Amber D. Bledsoe

Nitric oxide and passive limb movement: a new approach to assess vascular function

•  Passive limb movement elicits a robust increase in limb blood flow (LBF) and limb vascular conductance (LVC) without a concomitant increase in skeletal muscle metabolism. •  The peripheral vascular mechanisms associated with the increase in LBF and LVC are unknown. •  Using an intra‐arterial infusion of NG‐monomethyl‐l‐arginine (l‐NMMA) to inhibit nitric oxide synthase (NOS) the hyperaemic and vasodilatory response to passive limb movement was attenuated by nearly 80%. •  This finding demonstrates that the increases in LBF and LVC during passive limb movement are primarily NO dependent. •  Passive limb movement appears to have significant promise as a new approach to assess NO‐mediated vascular function, an important predictor of cardiovascular disease risk.

Group III/IV muscle afferents limit the intramuscular metabolic perturbation during whole body exercise in humans

The purpose of this study was to determine the role of group III/IV muscle afferents in limiting the endurance exercise‐induced metabolic perturbation assayed in muscle biopsy samples taken from locomotor muscle. Lumbar intrathecal fentanyl was used to attenuate the central projection of μ‐opioid receptor‐sensitive locomotor muscle afferents during a 5 km cycling time trial. The findings suggest that the central projection of group III/IV muscle afferent feedback constrains voluntary neural ‘drive’ to working locomotor muscle and limits the exercise‐induced intramuscular metabolic perturbation. Therefore, the CNS might regulate the degree of metabolic perturbation within locomotor muscle and thereby limit peripheral fatigue. It appears that the group III/IV muscle afferents are an important neural link in this regulatory mechanism, which probably serves to protect locomotor muscle from the potentially severe functional impairment as a consequence of severe intramuscular metabolic disturbance.

Passive leg movement and nitric oxide-mediated vascular function: the impact of age

UNLABELLED In young healthy men, passive leg movement (PLM) elicits a robust nitric oxide (NO)-dependent increase in leg blood flow (LBF), thus providing a novel approach to assess NO-mediated vascular function. While the magnitude of the LBF response to PLM is markedly reduced with age, the role of NO in this attenuated response in the elderly is unknown. Therefore, this study sought to determine the contribution of NO in the PLM-induced LBF with age. Fourteen male subjects (7 young, 24 ± 1 yr; and 7 old, 75 ± 3 yr) underwent PLM with and without NO synthase (NOS) inhibition achieved by intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA). LBF was determined second-by-second by Doppler ultrasound, and central hemodynamics were measured by finger photoplethysmography. NOS inhibition blunted the PLM-induced peak increase in LBF in the young (control: 668 ± 106; L-NMMA 431 ± 95 Δml/min; P = 0.03) but had no effect in the old (control: 266 ± 98; L-NMMA 251 ± 92 Δml/min; P = 0.59). Likewise, the magnitude of the reduction in the overall (i.e., area under the curve) PLM-induced LBF response to NOS inhibition was less in the old (LBF: -31 ± 18 ml) than the young (LBF: -129 ± 21 ml; P < 0.01). These findings suggest that the age-associated reduction in PLM-induced LBF in the elderly is primarily due to a reduced contribution to vasodilation from NO and therefore support the use of PLM as a novel approach to assess NO-mediated vascular function across the lifespan.

Taming the “sleeping giant”: the role of endothelin-1 in the regulation of skeletal muscle blood flow and arterial blood pressure during exercise

The cardiovascular response to exercise is governed by a combination of vasodilating and vasoconstricting influences that optimize exercising muscle perfusion while protecting mean arterial pressure (MAP). The degree to which endogenous endothelin (ET)-1, the bodys most potent vasoconstrictor, participates in this response is unknown. Thus, in eight young (24 ± 2 yr), healthy volunteers, we examined leg blood flow, MAP, tissue oxygenation, heart rate, leg arterial-venous O(2) difference, leg O(2) consumption, pH, and net ET-1 and lactate release at rest and during knee extensor exercise (0, 5, 10, 15, 20, and 30 W) before and after an intra-arterial infusion of BQ-123 [ET subtype A (ET(A)) receptor antagonist]. At rest, BQ-123 did not evoke a change in leg blood flow or MAP. During exercise, net ET-1 release across the exercising leg increased approximately threefold. BQ-123 increased leg blood flow by ~20% across all work rates (changes of 113 ± 76, 176 ± 83, 304 ± 108, 364 ± 130, 502 ± 117, and 570 ± 178 ml/min at 0, 5, 10, 15, 20, and 30 W, respectively) and attenuated the exercise-induced increase in MAP by ~6%. The increase in leg blood flow was accompanied by a ~9% increase in leg O(2) consumption with an unchanged arterial-venous O(2) difference and deoxyhemoglobin, suggesting a decline in intramuscular efficiency after ET(A) receptor blockade. Together, these findings identify a significant role of the ET-1 pathway in the cardiovascular response to exercise, implicating vasoconstriction via the ET(A) receptor as an important mechanism for both the restraint of blood flow in the exercising limb and maintenance of MAP in healthy, young adults.

