RESUMEN
Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization ( V Ì 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 Ì 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 Ì 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 Ì 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 Ì 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.
Asunto(s)
Ejercicio Físico , Insuficiencia Cardíaca , Músculo Esquelético , Volumen Sistólico , Humanos , Masculino , Femenino , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/metabolismo , Anciano , Músculo Esquelético/irrigación sanguínea , Ejercicio Físico/fisiología , Persona de Mediana Edad , Fentolamina/farmacología , Flujo Sanguíneo Regional , Fenilefrina/farmacología , Consumo de Oxígeno , Antagonistas Adrenérgicos alfa/farmacología , Pierna/irrigación sanguíneaRESUMEN
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.
Asunto(s)
Endotelio Vascular/fisiología , Hiperemia , Movimiento , Contracción Muscular , Músculo Esquelético/irrigación sanguínea , Óxido Nítrico/metabolismo , Vasodilatación , Adulto , Factores Biológicos/metabolismo , Velocidad del Flujo Sanguíneo , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores Enzimáticos del Citocromo P-450/administración & dosificación , Endotelio Vascular/metabolismo , Voluntarios Sanos , Humanos , Infusiones Intraarteriales , Pierna , Masculino , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Prostaglandinas/metabolismo , Flujo Sanguíneo Regional , Transducción de Señal , Factores de Tiempo , Adulto JovenRESUMEN
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.
Asunto(s)
Ejercicio Físico , Hipertensión/fisiopatología , Músculo Esquelético/irrigación sanguínea , Receptor de Endotelina A/fisiología , Flujo Sanguíneo Regional , Presión Sanguínea , Antagonistas de los Receptores de Endotelina/farmacología , Endotelina-1/fisiología , Humanos , Péptidos Cíclicos/farmacologíaRESUMEN
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 mgâ dl-1â 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 mlâ min-1) and ΔLVCpeak (10.7 ± 3.6 mlâ min-1â mmHg-1) responses that were significantly attenuated (704 ± 196 mlâ min-1 and 6.7 ± 2 mlâ min-1â mmHg-1) immediately following L-NMMA infusion. Likewise, control condition PLM ΔLBFAUC (455 ± 202 ml) and ΔLVCAUC (4.0 ± 1.4 mlâ mmHg-1) were significantly attenuated (141 ± 130 ml and 1.3 ± 1.2 mlâ 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.
Asunto(s)
Inhibidores Enzimáticos/farmacocinética , Óxido Nítrico Sintasa/antagonistas & inhibidores , omega-N-Metilarginina/farmacocinética , Adulto , Arteria Femoral/fisiología , Hemodinámica/efectos de los fármacos , Humanos , Pierna/irrigación sanguínea , Masculino , Óxido Nítrico/metabolismo , Flujo Sanguíneo Regional/efectos de los fármacos , Factores de Tiempo , Adulto JovenRESUMEN
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.
Asunto(s)
Arterias/metabolismo , Autofagia , Células Endoteliales/metabolismo , Ejercicio Físico , Óxido Nítrico Sintasa de Tipo III/metabolismo , Adulto , Arterias/citología , Arterias/fisiología , Células Cultivadas , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Fuerza de la Mano , Humanos , Masculino , Óxido Nítrico/metabolismoRESUMEN
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.
Asunto(s)
Arterias/inervación , Tolerancia al Ejercicio , Insuficiencia Cardíaca/fisiopatología , Músculo Esquelético/irrigación sanguínea , Receptores Adrenérgicos beta 1/metabolismo , Volumen Sistólico , Sistema Nervioso Simpático/fisiopatología , Vasoconstricción , Función Ventricular Izquierda , Antagonistas Adrenérgicos/administración & dosificación , Anciano , Velocidad del Flujo Sanguíneo , Estudios de Casos y Controles , Tolerancia al Ejercicio/efectos de los fármacos , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/metabolismo , Humanos , Extremidad Inferior , Masculino , Persona de Mediana Edad , Contracción Muscular , Flujo Sanguíneo Regional , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Factores de Tiempo , Vasoconstricción/efectos de los fármacos , VasodilataciónRESUMEN
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.
Asunto(s)
Disección Aórtica/diagnóstico por imagen , Ecocardiografía Transesofágica , Oxigenación por Membrana Extracorpórea , Paro Cardíaco/etiología , Paro Cardíaco/terapia , Servicio de Urgencia en Hospital , Paro Cardíaco/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Sistemas de Atención de PuntoRESUMEN
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.
