Sympathetic nervous system contributes to the age-related impairment of flow-mediated dilation of the superficial femoral artery

The physiological aging process is associated with endothelial dysfunction, as assessed by flow-mediated dilation (FMD). Aging is also characterized by increased sympathetic tone. Therefore, the aim of the present study is to assess whether acute changes in sympathetic activity alter FMD in the leg. For this purpose, the FMD of the superficial femoral artery was determined in 10 healthy young (22 +/- 1 yr) and 8 healthy older (69 +/- 1 yr) men in three different conditions: 1) at baseline, 2) during reduction of sympathetic activity, and 3) during sympathetic stimulation. Reduction of sympathetic activity was achieved by performing a maximal cycling exercise, leading to postexercise attenuation of the sympathetic responsiveness in the exercised limb. A cold pressor test was used to increase sympathetic activity. Nitroglycerin (NTG) was used to assess endothelium-independent vasodilation in all three conditions. Our results showed that, in older men, the FMD and NTG responses were significantly lower compared with young men (P = 0.001 and P = 0.02, respectively). In older men, sympathetic activity significantly affected the FMD response [repeated-measures (RM) ANOVA: P = 0.01], with a negative correlation between the level of sympathetic activity and FMD (R = -0.41, P = 0.049). This was not the case for NTG responses (ANOVA; P = 0.48). FMD and NTG responses in young men did not differ among the three conditions (RM-ANOVA: P = 0.32 and P = 0.31, respectively). In conclusion, in older men, FMD of the femoral artery is impaired. Local attenuation of the sympathetic responsiveness partly restores the FMD in these subjects. In contrast, in young subjects, acute modulation of the sympathetic nervous system activity does not alter flow-mediated vasodilation in the leg.     

Extra-adipocyte leptin release in human obesity and its relation to sympathoadrenal function

The link between the human sympathoadrenalmedullary system and the adipocyte hormone leptin is controversial. We measured total and regional norepinephrine spillover, epinephrine secretion rate, and extra-adipocyte leptin release in 22 lean [body mass index (BMI) < 26] and 20 obese (BMI > 28) normotensive men who underwent arterial and central venous catheterization. Because plasma clearance of leptin is primarily by renal removal, for men at steady state we could estimate whole body leptin release to plasma from renal plasma leptin extraction. Whole body leptin release was 1,950 +/- 643 (means +/- SE) ng/min in obese men and 382 +/- 124 ng/min in lean men (P < 0.05). Total and renal norepinephrine spillover rates correlated directly with whole body leptin secretion rate. Leptin is released from multiple nonadipocyte sites, which we tested by use of simultaneous arteriovenous blood sampling. We found a surprisingly large contribution of brain leptin release to the plasma leptin pool, 529 +/- 175 ng/min (> 40% whole body leptin release), with greater leptin release in obese than in lean men, 935 +/- 321 vs. 160 +/- 59 ng/min (P = 0.045). In parallel with leptin measurements, we also quantified brain serotonin turnover and jugular overflow of neuropeptide Y (NPY). Brain serotonin turnover was higher in obese than in lean men, 227 +/- 112 vs. 21 +/- 14 ng/min (P = 0.019), as was overflow of NPY from the brain, 12.9 +/- 1.4 vs. 5.3 +/- 2.2 ng/min (P = 0.042). These results suggest that leptin is released within the brain and at an increased rate in obese humans, in whom activation of brain serotonergic and NPY mechanisms also exists.     

Age diminishes the testicular steroidogenic response to repeated intravenous pulses of recombinant human LH during acute GnRH-receptor blockade in healthy men

Testosterone (Te) concentrations fall gradually in healthy aging men. Postulated mechanisms include relative failure of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and/or gonadal Te secretion. Available methods to test Leydig cell Te production include pharmacological stimulation with human chorionic gonadotropin (hCG). We reasoned that physiological lutropic signaling could be mimicked by pulsatile infusion of recombinant human (rh) LH during acute suppression of LH secretion. To this end, we studied eight young (ages 19-30 yr) and seven older (ages 61-73 yr) men in an experimental paradigm comprising 1) inhibition of overnight LH secretion with a potent selective GnRH-receptor antagonist (ganirelix, 2 mg sc), 2) intravenous infusion of consecutive pulses of rh LH (50 IU every 2 h), and 3) chemiluminometric assay of LH and Te concentrations sampled every 10 min for 26 h. Statistical analyses revealed that 1) ganirelix suppressed LH and Te equally (> 75% median inhibition) in young and older men, 2) infused LH pulse profiles did not differ by age, and 3) successive intravenous pulses of rh LH increased concentrations of free Te (ng/dl) to 4.6 +/- 0.38 (young) and 2.1 +/- 0.14 (older; P < 0.001) and bioavailable Te (ng/dl) to 337 +/- 20 (young) and 209 +/- 16 (older; P = 0.002). Thus controlled pulsatile rh LH drive that emulates physiological LH pulses unmasks significant impairment of short-term Leydig cell steroidogenesis in aging men. Whether more prolonged pulsatile LH stimulation would normalize this inferred defect is unknown.     

