Preserved ß-adrenergic-mediated vasodilation in skeletal muscle of young adults with obesity despite shifts in cyclooxygenase and nitric oxide synthase.

Central adiposity is associated with greater sympathetic support of blood pressure. ß-adrenergic receptors (ß-AR) buffer sympathetically mediated vasoconstriction and ß-AR-mediated vasodilation is attenuated in preclinical models of obesity. With this information, we hypothesized ß-AR vasodilation would be lower in obese compared with normal weight adults. Because ß-AR vasodilation in normal weight adults is limited by cyclooxygenase (COX) restraint of nitric oxide synthase (NOS), we further explored the contributions of COX and NOS to ß-AR vasodilation in this cohort. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured and forearm vascular conductance (FVC) was calculated (FVC = FBF/MAP). The rise in FVC from baseline (ΔFVC) was quantified during graded brachial artery infusion of isoproterenol (Iso, 1-12 ng/100 g/min) in normal weight (n = 36) and adults with obesity (n = 22) (18-40 yr old). In a subset of participants, Iso-mediated vasodilation was examined before and during inhibition of NOS [NG-monomethyl-l-arginine (l-NMMA)], COX (ketorolac), and NOS + COX (l-NMMA + ketorolac). Iso-mediated increases in FVC did not differ between groups (P = 0.57). l-NMMA attenuated Iso-mediated ΔFVC in normal weight (P = 0.03) but not adults with obesity (P = 0.27). In normal weight adults, ketorolac increased Iso-mediated ΔFVC (P < 0.01) and this response was lost with concurrent l-NMMA (P = 0.67). In contrast, neither ketorolac (P = 0.81) nor ketorolac + l-NMMA (P = 0.40) altered Iso-mediated ΔFVC in adults with obesity. Despite shifts in COX and NOS, ß-AR vasodilation is preserved in young adults with obesity. These data highlight the presence of a compensatory shift in microvascular control mechanisms in younger humans with obesity.NEW & NOTEWORTHY We examined ß-adrenergic receptor-mediated vasodilation in skeletal muscle of humans with obesity and normal weight. Results show that despite shifts in the contribution of cyclooxygenase and nitric oxide synthase, ß-adrenergic-mediated vasodilation is relatively preserved in young, otherwise healthy adults with obesity. These data highlight the presence of subclinical changes in microvascular control mechanisms early in the obesity process and suggest duration of obesity and/or the addition of primary aging may be necessary for overt dysfunction.

Greater Beta-Adrenergic Receptor Mediated Vasodilation in Women Using Oral Contraceptives.

BACKGROUND: ß-adrenergic receptors play an important role in mitigating the pressor effects of sympathetic nervous system activity in young women. Based on recent data showing oral contraceptive use in women abolishes the relationship between muscle sympathetic nervous system activity and blood pressure, we hypothesized forearm blood flow responses to a ß-adrenergic receptor agonist would be greater in young women currently using oral contraceptives (OC+, n = 13) when compared to those not using oral contraceptives (OC-, n = 10). METHODS: Women (18-35 years) were studied during the early follicular phase of the menstrual cycle (days 1-5) or placebo phase of oral contraceptive use. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured at baseline and during graded brachial artery infusion of the ß-adrenergic receptor agonist, Isoproterenol (ISO), as well as Acetylcholine (ACH, endothelium-dependent vasodilation) and Nitroprusside (NTP, endothelium-independent vasodilation). Forearm vascular conductance was calculated (FVC = FBF/MAP, ml/min/100 mmHg) and the rise in FVC from baseline during infusion quantified vasodilation (ΔFVC = FVCinfusion - FVCbaseline). RESULTS: ISO increased FVC in both groups (p < 0.01) and ISO-mediated ΔFVC was greater in OC+ compared to OC- (Main effect of group, p = 0.02). Expressing data as FVC and FBF resulted in similar conclusions. FVC responses to both ACH and NTP were also greater in OC+ compared to OC-. CONCLUSIONS: These data are the first to demonstrate greater ß-adrenergic receptor-mediated vasodilation in the forearm of women currently using oral contraceptives (placebo phase) when compared to those not using oral contraceptives (early follicular phase), and suggest oral contraceptive use influences neurovascular control.