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 predicts that the capacity of each step of the oxygen cascade is attuned to the task demanded of it during aerobic exercise at maximal rates of oxygen consumption ( V̇O2 max ) such that no single process is limiting or in excess at V̇O2 max . The present study challenges the applicability of this concept to humans by revealing clear, albeit very different, limitations and excesses in oxygen supply and consumption among untrained and endurance‐trained humans. Among untrained individuals, V̇O2 max is limited by the capacity of the mitochondria to consume oxygen, despite an excess of oxygen supply, whereas, among trained individuals, V̇O2 max is limited by the supply of oxygen to the mitochondria, despite an excess of mitochondrial respiratory capacity.

Endothelin-A-Mediated Vasoconstriction During Exercise With Advancing Age

The endothelin-1 vasoconstrictor pathway contributes to age-related elevations in resting peripheral vascular tone primarily through activation of the endothelin subtype A (ET(A)) receptor. However, the regulatory influence of ET(A)-mediated vasoconstriction during exercise in the elderly is unknown. Thus, in 17 healthy volunteers (n = 8 young, 24±2 years; n = 9 old, 70±2 years), we examined leg blood flow, mean arterial pressure, leg arterial-venous oxygen (O2) difference, and leg O2 consumption (VO2) at rest and during knee-extensor exercise before and after intra-arterial administration of the ET(A) antagonist BQ-123. During exercise, BQ-123 administration increased leg blood flow to a greater degree in the old (+29±5 mL/min/W) compared with the young (+16±3 mL/min/W). The increase in leg blood flow with BQ-123 was accompanied by an increase in leg VO2 in both groups, suggesting a reduced efficiency following ET(A) receptor blockade. Together, these findings have identified an age-related increase in ET(A)-mediated vasoconstrictor activity that persists during exercise, suggesting an important role of this pathway in the regulation of exercising skeletal muscle blood flow and maintenance of arterial blood pressure in the elderly.

GlideScope Versus Flexible Fiber Optic for Awake Upright Laryngoscopy

STUDY OBJECTIVES We compare laryngoscopic quality and time to highest-grade view between a face-to-face approach with the GlideScope and traditional flexible fiber-optic laryngoscopy in awake, upright volunteers. METHODS This was a prospective, randomized, crossover study in which we performed awake laryngoscopy under local anesthesia on 23 healthy volunteers, using both a GlideScope video laryngoscopy face-to-face technique with the blade held upside down and flexible fiber-optic laryngoscopy. Operator reports of Cormack-Lehane laryngoscopic views and video-reviewed time to highest-grade view, as well as number of attempts, were recorded. RESULTS Ten women and 13 men participated. A grade II or better view was obtained with GlideScope video laryngoscopy in 22 of 23 (95.6%) participants and in 23 of 23 (100%) participants with flexible fiber-optic laryngoscopy (relative risk GlideScope video laryngoscopy versus flexible fiber-optic laryngoscopy 0.96; 95% confidence interval 0.88 to 1.04). Median time to highest-grade view for GlideScope video laryngoscopy was 16 seconds (interquartile range 9 to 34) versus 51 seconds (interquartile range 35 to 96) for flexible fiber-optic laryngoscopy. A distribution of interindividual differences demonstrated that GlideScope video laryngoscopy was, on average, 39 seconds faster than flexible fiber-optic laryngoscopy (95% confidence interval 0.2 to 76.9 seconds). CONCLUSION GlideScope video laryngoscopy can be used to obtain a Cormack-Lehane grade II or better view in the majority of awake, healthy volunteers when an upright face-to-face approach is used and was slightly faster than traditional flexible fiber-optic laryngoscopy. However, flexible fiber-optic laryngoscopy may be more reliable at obtaining high-grade views of the larynx. Awake, face-to-face GlideScope use may offer an alternative approach to the difficulty airway, particularly among providers uncomfortable with flexible fiber-optic laryngoscopy.

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 NG‐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.

Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans

We investigated the influence of aging on the group III/IV muscle afferents in the exercise pressor reflex-mediated cardiovascular response to rhythmic exercise. Nine old (OLD; 68 ± 2 yr) and nine young (YNG; 24 ± 2 yr) males performed single-leg knee extensor exercise (15 W, 30 W, 80% max) under control conditions and with lumbar intrathecal fentanyl impairing feedback from group III/IV leg muscle afferents. Mean arterial pressure (MAP), cardiac output, leg blood flow (QL), systemic (SVC) and leg vascular conductance (LVC) were continuously determined. With no hemodynamic effect at rest, fentanyl blockade during exercise attenuated both cardiac output and QL ∼17% in YNG, while the decrease in cardiac output in OLD (∼5%) was significantly smaller with no impact on QL (P = 0.8). Therefore, in the face of similar significant ∼7% reduction in MAP during exercise with fentanyl blockade in both groups, LVC significantly increased ∼11% in OLD, but decreased ∼8% in YNG. The opposing direction of change was reflected in SVC with a significant ∼5% increase in OLD and a ∼12% decrease in YNG. Thus while cardiac output seems to account for the majority of group III/IV-mediated MAP responses in YNG, the impact of neural feedback on the heart may decrease with age and alterations in SVC become more prominent in mediating the similar exercise pressor reflex in OLD. Interestingly, in terms of peripheral hemodynamics, while group III/IV-mediated feedback plays a clear role in increasing LVC during exercise in the YNG, these afferents seem to actually reduce LVC in OLD. These peripheral findings may help explain the limited exercise-induced peripheral vasodilation often associated with aging.

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.