(Hypertension. 1999;33:591-597.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Daily Aerobic Exercise Improves Reactive Hyperemia in Patients With Essential Hypertension
Correspondence to Yukihito Higashi, MD, PhD, Hiroshima University School of Medicine, First Department of Internal Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E mail yhigashi@mcai.med.hiroshima-u.ac.jp
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Abstract |
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Abstract—The effects of long-term aerobic exercise on endothelial function in patients with essential hypertension remain unclear. To determine whether endothelial function relating to forearm hemodynamics in these patients differs from normotensive subjects and whether endothelial function can be modified by continued physical exercise, we randomized patients with essential hypertension into a group that engaged in 30 minutes of brisk walking 5 to 7 times weekly for 12 weeks (n=20) or a group that underwent no activity modifications (control group, n=7). Forearm blood flow was measured using strain-gauge plethysmography during reactive hyperemia to test for endothelium-dependent vasodilation and after sublingual nitroglycerin administration to test endothelium-independent vasodilation. Forearm blood flow in hypertensive patients during reactive hyperemia was significantly less than that in normotensive subjects (n=17). Increases in forearm blood flow after nitroglycerin were similar between hypertensive and normotensive subjects. Exercise lowered mean blood pressure from 115.7±5.3 to 110.2±5.1 mm Hg (P<0.01) and forearm vascular resistance from 25.6±3.2 to 23.2±2.8 mm Hg/mL per minute per 100 mL tissue (P<0.01); no change occurred in controls. Basal forearm blood flow, body weight, and heart rate did not differ with exercise. After 12 weeks of exercise, maximal forearm blood flow response during reactive hyperemia increased significantly, from 38.4±4.6 to 47.1±4.9 mL/min per 100 mL tissue (P<0.05); this increase was not seen in controls. Changes in forearm blood flow after sublingual nitroglycerin administration were similar before and after 12 weeks of exercise. Intra-arterial infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine abolished the enhancement of reactive hyperemia induced by 12 weeks of exercise. These findings suggest that through increased release of nitric oxide, continued physical exercise alleviates impairment of reactive hyperemia in patients with essential hypertension.
Key Words: exercise, aerobic • hyperemia, reactive • nitroglycerin • nitric oxide • NG-monomethyl-L-arginine • endothelium • hypertension, essential
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Introduction |
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Regular aerobic exercise by patients with essential hypertension is associated with beneficial changes in blood pressure, lipoprotein profile, glucose metabolism, and neurohormonal release. Recent epidemiological studies have shown that physical exercise reduces cardiovascular morbidity and mortality in the general population, including individuals with hypertension.1 2 However, the mechanism underlying antihypertensive and antiatherogenic effects of exercise remains unclear.
Several lines of evidence indicate impairment of endothelium-dependent vasorelaxation in the vessels of the forearm3 4 and in the coronary5 and renal6 7 circulation of patients with essential hypertension. Recent experiments have demonstrated that continued exercise augmented vasodilation evoked by the endothelium-dependent vasodilator acetylcholine in dogs8 and rats,9 whereas in clinical studies, physical training enhanced endothelium-dependent vasodilation in the forearm in healthy subjects10 and patients with chronic heart failure.11 Whether impaired endothelium-dependent vasodilation is restored by aerobic exercise in patients with essential hypertension is, therefore, an important issue.
First, to determine whether endothelial dysfunction is demonstrable in the forearm circulation of patients with essential hypertension, we measured responses of forearm blood flow (FBF) to reactive hyperemia, an index of endothelium-dependent vasodilation, and sublingually administered nitroglycerin, an index of endothelium-independent vasodilation. Second, we evaluated effects of long-term regular aerobic exercise on endothelial function in patients with mild to moderate essential hypertension. To do this, we determined endothelium-dependent vasodilation at the beginning and end of a 12-week period of regular exercise.