Asunto(s)
Vías Aferentes/fisiología , Metabolismo Energético , Ejercicio Físico , Contracción Muscular , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Adenosina Trifosfato/metabolismo , Adulto , Analgésicos Opioides/administración & dosificación , Fentanilo/administración & dosificación , Humanos , Masculino , Músculo Esquelético/efectos de los fármacosRESUMEN
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 (VÌO2 max ) in humans is unclear. Therefore, in vitro skeletal muscle mitochondrial VÌO2 max (Mito VÌO2 max , mitochondrial respiration of fibres biopsied from vastus lateralis) was compared with in vivo skeletal muscle VÌO2 max during single leg knee extensor exercise (KE VÌO2 max , direct Fick by femoral arterial and venous blood samples and Doppler ultrasound blood flow measurements) and whole-body VÌO2 max during cycling (Body VÌO2 max , indirect calorimetry) in 10 endurance exercise-trained and 10 untrained young males. In untrained subjects, during KE exercise, maximal O2 supply (KE QÌO2max ) exceeded (462 ± 37 ml kg(-1) min(-1) , P < 0.05) and KE VÌO2 max matched (340 ± 22 ml kg(-1) min(-1) , P > 0.05) Mito VÌO2 max (364 ± 16 ml kg(-1) min(-1) ). Conversely, in trained subjects, both KE QÌO2max (557 ± 35 ml kg(-1) min(-1) ) and KE VÌO2 max (458 ± 24 ml kg(-1) min(-1) ) fell far short of Mito VÌO2 max (743 ± 35 ml kg(-1) min(-1) , P < 0.05). Although Mito VÌO2 max was related to KE VÌO2 max (r = 0.69, P < 0.05) and Body VÌO2 max (r = 0.91, P < 0.05) in untrained subjects, these variables were entirely unrelated in trained subjects. Therefore, in untrained subjects, VÌO2 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 VÌO2 max being markedly limited by O2 supply. Taken together, these in vivo and in vitro measures reveal clearly differing limitations and excesses at VÌO2 max in untrained and trained humans and challenge the concept of symmorphosis as it applies to O2 supply and demand in humans.
Asunto(s)
Ejercicio Físico , Músculo Esquelético/metabolismo , Consumo de Oxígeno , Estudios de Casos y Controles , Humanos , Masculino , Mitocondrias Musculares/metabolismo , Músculo Esquelético/fisiología , Adulto JovenRESUMEN
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.
Asunto(s)
Envejecimiento/fisiología , Arteria Femoral/fisiología , Pierna/irrigación sanguínea , Pierna/fisiología , Óxido Nítrico/fisiología , Vasodilatación/fisiología , Adolescente , Adulto , Hemodinámica , Humanos , Masculino , Movimiento/fisiología , Adulto Joven , omega-N-Metilarginina/farmacologíaRESUMEN
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.
Asunto(s)
Arteria Femoral/metabolismo , Contracción Muscular , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/metabolismo , Óxido Nítrico/metabolismo , Vasodilatación , Adulto , Factores de Edad , Anciano , Presión Arterial , Velocidad del Flujo Sanguíneo , Inhibidores Enzimáticos/administración & dosificación , Arteria Femoral/diagnóstico por imagen , Frecuencia Cardíaca , Humanos , Infusiones Intraarteriales , Extremidad Inferior , Masculino , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Flujo Sanguíneo Regional , Volumen Sistólico , Ultrasonografía , Vasodilatación/efectos de los fármacos , Adulto Joven , omega-N-Metilarginina/administración & dosificaciónRESUMEN
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.
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Antioxidantes/uso terapéutico , Ejercicio Físico , Pierna/irrigación sanguínea , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Flujo Sanguíneo Regional , Administración Oral , Anciano , Antioxidantes/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatologíaRESUMEN
OBJECTIVE: Review the findings and use of rescue echocardiography performed by the Division of Perioperative Echocardiography and its impact on patient management. DESIGN: Retrospective observational study. SETTING: Single institution, tertiary care hospital. PARTICIPANTS: Three hundred sixty-four consecutive rescue echocardiograms in the perioperative setting. INTERVENTIONS: Rescue transesophageal or rescue transthoracic echocardiography. MEASUREMENTS AND MAIN RESULTS: Of a total of 1,675 perioperative echocardiograms performed in a 28-month period, 364 (21.8%) were rescue studies. Of these, 95.9% were transesophageal and 4.1% were transthoracic. Location at time of rescue echocardiography was intraoperative (55.5%), postoperative (44.2%), and preoperative (0.3%). No single diagnosis predominated the intraoperative or postoperative environment, and the frequency of common etiologies did not allow for assumption. There was a change in management for 214 patients (59%) as the result of findings. The methods used in performing rescue echocardiography at the authors' institution are reported. CONCLUSIONS: The heterogeneity of diagnoses and the frequency with which rescue echocardiography changed management further supports the growing body of evidence that the hemodynamically unstable perioperative patient benefits from its use.