ß-Adrenergic-mediated vasodilation in young men and women: cyclooxygenase restrains nitric oxide synthase.

We tested the hypothesis that women exhibit greater vasodilator responses to ß-adrenoceptor stimulation compared with men. We further hypothesized women exhibit a greater contribution of nitric oxide synthase and cyclooxygenase to ß-adrenergic-mediated vasodilation compared with men. Forearm blood flow (Doppler ultrasound) was measured in young men (n = 29, 26 ± 1 yr) and women (n = 33, 25 ± 1 yr) during intra-arterial infusion of isoproterenol (ß-adrenergic agonist). In subset of subjects, isoproterenol responses were examined before and after local inhibition of nitric oxide synthase [N(G)-monomethyl-l-arginine (l-NMMA); 6 male/10 female] and/or cyclooxygenase (ketorolac; 5 male/5 female). Vascular conductance (blood flow ÷ mean arterial pressure) was calculated to assess vasodilation. Vascular conductance increased with isoproterenol infusion (P < 0.01), and this effect was not different between men and women (P = 0.41). l-NMMA infusion had no effect on isoproterenol-mediated dilation in men (P > 0.99) or women (P = 0.21). In contrast, ketorolac infusion markedly increased isoproterenol-mediated responses in both men (P < 0.01) and women (P = 0.04) and this rise was lost with subsequent l-NMMA infusion (men, P < 0.01; women, P < 0.05). ß-Adrenergic vasodilation is not different between men and women and sex differences in the independent contribution of nitric oxide synthase and cyclooxygenase to ß-mediated vasodilation are not present. However, these data are the first to demonstrate ß-adrenoceptor activation of cyclooxygenase suppresses nitric oxide synthase signaling in human forearm microcirculation and may have important implications for neurovascular control in both health and disease.

Exercise vasodilation is greater in women: contributions of nitric oxide synthase and cyclooxygenase.

PURPOSE: We hypothesized exercise vasodilation would be greater in women due to nitric oxide synthase (NOS) and cyclooxygenase (COX) signaling. METHODS: 45 healthy adults (23 women, W, 22 men, M, 26 ± 1 years) completed two 10-min trials of dynamic forearm exercise at 15 % intensity. Forearm blood flow (FBF; Doppler ultrasound), arterial pressure (brachial catheter), and forearm lean mass were measured to calculate relative forearm vascular conductance (FVCrel) = FBF 100 mmHg(-1) 100 g(-1) lean mass. Local intra-arterial infusion of L-NMMA or ketorolac acutely inhibited NOS and COX, respectively. In Trial 1, the first 5 min served as control exercise (CON), followed by 5 min of L-NMMA or ketorolac over the last 5 min of exercise. In Trial 2, the remaining drug was infused during 5-10 min, to achieve combined NOS-COX inhibition (double blockade, DB). RESULTS: Are mean ± SE. Women exhibited 29 % greater vasodilation in CON (ΔFVCrel, 19 ± 1 vs. 15 ± 1, p = 0.01). L-NMMA reduced ΔFVCrel (p < 0.001) (W: Δ -2.3 ± 1.3 vs. M: Δ -3.7 ± 0.8, p = 0.25); whereas, ketorolac modestly increased ΔFVCrel (p = 0.04) similarly between sexes (W: Δ 1.6 ± 1.1 vs. M: Δ 2.0 ± 1.6, p = 0.78). DB was also found to be similar between the sexes (p = 0.85). CONCLUSION: These data clearly indicate women produce a greater exercise vasodilator response. Furthermore, contrary to experiments in animal models, these data are the first to demonstrate vascular control by NOS and COX is similar between sexes.

Complications of spinal fluid drainage in thoracic and thoracoabdominal aortic aneurysm surgery in 724 patients treated from 1987 to 2013.