Thermogenic responsiveness to nonspecific beta-adrenergic stimulation is not related to genetic variation in codon 16 of the beta2-adrenergic receptor

Stimulation of beta-adrenergic receptors (beta-AR) by the sympathetic nervous system (SNS) modulates energy expenditure (EE), but substantial interindividual variability is observed. We determined whether the thermogenic response to beta-AR stimulation is related to genetic variation in codon 16 of the beta(2)-AR, a biologically important beta-AR polymorphism, and whether differences in SNS activity (i.e., the stimulus for agonist-promoted downregulation) are involved. The increase in EE (DeltaEE, indirect calorimetry, ventilated hood) above resting EE in response to nonspecific beta-AR stimulation [iv isoproterenol: 6, 12, and 24 ng/kg fat-free mass (FFM)/min] was measured in 46 healthy adult humans [Arg16Arg: 9 male, 7 female, 48 +/- 5 yr; Arg16Gly: 11 male, 4 female, 53 +/- 5 yr; Gly16Gly: 3 male, 12 female, 48 +/- 5 yr (means +/- SE)]. Neither FFM-adjusted baseline resting EE (P = 0.83) nor the dose of isoproterenol required to increase EE 10% above resting (P = 0.87) differed among the three groups (Arg16Arg: 5,409 +/- 209 kJ/day, 11.2 +/- 2.1 ng x kg FFM(-1) x min(-1); Arg16Gly: 5,367 +/- 272 kJ/day, 11.1 +/- 2.1 ng x kg FFM(-1) x min(-1); Gly16Gly: 5,305 +/- 159 kJ/day, 10.5 +/- 1.4 ng x kg FFM(-1) x min(-1)). Consistent with this, muscle sympathetic nerve activity and plasma norepinephrine concentrations were not different among the groups. Group differences in sex composition did not influence the results. Our findings indicate that the thermogenic response to nonspecific beta-AR stimulation, an important mechanistic component of overall beta-AR modulation of EE, is not related to this beta(2)-AR polymorphism in healthy humans. This may be explained in part by a lack of association between this gene variant and tonic SNS activity.     

Aging and aerobic fitness affect the contribution of noradrenergic sympathetic nerves to the rapid cutaneous vasodilator response to local heating

Sedentary aging results in a diminished rapid cutaneous vasodilator response to local heating. We investigated whether this diminished response was due to altered contributions of noradrenergic sympathetic nerves by assessing 1) the age-related decline and 2) the effect of aerobic fitness. Using laser-Doppler flowmetry, we measured skin blood flow (SkBF) in young (24 ± 1 yr) and older (64 ± 1 yr) endurance-trained and sedentary men (n = 7 per group) at baseline and during 35 min of local skin heating to 42°C at 1) untreated forearm sites, 2) forearm sites treated with bretylium tosylate (BT), which prevents neurotransmitter release from noradrenergic sympathetic nerves, and 3) forearm sites treated with yohimbine + propranolol (YP), which antagonizes α- and β-adrenergic receptors. SkBF was converted to cutaneous vascular conductance (CVC = SkBF/mean arterial pressure) and normalized to maximal CVC (%CVC(max)) achieved by skin heating to 44°C. Pharmacological agents were administered using microdialysis. In the young trained group, the rapid vasodilator response was reduced at BT and YP sites (P < 0.05); by contrast, in the young sedentary and older trained groups, YP had no effect (P > 0.05), but BT did (P > 0.05). Neither BT nor YP affected the rapid vasodilator response in the older sedentary group (P > 0.05). These data suggest that the age-related reduction in the rapid vasodilator response is due to an impairment of sympathetic-dependent mechanisms, which can be partly attenuated with habitual aerobic exercise. Rapid vasodilation involves noradrenergic neurotransmitters in young trained men and nonadrenergic sympathetic cotransmitters (e.g., neuropeptide Y) in young sedentary and older trained men, possibly as a compensatory mechanism. Finally, in older sedentary men, the rapid vasodilation appears not to involve the sympathetic system.     

