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Heterogeneous vasodilator responses of human limbs: influence of age and habitual endurance training

¹Department of Kinesiology, Pennsylvania State University, University Park; and ²Division of Cardiology, Department of Medicine, Pennsylvania State University, Hershey, Pennsylvania

Submitted 16 November 2004 ; accepted in final form 11 March 2005

	ABSTRACT

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Forearm endothelium-dependent vasodilation is impaired with age in sedentary, but not endurance-trained, men. The purpose of this investigation was to determine whether these age- and physical activity-related differences in endothelium-dependent vasodilation also occur in the leg. Brachial and common femoral arterial blood flow were measured with Doppler ultrasound during increasing doses of acetylcholine (1, 4, and 16 µg·100 ml limb tissue^–1·min^–1), substance P (8, 31, and 125 pg·100 ml limb tissue^–1·min^–1), and sodium nitroprusside (0.063, 0.25, and 1 µg·100 ml limb tissue^–1·min^–1) in 23 healthy men (8 younger sedentary, 8 older sedentary, and 7 older endurance trained). Increases in forearm blood flow to the highest dose of acetylcholine and sodium nitroprusside were smaller (P < 0.05) in older sedentary (841 ± 142%, 428 ± 74%) compared with younger sedentary (1,519 ± 256%, 925 ± 163%) subjects. Similarly, increases in forearm blood flow to sodium nitroprusside (1 µg·100 ml limb tissue^–1·min^–1) were smaller (P < 0.05) in older endurance-trained (505 ± 110%) compared with younger sedentary (925 ± 163%) subjects. In contrast, no differences in leg blood flow responses to intra-arterial infusions of acetylcholine, substance P, or sodium nitroprusside were noted between subject groups. These results demonstrate that 1) acetylcholine- and sodium nitroprusside-induced vasodilation are attenuated in the forearm vasculature and preserved in the leg vasculature of older sedentary subjects and 2) sodium nitroprusside-induced vasodilation remains attenuated in the forearm vasculature of healthy older endurance-trained men but preserved in the leg vasculature of these men.

endothelium; vascular smooth muscle; leg

It was recently suggested that heterogeneity of vascular dysfunction must be appreciated (30). Studies in animals have demonstrated that endothelium-dependent vasodilation is preserved with age in several peripheral circulations but impaired in others (16, 33). This suggests that the effects of age on endothelium-dependent vasodilation in the peripheral vasculature may not be uniform. Unfortunately, there is a paucity of human literature regarding the effects of age and/or habitual exercise on endothelial function outside the forearm and coronary circulations.

Thus the aims of the present study were 1) to determine whether age is associated with diminished endothelium-dependent vasodilation in both the forearm and leg vasculature and 2) to compare and contrast the effects of aerobic lower body exercise training on endothelium-dependent vasodilation in the leg of aged subjects to the effects in the arm. We hypothesized that there would be less of an age effect on endothelium-dependent vasodilation in the leg compared with the forearm. Furthermore, we hypothesized that endothelium-dependent vasodilation would be preserved in both the forearm and leg of lower body endurance-trained older men.

	METHODS

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Subjects. Twenty-three healthy men (8 younger sedentary, 8 older sedentary, and 7 older endurance trained) participated in this study. Data from the young sedentary subjects were reported previously (19). All subjects were normotensive (blood pressure <140/90 mmHg), nonobese (body mass index <30 kg/m²), nonsmokers, and free of cardiovascular disease as assessed by medical history, physical examination, blood chemistries, and maximal exercise electrocardiograms. No subjects were currently taking any medications that were known to have hemodynamic effects. Subjects not currently participating in >60 min/wk of purposeful aerobic exercise (walking, biking, or jogging) were classified as sedentary. However, all sedentary subjects participated in normal activities of daily living. Older subjects were classified as endurance trained based on their training history (competitive runners and cyclists averaging 11 h/wk of aerobic training over the past 26 yr) and peak oxygen consumption (O_{2 peak}) on a cycle ergometer. The protocol and equipment used for the measurement of O_{2 peak} on a cycle ergometer have been described previously (19, 20). Before participation, each subject was verbally informed of the potential risks and discomforts associated with the study and signed a written informed consent form approved by the Institutional Review Board of the Milton S. Hershey Medical Center.

