 ± 2 yr), we examined changes in leg blood flow (Doppler ultrasound) during intra-arterial infusion of phenylephrine (PE; an α1-adrenergic receptor agonist) and phentolamine (Phen; a nonspecific α-adrenergic receptor antagonist) at rest and during dynamic single-leg knee-extensor exercise (0, 5, and 10 W). At rest, the PE-induced reduction in blood flow was significantly attenuated in patients with HFrEF (-15 ± 7%) compared with controls (-36 ± 5%). During exercise, the controls exhibited a blunted reduction in blood flow induced by PE (-12 ± 4, -10 ± 4, and -9 ± 2% at 0, 5, and 10 W, respectively) compared with rest, while the PE-induced change in blood flow was unchanged compared with rest in the HFrEF group (-8 ± 5, -10 ± 3, and -14 ± 3%, respectively). Phen administration increased leg blood flow to a greater extent in the HFrEF group at rest (+178 ± 34% vs. +114 ± 28%, HFrEF vs. control) and during exercise (36 ± 6, 37 ± 7, and 39 ± 6% vs. 13 ± 3, 14 ± 1, and 8 ± 3% at 0, 5, and 10 W, respectively, in HFrEF vs. control). Together, these findings imply that a HFrEF-related increase in α-adrenergic vasoconstriction restrains exercising skeletal muscle blood flow, potentially contributing to diminished exercise capacity in this population.

Elevated arterial shear rate increases indexes of endothelial cell autophagy and nitric oxide synthase activation in humans.

Continuous laminar shear stress increases the process of autophagy, activates endothelial nitric oxide (NO) synthase phosphorylation at serine 1177 (p-eNOSS1177), and generates NO in bovine and human arterial endothelial cells (ECs) compared with static controls. However, the translational relevance of these findings has not been explored. In the current study, primary ECs were collected from the radial artery of 7 men using sterile J-wires before (Pre) and after (Post) 60 min of rhythmic handgrip exercise (HG) performed with the same arm. After ECs were identified by positive costaining for vascular endothelial cadherin and 4',6'-diamidino-2-phenylindole, immunofluorescent antibodies were used to assess indices of autophagy, NO generation, and superoxide anion (O2·-) production. Commercially available primary human arterial ECs were stained and processed in parallel to serve as controls. All end points were evaluated using 75 ECs from each subject. Relative to Pre-HG, HG elevated arterial shear rate ( P < 0.05) ~3-fold, whereas heart rate, arterial pressure, and cardiac output were not altered. Compared with values obtained from ECs Pre-HG, Post-HG ECs displayed increased ( P < 0.05) expression of p-eNOSS1177, NO generation, O2·- production, BECLIN1, microtubule-associated proteins 1A/1B light chain 3B, autophagy-related gene 3, and lysosomal-associated membrane protein 2A and decreased ( P < 0.05) expression (i.e., enhanced degradation) of the adaptor protein p62/sequestosome-1. These novel findings provide evidence that elevated arterial shear rate associated with functional hyperemia initiates autophagy, activates p-eNOSS1177, and increases NO and O2·- generation in primary human ECs. NEW & NOTEWORTHY Previously, our group reported in bovine arterial and human arterial endothelial cells (ECs) that shear stress initiates trafficking of the autophagosome to the lysosome and increases endothelial nitric oxide (NO) synthase phosphorylation at serine 1177, NO generation, and O2·- production. Here, the translational relevance of these findings is documented. Specifically, functional hyperemia induced by rhythmic handgrip exercise elevates arterial shear rate to an extent that increases indices of autophagy, NO generation, and O2·- production in primary arterial ECs collected from healthy men.

Influence of group III/IV muscle afferents on small muscle mass exercise performance: a bioenergetics perspective.