Smaller age-associated reductions in leg venous compliance in endurance exercise-trained men

We determined the independent and interactive influences of aging and habitual endurance exercise on calf venous compliance in humans. We tested the hypotheses that calf venous compliance is 1) reduced with age in sedentary and endurance-trained men, and 2) elevated in young and older endurance-trained compared with age-matched sedentary men. We studied 8 young (28 +/- 1 yr) and 8 older (65 +/- 1) sedentary, and 8 young (27 +/- 1) and 8 older (63 +/- 2) endurance-trained men. Calf venous compliance was measured in supine subjects by inflating a venous collecting cuff, placed above the knee, to 60 mmHg for 8 min and then decreasing cuff pressure at 1 mmHg/s to 0 mmHg. Calf venous compliance was determined using the first derivative of the pressure-volume relation during cuff pressure reduction (compliance = beta(1) + 2. beta(2). cuff pressure). Calf venous compliance was reduced with age in sedentary (approximately 40%) and endurance-trained men (approximately 20%) (both P < 0.01). Furthermore, calf venous compliance was approximately 70-120% greater in endurance-trained compared with age-matched sedentary men and approximately 30% greater in older endurance-trained compared with young sedentary men (both P < 0.01). These data indicate that calf venous compliance is reduced with age in sedentary and endurance-trained men, but compliance is better preserved in endurance-trained men.     

Age- and fitness-related differences in limb venous compliance do not affect tolerance to maximal lower body negative pressure in men and women.

Aging and chronic exercise training influence leg venous compliance. Venous compliance affects responses to an orthostatic stress; its effect on tolerance to maximal lower body negative pressure (LBNP) in the elderly is unknown. The purpose of this study was to determine the influence of age and fitness, a surrogate measure of exercise training, on calf venous compliance and tolerance to maximal LBNP in men and women. Forty participants, 10 young fit (YF; age = 22.6 +/- 0.5 yr, peak oxygen uptake = 57.1 +/- 2.0 ml.kg(-1).min(-1)), 10 young unfit (YU; 23.1 +/- 1.0 yr, 41.1 +/- 2.0 ml.kg(-1).min(-1)), 10 older fit (OF; 73.9 +/- 2.0 yr, 39.0 +/- 2.0 ml.kg(-1).min(-1)), and 10 older unfit (OU; 70.9 +/- 1.6 yr, 27.1 +/- 2.0 ml.kg(-1).min(-1)), underwent graded LBNP to presyncope or 4 min at -100 mmHg. By utilizing venous occlusion plethysmography, calf venous compliance was determined by using the first derivative of the pressure-volume relation during cuff pressure reduction. We found that the more fit groups had greater venous compliance than their unfit peers (P < 0.05) as did the young groups compared with their older peers (P < 0.05) such that OU < YU = OF < YF. LBNP tolerance did not differ between groups. In conclusion, these data suggest that aging reduces, and chronic exercise increases, venous compliance. However, these data do not support a significant influence of venous compliance on LBNP tolerance.     

Temporal adjustments in sympathoadrenal activity in rats with obesity-producing hypothalamic knife cuts

Sympathoadrenal activity was assessed in adult rats with obesity-producing hypothalamic knife cuts prior to and after the onset of gross obesity by measuring urinary excretion of norepinephrine and epinephrine and by determining rates of norepinephrine turnover in selected organs. Urinary excretion of norepinephrine, as an index of overall sympathetic nervous system activity, was approximately doubled throughout the 4-week study in knife-cut rats, as was intake of the high-fat diet. Three days after knife-cut surgery (before the onset of gross obesity) rates of norepinephrine turnover (ng X organ-1 X hr-1) were 23-33% lower in three of the four organs examined than in the corresponding organs of control rats; rates of norepinephrine turnover were depressed in pancreas, interscapular brown adipose tissue, and abdominal white adipose tissue and unchanged in hearts. Four weeks after surgery when gross obesity was evident, rates of norepinephrine turnover were accelerated in heart (+82%) and pancreas (+63%), but remained low in interscapular brown adipose tissue (-27%) and abdominal white adipose tissue (-28%). Adrenal medullary activity, assessed by urinary excretion of epinephrine, was suppressed within the 1st day after knife-cut surgery and remained suppressed for several weeks. Brown adipose tissue and white adipose tissue appear to be selectively excluded from the generalized activation of the sympathetic nervous system in adult hyperphagic rats with obesity-producing hypothalamic knife cuts. Activation of the sympathetic nervous system was associated with reciprocal suppression of adrenal medullary responses in knife-cut rats.     