Measurements. Endothelial and vascular smooth muscle function were assessed through intra-arterial infusions of endothelium-dependent and -independent vasodilators. Blood flow was measured in the brachial and common femoral arteries of the experimental limbs with high-resolution Doppler ultrasound during the last minute of drug infusion. Blood flow was calculated as a product of mean blood velocity and diameter. In an attempt to assess systemic effects, venous occlusion plethysmography was used to measure blood flow in the contralateral forearm and leg during drug infusions. Intra-arterial pressure and heart rate were measured continuously throughout drug infusions. The volumes of the experimental forearm and leg were measured with water displacement techniques. A detailed description of all measurement techniques, calculations, and assumptions was published previously (19).

Experimental procedures. Each subject reported at 0730 to the Milton S. Hershey Medical Center's General Clinical Research Center in a postabsorptive state and abstained from caffeine. On arrival subjects were directed to a temperature-controlled room and placed in a supine position. Under aseptic conditions, polyethylene catheters were inserted proximally into the brachial (2 cm proximal to antecubital crease) and common femoral (1 cm proximal to bifurcation) arteries of the nondominant limb under local anesthesia.

Intra-arterial infusions of acetylcholine and substance P were used to assess endothelium-dependent vasodilation. Acetylcholine and substance P were infused at rates of 1, 4, and 16 µg·100 ml limb tissue^–1·min^–1 and 8, 31, and 125 pg·100 ml limb tissue^–1·min^–1, respectively. Sodium nitroprusside was infused intra-arterially at rates of 0.063, 0.25, and 1 µg·100 ml limb tissue^–1·min^–1 to assess endothelium-independent vasodilation. These drug infusion rates were chosen on the basis of pilot studies that revealed marked increases in limb blood flow without significant systemic effects. In addition, a vehicle (saline) was infused at the highest infusion rate of the dose-response curve to rule out an effect of infusion rate on blood flow measurements.

Each dose of endothelium-dependent and -independent vasodilators was infused for 5 min. A 20-min washout period was allowed between drug infusions. The sequence of drugs was randomized to avoid any ordering effect.

Drugs. Acetylcholine (Novartis Ophthalmics, Duluth, GA), substance P (Clinalfa, Läufelfingen, Switzerland), and sodium nitroprusside (Abbott Laboratories, Chicago, IL) were diluted in saline to the desired concentration before drug infusion. Both substance P and sodium nitroprusside were protected from light by wrapping aluminum and wire insulation around the syringe and connective tubing.

Statistical analysis. Data were expressed as percent increases in blood flow above baseline as a result of the differences (P < 0.05) in forearm and leg baseline blood flow values between younger and older sedentary subjects (Table 1). The percent increase in blood flow was calculated as (Q_Intervention – Q_Baseline)/Q_Baseline x 100, where Q_Intervention is the limb blood flow response during pharmacological intervention and Q_Baseline is the blood flow before the intervention. In addition, vascular conductance was also calculated and expressed as the percent increase in conductance above baseline to account for potential changes in mean arterial pressure. Vascular conductance was calculated as blood flow divided by mean arterial pressure and expressed in arbitrary units. Subject characteristics were compared by means of a Bonferroni-corrected unpaired Student's t-test. A repeated-measures one-way ANOVA and Bonferroni correction were applied to compare hemodynamic variables to baseline. A repeated-measures ANOVA model was applied to compare age differences in response to intra-arterial infusions of acetylcholine, substance P, and sodium nitroprusside. For multiple comparisons of simple effects at the different drug infusion rates, a Bonferroni correction was made. Statistical significance was set at P < 0.05. All data are presented as means ± SE.

	RESULTS

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Acetylcholine infusions. In the forearm, the absolute blood flow response to increasing doses of acetylcholine was not significantly (P > 0.17) different between subject groups (Table 2), whereas the absolute forearm vascular conductance response to increasing doses of acetylcholine was significantly (P = 0.04) smaller in older sedentary compared with younger sedentary subjects (Table 2). However, the relative increase in forearm blood flow and vascular conductance to increasing doses of acetylcholine was significantly (P < 0.05) smaller in older sedentary compared with younger sedentary subjects (Fig. 1). Post hoc analysis demonstrated that the reductions in older sedentary subject forearm blood flow and vascular conductance responses were attributed to a significant (P < 0.004) difference at 16 µg·100 ml limb tissue^–1·min^–1.