KEY POINTS: This investigation assessed the influence of group III/IV muscle afferents on small muscle mass exercise performance from a skeletal muscle bioenergetics perspective. Group III/IV muscle afferent feedback was attenuated with lumbar intrathecal fentanyl during intermittent isometric single-leg knee-extensor all-out exercise, while 31 P-MRS was used to assess skeletal muscle bioenergetics. Attenuation of group III/IV muscle afferent feedback improved exercise performance during the first minute of exercise, due to an increase in total ATP production with no change in the ATP cost of contraction. However, exercise performance was not altered during the remainder of the protocol, despite a sustained increase in total ATP production, due to an exacerbated ATP cost of contraction. These findings reveal that group III/IV muscle afferents directly limit exercise performance during small muscle mass exercise, but, due to their critical role in maintaining skeletal muscle contractile efficiency, with time, the benefit of attenuating the muscle afferents is negated. ABSTRACT: The direct influence of group III/IV muscle afferents on exercise performance remains equivocal. Therefore, all-out intermittent isometric single-leg knee-extensor exercise and phosphorous magnetic resonance spectroscopy (31 P-MRS) were utilized to provide a high time resolution assessment of exercise performance and skeletal muscle bioenergetics in control conditions (CTRL) and with the attenuation of group III/IV muscle afferent feedback via lumbar intrathecal fentanyl (FENT). In both conditions, seven recreationally active men performed 60 maximal voluntary quadriceps contractions (MVC; 3 s contraction, 2 s relaxation), while knee-extensor force and 31 P-MRS were assessed during each MVC. The cumulative integrated force was significantly greater (8 ± 6%) in FENT than CTRL for the first minute of the all-out protocol, but was not significantly different for the second to fifth minutes. Total ATP production was significantly greater (16 ± 21%) in FENT than CTRL throughout the all-out exercise protocol, due to a significantly greater anaerobic ATP production (11 ± 13%) in FENT than CTRL with no significant difference in oxidative ATP production. The ATP cost of contraction was not significantly different between FENT and CTRL for the first minute of the all-out protocol, but was significantly greater (29 ± 34%) in FENT than in CTRL for the second to fifth minutes. These findings reveal that group III/IV muscle afferents directly limit exercise performance during small muscle mass exercise, but, due to their critical role in maintaining skeletal muscle contractile efficiency, with time, the benefit from muscle afferent attenuation is negated.

Single passive leg movement assessment of vascular function: contribution of nitric oxide.

Broxterman RM, Trinity JD, Gifford JR, Kwon OS, Kithas AC, Hydren JR, Nelson AD, Morgan DE, Jessop JE, Bledsoe AD, Richardson RS. Single passive leg movement assessment of vascular function: contribution of nitric oxide. J Appl Physiol 123: 1468-1476, 2017. First published August 31, 2017; doi:10.1152/japplphysiol.00533.2017.-The assessment of passive leg movement (PLM)-induced leg blood flow (LBF) and vascular conductance (LVC) is a novel approach to assess vascular function that has recently been simplified to only a single PLM (sPLM), thereby increasing the clinical utility of this technique. As the physiological mechanisms mediating the robust increase in LBF and LVC with sPLM are unknown, we tested the hypothesis that nitric oxide (NO) is a major contributor to the sPLM-induced LBF and LVC response. In nine healthy men, sPLM was performed with and without NO synthase inhibition by intra-arterial infusion of NG-monomethyl-l-arginine (l-NMMA). Doppler ultrasound and femoral arterial pressure were used to determine LBF and LVC, which were characterized by the peak change (ΔLBFpeak and ΔLVCpeak) and area under the curve (LBFAUC and LVCAUC). l-NMMA significantly attenuated ΔLBFpeak [492 ± 153 (l-NMMA) vs. 719 ± 238 (control) ml/min], LBFAUC [57 ± 34 (l NMMA) vs. 147 ± 63 (control) ml], ΔLVCpeak [4.7 ± 1.1 (l-NMMA) vs. 8.0 ± 3.0 (control) ml·min-1·mmHg-1], and LVCAUC [0.5 ± 0.3 (l-NMMA) vs. 1.6 ± 0.9 (control) ml/mmHg]. The magnitude of the NO contribution to LBF and LVC was significantly correlated with the magnitude of the control responses ( r = 0.94 for ΔLBFpeak, r = 0.85 for LBFAUC, r = 0.94 for ΔLVCpeak, and r = 0.95 for LVCAUC). These data establish that the sPLM-induced hyperemic and vasodilatory response is predominantly (~65%) NO-mediated. As such, sPLM appears to be a promising, simple, in vivo assessment of NO-mediated vascular function and NO bioavailability. NEW & NOTEWORTHY Passive leg movement (PLM), a novel assessment of vascular function, has been simplified to a single PLM (sPLM), thereby increasing the clinical utility of this technique. However, the role of nitric oxide (NO) in mediating the robust sPLM hemodynamic responses is unknown. This study revealed that sPLM induces a hyperemic and vasodilatory response that is predominantly NO-mediated and, as such, appears to be a promising simple, in vivo, clinical assessment of NO-mediated vascular function and, therefore, NO bioavailability.