Effect of angiotensin II receptor blockade on autonomic nervous system function in patients with essential hypertension

It has long been proposed that the renin-angiotensin system exerts a stimulatory influence on the sympathetic nervous system, including augmentation of central sympathetic outflow and presynaptic facilitation of norepinephrine release from sympathetic nerves. We tested this proposition in 19 patients with essential hypertension, evaluating whether the angiotensin receptor blockers (ARBs) eprosartan and losartan had identifiable antiadrenergic properties. This was done in a prospective, randomized, three-way placebo-controlled study of crossover design. Patients were randomized to 600 mg of eprosartan daily, 50 mg of losartan daily, or placebo. The treatment period was 4 wk, with 2-wk washout periods. Multiunit firing rates in efferent sympathetic nerves distributed to skeletal muscle vasculature (muscle sympathetic nerve activity, MSNA) were measured with microneurography, testing whether ARBs inhibit central sympathetic outflow. In parallel, isotope dilution methodology was used to measure whole body norepinephrine spillover to plasma. Mean blood pressure on placebo was 151/98 mmHg, with both ARBs causing reductions of approximately 11 mmHg systolic and 6 mmHg diastolic pressure, placebo corrected. Both MSNA [35 +/- 12 bursts/min (mean +/- SD) on placebo] and whole body norepinephrine spillover [366 +/- 247 ng/min] were unchanged by ARB administration, indicating that the ARBs did not materially inhibit central sympathetic outflow or act presynaptically to reduce norepinephrine release at existing rates of nerve firing. These findings contrast with the easily demonstrable reduction in sympathetic nervous activity produced by antihypertensive drugs of the imidazoline-binding class, which are known to act within the brain to inhibit sympathetic nervous outflow. We conclude that sympathetic nervous inhibition is not a major component of the blood pressure-lowering action of ARBs in essential hypertension.     

Aging, exercise, and endothelial progenitor cell clonogenic and migratory capacity in men.

Numerical and functional impairment of circulating endothelial progenitor cells (EPCs) is thought to contribute to vascular aging and the associated increase in cardiovascular risk. We tested the following hypotheses: 1) EPC clonogenic and migratory capacity decrease progressively with age in healthy, sedentary adult men; and 2) regular aerobic exercise will improve EPC clonogenic and migratory capacity in previously sedentary middle-aged and older men. Peripheral blood samples were collected from 46 healthy sedentary men: 10 young (26 +/- 1 yr), 15 middle-aged (47 +/- 1 yr), and 21 older (63 +/- 1 yr). Mononuclear cells were isolated and preplated for 2 days, and nonadherent cells were further cultured for 7 days to determine EPC colony-forming units. Migratory activity of EPCs was determined using a modified Boyden chamber. Ten sedentary middle-aged and older men (59 +/- 3 yr) were studied before and after a 3-mo aerobic exercise intervention. The number of EPC colony-forming units was approximately 75% lower (P < 0.01) in middle-aged (12 +/- 3) and older (8 +/- 2) compared with young (40 +/- 7) men. There was no difference in colony count between middle-aged and older men. EPC migration (fluorescent units) was significantly reduced in older (453 +/- 72) compared with young (813 +/- 114) and middle-aged (760 +/- 114) men. The exercise intervention increased (P < 0.05) both EPC colony-forming units (10 +/- 3 to 22 +/- 5) and migratory activity (683 +/- 96 to 1,022 +/- 123) in previously sedentary middle-aged and older men. These results provide further evidence that aging adversely affects EPC function. Regular aerobic-endurance exercise, however, is an effective lifestyle intervention strategy for improving EPC clonogenic and migratory capacity in middle-aged and older healthy men.     

Enhanced endothelin-1-mediated leg vascular tone in healthy older subjects.

