The recent report by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommended aerobic exercise as a lifestyle modification to manage hypertension and reduce the risk of cardiovascular disease (6). Although much is known about the effects of aerobic exercise training on cardiovascular hemodynamics and BP (14), to date little is known of its effects on renal hemodynamics. Individuals with essential hypertension are often characterized by elevated renal vascular resistance, decreased renal plasma flow (RPF), normal glomerular filtrate rate (GFR), and an increase in filtration fraction (FF) (9,24). These abnormalities in renal hemodynamics not only affect fluid volumes (16), but also affect an individual's sensitivity to dietary sodium (Na+) (3), both of which can lead to an increase in blood pressure (BP) (12).
It has been demonstrated in both normotensive and hypertensive individuals that acute bouts of aerobic exercise decrease both GFR and RPF (5,23,25). Kohno et al. (18) examined the effects of a short-term (3 wk) hospital-based program of aerobic exercise combined with caloric and Na+ restriction on BP, GFR, and RPF in a group of mild to moderate middle-aged hypertensive persons. Although this short-term program lowered BP, it did not significantly alter GFR or RPF (18). Because of the design of this study (18), however, it is not possible to determine whether the decline in BP was caused by the aerobic exercise training program or the diet intervention of caloric and Na+ restriction. In addition, it is possible that a 3-wk program of aerobic exercise is not long enough to bring about any significant changes in renal hemodynamics. Also, older hypertensive persons may have a different response to the effects of aerobic exercise training on BP and renal hemodynamics than those who are middle-aged and hypertensive.
We hypothesized, therefore, that BP-lowering effects of aerobic exercise training in older hypertensive individuals are brought about by improvements in renal hemodynamics as well as in Na+ handling. To test this hypothesis, we evaluated renal function on high and low Na+ diets before and after 6 months of aerobic exercise training in older hypertensive persons.
MATERIALS AND METHODS
A total of 31 subjects (12 men and 19 women) with mild hypertension were recruited through newspaper advertisement, from the University of Michigan Turner Geriatric Clinic, and from the human research participant core of the University of Michigan Geriatrics Center. All subjects were community dwelling and in good health apart from their hypertension. Subjects were screened before participation with a medical history and physical examination, a complete blood count, routine blood chemistries, and a urinalysis. Individuals were excluded from the study if they had clinically significant concomitant medical illness such as cardiac, renal (serum creatinine >135 mmol·L−1), hepatic, or gastrointestinal disease, or if they required medications that might affect glucose metabolism, BP, or renal function. Also excluded were individuals with a recent history of smoking or drug or alcohol abuse, or clinically relevant mental disorders. Absence of diabetes mellitus was confirmed in all subjects by a 2-h 75-g oral glucose tolerance test (1). The presence of hypertension was defined in subjects who were receiving antihypertensive treatment or had a seated systolic BP ≥ 140 mm Hg or a seated diastolic BP ≥ 90 mm Hg (6).
Following a screening visit to determine their eligibility for participation as described above, subjects signed an informed consent form approved by the University of Michigan institutional review board. Hypertensive subjects who were being treated with antihypertensive medications were tapered off their medications and were studied following a 4-wk period during which no antihypertensive medications were taken. Throughout the duration of the study, subjects remained off their antihypertensive medication. Subjects were randomized in a double-blind, crossover design to begin either a 20 or 200 mmol·L−1·d−1 Na+ diet, which they consumed over an 8-d period. All meals during the 8-d Na+ diet period were prepared by the general clinical research center metabolic kitchen at the University of Michigan. The two diets were identical in composition except for Na+ content, and consisted of 50-55% of calories as carbohydrate, 30-35% as fat, 15-20% as protein, and 300-350 mg·d−1 of cholesterol. After completion of the first diet, the subjects consumed their own diet for a 1-wk washout period and then were switched to the alternative Na+ diet, which they consumed for a second 8-d period. Compliance with the diet was monitored by 24-h urine collections for Na+.