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Methods |
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Study Protocol 1: Endothelial Function in Normotensive and Hypertensive Subjects
We studied 27 Japanese patients with mild to moderate essential hypertension (20 men and 7 women; mean age 52±9 years) and 17 normotensive subjects (12 men and 5 women; mean age 49±7 years). Hypertension was defined as a systolic blood pressure >160 mm Hg and/or a diastolic blood pressure >95 mm Hg measured in a sitting position on at least 3 different occasions in the outpatient clinic of Hiroshima University School of Medicine. Mild to moderate essential hypertension was defined as a systolic pressure between 140 and 170 mm Hg and a diastolic pressure between 90 and 110 mm Hg, with no objective signs of hypertensive end-organ disease. Patients with secondary forms of hypertension were excluded on the basis of a complete history and physical examination, radiologic and ultrasound examinations, and urinalysis. Plasma renin activity and plasma aldosterone and norepinephrine concentrations and serum creatinine, potassium, calcium, and free thyroxine concentrations were determined, as well as 24-hour urinary excretion of 17-hydroxycorticosteroids, 17-ketogenic steroids, and vanillylmandelic acid. No patient had a history of cardiovascular or cerebrovascular disease, diabetes mellitus, hypercholesterolemia, liver disease, or renal disease. All patients were essentially sedentary and did not exercise regularly. Normal blood pressure was defined as a systolic blood pressure <140 mm Hg and a diastolic blood pressure <80 mm Hg. The normotensive control subjects had no history of serious disease. An alcohol intake greater than ethanol 30 mL/d also was an exclusion criterion. The study protocol was approved by the ethics committee of the First Department of Internal Medicine of Hiroshima University. Informed consent for participation was obtained from all subjects.
Vasodilatory responses to reactive hyperemia and sublingual nitroglycerin were evaluated in normotensive control subjects and essential hypertensive patients. The study began at 8:30 AM. Subjects fasted the previous night for at least 12 hours and were kept in a supine position in a quiet, dark, air-conditioned room (constant temperature, 22°C to 25°C) throughout the study. After subjects rested for 30 minutes in the supine position, their basal FBF was measured as described below. Then, the effects of reactive hyperemia and sublingual nitroglycerin on FBF were measured. To obtain flow-mediated vasodilation, FBF was occluded by inflating a cuff over the left upper arm to a pressure of 280 mm Hg for 5 minutes. After release of ischemic cuff occlusion, FBF was measured for 3 minutes. A nitroglycerin tablet (0.3 mg, Nihonkayaku Co) was administered sublingually, and again FBF was measured for 3 minutes. These studies were carried out in random order, proceeding after FBF had returned to baseline; because in a preliminary study FBF returned to baseline within 10 minutes after release of cuff occlusion or the sublingual administration of nitroglycerin, the response to reactive hyperemia or sublingual nitroglycerin was followed by a 15-minute recovery period. Baseline fasting serum concentrations of total cholesterol, HDL cholesterol, TG, creatinine, insulin, glucose, electrolytes, plasma renin activity, and norepinephrine concentration were obtained after a 30-minute rest period.
Measurement of Forearm Blood Flow
FBF was measured by using a mercury-filled Silastic
strain-gauge plethysmograph (EC-5R, D.E. Hokanson, Inc) as previously
described.3 4 Briefly, the strain gauge was secured to the
upper part of the left arm, connected to the plethysmography device,
and supported above the level of the right atrium. One minute before
each measurement and throughout measurement of FBF, a wrist cuff was
inflated to a pressure of 50 mm Hg greater than the
systolic blood pressure to exclude the hand circulation from
the measurements. The upper arm cuff was inflated to 40 mm Hg for
7 seconds in each 15-second cycle to occlude venous outflow from the
arm, using a rapid cuff inflator (EC-20, D.E. Hokanson, Inc). The FBF
output signal was transmitted to a recorder (U-228, Advance Co).
FBF was expressed as milliliters per minute per 100 mL of forearm
tissue volume. Four plethysmographic measurements were averaged to
obtain FBF at baseline and during reactive hyperemia and
administration of sublingual nitroglycerin.
Study Protocol 2. Effect of Aerobic Exercise on
Endothelial Function in Patients With Essential
Hypertension
Among 27 patients, 20 (14 men and 6 women; mean age 53±10
years) were randomized to regular aerobic exercise. A 4-week run-in
period was followed by a 12-week physical exercise period. The other 7
patients (6 men and 1 woman; mean age 51±8 years) continued 12 weeks
of follow-up with no lifestyle modification.