Advanced age is associated with a decreased leg blood flow and reduced physical activity. Endothelin (ET-1), a powerful vasoconstrictor, may play a role in the increased leg vascular tone in older men. objectives: to assess the ET-1-mediated vascular tone in the legs of healthy sedentary older men, both before and after 8 wk of exercise training. methods: in 8 younger subjects (19-50 yr) and 8 older men (67-76 yr), bilateral leg blood flow was measured using venous occlusion plethysmography before and after antagonizing ET-1 (using selective ET(A/B)-receptor antagonists). In older men, reversibility of the observations was assessed after 8 wk of cycling. results: ET-receptor inhibition increased leg blood flow significantly more in older men compared with younger individuals (29 +/- 9% and 10 +/- 4%, respectively, P < 0.05). Eight-week cycling training increased baseline blood flow in older men. The blood flow response to ET-receptor inhibition in older men was not affected by the training program (25 +/- 8%, P > 0.05 for comparison with pretraining). The flow ratio (blood flows infused leg/noninfused leg) decreased significantly by training from 26 +/- 8% to 7+3% (P < 0.05). CONCLUSION: the increased baseline vascular tone in aging is at least in part mediated by the endothelin. Eight-weeks cycling training in older sedentary men decreased leg vascular tone and seems to partly decrease the ET-1-mediated vascular tone.     

Gender affects calf venous compliance at rest and during baroreceptor unloading in humans

Leg venous compliance is a determinant of peripheral venous pooling during orthostatic stress such that high venous compliance could contribute to reduced orthostatic tolerance. We tested the hypotheses that 1) calf venous compliance is reduced during baroreceptor unloading, and 2) calf venous compliance is greater in women than men. Twelve men (27 +/- 2 yr) and 12 women (25 +/- 2 yr) were studied in the supine posture. Calf venous compliance was determined by inflating a thigh venous collecting cuff to 60 mmHg for 8 min and then decreasing cuff pressure at a rate of 1 mmHg/s to 0 mmHg. The slope of the pressure-compliance relation (compliance = beta(1) + 2.beta(2).cuff pressure), which is the first derivative of the quadratic pressure-volume relation [(Deltalimb volume) = beta(0) + beta(1).(cuff pressure) + beta(2).(cuff pressure)(2)] during the reduction in collecting cuff pressure, was used to assess venous compliance at baseline and during one-legged lower body negative pressure (LBNP; -50 mmHg). At baseline, calf venous compliance was 48% lower (P < 0.001) in women than men and decreased in men (Delta-25 +/- 8%; P < 0.05) but not women (Delta1 +/- 11%) during LBNP. Rhythmic ischemic handgrip (Delta6 +/- 9%) and cold pressor testing (Delta-9 +/- 7%) did not alter calf venous compliance in a subgroup of men (n = 6). These data indicate gender-dependent effects on calf venous compliance under conditions associated with low sympathetic outflow (i.e., rest) and high sympathetic outflow (i.e., LBNP). However, they cannot explain gender-associated differences in orthostatic tolerance.     

Age-associated arterial wall thickening is related to elevations in sympathetic activity in healthy humans

Arterial wall hypertrophy occurs with age in humans and is a strong predictor of cardiovascular disease risk. The responsible mechanism is unknown, but data from studies in experimental animals suggest that elevated sympathetic-adrenergic tone may be involved. To test this hypothesis in humans we studied 11 young (29 +/- 1 yr; means +/- SE) and 13 older (63 +/- 1) healthy normotensive men under supine resting conditions. Muscle sympathetic nerve activity (MSNA) burst frequency (peroneal microneurography) was 70% higher in the older men (39 +/- 1 vs. 23 +/- 2 bursts/min; P < 0.001). Femoral artery intima media thickness (IMT; B-mode ultrasound) and the femoral IMT-to-lumen diameter ratio (IMT/lumen) were approximately 75% greater in the older men (both P < 0.001). Femoral IMT (r = 0. 82) and the femoral IMT/lumen (r = 0.85) were strongly and positively related to MSNA (both P < 0.001). The significant age group differences in femoral IMT and the IMT/lumen were abolished when the influence of MSNA was removed. In contrast, the relationship between MSNA and femoral wall thickness remained significant after removing the influence of age. We conclude that 1) primary aging is associated with femoral artery hypertrophy in humans and 2) this is strongly related to elevations in sympathetic nerve activity to the vasculature. These results support the hypothesis that tonic elevations in sympathetic nerve activity may be an important mechanism in the arterial remodeling that occurs with human aging.     