Determination of Renal Hemodynamics
On the eight day of each Na+ diet, BP measurements were made while the subject rested in the seated position, following a 20-min resting period. Mean arterial blood pressure (MABP) was continuously monitored for a 30-min period using Ohmeda 2300 Finapress BP monitor. Following the determination of seated BP, GFR (99mTc-DTPA) and RPF (131I-hippuran serum disappearance) were measured. GFR and RPF were measured after an overnight fast,as follows. One hour before the determination of GFR and RPF, subjects consumed an oral water load of 10-15 mL·kg−1 body weight to establish a brisk urine flow. An intravenous bolus injection of 100 μCi of 99mTc-DTPA and 60 μCi of 131I-hippuran was then given and, after 60 min, the patient's bladder was emptied, blood samples were drawn, and three timed sequential 1-h urine collections were obtained, after which additional blood samples were drawn (17). The 99mTc-DTPA and 131I-hippuran activity in the samples was determined by liquid scintillation counting. Urinary clearances of 99mTc-DTPA and 131I-hippuran were calculated for each 1-h collection period as urine activity times urine flow rate divided by average plasma activity. Average plasma activity was calculated as the mean of the three 1-h collection values. The GFR and the RPF were expressed as the average of the three 1-h collection values. RPF was determined by measuring the131I-hippuran disappearance from the serum (26). Filtration fraction was calculated by dividing GFR by RPF. The creatinine and Na+ clearance was determined by multiplying the concentration in urine by the quantity in a 24-h urine sample and dividing product by the plasma concentration (11). All clearance values are expressed per 1.73 m2 of surface area. Fractional excretion of Na+ was calculated as the clearance of Na+ divided by the clearance of creatinine (18).
Determination of Plasma and Urinary Values
Before the determination of renal hemodynamics on each Na+ diet, blood samples were collected into chilled glass tubes containing heparin sodium, stored on ice, and separated immediately after each study. Plasma and urine samples for aldosterone, renin, creatinine, urea, potassium, protein, chloride, and sodium were measured in the University of Michigan Medical Center Laboratory. Blood samples for norepinephrine were collected into chilled tubes containing EGTA and reduced glutathione, stored on ice, and separated immediately after each study. Plasma norepinephrine was quantified by a single-isotope radioenzymatic assay (10).
Determination of Body Composition
Body composition was determined by dual x-ray absorptiometry (DXA, Model DPX-IQ Bone Densitometer, Lunar Radiation Corporation, Madison, WI). Body mass index (BMI, kg·m−2) was determined by the subject's weight (kg) divided by the square of his or her height (m). The waist-to-hip circumference ratio (WHR) was calculated as the ratio of the minimal circumference of the abdomen to the circumference of the buttocks at the maximal gluteal protuberance.
Determination of Cardiovascular Fitness
A maximal exercise test was performed at baseline, after 3 months of exercise training, and again after 6 months of exercise training. The initial treadmill speed was set to elicit 75% of each subject's maximal oxygen uptake (V̇O2max) measured during the screening treadmill test. The treadmill elevation was increased every 2 min until the subject was exhausted and could not continue. Oxygen uptake (V̇O2) and carbon dioxide production (V̇CO2) were measured continuously, and BP and a 12-lead electrocardiogram were recorded every 3 min during the test. A true V̇O2max was considered to be attained if two of the following three criteria were achieved: (a) respiratory exchange ratio > 1.10, (b) maximal heart rate > 90% of age-predicted maximum (220-age), and (c) a plateau in V̇O2 (change in V̇O2 < 0.2 L·min−1 with increasing workload).
Aerobic Exercise Training Program
Exercise training consisted of three sessions per week of supervised treadmill walking. The intensity and duration of exercise was progressively increased so that subjects completed 40 min per session at 75-85% of their heart rate reserve for the last 3 months of training. No one dropped out during the course of this study, and compliance with the training program in all subjects was approximately 91% (range 85-100%).
To determine the effects of aerobic exercise training on BP, three measurements were made 1 wk apart by auscultation using the appropriate cuff size. All measurements were made while subjects consumed their normal diet. Subjects had been seated comfortably for more than 15 min with the cuffed arm supported at heart level before measurements were taken. The mean of these three BP measurements is reported.
Data were analyzed using Statview (Abacus Concepts, Inc., Berkeley, CA). An alpha level of 0.05 was accepted for statistical significance. Sample sizes were chosen to provide statistical power of 80%. Sample size values were determined via power analysis of data from previous work and pilot studies (nQuery Advisor 3.0, Statistical Solutions, Saugus, MA). Comparisons between pre- and posttraining characteristics of subjects were made using an ANOVA. A two-way ANOVA with exercise training (pre- and posttraining) as one variable and dietary Na+ (low Na+ and high Na+) as the other variable was used to examine within- and between-group differences.
Physical Characteristics of Subjects
Subject characteristics are presented in Table 1. A total of 31 older (62.9 ± 1.3 yr), moderately overweight (BMI: 28.9 ± 0.8 kg·m−2) subjects with essential hypertension were studied. The 6-month program of aerobic exercise training did not significantly alter body weight (P = 0.781), percent fat (P = 0.491), or WHR (P = 0.786). As expected, the 6-month program of aerobic exercise training did result in a significant (P = 0.017) increase in V̇O2max.
