The effect of aging on adrenergic and nonadrenergic receptor expression and responsiveness in canine skeletal muscle.

We tested the hypothesis that adrenergic and nonadrenergic receptor responsiveness and protein expression would be altered with advancing age. Young (n = 6; 22 ± 1 mo; mean ± SE) and old (n = 6; 118 ± 9 mo) beagles were instrumented with flow probes and an indwelling catheter for continuous measurement of external iliac blood flow and arterial blood pressure. Vascular conductance (VC) was calculated as hindlimb blood flow/mean arterial pressure. Selective agonists for α-1, α-2, neuropeptide-Y (NPY), and purinergic (P2X) receptors were infused at rest and during treadmill running at moderate (2.5 mph) and heavy (4 mph with 2.5% grade) exercise intensities. Feed arteries were dissected from gracilis muscles, and α-1D, α-1B, α-2A, P2X-4, P2X-1, and NPY-Y1 receptor protein expression was determined. Phenylephrine produced similar decreases (P > 0.05) in VC in young and old beagles at rest (young: -62 ± 5%; old: -59 ± 5%) and during moderate (young: -67 ± 5%; old: -62 ± 4%) and heavy (young: -54 ± 4%; old: -49 ± 3%) exercise. Clonidine caused similar (P > 0.05) decreases in VC in old compared with young dogs at rest (young: -59 ± 8%; old: -70 ± 6%) and during moderate (young: -52 ± 6%; old: -47 ± 5%)- and heavy (young: -42 ± 5%; old: -43 ± 5%)-intensity exercise. NPY infusion resulted in a similar decline in VC in young and old beagles at rest (young: -40 ± 7%; old: -39 ± 9%) and during moderate (young: -47 ± 6%; old: -40 ± 6%)- and heavy (young: -40 ± 3%; old: -38 ± 4%)-intensity exercise. α-ß-Methylene-ATP also produced similar decreases in VC in young and old beagles at rest (young: -36 ± 6%; old: -40 ± 8%) and during exercise at moderate (young: -42 ± 5%; old: -40 ± 9%) and heavy (young: -47 ± 5%; old: -42 ± 8%) intensities. α-1B receptor protein expression was elevated (P < 0.05) in old compared with young dogs, whereas there were no age-related differences in α-1D or α-2A receptor expression and nonadrenergic P2X-4, P2X-1, and NPY-Y1 receptor expression. The present findings indicate that postsynaptic adrenergic and nonadrenergic receptor responsiveness was not altered by advancing age. Moreover, the expression of adrenergic and nonadrenergic receptors in skeletal-muscle feed arteries was largely unaffected by aging.

Autonomic nervous system dysfunction in obesity and Prader-Willi syndrome: current evidence and implications for future obesity therapies.

The autonomic nervous system (ANS) controls essential functions like breathing, heart rate, digestion, body temperature and hormone levels. Evidence suggests that ANS dysfunction is associated with adult and childhood obesity and plays a role in the distribution of total body fat and the development of obesity-related complications in humans. This review summarizes our current understanding of ANS involvement in the pathogenesis of obesity and Prader-Willi syndrome. Available evidence of ANS dysfunction in the control of energy balance is limited and, in some cases, contradictory. Further investigation in this area is warranted in order to better understand the important contributions of the ANS to regulation of body fat, development of obesity and its comorbidities. Results from these studies will guide the development of novel obesity therapeutics targeting specific ANS dysfunction.

Is tonic sympathetic vasoconstriction increased in the skeletal muscle vasculature of aged canines?

We tested the hypothesis that tonic adrenergic and nonadrenergic receptor-mediated sympathetic vasoconstriction would increase at rest and during exercise with advancing age. Young (n = 6; 22 ± 1 mo; means ± SE) and old (n = 6; 118 ± 9 mo) beagles were studied. Selective antagonists for alpha-1, alpha-2, neuropeptide Y (NPY), and purinergic (P(2x)) receptors were infused at rest and during treadmill running at 2.5 mph and 4 mph with 2.5% grade. Prazosin produced similar increases in vascular conductance in young and old beagles at rest (Young: 158 ± 34%; Old: 98 ± 19%) and during exercise at 2.5 mph (Young: 80 ± 10%; Old: 58 ± 12%) and 4 mph and 2.5% grade (Young: 57 ± 5%; Old: 26 ± 4%). Rauwolscine caused similar (P > 0.05) increases in vascular conductance in old compared with young dogs at rest (Young: 119 ± 25%; Old: 64 ± 22%) and at 2.5 mph (Young: 86 ± 13%; Old: 60 ± 7%) and 4 mph with 2.5% grade (Young: 61 ± 5%; Old: 43 ± 7%). N2-(diphenylacetyl)-N-[4-hydroxyphenyl)methyl]-d-arginine amide (BIBP) caused a smaller increase (P < 0.05) in vascular conductance in old compared with young dogs at rest (Young: 179 ± 44%; Old: 91 ± 22%), whereas similar increases (P > 0.05) of experimental limb vascular conductance in young and old dogs occurred following BIBP during exercise at 2.5 mph (Young: 56 ± 16%; Old: 50 ± 12%) and 4 mph and 2.5% grade (Young: 45 ± 10%; Old: 25 ± 7%). Pyridoxal-phosphate-6-azophenyl-2'-4'-disulfonic acid infusion produced a larger increase in vascular conductance in old compared with young beagles at rest (Young: 88 ± 14%; Old: 191 ± 58%), whereas similar increases were observed at 2.5 mph (Young: 47 ± 18%; Old: 31 ± 11%) and 4 mph with 2.5% grade (Young: 26 ± 13%; Old: -18 ± 8%). At rest, NPY receptor-mediated restraint of skeletal muscle blood flow was reduced with advancing age, whereas P(2x) receptor-mediated restraint of skeletal muscle blood flow was increased. During exercise, the magnitude of adrenergic and nonadrenergic sympathetic vasoconstriction was not different between young and old dogs. Overall, these data demonstrate that adrenergic receptor-mediated vasoconstriction was not elevated at rest, but nonadrenergic sympathetic vasoconstriction was altered under basal conditions in aged beagles.