OBJECTIVE: To study complications from spinal fluid drainage in open thoracic/thoracoabdominal and thoracic endovascular aortic aneurysm repairs to define risks of spinal fluid drainage. DESIGN: Retrospective, prospectively maintained, institutionally approved database. SETTING: Single institution university center. PARTICIPANTS: 724 patients treated from 1987 to 2013 INTERVENTIONS: The authors drained spinal fluid to a pressure≤6 mmHg during thoracic aortic occlusion/reperfusion in open and ≤8 mmHg after stent deployment in endovascular procedures. Low pressure was maintained until leg strength was documented. If bloody fluid appeared, drainage was stopped. Head computed tomography (CT) and, if indicated, spine CT and magnetic resonance imaging (MRI) were performed for bloody spinal fluid or neurologic deficit. MEASUREMENTS AND MAIN RESULTS: Spinal fluid drainage was studied for bloody fluid, CT/MRI-identified intracranial and spinal bleeding, neurologic deficit, and death. Seventy-three patients (10.1%) had bloody fluid; 38 (5.2%) had intracranial blood on CT. One patient had spinal epidural hematoma. Higher volume of fluid drained and higher central venous pressure during proximal clamping were associated with intracranial blood. Most patients with intracranial blood were asymptomatic. Six patients had neurologic deficits: of the 6, 3 died (0.4%), 1 (0.1%) had permanent hemiparesis, and 2 recovered. Three of the six deficits were delayed, associated with heparin anticoagulation. CONCLUSIONS: 10% of patients had bloody spinal fluid; half of these had intracranial bleeding, which was almost always asymptomatic. In these patients, immediately stopping drainage and correcting coagulopathy may decrease the risk of serious complications. Neurologic deficit from spinal fluid drainage is uncommon (0.8%), but has high morbidity and mortality.

Preserved Microvascular Endothelial Function in Young, Obese Adults with Functional Loss of Nitric Oxide Signaling.

Data indicate endothelium-dependent dilation (EDD) may be preserved in the skeletal muscle microcirculation of young, obese adults. Preserved EDD might be mediated by compensatory mechanisms, impeding insight into preclinical vascular dysfunction. We aimed to determine the functional roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) toward EDD in younger obese adults. We first hypothesized EDD would be preserved in young, obese adults. Further, we hypothesized a reduced contribution of NOS in young, obese adults would be replaced by increased COX signaling. Microvascular EDD was assessed with Doppler ultrasound and brachial artery infusion of acetylcholine (ACh) in younger (27 ± 1 year) obese (n = 29) and lean (n = 46) humans. Individual and combined contributions of NOS and COX were examined with intra-arterial infusions of l-NMMA and ketorolac, respectively. Vasodilation was quantified as an increase in forearm vascular conductance (ΔFVC). Arterial endothelial cell biopsies were analyzed for protein expression of endothelial nitric oxide synthase (eNOS). ΔFVC to ACh was similar between groups. After l-NMMA, ΔFVC to ACh was greater in obese adults (p < 0.05). There were no group differences in ΔFVC to ACh with ketorolac. With combined NOS-COX inhibition, ΔFVC was greater in obese adults at the intermediate dose of ACh. Surprisingly, arterial endothelial cell eNOS and phosphorylated eNOS were similar between groups. Younger obese adults exhibit preserved EDD and eNOS expression despite functional dissociation of NOS-mediated vasodilation and similar COX signaling. Compensatory NOS- and COX-independent vasodilatory mechanisms conceal reduced NOS contributions in otherwise healthy obese adults early in life, which may contribute to vascular dysfunction.

Exercise-mediated vasodilation in human obesity and metabolic syndrome: effect of acute ascorbic acid infusion.