DISTRIBUTION AND TURNOVER OF OCTOPAMINE IN TISSUES

Abstract— Octopamine is a normally occurring amine in several species of animals. Particularly high concentrations are found in the crustacean central nerve cord. In the rat it is specifically localized to sympathetic nerve endings, has a subcellular distribution similar to that of norepinephrine, and is asymmetrically distributed in the CNS. It has a turnover rate in heart about six times that of norepinephrine. The physiological role of octopamine has not been established but it appears likely that it is a cotransmitter together with norepinephrine in the peripheral sympathetic nervous system.     

Alteration of neurotransmitter phenotype in noradrenergic neurons of transgenic mice.

The normal complement of neurotransmitters in noradrenergic neurons was altered by expressing the structural gene for the enzyme phenylethanolamine-N-methyltransferase (PNMT) under the control of the dopamine-beta-hydroxylase gene promoter in transgenic mice. This resulted in accumulation of large amounts of epinephrine in neurons of the sympathetic nervous system (SNS) and central nervous system (CNS) but did not reduce norepinephrine levels. Adrenalectomy reduced PNMT levels in the SNS and CNS, suggesting that the transgene is positively regulated by adrenal steroids. Epinephrine levels were unaffected by this treatment in the CNS, suggesting that PNMT is not rate limiting for epinephrine synthesis. However, catecholamines were elevated in a sympathetic ganglion and a target tissue of the SNS, perhaps due to up-regulation of tyrosine hydroxylase in response to adrenalectomy. These transgenic mice also reveal a marked difference in the ability of chromaffin cells and neurons to synthesize epinephrine.     

Delayed distribution of active vasodilation and altered vascular conductance in aged skin.

Reflex vasodilation is attenuated in aged skin during hyperthermia. We used laser-Doppler imaging (LDI) to test the hypothesis that the magnitude of conductance and the spatial distribution of vasodilation are altered with aging. LDI of forearm skin was compared in 12 young (19- to 29-yr-old) and 12 older (64- to 75-yr-old) men during supine passive heating. Additionally, iontophoresis of bretylium tosylate was performed in a subset of subjects to explore the involvement of sympathetic vasoconstriction in limiting skin blood flow. Passive heating with water-perfused suits clamped mean skin temperature at 41.0 +/- 0.5 degrees C, causing a ramp increase in esophageal temperature (T(es)) to 相似文献   

Gender influence on vasoactive hormones at rest and during a 70 degrees head-up tilt in healthy humans.

To evaluate the influence of age and gender on the neuroendocrine control of blood pressure in normal subjects, a 13-min 70 degrees head-up tilt (HUT) was applied after 3 h of recumbency to 109 healthy men and women aged 23-50 yr (age group I) and 51-77 yr (age group II). We found that age and gender had a significant influence on plasma norepinephrine (PNE) concentration at baseline and in the upright position. PNE was significantly higher in older men compared with the younger men and women of both age groups, suggesting a divergent age-related activation of the sympathetic nervous system between genders at baseline as well as during a sustained orthostatic challenge. There was no significant influence of age or gender on plasma epinephrine at baseline or during HUT. Plasma renin activity was significantly higher at baseline as well as in the upright position during HUT in elderly men than in women. Age or gender had no influence on plasma vasopressin (PAVP), and, regardless of age, nonhypotensive HUT induced an extremely modest increase in PAVP. The syncopal subjects displayed a hormonal pattern associating increased PNE and a surge in plasma epinephrine and PAVP minutes before syncope during HUT. The orthostatic intolerance appears not to be a feature of healthy aging per se. In healthy subjects, both age and gender modulate markedly the cardiovascular and neuroendocrine responses to an orthostatic challenge and must be taken into consideration, particularly when catecholamine responses are studied.     