Mild-to-moderate obesity: implications for respiratory mechanics at rest and during exercise in young men.

OBJECTIVE: To investigate the effect of mild-to-moderate obesity on respiratory mechanics at rest and during exercise in obese men. We hypothesized that the simple mass loading of obesity would alter both end-expiratory lung volume (EELV) and respiratory pressures (gastric, P(ga) and transpulmonary, P(TP)) in resting body positions and during graded cycle ergometry to exhaustion. SUBJECTS: A total of 10 obese (38+/-5% body fat; mean+/-s.d.) and nine lean (18+/-4%) men were studied. METHODS: Body composition (by body circumferences and hydrostatic weighing) and pulmonary function were measured at rest. Breathing mechanics were measured at rest in the upright-seated position, supine, and during cycling exercise. Data were analyzed by independent t-test. RESULTS: EELV was significantly lower in the obese men in the supine (30+/-4 vs 37+/-6% total lung capacity (TLC)) and seated (39+/-6 vs 47+/-5%TLC) positions and at ventilatory threshold (35+/-5 vs 45+/-7%TLC) (P<0.01). In contrast, at peak exercise, EELV was not different between groups. Respiratory pressures (P(ga) and P(TP)) were elevated (P<0.05) during one or more phases of the breathing cycle at rest and during exercise in obese men. CONCLUSION: These data demonstrate that mild-to-moderate obesity in young men results in reduced lung volumes and alterations in respiratory mechanics when supine, seated at rest, and during exercise. During moderate exercise, obesity does not appear to limit changes in EELV; however, the regulation of EELV during heavy exercise appears to be affected.

Mild obesity does not limit change in end-expiratory lung volume during cycling in young women.

To investigate the effects of obesity on the regulation of end-expiratory lung volume (EELV) during exercise we studied nine obese (41 +/- 6% body fat and 35 +/- 7 yr, mean +/- SD) and eight lean (18 +/- 3% body fat and 34 +/- 4 yr) women. We hypothesized that the simple mass loading of obesity would constrain the decrease in EELV in the supine position and during exercise. All subjects underwent respiratory mechanics measurements in the supine and seated positions, and during graded cycle ergometry to exhaustion. Data were analyzed between groups by independent t-test in the supine and seated postures, and during exercise at ventilatory threshold and peak. Total lung capacity (TLC) was reduced in the obese women (P < 0.05). EELV was significantly lower in the obese subjects in the supine (37 +/- 6 vs. 45 +/- 5% TLC) and seated (45 +/- 6 vs. 53 +/- 5% TLC) positions and at ventilatory threshold (41 +/- 4 vs. 49 +/- 5% TLC) (P < 0.01). In conclusion, despite reduced resting lung volumes and alterations in respiratory mechanics during exercise, mild obesity in women does not appear to constrain EELV during cycling nor does it limit exercise capacity. Also, these data suggest that other nonmechanical factors also regulate the level of EELV during exercise.

Progressive mechanical ventilatory constraints with aging.

To investigate the progressive nature of mechanical ventilatory constraints with aging, we studied 20 young (age 39 +/- 3 yr), 14 senior (70 +/- 2 yr), and 11 elderly (88 +/- 2 yr) men and women during exercise. All subjects had normal pulmonary function and performed graded cycle ergometry to exhaustion. Minute ventilation (V E), lung volume, and expiratory airflow limitation (EAFL) were measured during each 1-min increment in work rate. Data were analyzed by two-way analysis of variance (ANOVA; age x gender) at rest, ventilatory threshold (VTh), and peak exercise. If an interaction was present, each gender was analyzed with a one-way ANOVA. Aging resulted in an increased V E for a given submaximal work rate, although V E during peak exercise was lowest in the elderly group (p < 0.01). End-expiratory lung volume (EELV, % of TLC) in men increased progressively with age and all groups were different at VTh (p < 0.01) and peak exercise (p < 0.01). In women, EELV (% of TLC) also increased with aging, the senior and elderly subjects had a greater EELV at VTh (p < 0.01) and peak exercise (p < 0.01) than the young group. Additionally, the normal decrease in EELV during the early stages of exercise was not observed in elderly subjects. End-inspiratory lung volume (EILV) also progressively increased with aging; senior and elderly subjects had a higher EILV at rest (p < 0.05), VTh (p < 0.01), and peak exercise (p < 0.01) than young subjects. EAFL (% of VT) increased with aging; elderly subjects experienced greater EAFL at rest (p < 0.05), VTh (p < 0.01), and peak exercise (p < 0.01) than both young and senior subjects. We conclude that mechanical ventilatory constraints are progressive with aging, elderly subjects demonstrating marked mechanical ventilatory constraints during exercise. The impact of these constraints on exercise tolerance cannot be determined from this investigation and remains unclear.