View larger version (21K): [in this window] [in a new window]   Fig. 1. Blood flow and conductance responses () to acetylcholine in forearm and leg of younger sedentary, older sedentary, and older trained subjects. Values are means ± SE and are expressed as % above baseline. *P < 0.05 vs. older sedentary.

View larger version (20K): [in this window] [in a new window]   Fig. 2. Blood flow and conductance responses to substance P in forearm and leg of younger sedentary, older sedentary, and older trained subjects. Values are means ± SE and are expressed as % above baseline.

View larger version (19K): [in this window] [in a new window]   Fig. 3. Blood flow and conductance responses to sodium nitroprusside (NTP) in forearm and leg of younger sedentary, older sedentary, and older trained subjects. Values are means ± SE and are expressed as % above baseline. *P < 0.05 vs. older sedentary; P < 0.05 vs. older trained.

	DISCUSSION

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The primary new findings of this study are as follows. 1) Acetylcholine- and sodium nitroprusside-induced dilation are blunted in the forearm of healthy older sedentary compared with younger sedentary men. 2) In contrast to the results for the forearm, acetylcholine- and sodium nitroprusside-induced dilation are preserved in the leg of healthy older sedentary compared with younger sedentary men. 3) Sodium nitroprusside-induced vasodilation remains blunted in the forearm of healthy older endurance-trained men but is preserved in the leg of these men. To our knowledge, this is the first study in humans to demonstrate that vascular dysfunction is not uniformly expressed throughout the peripheral vasculature with age.

Effects of age on limb vasodilator function. In the present study, acetylcholine-induced vasodilation was impaired in the forearm vasculature of older sedentary men. This observation is consistent with previous studies that demonstrated that aging is associated with reduced acetylcholine-induced vasodilation in the forearm vasculature (3, 4, 8, 23, 24). The present study is also in agreement with a previous study by DeSouza et al. (3) demonstrating preserved substance P-induced vasodilation in the forearm vasculature of older sedentary men. These heterogeneous effects of endothelium-dependent vasodilators in the forearm vasculature of older men confirm the previous work of DeSouza et al. (3), which suggested that age-associated endothelial dysfunction is agonist specific.

It is interesting that sodium nitroprusside-induced vasodilation was impaired in the forearm vasculature of older sedentary men in our study. Interestingly, a similar finding was reported by Taddei et al. (24) in one of the first studies examining the effects of age on endothelium-dependent and -independent vasodilation in the human forearm. However, since the initial observation by Taddei et al., the majority of studies have not reported impaired sodium nitroprusside-induced vasodilation in the forearm vasculature with age (3, 4, 8, 23). One potential explanation for these divergent sodium nitroprusside findings may be attributed to how the data were expressed. A significant reduction in sodium nitroprusside-induced vasodilation with age is observed in the current study and in past studies (24) when the data are expressed as a relative change in blood flow, whereas only a trend toward impaired sodium nitroprusside-induced vasodilation with age is reported when the data are expressed as absolute blood flows (3, 4, 23). We chose to express the current data as a percent increase in blood flow because previous evidence indicates that this is the preferred method of expression of these data when interventions cause either vasodilation or vasoconstriction and baseline blood flow values are significantly different (Table 1; Refs. 2, 21, 25, 27). When our results are expressed as absolute vascular conductance, the results also support the conclusion that age is associated with reduced sodium nitroprusside-induced vasodilation (Table 2). This observation suggests that our interpretation of an age-related decrease in sodium nitroprusside-induced dilation is not an artifact of the means by which our results are expressed. An alternative explanation for the discrepancies between the current and previous sodium nitroprusside data is that they result from different blood flow measurement techniques. Although there is a high correlation between venous occlusion plethysmography and Doppler ultrasound in the forearm vasculature of younger men (26), it is unknown whether this same correlation exists in the forearm vasculature of older men. It is plausible that alterations in the elastic components of the skin with increasing age (29) may impact the ability of venous occlusion plethysmography to detect small changes in blood flow. Therefore, the current findings of reduced sodium nitroprusside-induced vasodilation with age suggest that aging is associated with forearm vascular smooth muscle dysfunction that could, at the very least, partially account for the impaired acetylcholine-induced vasodilation observed in the older sedentary subjects. Future investigations will need to determine why substance P-induced vasodilation, which is believed to be more reliant on nitric oxide than acetylcholine in the forearm vasculature of young men (18), is preserved with age in the presence of impaired vascular smooth muscle function.

