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1.
Am J Physiol Heart Circ Physiol ; 310(6): H765-74, 2016 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-26801312

RESUMEN

The proposed mechanistic link between the age-related attenuation in vascular function and free radicals is an attractive hypothesis; however, direct evidence of free radical attenuation and a concomitant improvement in vascular function in the elderly is lacking. Therefore, this study sought to test the hypothesis that ascorbic acid (AA), administered intra-arterially during progressive handgrip exercise, improves brachial artery (BA) vasodilation in a nitric oxide (NO)-dependent manner, by mitigating free radical production. BA vasodilation (Doppler ultrasound) and free radical outflow [electron paramagnetic resonance (EPR) spectroscopy] were measured in seven healthy older adults (69 ± 2 yr) during handgrip exercise at 3, 6, 9, and 12 kg (∼13-52% of maximal voluntary contraction) during the control condition and nitric oxide synthase (NOS) inhibition via N(G)-monomethyl-L-arginine (L-NMMA), AA, and coinfusion of l-NMMA + AA. Baseline BA diameter was not altered by any of the treatments, while L-NMMA and L-NMMA + AA diminished baseline BA blood flow and shear rate. AA improved BA dilation compared with control at 9 kg (control: 6.5 ± 2.2%, AA: 10.9 ± 2.5%, P = 0.01) and 12 kg (control: 9.5 ± 2.7%, AA: 15.9 ± 3.7%, P < 0.01). NOS inhibition blunted BA vasodilation compared with control and when combined with AA eliminated the AA-induced improvement in BA vasodilation. Free radical outflow increased with exercise intensity but, interestingly, was not attenuated by AA. Collectively, these results indicate that AA improves BA vasodilation in the elderly during handgrip exercise through an NO-dependent mechanism; however, this improvement appears not to be the direct consequence of attenuated free radical outflow from the forearm.


Asunto(s)
Ácido Ascórbico/farmacología , Arteria Braquial/efectos de los fármacos , Ejercicio Físico , Fuerza de la Mano , Flujo Sanguíneo Regional/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Anciano , Arteria Braquial/metabolismo , Inhibidores Enzimáticos/farmacología , Femenino , Radicales Libres/metabolismo , Humanos , Infusiones Intraarteriales , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Vasodilatación/fisiología , omega-N-Metilarginina/farmacología
2.
Am J Physiol Heart Circ Physiol ; 309(5): H977-85, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26188020

RESUMEN

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.


Asunto(s)
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/fisiopatología
3.
Am J Physiol Regul Integr Comp Physiol ; 305(8): R893-9, 2013 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-23948773

RESUMEN

UNLABELLED: The reduction in nitric oxide (NO)-mediated vascular function with age has largely been determined by flow-mediated dilation (FMD). However, in light of recent uncertainty surrounding the NO dependency of FMD and the recognition that brachial artery (BA) vasodilation during handgrip exercise is predominantly NO-mediated in the young, we sought to determine the contribution of NO to BA vasodilation in the elderly using the handgrip paradigm. BA vasodilation during progressive dynamic (1 Hz) handgrip exercise performed at 3, 6, 9, and 12 kg was assessed with and without NO synthase (NOS) inhibition [intra-arterial N(G)-monomethyl-l-arginine (l-NMMA)] in seven healthy older subjects (69 ± 2 yr). Handgrip exercise in the control condition evoked significant BA vasodilation at 6 (4.7 ± 1.4%), 9 (6.5 ± 2.2%), and 12 kg (9.5 ± 2.7%). NOS inhibition attenuated BA vasodilation, as the first measurable increase in BA diameter did not occur until 9 kg (4.0 ± 1.8%), and the change in BA diameter at 12 kg was reduced by ∼30% (5.1 ± 2.2%), with unaltered shear rate ( CONTROL: 407 ± 57, l-NMMA: 427 ± 67 s(-1)). Although shifted downward, the slope of the relationship between BA diameter and shear rate during handgrip exercise was unchanged ( CONTROL: 0.0013 ± 0.0004, l-NMMA: 0.0011 ± 0.007, P = 0.6) as a consequence of NOS inhibition. Thus, progressive handgrip exercise in the elderly evokes a robust BA vasodilation, the magnitude of which was only minimally attenuated following NOS inhibition. This modest contribution of NO to BA vasodilation in the elderly supports the use of the handgrip exercise paradigm to assess NO-dependent vasodilation across the life span.