We tested the hypothesis that infusion of ascorbic acid (AA), a potent antioxidant, would alter vasodilator responses to exercise in human obesity and metabolic syndrome (MetSyn). Forearm blood flow (FBF, Doppler ultrasound) was measured in lean, obese, and MetSyn adults (n = 39, 32 ± 2 yr). A brachial artery catheter was inserted for blood pressure monitoring and local infusion of AA. FBF was measured during dynamic handgrip exercise (15% maximal effort) with and without AA infusion. To account for group differences in blood pressure and forearm size, and to assess vasodilation, forearm vascular conductance (FVC = FBF/mean arterial blood pressure/lean forearm mass) was calculated. We examined the time to achieve steady-state FVC (mean response time, MRT) and the rise in FVC from rest to steady-state exercise (Δ, exercise - rest) before and during acute AA infusion. The MRT (P = 0.26) and steady-state vasodilator responses to exercise (ΔFVC, P = 0.31) were not different between groups. Intra-arterial infusion of AA resulted in a significant increase in plasma total antioxidant capacity (174 ± 37%). AA infusion did not alter MRT or steady-state FVC in any group (P = 0.90 and P = 0.85, respectively). Interestingly, higher levels of C-reactive protein predicted longer MRT (r = 0.52, P < 0.01) and a greater reduction in MRT with AA infusion (r = -0.43, P = 0.02). We concluded that AA infusion during moderate-intensity, rhythmic forearm exercise does not alter the time course or magnitude of exercise-mediated vasodilation in groups of young lean, obese, or MetSyn adults. However, systemic inflammation may limit the MRT to exercise, which can be improved with AA.

Neural control of blood flow during exercise in human metabolic syndrome.

α-Adrenergic-mediated vasoconstriction is greater during simulated exercise in animal models of metabolic syndrome (MetSyn) when compared with control animals. In an attempt to translate such findings to humans, we hypothesized that adults with MetSyn (n = 14, 35 ± 3 years old) would exhibit greater α-adrenergic responsiveness during exercise when compared with age-matched healthy control subjects (n = 16, 31 ± 3 years old). We measured muscle sympathetic nerve activity (MSNA; microneurography) and forearm blood flow (Doppler ultrasound) during dynamic forearm exercise (15% of maximal voluntary contraction). α-Adrenergic agonists (phenylephrine and clonidine) and an antagonist (phentolamine) were infused intra-arterially to assess α-adrenergic receptor responsiveness and restraint, respectively. Resting MSNA was ∼35% higher in adults with MetSyn (P < 0.05), but did not change in either group with dynamic exercise. Clonidine-mediated vasoconstriction was greater in adults with MetSyn (P < 0.01). Group differences in vascular responses to phenylephrine and phentolamine were not detected (P > 0.05). Interestingly, exercise-mediated vasodilatation was greater in MetSyn (P < 0.05). Adults with MetSyn exhibit greater resting MSNA and clonidine-mediated vasoconstriction, yet preserved functional sympatholysis and higher exercise blood flow during low-intensity hand-grip exercise when compared with age-matched healthy control subjects. These results suggest that adults with MetSyn exhibit compensatory vascular control mechanisms capable of preserving blood flow responses to exercise in the face of augmented sympathetic adrenergic activity.

Microvascular function in younger adults with obesity and metabolic syndrome: role of oxidative stress.

Older adults with cardiovascular disease exhibit microvascular dysfunction and increased levels of reactive oxygen species (ROS). We hypothesized that microvascular impairments begin early in the disease process and can be improved by scavenging ROS. Forearm blood flow (Doppler ultrasound) was measured in 45 young (32 ± 2 yr old) adults (n = 15/group) classified as lean, obese, and metabolic syndrome (MetSyn). Vasodilation in response to endothelial (ACh) and vascular smooth muscle [nitroprusside (NTP) and epoprostenol (Epo)] agonists was tested before and after intra-arterial infusion of ascorbic acid to scavenge ROS. Vasodilation was assessed as a rise in relative vascular conductance (ml·min(-1)·dl(-1)·100 mmHg(-1)). ACh and NTP responses were preserved (P = 0.825 and P = 0.924, respectively), whereas Epo responses were lower in obese and MetSyn adults (P < 0.05) than in lean controls. Scavenging of ROS via infusion of ascorbic acid resulted in an increase in ACh-mediated (P < 0.001) and NTP-mediated (P < 0.001) relative vascular conductance across all groups, suggesting that oxidative stress influences vascular responsiveness in adults with and without overt cardiovascular disease risk. Ascorbic acid had no effect on Epo-mediated vasodilation (P = 0.267). These results suggest that obese and MetSyn adults exhibit preserved endothelium-dependent vasodilation with reduced dependence on prostacyclin and are consistent with an upregulation of compensatory vascular control mechanisms.