Although the Na+ high versus low diet did not result in a change in diastolic BP (P = 0.427), a significant increase was seen in both systolic BP (P = 0.019) and MABP (P=0.005) (Fig. 1). Following the 6-month aerobic exercise training program, a significant decrease was noted in resting systolic BP (P = 0.037) and MABP (P = 0.021) when subjects consumed their normal diet (Table 1). No significant change was seen in the BP response to alterations in dietary Na+ following the aerobic exercise training program (Fig. 1).
At baseline, no significant effect was seen of Na+ loading on RPF (P = 0.918), GRF (P = 0.468), or FF (P = 0.605) (Fig. 2). No significant effect was found of Na+ loading on creatinine clearance (Table 2). As expected, the fractional excretion of Na+ was significantly (P < 0.0001) increased with dietary Na+ loading (Table 2). Following the 6-month aerobic exercise program, no significant (P < 0.05) change was seen in RPF (208.8 ± 12.2 vs 197.1 ± 13.1 mL·min−1·1.73 m−2), GFR (68.9 ± 3.6 vs 69.0 ± 3.9mL·min−1·1.73 m−2), or filtration fraction (35.3 ± 2.3 vs 37.1 ± 2.4%) on the low Na+ diet or RPF (210.6 ± 12.8 vs 212.1 ± 11.7 mL·min−1•1.73 m−2), GFR (72.9 ± 4.1 vs 77.3 ± 4.3 mL•min−1·1.73 m−2), or filtration fraction (37.1 ± 2.5 vs 37.7 ± 3.0%) on the high Na+ diet (Fig. 2). In addition, no significant changes were found in either fractional excretion of Na+ or creatinine clearance with aerobic exercise training or the response in these variables to dietary Na+ loading (Table 2).
Plasma and Urine Values
As expected, Na+ loading resulted in an increase in urinary sodium (P < 0.0001) and urinary volume (P = 0.037) (Table 2). Urine levels of creatinine (P = 0.873) and protein (P = 0.104) were unchanged with the increase in dietary Na+ (Table 2). At baseline, Na+ loading also resulted in a significant decrease in serum levels of urea (P = 0.001) and norepinephrine (P = 0.047) and an increase in serum chloride (P < 0.0001) (Table 2). Plasma levels of both renin and aldosterone significantly (P < 0.0001) decreased with Na+ loading; however, no change was seen in the aldosterone:renin ratio (Fig. 3). No significant change occurred in serum potassium (P = 0.105), Na+ (P = 0.071), or creatinine (0.246) because of Na+ loading (Table 2). Little changes were seen in plasma or urine variables in response to 6 months of aerobic exercise training, except in plasma chloride and aldosterone levels. A significant (P = 0.004) increase occurred in plasma chloride and a significant decrease in norepinephrine (P = 0.038) levels following aerobic exercise training (Table 2). Although plasma aldosterone levels significantly (P = 0.042) decreased with aerobic exercise training, no change was seen in the aldosterone:renin ratio (Fig. 3).
The results of the present study did not support our original hypothesis that reduction in BP observed with aerobic exercise training would correspond to alterations in renal hemodynamics. Although we observed significant reductions in resting BP following the 6 months of aerobic exercise training, we did not observe any significant alterations in GFR, RPF, and FF on either high or low Na+ diets. To the best of our knowledge, this is the first study to examine the effects of aerobic exercise program on renal hemodynamics in older hypertensive persons. These results are similar to those of Kohno et al. (18), who examined the effects of a short-term (3 wk) hospital program of aerobic exercise training combined with Na+ and caloric restriction on GFR or RPF in a group of middle-aged mild to moderate hypertensive persons. The results of the present study combined with those of Kohno et al. (18) suggest that the BP-lowering effects of aerobic exercise training are not caused by a change in renal hemodynamics.
In addition to the significant decrease in resting BP in the present study, a significant reduction occurred in plasma norepinephrine levels on both the low and high Na+ diet. It has been previously reported that aerobic exercise training in normotensive as well as hypertensive individuals results in a reduction in plasma norepinephrine levels (15,21,22). Meredith et al. (21) examined the effects of 1 month of aerobic exercise training on BP as well as cardiac and renal norepinephrine kinetics in middle-aged normotensive persons. This 1-month aerobic exercise training program resulted in a significant decrease in BP as well as a significant decrease in renal but not cardiac norepinephrine spillover. The decrease in renal norepinephrine spillover resulted in a decrease in plasma norepinephrine levels as well as an increase in renal vascular conductance (21). Changes in renal vascular conductance can influence both GFR and RPF, as well as influence tubular Na+ and water reabsorption (8). Meredith et al. (21) hypothesized that this reduction in renal norepinephrine kinetics may alter RPF and GFR, resulting in a reduction in BP. Although we did observe a significant reduction in resting BP and plasma norepinephrine levels, we did not observe a corresponding change in GFR, RPF, or FF on either the high or low Na+ diets.