Effect of aging on renal blood flow velocity during static exercise

During exercise, activation of the sympathetic nervous system causes reflex renal vasoconstriction. The effects of aging on this reflex are poorly understood. This study evaluated the effects of age on renal vasoconstrictor responses to handgrip. Seven older (65 +/- 9 yr) and nine younger (25 +/- 2 yr) subjects were studied. Beat-by-beat analyses of changes in renal blood flow velocity (RBV; duplex ultrasound) were performed during two handgrip paradigms. Arterial blood pressure (BP) and heart rate were also measured, and an index of renal vascular resistance (RVR) was calculated (BP/RBV). In protocol 1, fatiguing handgrip [40% of maximal voluntary contraction (MVC)] caused a greater increase in RVR in the older subjects (old 90% +/- 15 increase, young 52% +/- 4 increase; P = 0.03). During posthandgrip circulatory arrest (isolates muscle metaboreflex), the increases in RVR were only approximately 1/2 of the increase seen at end grip. In protocol 2, 15-s bouts of handgrip at graded intensities led to increases in RVR in both subject groups. This effect was not seen until 50% MVC workload (P < 0.05). RVR responses occurred early and were greater in older than in younger subjects at 50% MVC (32 +/- 6% vs. 16 +/- 5%; P = 0.02) and 70% MVC (39 +/- 11% vs. 24 +/- 8%; P = 0.02). Static exercise-induced renal vasoconstriction is enhanced with aging. Because the characteristics of this response suggest a predominant role for mechanoreceptor engagement, we hypothesize that mechanoreceptor responses are augmented with aging.     

Venous smooth muscle tone and responsiveness in older adults.

Venous compliance is lower in older adults compared with younger adults. It is possible that alterations in venous smooth muscle tone and responsiveness may contribute to the age-related differences in venous compliance. To determine the effects of sympathetic activation [cold pressor test (cold pressor test); rhythmic ischemic handgrip (rhythmic ischemic handgrip)] and endothelium-independent decreases in smooth muscle tone [sublingual nitroglycerin (nitroglycerin)] on venous compliance in young and older adults, forearm and calf venous compliance was measured in 12 young (22 +/- 1 yr) and 12 old (65 +/- 1 yr) supine subjects using venous occlusion plethysmography. Venous compliance was assessed at baseline, during the cold pressor test and rhythmic ischemic handgrip tests, and after nitroglycerin administration. All pressure-volume relationships were modeled with a quadratic regression equation, and beta1 and beta2 were used as indexes of venous compliance. A repeated-measures ANOVA was used to determine the effect of the age and trial on venous compliance. Calf regression parameters beta1 (0.0639 +/- 0.0126 vs. 0.0503 +/- 0.0059, young vs. older; P < 0.05) and beta2 (-0.00054 +/- 0.00011 vs. -0.00041 +/- 0.00005, young vs. older; P < 0.05) were significantly less in older adults at baseline. Similarly, forearm regression parameters, beta1 and beta2 were lower in older adults at baseline. Venous compliance was not effected by the cold pressor test test, rhythmic ischemic handgrip, or sublingual nitroglycerin in either group. Data suggest that forearm and calf venous compliance is lower in older adults compared with young. However, this difference probably cannot be explained by alterations in smooth muscle tone or responsiveness.     

Are NPY and enkephalins costored in the same noradrenergic neurons and vesicles?

Separate studies show that NPY and enkephalins are widely distributed in peripheral noradrenergic neurons. In the present study, the subcellular costorage and release in response to intense sympathetic stimulation and reserpine at near therapeutic doses (0.05 mg/kg every other day) were examined. In young pig arteries and vas deferens, enkephalin and D beta H immunofluorescence show consistent but not total overlap. Also NPY is colocalized with D beta H in many fibers but with VIP (nonnoradrenergic) in others. Ultrastructural immunogold labeling indicates that individual terminals contain large dense cored vesicles (LDVs) which store either NPY or enkephalins, even though costorage of both peptides occurs. Some LDVs costore NPY and VIP, especially in the middle cerebral artery and in the lamina propria of vas deferens. Acute CNS ischemia depletes enkephalins and norepinephrine in all tissues analyzed without parallel loss of NPY. Reserpine depletes norepinephrine 70-85% but does not deplete NPY or enkephalins. The latter is in contrast to commonly used high doses known to produce nonspecific, detergent-like effects. In fact, low doses of reserpine induce a time-dependent new synthesis and processing of NPY precursor peptides in vas deferns. Contrasting effects of reserpine on NPY and enkephalin contents, new synthesis and apparent processing, and a differential response to acute CNS ischemia were found in every tissue studied. Activation of precursor neuropeptide processing occurred immediately upon intense sympathetic stimulation in most tissues. Dual localization of NPY in noradrenergic and nonnoradrenergic fibers and differences in subcellular LDV storage help explain why enkephalin correlates better than NPY with norepinephrine loss in response to acute CNS ischemia. Furthermore, the costorage of NPY and enkephalins in distinct subpopulations of noradrenergic fibers, which varies according to tissue, is likely to be under separate CNS control.