During the run-in period, blood pressures were stable. Vasodilatory responses to reactive hyperemia and sublingual nitroglycerin were evaluated in a protocol identical to the study protocol 1 at the beginning and end of the 12-week follow-up period.
To examine the effect of exercise on release of nitric oxide (NO), we measured FBF during reactive hyperemia and sublingual administration of nitroglycerin in the presence of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; Sigma Chemical Co) in 9 of 20 hypertensive patients randomized to aerobic exercise. The responses of forearm vasculature to reactive hyperemia and sublingual nitroglycerin after the infusion of L-NMMA were evaluated at the beginning and end of the 12-week exercise period. A 23-gauge polyethylene catheter (Hakkow Co) was inserted into the left brachial artery under local anesthesia (1% lidocaine) for infusion of L-NMMA. After the subject maintained the supine position for 30 minutes, we measured basal FBF. Then, the effects of reactive hyperemia and sublingual nitroglycerin on forearm hemodynamics were measured. FBF was measured during the last 2 minutes of the infusion. Each study was initiated after FBF had returned to baseline. After a 15-minute recovery period was completed, L-NMMA was infused intra-arterially at a dose of 8 µmol/min for 5 minutes for basal FBF measurement. We performed reactive hyperemia and sublingual nitroglycerin after initiation of a 5-minute infusion of L-NMMA; FBF was measured during the last 2 minutes of infusion.
Aerobic Exercise
Subjects performed 30 minutes of brisk walking 5 to 7 times per
week for 12 weeks. A 5-minute warm-up period was followed by 30 minutes
of exercise and a 5-minute cool-down period. We explained the method of
aerobic exercise in detail (exercise type, frequency, duration, and
intensity) and demonstrated brisk walking for the subjects.
Participants were asked to record exercise performed but otherwise
maintain their original behavioral and dietary habits, especially their
intake of sodium, potassium, calories, and alcohol. To monitor
compliance, we checked the exercise performance sheet, measured
24-hour urinary excretion of sodium and potassium, and interviewed all
subjects every 4 weeks. In a preliminary study, the intensity of brisk
walking ordered was equivalent to 52±6% of maximum oxygen consumption
(n=5).
Analytical Methods
Samples of venous blood were placed in tubes containing sodium
EDTA (1 mg/mL) and in polystyrene tubes. The EDTA-containing tubes were
chilled promptly in an ice bath preceding immediate separation of
plasma by centrifugation at 3100 rpm at 4°C for 10
minutes; serum was separated at 1000 rpm at room temperature for 10
minutes. Samples were stored at -80°C until assayed. Routine
chemical methods were used to determine serum concentrations of total
cholesterol, HDL cholesterol, TG,
creatinine, glucose, and electrolytes. Serum concentration
of low-density lipoprotein (LDL) was determined using Friedewald's
method.12 PRA (Gamma Coat PRA, Baxter Travenol Co)
was assayed by radioimmunoassay. The plasma concentration of
norepinephrine was measured by high-performance
liquid chromatography.
Statistical Analysis
Results are presented as the mean±SD. Values of
P<0.05 were considered significant. The Mann-Whitney
U test was used to evaluate differences between hypertensive
subjects and normotensives concerning parameters at
baseline. Comparisons of parameters before and after
exercise were performed with adjusted means by ANCOVA using baseline
data as covariates. Comparisons of time course curves of
parameters during reactive hyperemia were
analyzed by 2-way ANOVA for repeated measures. The data were
processed using the software packages StatView IV (Brainpower) or Super
ANOVA (Abacus Concepts).
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Results |
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Study Protocol 1. Effects of Reactive Hyperemia and Sublingual Nitroglycerin on Forearm Blood Flow in Patients With Essential Hypertension and Normotensive Subjects
Baseline clinical characteristics in the 27 hypertensive patients before exercise and the 17 normotensive control subjects are summarized in Table 1
.