In the present study, a significant reduction was noted in plasma aldosterone, but no change in plasma renin following aerobic exercise training. To date, studies examining the effect of aerobic exercise training on plasma aldosterone and renin levels are somewhat mixed. Carroll et al. (4) reported that 6 months of aerobic exercise training in elderly men and women had no effect on plasma aldosterone levels. Similarly, Hespel et al. (15) reported that 4 months of aerobic exercise training did not significantly alter plasma renin or aldosterone levels. Braith et al. (2) reported that 4 months of aerobic exercise training in patients with heart failure significantly reduced plasma aldosterone levels. Hagberg et al. (13) observed that 9 months of aerobic exercise training in older adults did not change plasma renin activity. On the other hand, Kohno et al. (18) reported a significant reduction in plasma renin, but not plasma aldosterone, with 3 wk of aerobic exercise training. Some of the differences between our results and those of others may lie in the fact that we examined plasma aldosterone and renin on both high and low Na+ diets, whereas the other studies (2,4,13,15,18) examined changes in either plasma aldosterone or renin while subjects consumed their own diet. The fall in plasma aldosterone concentration following the aerobic exercise training program may be caused by an adaptation of the adrenal gland to adrenocorticotrophin stimulation (15). It has been shown that adrenocorticotrophin-induced release of corticosterone by the adrenal gland is reduced in aerobic exercise-trained compared with sedentary rats (27). It should be pointed out that, although in aldosterone levels decreased with aerobic exercise training, when we examined the aldosterone:renin ratio no significant change resulted from dietary Na+ or aerobic exercise training. It has been suggested that the aldosterone: renin ratio is an index of renin-angiotensin-aldosterone system dysfunction and may be responsible for the development of hypertension (20). Lim et al. (19) reported that the aldosterone:renin ratio was a predictor of exercising BP in middle-aged hypertensive persons. In the present study, it appears that the change in aldosterone was balanced by a change in renin to maintain a constant aldosterone:renin ratio.
Although we did not find any significant change in MABP responses to the change in dietary Na+, we did observe a significant reduction in resting BP following 6 months of aerobic exercise training when the subjects consumed their normal diet. This is similar to data that we and others have previously reported in this population (4,7,13,18). It is important to remember that the resting BP was the average of three readings on three separate days on each participant's normal diet. Although BP measured on either the high or low Na+ diet was the average of multiple readings, it was measured on a single day. It may be that BP during the consumption of an individual's normal diet is reduced with aerobic exercise training; however, the BP responses to alterations in dietary Na+ remain unchanged.
One might argue that the sample size in this study was too small to detect significant changes in renal hemodynamics with this 6-month aerobic exercise training program. Using the changes observed in RPF and GFR in this study, however, it would take a sample of approximately 700 subjects to detect significant changes in these measures of renal hemodynamics. In addition, these changes in RPF (6.6 mL·min−1·1.73 m−2) and GFR (2.2mL·min−1·1.73 m−2) would be very small and have little if any clinical significance. In conclusion, although our 6-month aerobic exercise training program resulted in a significant reduction in BP, we did not observe any significant alteration in renal hemodynamics in this population of older hypertensive persons. These data demonstrate that the exercise-induced reduction in BP observed in older hypertensive persons is not caused by a change in renal hemodynamics or Na+ handling.9
We thank all the subjects who volunteered, the nursing and dietary staffs at the University of Michigan General Clinical Research Center for their assistance with the research studies, and Marla Smith for her technical assistance.
Supported by National Institutes of Health Research Scientist Development Award in Aging KO1 AG0072301 (DRD), Department of Veterans Affairs Medical Research Service (MAS) and Geriatric Research, Education and Clinical Center (DRD, MAS) at Ann Arbor, University of Michigan, Claude D. Pepper Older Americans Independence Center (AG-08808), University of Michigan Clinical Research Center (RR-00042).
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Keywords:©2006The American College of Sports Medicine
AGING; BLOOD PRESSURE; GLOMERULAR FILTRATION RATE; RENAL PLASMA FLOW