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Anestesiología/métodos , Ecocardiografía Transesofágica/métodos , Atención Perioperativa/métodos , Médicos , Adulto , Anciano , Anestesiología/normas , Ecocardiografía Transesofágica/normas , Registros Electrónicos de Salud/normas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atención Perioperativa/normas , Médicos/normas , Estudios RetrospectivosRESUMEN
We investigated the influence of group III/IV lower limb muscle afferents on the development of supraspinal fatigue and the responsiveness of corticospinal projections to an arm muscle. Eight males performed constant-load leg cycling exercise (80% peak power output) for 30 s (non-fatiguing) and to exhaustion (â¼9 min; fatiguing) both under control conditions and with lumbar intrathecal fentanyl impairing feedback from µ-opioid receptor-sensitive lower limb muscle afferents. Voluntary activation (VA) of elbow flexors was assessed via transcranial magnetic stimulation (TMS) during maximum voluntary contraction (MVC) and corticospinal responsiveness was monitored via TMS-evoked potentials (MEPs) during a 25% MVC. Accompanied by a significant 5 ± 1% reduction in VA from pre- to post-exercise, elbow flexor MVC progressively decreased during the fatiguing trial (P < 0.05). By contrast, with attenuated feedback from locomotor muscle afferents, MVC and VA remained unchanged during fatiguing exercise (P > 0.3). MEPs decreased by 36 ± 6% (P < 0.05) from the start of exercise to exhaustion under control conditions, but this reduction was prevented with fentanyl blockade. Furthermore, fentanyl blockade prevented the significant increase in elbow flexor MEP observed from rest to non-fatiguing exercise under control conditions and resulted in a 14% lower corticospinal responsiveness during this short bout (P < 0.05). Taken together, in the absence of locomotor muscle fatigue, group III/IV-mediated leg muscle afferents facilitate responsiveness of the motor pathway to upper limb flexor muscles. By contrast, in the presence of cycling-induced leg fatigue, group III/IV locomotor muscle afferents facilitate supraspinal fatigue in remote muscle not involved in the exercise and disfacilitate, or inhibit, the responsiveness of corticospinal projections to upper limb muscles.
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Extremidades/inervación , Fatiga Muscular , Músculo Esquelético/fisiología , Tractos Piramidales/fisiología , Receptores Opioides mu/agonistas , Adulto , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiología , Potenciales Evocados Motores , Extremidades/fisiología , Retroalimentación Fisiológica , Fentanilo/farmacología , Humanos , Masculino , Contracción Muscular , Músculo Esquelético/inervaciónRESUMEN
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 body's 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.
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Presión Arterial , Endotelina-1/metabolismo , Ejercicio Físico , Contracción Muscular , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/metabolismo , Vasoconstricción , Adulto , Presión Arterial/efectos de los fármacos , Antagonistas de los Receptores de la Endotelina A , Frecuencia Cardíaca , Humanos , Concentración de Iones de Hidrógeno , Infusiones Intraarteriales , Ácido Láctico/metabolismo , Músculo Esquelético/efectos de los fármacos , Consumo de Oxígeno , Péptidos Cíclicos/administración & dosificación , Receptor de Endotelina A/metabolismo , Flujo Sanguíneo Regional , Factores de Tiempo , Vasoconstricción/efectos de los fármacos , Adulto JovenRESUMEN
Aging is characterized by increased sympatho-excitation, expressed through both the α-adrenergic and RAAS (renin-angiotensin-aldosterone) pathways. Although the independent contribution of these two pathways to elevated vasoconstriction with age may be substantial, significant cross-talk exists that could produce potentiating effects. To examine this interaction, 14 subjects (n=8 young, n=6 old) underwent brachial artery catheterization for administration of AngII (angiotensin II; 0.8-25.6 ng/dl per min), NE [noradrenaline (norepinephrine); 2.5-80 ng/dl per min] and AngII with concomitant α-adrenergic antagonism [PHEN (phentolamine); 10 µg/dl per min]. Ultrasound Doppler was utilized to determine blood flow, and therefore vasoconstriction, in both infused and contralateral (control) limbs. Arterial blood pressure was measured directly, and sympathetic nervous system activity was assessed via microneurography and plasma NE analysis. AngII sensitivity was significantly greater in the old, indicated by both greater maximal vasoconstriction (-59±4% in old against -48±3% in young) and a decreased EC50 (half-maximal effective concentration) (1.4±0.2 ng/dl per min in old against 2.6±0.7 µg/dl per min in young), whereas the maximal NE-mediated vasoconstriction was similar between these groups (-58±9% in old and -62±5% in young). AngII also increased venous NE in the old group, but was unchanged in the young group. In the presence of α-adrenergic blockade (PHEN), maximal AngII-mediated vasoconstriction in the old was restored to that of the young (-43±8% in old and -39±6% in young). These findings indicate that, with healthy aging, the increased AngII-mediated vasoconstriction may be attributed, in part, to potentiation of the α-adrenergic pathway, and suggest that cross-talk between the RAAS and adrenergic systems may be an important consideration in therapeutic strategies targeting these two pathways.