Altered neurovascular control of the resting circulation in human metabolic syndrome.

Young healthy adults exhibit an inverse linear relationship between muscle sympathetic nerve activity (MSNA) and α-adrenergic responsiveness. This balance may be reversed in metabolic syndrome (MetSyn) as animal models exhibit increased sympathetic activity and α-mediated vasoconstriction. We hypothesized humans with MetSyn would demonstrate increased α-adrenergic vasoconstriction and the inverse relationship between MSNA and adrenergic responsiveness would be lost. We measured MSNA (microneurography of the peroneal nerve) and forearm blood flow (FBF, Doppler ultrasound) in 16 healthy control subjects (31 ± 3 years) and 14 adults with MetSyn (35 ± 3 years; P > 0.05) during local administration of α-adrenergic agonists (phenylephrine (PE), α(1); clonidine (CL), α(2)). MSNA was greater in MetSyn subjects than in healthy controls (P < 0.05). A group difference in vasoconstriction to PE was not detected (P = 0.08). The level of α(1)-mediated vasoconstriction was inversely related to MSNA in control subjects (r = 0.5, P = 0.04); this balance between MSNA and α(1) responsiveness was lost in adults with MetSyn. MetSyn subjects exhibited greater vasoconstriction to CL infusion as compared with healthy controls (P < 0.01). A relationship between MSNA and α(2)-mediated vasoconstriction was not detected in either group. In summary, altered neurovascular control in human MetSyn is receptor specific. The observed uncoupling between MSNA and α(1)-adrenergic responsiveness and increased α(2) vasoconstriction may lead to reduced FBF, altered flow distribution, and/or severe hypertension with the progression toward diabetes and cardiovascular disease.

Effect of obesity and metabolic syndrome on hypoxic vasodilation.

This study was designed to test whether obese adults and adults with metabolic syndrome (MetSyn) exhibit altered hyperemic responses to hypoxia at rest and during forearm exercise when compared with lean controls. We hypothesized blood flow responses due to hypoxia would be lower in young obese subjects (n = 11, 24 ± 2 years, BMI 36 ± 2 kg m(-2)) and subjects with MetSyn (n = 8, 29 ± 3 years BMI 39 ± 2 kg m(-2)) when compared with lean adults (n = 13, 29 ± 2 years, BMI 24 ± 1 kg m(-2)). We measured forearm blood flow (FBF, Doppler Ultrasound) and arterial oxygen saturation (pulse oximetry) during rest and steady-state dynamic forearm exercise (20 contractions/min at 8 and 12 kg) under two conditions: normoxia (0.21 F(i)O(2), ~98% S(a)O(2)) and hypoxia (~0.10 F(i)O(2), 80% S(a)O(2)). Forearm vascular conductance (FVC) was calculated as FBF/mean arterial blood pressure. At rest, the percent change in FVC with hypoxia was greater in adults with MetSyn when compared with lean controls (p = 0.02); obese and lean adult responses were not statistically different. Exercise increased FVC from resting levels in all groups (p < 0.05). Hypoxia caused an additional increase in FVC (p < 0.05) that was not different between groups; responses to hypoxia were heterogeneous within and between groups. Reporting FVC responses as absolute or percent changes led to similar conclusions. These results suggest adults with MetSyn exhibit enhanced hypoxic vasodilation at rest. However, hypoxic responses during exercise in obese adults and adults with MetSyn were not statistically different when compared with lean adults. Individual hypoxic vasodilatory responses were variable, suggesting diversity in vascular control.