Systolic and diastolic blood pressures as well as
forearm vascular resistance (FVR) were significantly higher in
hypertensive patients than in normotensive subjects. Other
parameters were similar in the 2 groups. The FBF of the
hypertensive patients during reactive hyperemia, an index of
endothelium-dependent vasorelaxation, was significantly
less than in normotensive subjects (Figure 1A), whereas the increase in FBF after
sublingually administered nitroglycerin, an index of
endothelium-independent vasodilation, was similar in
the 2 groups (Figure 1B).
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Study Protocol 2. Effects of Aerobic Exercise on Baseline
Clinical Characteristics
The baseline clinical characteristics in the 20 hypertensive
patients undergoing the aerobic exercise program (exercise group) and
the 7 hypertensive patients with no change in activities (control
group) are summarized in Table 2, both
before and after the 12-week period. The baseline values for all
parameters were similar in the 2 groups. A 12-week period
of exercise significantly decreased systolic and
diastolic blood pressures, the concentration of LDL
cholesterol, and FVR, and increased significantly the
concentration of HDL cholesterol, while no changes occurred
in the control group. Other parameters, such as basal FBF
and blood glucose, remained unchanged after 12 weeks in both
groups.
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Effects of Aerobic Exercise on Endothelial Function
At the baseline measurement, reactive hyperemia was
similar in the exercise and control groups. After 12 weeks of exercise,
the maximal FBF response in reactive hyperemia increased
significantly in the exercise group, from 38.4±4.6 to 47.1±4.9 mL/min
per 100 mL tissue (P<0.05) (Figure 2A), but no change was detected in the
control group. Changes in FBF after sublingual
nitroglycerin administration were similar before and
after the 12-week interval in both groups (Figure 2B).
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The increase in maximal FBF with reactive hyperemia after 12
weeks of exercise significantly correlated with the decrease in LDL
cholesterol in the exercise group (r=-0.46,
P<0.05); (Figure 3). No
significant correlation was seen between maximal FB with reactive
hyperemia and changes in blood pressure or other
parameters.
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Effects of L-NMMA on the Forearm Vascular Response to Reactive
Hyperemia and Nitroglycerin Before and After
the 12-Week Exercise Period
The FBF response was evaluated both in the absence and
presence of L-NMMA. In 9 of 20 hypertensive patients performing aerobic
exercise, reactive hyperemia had increased significantly after
12 weeks (Figure 4A).
Intra- arterial infusion of the NO synthase
inhibitor L-NMMA significantly decreased basal FBF, from
4.8±1.1 to 3.0±0.6 mL/min per 100 mL tissue (P<0.05). The
change in basal forearm vascular responses to L-NMMA was similar at the
0- and 12-week time points. No significant changes in
arterial blood pressure or heart rate were detected during
infusion of L-NMMA at 0 and 12 weeks.
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Intra-arterial infusion of L-NMMA decreased the response to
reactive hyperemia at both time points and abolished
enhancement of reactive hyperemia induced by 12 weeks of
exercise (Figure 4B
).
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Discussion |
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In the present study, lifestyle characteristics, including body weight control, alcohol intake (<30 mL per day of ethanol), sodium intake, potassium intake, and cigarette smoking were similar in both exercise and control groups throughout the study, suggesting that increased regular physical activity enhanced endothelium-dependent vasodilation, reduced blood pressure, and improved the lipoprotein profile.
Long-term aerobic exercise in hypertensive patients improved reactive hyperemia, an index of endothelium-dependent vasorelaxation, through an increase in release of NO. Reactive hyperemia in peripheral arteries has been shown to be mediated largely by release of NO.13 In the present study, L-NMMA, an inhibitor of NO synthase, substantially inhibited the enhanced FBF response to reactive hyperemia by exercise, indicating that the exercise-improved endothelium-dependent vasodilation probably resulted from augmented release of NO.
Recently we reported that patients with essential hypertension demonstrate impaired endothelium-dependent renal vascular relaxation.6 7 Reactive hyperemia in forearm arteries also was significantly blunted in patients with essential hypertension versus normotensive control subjects in the present study. Our findings are consistent with results of previous studies showing that endothelium-dependent forearm vasodilation in response to endothelium-dependent vasodilator acetylcholine is reduced in hypertensive patients.3 4 These findings suggest that endothelial dysfunction is important in the increased vascular resistance observed in hypertensive patients.