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Angiotensina II/farmacología , Vasoconstricción/efectos de los fármacos , Adulto , Anciano , Envejecimiento/fisiología , Sinergismo Farmacológico , Humanos , Norepinefrina/farmacología , Fentolamina/farmacología , Receptores Adrenérgicos alfa/fisiología , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
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.
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Pierna , Vasodilatación , Humanos , Anciano , Vasodilatación/fisiología , Pierna/irrigación sanguínea , Adrenérgicos/farmacología , Movimiento/fisiología , Hemodinámica , Flujo Sanguíneo Regional/fisiologíaRESUMEN
We investigated the role of skeletal muscle afferent feedback in circulatory control during rhythmic exercise in humans. Nine healthy males performed single leg knee-extensor exercise (15/30/45 watts, 3 min each) under both control conditions (Ctrl) and with lumbar intrathecal fentanyl impairing µ-opioid receptor-sensitive muscle afferents. Cardiac output and femoral blood flow were determined, and femoral arterial/venous blood samples were collected during the final minute of each workload. To rule out cephalad migration of fentanyl to the brainstem,we documented unchanged resting ventilatory responses to different levels of hypercapnia. There were no haemodynamic differences between conditions at rest. However, during exercise cardiac output was -2 % lower with fentanyl blockade compared to control (P < 0.05), secondary to a 6% and 13% reduction in heart rate and stroke volume, respectively. Throughout exercise mean arterial pressure (MAP) was reduced by 7% (P < 0.01) which is likely to have contributed to the 15% fall in femoral blood flow. However, MAP was not completely responsible for this peripheral haemodynamic change as vascular conductance was also attenuated (-9%). Evidence of increasing noradrenaline spillover (P = 0.09) implicated an elevation in sympathetic outflow in this response. The attenuated femoral blood flow during exercise with fentanyl was associated with a 17%reduction in leg O2 delivery (P < 0.01) and a concomitant rise in the arteriovenous O2 difference (49%), but leg O2 consumption remained 713% lower than control (P < 0.05). Our findings reveal an essential contribution of continuous muscle afferent feedback to ensure the appropriate haemodynamic and ultimately metabolic response to rhythmic exercise in humans
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Ejercicio Físico/fisiología , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/inervación , Neuronas Aferentes/fisiología , Flujo Sanguíneo Regional/fisiología , Adulto , Presión Sanguínea/fisiología , Dióxido de Carbono/administración & dosificación , Gasto Cardíaco/fisiología , Retroalimentación , Fentanilo/farmacología , Frecuencia Cardíaca/fisiología , Hemodinámica/fisiología , Humanos , Hipercapnia/fisiopatología , Pierna/irrigación sanguínea , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Norepinefrina/sangre , Norepinefrina/metabolismo , Consumo de Oxígeno/fisiología , Flujo Sanguíneo Regional/efectos de los fármacos , Descanso/fisiología , Volumen Sistólico/fisiologíaRESUMEN
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.
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Laringoscopios , Laringoscopía , Bronquios , Broncoscopía , Humanos , Intubación IntratraquealRESUMEN
The purpose of this investigation was to partially remove feedback from type III/IV skeletal muscle afferents and determine how this feedback influences the central and peripheral hemodynamic responses to passive leg movement. Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure, leg vascular conductance (LVC), and leg blood flow (LBF) were measured during 2 min of passive knee extension in eight young men before and after intrathecal fentanyl injection. Passive movement increased HR by 14 beats/min from baseline to maximal response during control (CON) (65 ± 4 to 79 ± 5 beats/min, P < 0.05), whereas HR did not significantly increase with the fentanyl block (BLK). LBF and LVC increased in both conditions; however, these increases were attenuated and delayed during BLK [%change from baseline to maximum, LBF: CON 295 ± 109 vs. BLK 210 ± 86%, (P < 0.05); LVC: CON 322 ± 40% vs. BLK 231 ± 32%, (P < 0.04)]. In CON, HR, SV, CO, and LVC increased contributing to the hyperemic response. However, under BLK conditions, statistically insignificant increases in HR and SV combined to yield a small, but significant, increase in CO and an attenuated hyperemic response. Therefore, partially blocking skeletal muscle afferent feedback blunts the central hemodynamic response due to passive limb movement, which then results in an attenuated and delayed movement-induced hyperemia. In combination, these findings provide evidence that limb movement-induced hyperemia has a significant central hemodynamic component induced by peripheral nerve activation.