Heterogeneous vascular responses to hypoxic forearm exercise in young and older adults.

We aimed to assess age-related differences in compensatory hypoxic vasodilation during moderate-to-high dynamic exercise at absolute workloads. We hypothesized healthy older adults (n = 12, 61 ± 1 years) would exhibit impaired hypoxic vasodilation at a moderate absolute workload, and this effect would be exaggerated at a higher workload when compared to young adults (n = 17, 27 ± 2 years). Forearm blood flow (FBF) was measured with Doppler ultrasound. Dynamic forearm exercise (20 contractions/min) was completed at two absolute workloads (8 and 12 kg) under normoxic (0.21 FiO2, ~98% SpO2) and isocapnic hypoxic (~0.10 FiO2, 80% SpO2) conditions performed in random order. FBF was normalized as forearm vascular conductance (FBF / mean arterial blood pressure = FVC) to control for differences in blood pressure and to assess vasodilation. FVC increased with exercise and hypoxia (main effects, p < 0.05); vascular responses were not different between young and older adults (interaction effect exercise × group p = 0.37 and hypoxia × group p = 0.96). Results were confirmed when analyzed as either an absolute or relative change in FVC (ΔFVC and %ΔFVC, respectively). Although group responses to hypoxia were not different, individual results were highly variable (i.e., some adults constricted and others dilated to hypoxia). These data suggest (1) compensatory hypoxic vasodilation in older adults is not impaired during forearm exercise at both moderate and higher absolute exercise intensities, and (2) vascular responses to hypoxia are heterogeneous in both young and older adults. Results suggest unique individual differences exist in factors regulating vascular responses to hypoxia.

Implications of group III and IV muscle afferents for high-intensity endurance exercise performance in humans.

We investigated the influence of group III/IV muscle afferents on peripheral fatigue, central motor drive (CMD) and endurance capacity during high-intensity leg-cycling. In a double-blind, placebo-controlled design, seven males performed constant-load cycling exercise (318 ± 9 W; 80% of peak power output (W(peak))) to exhaustion under placebo conditions and with lumbar intrathecal fentanyl impairing spinal µ-opioid receptor-sensitive group III/IV muscle afferents. Peripheral fatigue was assessed via changes in pre- vs. post-exercise quadriceps force in response to supramaximal magnetic femoral nerve stimulation (ΔQ(tw,pot)). CMD was estimated via quadriceps electromyogram. To rule out a direct central effect of fentanyl, we documented unchanged resting cardioventilatory responses. Compared to placebo, significant hypoventilation during the fentanyl trial was indicated by the 9% lower V(E)/V(CO(2)), causing a 5 mmHg increase in end-tidal P(CO(2)) and a 3% lower haemoglobin saturation. Arterial pressure and heart rate averaged 8 and 10% lower, respectively, during the fentanyl trial and these differences progressively diminished towards end-exercise. Although initially similar, the percent change in CMD was 9 ± 3% higher at end-exercise with fentanyl vs. placebo (P < 0.05). Time to exhaustion was shorter (6.8 ± 0.3 min vs. 8.7 ± 0.3 min) and end-exercise ΔQ(tw,pot) was about one-third greater (-44 ± 2% vs. -34 ± 2%) following fentanyl vs. placebo. The rate of peripheral fatigue development was 67 ± 10% greater during the fentanyl trial (P < 0.01). Our findings suggest that feedback from group III/IV muscle afferents limits CMD but also minimizes locomotor muscle fatigue development by stimulating adequate ventilatory and circulatory responses to exercise. In the face of blocked group III/IV muscle afferents, CMD is less inhibited but O(2) transport compromised and locomotor muscle fatigability is exacerbated with a combined net effect of a reduced endurance performance.

Alpha-adrenergic control of blood flow during exercise: effect of sex and menstrual phase.