Bioenergetics and ATP Synthesis during Exercise: Role of Group III/IV Muscle Afferents.

PURPOSE: The purpose of this study was to investigate the role of the group III/IV muscle afferents in the bioenergetics of exercising skeletal muscle beyond constraining the magnitude of metabolic perturbation. METHODS: Eight healthy men performed intermittent isometric knee-extensor exercise to task failure at ~58% maximal voluntary contraction under control conditions (CTRL) and with lumbar intrathecal fentanyl to attenuate group III/IV leg muscle afferents (FENT). Intramuscular concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), diprotonated phosphate (H2PO4), adenosine triphosphate (ATP), and pH were determined using phosphorous magnetic resonance spectroscopy (P-MRS). RESULTS: The magnitude of metabolic perturbation was significantly greater in FENT compared with CTRL for [Pi] (37.8 ± 16.8 vs 28.6 ± 8.6 mM), [H2PO4] (24.3 ± 12.2 vs 17.9 ± 7.1 mM), and [ATP] (75.8% ± 17.5% vs 81.9% ± 15.8% of baseline), whereas there was no significant difference in [PCr] (4.5 ± 2.4 vs 4.4 ± 2.3 mM) or pH (6.51 ± 0.10 vs 6.54 ± 0.14). The rate of perturbation in [PCr], [Pi], [H2PO4], and pH was significantly faster in FENT compared with CTRL. Oxidative ATP synthesis was not significantly different between conditions. However, anaerobic ATP synthesis, through augmented creatine kinase and glycolysis reactions, was significantly greater in FENT than in CTRL, resulting in a significantly greater ATP cost of contraction (0.049 ± 0.016 vs 0.038 ± 0.010 mM·min·N). CONCLUSION: Group III/IV muscle afferents not only constrain the magnitude of perturbation in intramuscular Pi, H2PO4, and ATP during small muscle mass exercise but also seem to play a role in maintaining efficient skeletal muscle contractile function in men.

Group III/IV locomotor muscle afferents alter motor cortical and corticospinal excitability and promote central fatigue during cycling exercise.

OBJECTIVE: To investigate the influence of group III/IV muscle afferents on the development of central fatigue and corticospinal excitability during exercise. METHODS: Fourteen males performed cycling-exercise both under control-conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from leg muscle afferents. Transcranial magnetic- and cervicomedullary stimulation was used to monitor cortical versus spinal excitability. RESULTS: While fentanyl-blockade during non-fatiguing cycling had no effect on motor-evoked potentials (MEPs), cervicomedullary-evoked motor potentials (CMEPs) were 13±3% higher (P<0.05), resulting in a decrease in MEP/CMEP (P<0.05). Although the pre- to post-exercise reduction in resting twitch was greater in FENT vs. CTRL (-53±3% vs. -39±3%; P<0.01), the reduction in voluntary muscle activation was smaller (-2±2% vs. -10±2%; P<0.05). Compared to the start of fatiguing exercise, MEPs and CMEPs were unchanged at exhaustion in CTRL. In contrast, MEPs and MEP/CMEP increased 13±3% and 25±6% in FENT (P<0.05). CONCLUSION: During non-fatiguing exercise, group III/IV muscle afferents disfacilitate, or inhibit, spinal motoneurons and facilitate motor cortical cells. In contrast, during exhaustive exercise, group III/IV muscle afferents disfacilitate/inhibit the motor cortex and promote central fatigue. SIGNIFICANCE: Group III/IV muscle afferents influence corticospinal excitability and central fatigue during whole-body exercise in humans.

The Effect of Perioperative Rescue Transesophageal Echocardiography on the Management of Trauma Patients.

To evaluate the effect of rescue transesophageal echocardiography (TEE) on the management of trauma patients, we reviewed imaging and charts of unstable trauma patients at a level I trauma center. Critical rescue TEE findings included acute right ventricular failure, stress cardiomyopathy, type B aortic dissection, mediastinal air, and dynamic left ventricular outflow tract obstruction. Left ventricular filling was classified as low (underfilled) in 57% of all cases. Rescue TEE revealed a variety of new diagnoses and led to a change in resuscitation strategy about half of the time.

Endogenous endothelin-1 and femoral artery shear rate: impact of age and implications for atherosclerosis.