Unique to this investigation is the fact that we observed preserved acetylcholine-, substance P-, and sodium nitroprusside-induced vasodilation in the leg vasculature of the same older sedentary subjects in which forearm vascular dysfunction was observed. Interestingly, divergent effects of age on acetylcholine-induced vasodilation have been reported in the feed arteries of aged rats (16, 33). More specifically, acetylcholine-induced increases in vasodilation have been reported to be well maintained with age in feed arteries supplying the gastrocnemius muscle and impaired in feed arteries supplying the soleus muscle of rats. It was hypothesized that muscle fiber type differences between the gastrocnemius and soleus muscle may be the underlying mechanism for muscle-specific impairment of acetylcholine-induced vasodilation in aged rats. However, fiber type differences are most likely not the cause of preserved acetylcholine-induced vasodilation in the legs of our older sedentary subjects, because human skeletal muscle in both the forearm and the leg is made up of a mosaic of muscle fiber types (22). A more plausible explanation for our findings of preserved acetylcholine-induced vasodilation in the leg vasculature is that high blood flow requirements during bipedal locomotion expose the vasculature of the legs to relatively high shear stresses compared with those in the forearm vasculature. It is well documented in both in vitro and in vivo models that increased shear stress augments the expression of both endothelial nitric oxide synthase and cytosolic copper/zinc superoxide dismutase mRNA and protein (11, 17, 28, 32). It is therefore likely that preserved acetylcholine-induced vasodilation in the leg vasculature of our older sedentary subjects is directly linked to the greater bioavailability of nitric oxide in the leg compared with forearm vasculature. However, future investigations will need to elucidate the impact of bipedal locomotion on preserved leg vascular function with age.

Effects of chronic lower body endurance training on limb vasodilator function in older men. Regular aerobic exercise has been reported to preserve endothelium-dependent vasodilation in the forearm vasculature of older men (4, 23). Therefore, the current findings of preserved acetylcholine- and substance P-induced vasodilation in the forearm vasculature of older endurance-trained men are not surprising and support the notion that endurance training can ameliorate age-associated reductions in endothelial dysfunction.

Interestingly, sodium nitroprusside-induced vasodilation was significantly reduced in the forearm vasculature of our older endurance-trained subjects. These findings contradict previous reports of preserved sodium nitroprusside-induced vasodilation in the forearm vasculature of older athletes (4, 23). However, a nonsignificant reduction in sodium nitroprusside-induced vasodilation in the forearm vasculature of older athletes compared with younger sedentary subjects has been previously reported (23). It is unlikely that these inconsistencies between the current study and previous literature describing the effects of exercise on sodium nitroprusside-induced vasodilation in the forearm vasculature of older men can be attributed to differences in how the data were expressed and analyzed because the current findings indicate preserved sodium nitroprusside responses regardless of the means by which the data are expressed (absolute vs. relative change). As previously discussed, a more plausible explanation for discrepancies may be potential differences in the blood flow measurement techniques of Doppler ultrasound and venous occlusion plethysmography. The current study suggests that endurance-trained older men have decrements in forearm vascular smooth muscle function similar to those in sedentary older men. It is interesting to note that endothelium-dependent vasodilation is preserved in the forearm vasculature of these older endurance-trained men even in the presence of this vascular smooth muscle dysfunction. This finding suggests that alternative pathways to the nitric oxide-guanylyl cyclase signaling pathway are utilized in the vascular smooth muscle of endurance-trained older men during both acetylcholine- and substance P-induced vasodilation.

The current data also suggest that habitual lower body exercise in older men does not increase endothelium-dependent and -independent vasodilation in the leg vasculature above that observed in younger and older sedentary subjects. This observation is consistent with data suggesting that endothelium-dependent vasodilation is only enhanced in subjects with preexisting chronic vascular impairments (4, 7, 9, 13, 23). However, it is important to note that femoral artery diameters were significantly larger in the older endurance-trained subjects compared with the younger sedentary subjects (Table 1), suggesting that habitual leg exercise causes structural alterations to the vasculature in the absence of functional changes as assessed by intra-arterial infusions of endothelium-dependent and -independent vasodilators. These findings are consistent with previous studies that demonstrated greater femoral artery diameters in endurance-trained compared with sedentary men (5). More importantly, these data support the current theory that elevated shear stress during endurance training leads to vascular remodeling, as indicated by increased femoral diameter, which in turn normalizes shear stress (10). It is interesting to note that these structural alterations to the vasculature manifest themselves predominantly in the exercised limb, suggesting a limited systemic effect of leg exercise on vascular remodeling.