Sex differences exist in autonomic control of the cardiovascular system. This study was designed to directly test sex or female menstrual phase-related differences in α-adrenergic control of blood flow during exercise. We hypothesized that women would exhibit reduced α-adrenergic vasoconstriction compared with men during exercise; in addition, women would constrict less during the early luteal than the early follicular phase of the female menses. Young men (n = 10) were studied once and women (n = 9) studied twice, once during the early follicular phase and once during the early luteal phase of female menses. We measured forearm blood flow (FBF; Doppler ultrasound of the brachial artery) during rest and steady-state dynamic exercise (15 and 30% of maximal voluntary contraction, 20 contractions/min). A brachial artery catheter was inserted for the local administration of α-adrenergic agonists [phenylephrine (PE; α(1)) or clonidine (CL; α(2))]. Blood flow responses to exercise [forearm vascular conductance (FVC)] were similar between all groups. At rest, infusion of PE or CL decreased FVC in all groups (40-60% reduction). Vasoconstriction to PE was abolished in all groups at 15 and 30% exercise intensity. Vasoconstriction to CL was reduced at 15% and abolished at 30% intensity in all groups; women had less CL-induced constriction during the early luteal than early follicular phase (P < 0.017, 15% intensity). These results indicate that vasodilator responses to forearm exercise are comparable between men and women and are achieved through similar paths of α-adrenergic vascular control at moderate intensities; this control may differ at low intensities specific to the female menstrual phase.

Group III and IV muscle afferents contribute to ventilatory and cardiovascular response to rhythmic exercise in humans.

We investigated the role of somatosensory feedback on cardioventilatory responses to rhythmic exercise in five men. In a double-blind, placebo-controlled design, subjects performed the same leg cycling exercise (50/100/150/325 ± 19 W, 3 min each) under placebo conditions (interspinous saline, L(3)-L(4)) and with lumbar intrathecal fentanyl impairing central projection of spinal opioid receptor-sensitive muscle afferents. Quadriceps strength was similar before and after fentanyl administration. To evaluate whether a cephalad migration of fentanyl affected cardioventilatory control centers in the brain stem, we compared resting ventilatory responses to hypercapnia (HCVR) and cardioventilatory responses to arm vs. leg cycling exercise after each injection. Similar HCVR and minor effects of fentanyl on cardioventilatory responses to arm exercise excluded direct medullary effects of fentanyl. Central command during leg exercise was estimated via quadriceps electromyogram. No differences between conditions were found in resting heart rate (HR), ventilation [minute ventilation (VE)], or mean arterial pressure (MAP). Quadriceps electromyogram, O(2) consumption (VO(2)), and plasma lactate were similar in both conditions at the four steady-state workloads. Compared with placebo, a substantial hypoventilation during fentanyl exercise was indicated by the 8-17% reduction in VE/CO(2) production (VCO(2)) secondary to a reduced breathing frequency, leading to average increases of 4-7 Torr in end-tidal PCO(2) (P < 0.001) and a reduced hemoglobin saturation (-3 ± 1%; P < 0.05) at the heaviest workload (∼90% maximal VO(2)) with fentanyl. HR was reduced 2-8%, MAP 8-13%, and ratings of perceived exertion by 13% during fentanyl vs. placebo exercise (P < 0.05). These findings demonstrate the essential contribution of muscle afferent feedback to the ventilatory, cardiovascular, and perceptual responses to rhythmic exercise in humans, even in the presence of unaltered contributions from other major inputs to cardioventilatory control.

Opioid-mediated muscle afferents inhibit central motor drive and limit peripheral muscle fatigue development in humans.