Asunto(s)
Arteria Braquial/fisiología , Endotelio Vascular/metabolismo , Fuerza de la Mano/fisiología , Óxido Nítrico/metabolismo , Vasodilatación/fisiología , Anciano , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Arteria Braquial/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Óxido Nítrico Sintasa/antagonistas & inhibidores , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Vasodilatación/efectos de los fármacos , omega-N-Metilarginina/farmacología
4.
Clin Sci (Lond) ; 124(6): 413-22, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22985469

RESUMEN

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.


Asunto(s)
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 fármacos
5.
Am J Physiol Heart Circ Physiol ; 300(3): H1101-7, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21217074

RESUMEN

In the peripheral circulation, nitric oxide (NO) is released in response to shear stress across vascular endothelial cells. We sought to assess the degree to which NO contributes to exercise-induced vasodilation in the brachial artery (BA) and to determine the potential of this approach to noninvasively evaluate NO bioavailability. In eight young (25 ± 1 yr) healthy volunteers, we used ultrasound Doppler to examine BA vasodilation in response to handgrip exercise (4, 8, 12, 16, 20, and 24 kg) with and without endothelial NO synthase blockade [intra-arterial N(G)-monomethyl-L-arginine (L-NMMA), 0.48 mg · dl(-1) · min(-1)]. Higher exercise intensities evoked significant BA vasodilation (4-12%) that was positively correlated with the hyperemic stimulus (r = 0.98 ± 0.003, slope = 0.005 ± 0.001). During NO blockade, BA vasodilation at the highest exercise intensity was reduced by ∼70% despite similar exercise-induced increases in shear rate (control, +224 ± 30 s(-1); L-NMMA, +259 ± 46 s(-1)). The relationship and slope of BA vasodilation with increasing shear rate was likewise reduced (r = 0.48 ± 0.1, slope = 0.0007 ± 0.0005). We conclude that endothelial NO synthase inhibition with L-NMMA abolishes the relationship between shear stress and BA vasodilation during handgrip exercise, providing clear evidence of NO-dependent vasodilation in this experimental model. These results support this paradigm as a novel and valid approach for a noninvasive assessment of NO-dependent vasodilation in humans.


Asunto(s)
Ejercicio Físico/fisiología , Fuerza de la Mano/fisiología , Mano/irrigación sanguínea , Mano/fisiología , Óxido Nítrico/fisiología , Vasodilatación/fisiología , Adulto , Arteria Braquial/diagnóstico por imagen , Arteria Braquial/fisiología , Femenino , Mano/diagnóstico por imagen , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Humanos , Hiperemia/fisiopatología , Masculino , Óxido Nítrico Sintasa/antagonistas & inhibidores , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Ultrasonografía , Vasodilatadores/metabolismo , Adulto Joven , omega-N-Metilarginina/fisiología
6.
Hypertension ; 62(2): 345-51, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23774225

RESUMEN

This study sought to better define the role of NO in brachial artery flow-mediated vasodilation (FMD) in young, healthy humans. Brachial artery blood velocity and diameter were determined (ultrasound Doppler) in 8 volunteers (26 ± 1 year) before and after 5-minute forearm circulatory occlusion with and without intra-arterial infusion of the endothelial NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA; 0.48 mg/dL per minute). Control (CON) and L-NMMA trials were performed with the occlusion cuff placed in the traditional distal position, as well as proximal to the measurement site. FMD was significantly reduced, but not abolished, by L-NMMA in the distal cuff trial (8.9 ± 1.3%-6.0 ± 0.7%, CON versus L-NMMA; P=0.02), with no effect of L-NMMA on FMD with proximal cuff placement (10.6 ± 1.2%-12.4 ± 1.7%, CON versus L-NMMA; P=0.39). When the reduction in shear stimulus after L-NMMA was taken into account, no drug difference was observed for either distal (0.26 ± 0.02-0.23 ± 0.03, CON versus L-NMMA; P=0.40) or proximal (0.23 ± 0.08-0.23 ± 0.03, CON versus L-NMMA; P=0.89) FMD trials. These findings challenge the assertion that NO is obligatory for brachial artery FMD and call into question the sensitivity of this procedure for noninvasive determination of NO bioavailability in young, healthy humans.


Asunto(s)
Arteria Braquial/fisiología , Óxido Nítrico/fisiología , Vasodilatación , Adulto , Bioensayo , Femenino , Humanos , Masculino , Flujo Sanguíneo Regional , omega-N-Metilarginina/farmacología
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