BACKGROUND: Both altered shear rate and endothelin-1 (ET-1) are associated with the age-related development of atherosclerosis. However, the role of ET-1, a potent endogenous vasoconstrictor, in altering shear rate in humans, especially in the atherosclerotic-prone vasculature of the leg, is unknown. Therefore, this study examined the contribution of ET-1 to the age-related alterations in common femoral artery (CFA) shear rate. METHOD: BQ-123, a specific endothelin type A (ET(A)) receptor antagonist, was infused into the CFA, and diameter and blood velocity were measured by Doppler ultrasound in young (n = 8, 24 ±â€Š2 years) and old (n = 9, 70 ±â€Š2 years) study participants. RESULTS AND CONCLUSION: The old had greater intima-media thickening in the CFA, indicative of a preatherogenic phenotype. Prior to infusion, the old study participants exhibited reduced mean shear rate (27 ±â€Š3/s) compared with the young study participants (62 ±â€Š9/s). This difference was likely driven by attenuated antegrade shear rate in the old as retrograde shear rate was similar in the young and old. Inhibition of ETA receptors, by BQ-123, increased leg blood flow in the old, but not in the young, abolishing age-related differences. Older study participants had a larger CFA (young: 0.82 ±â€Š0.03 cm, old: 0.99 ±â€Š0.03 cm) in which BQ-123 induced significant vasodilation (5.1 ±â€Š1.0%), but had no such effect in the young (-0.8 ±â€Š0.8%). Interestingly, despite the age-specific, BQ-123-induced increase in leg blood flow and CFA diameter, shear rate patterns remained largely unchanged. Therefore, ET-1, acting through the ETA receptors, exerts a powerful age-specific vasoconstriction. However, removal of this vasoconstrictor stimulus does not augment mean shear rate in the old.

Symmorphosis and skeletal muscle V̇O2 max : in vivo and in vitro measures reveal differing constraints in the exercise-trained and untrained human.

The concept of symmorphosis postulates a matching of structural capacity to functional demand within a defined physiological system, regardless of endurance exercise training status. Whether this concept applies to oxygen (O2 ) supply and demand during maximal skeletal muscle O2 consumption (V̇O2 max ) in humans is unclear. Therefore, in vitro skeletal muscle mitochondrial V̇O2 max (Mito V̇O2 max , mitochondrial respiration of fibres biopsied from vastus lateralis) was compared with in vivo skeletal muscle V̇O2 max during single leg knee extensor exercise (KE V̇O2 max , direct Fick by femoral arterial and venous blood samples and Doppler ultrasound blood flow measurements) and whole-body V̇O2 max during cycling (Body V̇O2 max , indirect calorimetry) in 10 endurance exercise-trained and 10 untrained young males. In untrained subjects, during KE exercise, maximal O2 supply (KE Q̇O2max ) exceeded (462 ± 37 ml kg(-1) min(-1) , P < 0.05) and KE V̇O2 max matched (340 ± 22 ml kg(-1) min(-1) , P > 0.05) Mito V̇O2 max (364 ± 16 ml kg(-1) min(-1) ). Conversely, in trained subjects, both KE Q̇O2max (557 ± 35 ml kg(-1) min(-1) ) and KE V̇O2 max (458 ± 24 ml kg(-1) min(-1) ) fell far short of Mito V̇O2 max (743 ± 35 ml kg(-1) min(-1) , P < 0.05). Although Mito V̇O2 max was related to KE V̇O2 max (r = 0.69, P < 0.05) and Body V̇O2 max (r = 0.91, P < 0.05) in untrained subjects, these variables were entirely unrelated in trained subjects. Therefore, in untrained subjects, V̇O2 max is limited by mitochondrial O2 demand, with evidence of adequate O2 supply, whereas, in trained subjects, an exercise training-induced mitochondrial reserve results in skeletal muscle V̇O2 max being markedly limited by O2 supply. Taken together, these in vivo and in vitro measures reveal clearly differing limitations and excesses at V̇O2 max in untrained and trained humans and challenge the concept of symmorphosis as it applies to O2 supply and demand in humans.

The Mechanoreflex and Hemodynamic Response to Passive Leg Movement in Heart Failure.