We investigated the role of somatosensory feedback from locomotor muscles on central motor drive (CMD) and the development of peripheral fatigue during high-intensity endurance exercise. In a double-blind, placebo-controlled design, eight cyclists randomly performed three 5 km time trials: control, interspinous ligament injection of saline (5K(Plac), L3-L4) or intrathecal fentanyl (5K(Fent), L3-L4) to impair cortical projection of opioid-mediated muscle afferents. Peripheral quadriceps fatigue was assessed via changes in force output pre- versus postexercise in response to supramaximal magnetic femoral nerve stimulation (DeltaQ(tw)). The CMD during the time trials was estimated via quadriceps electromyogram (iEMG). Fentanyl had no effect on quadriceps strength. Impairment of neural feedback from the locomotor muscles increased iEMG during the first 2.5 km of 5K(Fent) versus 5K(Plac) by 12 +/- 3% (P < 0.05); during the second 2.5 km, iEMG was similar between trials. Power output was also 6 +/- 2% higher during the first and 11 +/- 2% lower during the second 2.5 km of 5K(Fent) versus 5K(Plac) (both P < 0.05). Capillary blood lactate was higher (16.3 +/- 0.5 versus 12.6 +/- 1.0%) and arterial haemoglobin O(2) saturation was lower (89 +/- 1 versus 94 +/- 1%) during 5K(Fent) versus 5K(Plac). Exercise-induced DeltaQ(tw) was greater following 5K(Fent) versus 5K(Plac) (-46 +/- 2 versus -33 +/- 2%, P < 0.001). Our results emphasize the critical role of somatosensory feedback from working muscles on the centrally mediated determination of CMD. Attenuated afferent feedback from exercising locomotor muscles results in an overshoot in CMD and power output normally chosen by the athlete, thereby causing a greater rate of accumulation of muscle metabolites and excessive development of peripheral muscle fatigue.

Somatosensory feedback from the limbs exerts inhibitory influences on central neural drive during whole body endurance exercise.

We investigated whether somatosensory feedback from contracting limb muscles exerts an inhibitory influence on the determination of central command during closed-loop cycling exercise in which the subject voluntarily determines his second-by-second central motor drive. Eight trained cyclists performed two 5-km time trials either without (5K(Ctrl)) or with lumbar epidural anesthesia (5K(Epi); 24 ml of 0.5% lidocaine, vertebral interspace L(3)-L(4)). Percent voluntary quadriceps muscle activation was determined at rest using a superimposed twitch technique. Epidural lidocaine reduced pretime trial maximal voluntary quadriceps strength (553 +/- 45 N) by 22 +/- 3%. Percent voluntary quadriceps activation was also reduced from 97 +/- 1% to 81 +/- 3% via epidural lidocaine, and this was unchanged following the 5K(Epi), indicating the presence of a sustained level of neural impairment throughout the trial. Power output was reduced by 9 +/- 2% throughout the race (P < 0.05). We found three types of significant effects of epidural lidocaine that supported a substantial role for somatosensory feedback from the exercising limbs as a determinant of central command throughout high-intensity closed-loop cycling exercise: 1) significantly increased relative integrated EMG of the vastus lateralis; 2) similar pedal forces despite the reduced number of fast-twitch muscle fibers available for activation; 3) and increased ventilation out of proportion to a reduced carbon dioxide production and heart rate and increased blood pressure out of proportion to power output and oxygen consumption. These findings demonstrate the inhibitory influence of somatosensory feedback from contracting locomotor muscles on the conscious and/or subconscious determination of the magnitude of central motor drive during high intensity closed-loop endurance exercise.

A tale of two stents: perioperative management of patients with drug-eluting coronary stents.

Drug-eluting stents were introduced into clinical practice to decrease coronary stent restenosis rates. Though remarkably effective in reducing this complication, recent data reveal that drug-eluting stents pose a significant risk for late stent thrombosis, an event strongly correlated with discontinuation of anti-platelet therapy. Because anti-platelet agents are often discontinued perioperatively, patients with DES are at risk for perioperative stent thrombosis and myocardial infarction. Along with a review of the recent literature, we present two cases of patients with drug-eluting stents scheduled for renal transplantation. Two distinct antithrombotic management strategies illustrate the risk of either approach-bleeding and transfusion versus stent thrombosis and myocardial infarction.