Limitations. A limitation of this study was that intra-arterial infusions of acetylcholine, substance P, and sodium nitroprusside in the leg caused significant reductions in mean arterial pressure at the highest rates of infusion. In most cases, these reductions in mean arterial pressure can be attributed to increased vasodilation within the leg vasculature and not systemic circulation of the drugs. This is supported by the fact that control limb blood flow (data not shown) was only significantly increased above baseline in older sedentary and endurance-trained men at the highest dose of substance P (125 pg·100 ml limb tissue^–1·min^–1). It is possible that reductions in mean arterial pressure led to increased sympathetic outflow through the unloading of the baroreceptors, as evidenced by increased heart rates (12 beats/min). If reflex sympathetic vasoconstriction was greater in the younger men, this may mask age differences in endothelium-dependent or -independent vasodilation in the leg. We believe this scenario is unlikely because in the younger subjects control limb blood flow (data not shown) was not significantly reduced during intra-arterial infusions of acetylcholine, substance P, or sodium nitroprusside in the leg.

Another limitation of this study was that systolic blood pressure, total cholesterol, and LDL cholesterol were elevated in both older sedentary and endurance-trained subjects. These three variables are associated with endothelial function (12) and may have contributed to the differences in forearm vascular function we attributed to age. However, it is important to note that all three of these variables are below clinically significant values.

A potential limitation of the current study was that a younger endurance-trained subject group was not included in this study. We chose not to incorporate this subject population into the current investigation based on the overwhelming data that suggest that habitual endurance training of healthy younger subjects has no significant effect on forearm endothelial and vascular smooth muscle function assessed by intra-arterial infusions of endothelium-dependent and -independent vasodilators (4, 7, 9, 10, 13, 23). Because of this mass of evidence we could not justify exposing normal young endurance-trained subjects to the risks of our experimental procedure. Although available evidence establishes that endurance training in normal subjects does not alter endothelial or vascular smooth muscle function, the absence of a young endurance-trained group in the current study focuses our interpretations on the effects of endurance training in the older subjects.

Clinical significance. The reported relationship between endothelial function in the forearm and coronary circulations (1) has led many investigators to speculate that vascular function is homogeneous throughout the peripheral vasculature (14, 30). However, our data strongly suggest that the impact of age and exercise on peripheral vascular function is not homogeneously distributed in the circulation. These findings emphasize the importance of future studies considering the nonhomogeneous effects in experimental design and acknowledging heterogeneous endothelial and vascular smooth muscle function in the description of clinically relevant populations in which forearm vascular dysfunction has previously been described. In addition, current and previous (3) findings of preserved substance P-induced vasodilation in the forearm vasculature of older men suggests that this endothelium-dependent vasodilator would not be ideal for the clinical assessment of endothelial function in older patients.

In conclusion, these results demonstrate that 1) acetylcholine- and sodium nitroprusside-induced vasodilation are attenuated in the forearm vasculature and preserved in the leg vasculature of older sedentary subjects and 2) sodium nitroprusside-induced vasodilation remains attenuated in the forearm vasculature of healthy older endurance-trained men but preserved in the leg vasculature of these men. In addition, these findings suggest that age and endurance training in older men have a heterogeneous impact on peripheral vasodilator function.

	GRANTS

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This work was supported by National Institutes of Health Grants RO1-AG-18246 (to D. N. Proctor), RO1-HL-68699 (to U. A. Leuenberger), MO1-RR-10732 (to the General Clinical Research Center), and T32-AG-00048 (to S. C. Newcomer).

	FOOTNOTES

 

Address for reprint requests and other correspondence: S. C. Newcomer, Univ. of Missouri, 1600 E. Rollins, E102 Vet Med Bldg., Columbia, MO 65211 (E-mail: newcomers{at}missouri.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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