BACKGROUND: Sensitization of mechanosensitive afferents, which contribute to the exercise pressor reflex, has been recognized as a characteristic of patients with heart failure (HF); however, the hemodynamic implications of this hypersensitivity are unclear. OBJECTIVES: The present study used passive leg movement (PLM) and intrathecal injection of fentanyl to blunt the afferent portion of this reflex arc to better understand the role of the mechanoreflex on central and peripheral hemodynamics in HF. METHODS: Femoral blood flow (FBF), mean arterial pressure, femoral vascular conductance, HR, stroke volume, cardiac output, ventilation, and muscle oxygenation of the vastus lateralis were assessed in 10 patients with New York Heart Association class II HF at baseline and during 3 min of PLM both with fentanyl and without (control). RESULTS: Fentanyl had no effect on baseline measures but increased (control vs fentanyl, P < 0.05) the peak PLM-induced change in FBF (493 ± 155 vs 804 ± 198 ΔmL·min(-1)) and femoral vascular conductance (4.7 ± 2 vs 8.5 ± 3 ΔmL·min(-1)·mm Hg)(-1) while norepinephrine spillover (103% ± 19% vs 58% ± 17%Δ) and retrograde FBF (371 ± 115 vs 260 ± 68 ΔmL·min(-1)) tended to be reduced (P < 0.10). In addition, fentanyl administration resulted in greater PLM-induced increases in muscle oxygenation, suggestive of increased microvascular perfusion. Fentanyl had no effect on the ventilation, mean arterial pressure, HR, stroke volume, or cardiac output response to PLM. CONCLUSIONS: Although movement-induced central hemodynamics were unchanged by afferent blockade, peripheral hemodynamic responses were significantly enhanced. Thus, in patients with HF, a heightened mechanoreflex seems to augment peripheral sympathetic vasoconstriction in response to movement, a phenomenon that may contribute to exercise intolerance 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.

The role of nitric oxide in passive leg movement-induced vasodilatation with age: insight from alterations in femoral perfusion pressure.

The passive leg movement (PLM) model is a novel approach to assess vascular function. Increasing femoral perfusion pressure (FPP) by moving from the supine to the upright-seated posture augments the vasodilatory response to PLM in the young, with no effect in the old, but whether this augmented vasodilatation is nitric oxide (NO) dependent is unknown. Using an intra-arterial infusion of N(G) -monomethyl-L -arginine (L -NMMA) to inhibit nitric oxide synthase (NOS), the posture-induced increases in the PLM responses in the young were nearly ablated, with no effect of NOS inhibition in the old. Therefore, PLM in combination with alterations in posture can be used to determine changes in NO-mediated vasodilatation with age, and thus, may be a clinically useful tool for assessing NO bioavailability across the human lifespan. We sought to better understand the contribution of nitric oxide (NO) to passive leg movement (PLM)-induced vasodilatation with age, with and without a posture-induced increase in femoral perfusion pressure (FPP). PLM was performed in eight young (24 ± 1 years) and eight old (74 ± 3 years) healthy males, with and without NO synthase inhibition via intra-arterial infusion of N(G) -monomethyl-L -arginine (L -NMMA) into the common femoral artery in both the supine and upright-seated posture. Central and peripheral haemodynamic responses were determined second-by-second with finger photoplethysmography and Doppler ultrasound, respectively. PLM-induced increases in heart rate, stroke volume, cardiac output and reductions in mean arterial pressure were similar between age groups and conditions. In the young, L -NMMA attenuated the peak change in leg vascular conductance (ΔLVCpeak ) in both the supine (control: 7.4 ± 0.9; L -NMMA: 5.2 ± 1.1 ml min(-1) mmHg(-1) , P < 0.05) and upright-seated (control: 12.3 ± 2.0; L -NMMA: 6.4 ± 1.0 ml min(-1) mmHg(-1) , P < 0.05) posture, with no significant change in the old (supine control: 4.2 ± 1.3; supine L -NMMA: 3.4 ± 0.8; upright-seated control: 4.5 ± 0.8; upright-seated L -NMMA: 3.4 ± 0.8 ml min(-1) mmHg(-1) , P > 0.05). Increased FPP augmented the ΔLVCpeak in the young control condition only (P < 0.05). In the upright-seated posture, NOS inhibition attenuated the FPP-induced augmentation of rapid vasodilatation in the young (control: 1.25 ± 0.23; L -NMMA: 0.74 ± 0.11 ml min(-1) mmHg(-1) s(-1) ; P < 0.05), but not the old (control: 0.37 ± 0.07; L -NMMA: 0.25 ± 0.07 ml ml min(-1) mmHg(-1) s(-1) ; P > 0.05). These data reveal that greater FPP increases the role of NO in PLM-induced vasodilatation in the young, but not the old, due to reduced NO bioavailability with age. Therefore, PLM involving alterations in posture may be useful to determine changes in NO bioavailability with age.