Long-term aerobic exercise improved endothelium-dependent vasodilation with reactive hyperemia but not endothelium-independent vasodilation in response to nitroglycerin. These findings suggest that exercise restored normal function mainly in vascular endothelium, not vascular smooth muscle. Although the present study did not determine the mechanism by which improved endothelial function resulted from regular aerobic exercise, some possibilities might be considered. First, aerobic exercise increases shear stress, which triggers release of NO. Repetitive increases in blood flow or shear stress with exercise may enhance NO release in the vascular endothelium; indeed, physiological levels of shear stress can induce NO release from cultured endothelial cells.14 Sessa et al recently demonstrated that increasing endothelial shear stress by continued exercise may increase NO production and levels of coding for mRNA NO synthase, which may contribute to beneficial effects of exercise in the epicardial coronary arteries of dogs.15 Increased blood flow and shear stress also have been shown to have beneficial effects on vascular structure and reactivity.16
A second possible mechanism is based on observations that oxidized LDL interferes with formation of NO17 and even directly inactivates NO.18 Several lines of evidence have shown that cholesterol-lowering and antioxidant therapy can restore impaired endothelium-dependent vasodilation in forearm arteries.19 Although we did not directly measure oxidized LDL levels in the present study, the increase in FBF response to reactive hyperemia correlated with a decrease in LDL cholesterol after 12 weeks of exercise. The reduction in LDL may result in less suppression of NO formation by oxidized LDL.
Finally, several experimental findings suggest that endothelial function is impaired in relation to the severity of blood pressure elevation.20 Thus, reduction of blood pressure per se may improve endothelial function. However, we found no significant correlation between reduction in blood pressure by exercise and increase in FBF response to reactive hyperemia. Previous studies also have concluded that decrease in blood pressures do not directly improve endothelial function in the brachial artery and small arteries of patients with essential hypertension.21 22 We therefore doubt this last possibility.
Reactive hyperemia is thought to have components of endothelium dependence and independence and to be multifactorial. In the present study, NO synthase inhibitor L-NMMA abolished reactive hyperemia by approximately 40% before exercise. Reactive hyperemia was reduced by adenosine receptor antagonist theophylline23 but not cyclooxygenase inhibitor aspirin.24 Endothelium-derived hyperpolarizing factor may also contribute to reactive hyperemia. Because the enhanced response of the forearm vasculature to reactive hyperemia by exercise in the exercising group was inhibited substantially by L-NMMA, we consider the augmentation of NO release to be involved in exercise-enhanced reactive hyperemia. It is reported that this endothelium-dependent vasodilation evoked by intra-arterial infusion of vasoactive agents has been substituted by vascular responses to reactive hyperemia, a noninvasive method.25 26 The use of agonists such as acetylcholine or methacholine to stimulate NO release would allow us to draw more specific conclusions concerning the role of the basal and stimulated release of NO by exercise in the forearm circulation.
In conclusion, moderately intense regular aerobic physical activity prevented impairment of reactive hyperemia in patients with essential hypertension, most likely because of an exercise-induced increase in production of NO. Aerobic exercise should be recommended to aid in prevention of hypertension, to reduce blood pressure in established hypertension, and to reserve endothelial dysfunction related to hypertension.
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Acknowledgments |
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This study was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture of Japan and Japan Heart Foundation grant for research on hypertension and vascular metabolism and a grant from Research Foundation for Community Medicine. The authors thank Dr Hiroaki Ikeda for the preparation of the L-NMMA, Dr Yoriaki Matsuishi for the recruitment of hypertensive patients, and Yuko Omura for her secretarial assistance.
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Footnotes |
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First Department of Internal Medicine (Y.H., S.S., N.S., K.N., T.U., A.Y., S.K., H.M., G.K.) and the Department of Clinical Laboratory Medicine (T.O.), Hiroshima University School of Medicine, Hiroshima, Japan.
Received September 15, 1998; first decision October 26, 1998; accepted November 5, 1998.
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