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Effects of antihypertensive therapy on cardiovascular response to exercise
Effects of Antihypertensive Therapy on Cardiovascular Response to Exercise
WON R. LEE, MO, FACC LAY M. FOX, MD, FACC LAWRENCE M. SLOTKOFF, MD Washington, D. C.
The effects of alpha methyldopa and hydrochlorothiazide therapy on exercise induced changes in arterial pressure, heart rate, rate-pressure product and total duration of exercise were evaluated with graded treadmill exercise. Although both agents were equally effective In reducing resting arterial pressure, alpha methyldopa appeared to provide slower build-up, a lower celling and more rapld recovery of arterial pressure In response to exercise stress than did hydrochlorothiazide. Alpha methyldopa signlflcantly reduced the degree of rise of the rate-pressure product (an Index of myocardlal oxygen consumption) during the exercise and recovery phases, whereas hydrochlorothlazlde failed to&doso. The total duration of exercise (an index of work capacity) was unchanged with either hydrochlorothlazlde or alpha methykfopa. Therapy with alpha methyldopa presumably reduced myocardlal oxygen demand wlthout reducing work capacity.
The exaggerated arterial pressure response to exercise in untreated hypertensive patients has been well documented.14 However, the effects of antihypertensive therapy on this increased pressure response to exercise have not been clearly characterized. Cardiovascular effects of antihypertensive therapy during exercise may differ from one agent to another depending on the mode of antihypertensive action even if they are all equally effective on resting arterial pressure. In our study, hydrochlorothiazide and alpha methyldopa were evaluated individually and in series, in random fashion, with each subject serving as his own control. Multistage treadmill testing was used for exercise stress. Exercise-induced changes in arterial pressure, heart rate, rate-pressure product and total duration of exercise as an index of work capacity were assessed before and during antihypertensive therapy. Methods
From the Georgetown Medical Division, District of Columbia General Hospital, Washington, D.C. Manuscript received December 17, 1978; revised manuscript received March 5. 1979, accepted March 7, 1979 Address for reprints: Won R. Lee, MD, District of Columbia General Hospital, 19th 8 Massachusetts Avenue, Southeast, Washington, DC. 20003.
Patients: Fifteen patients with hypertension were enrolled in our study and were seen at our Hypertension Clinic. Hypertension was defined as a systolic pressure of 150 mm Hg or more or a diastolic pressure of 90 mm Hg or more by the fifth Korotkoff sound, or both, on three occasions while sitting. Twelve of the 15 patients were men, all were black, and their ages ranged from 26 to49 years (mean 40.2). None of the patients had taken any antihypertensive medication for the previous several months. After the initial evaluation, all patients were considered to have essential hypertension. All patients were asymptomatic, without clinically detectable coronary heart disease, congestive heart failure, stroke, significant obesity or diabetes mellitus. Three patients had early grade JI and five patients had grade I retinal change as assessed with the KeithWagener-Barker criteria. Five patients had left ventricular hypertrophy as judged from electrocardiographic voltage criteria only and none had S-T or T wave abnormalities at rest. Protocol: After informed consent was obtained from each patient, multistage treadmill testing according to the Bruce protocol5 was performed to a level of
August 1979
The American Journal of CARDlOLOGY
Volume 44
325
ANTIHYPERTENSIVETHERAPY AND EXERCISE-LEE ET AL
“self-determined
maximal effort.” A bipolar CBS electrocar-
significantly reduced the rise in systolic pressure during the build-up (P
diogram was monitored and recorded for heart rate and assessment of electrocardiographic changes. Arterial pressure
was measured with a clinical sphygmomanometer utilizing the fifth Korotkoff sound as diastolic pressure. Both the electrocardiogram and arterial pressure were recorded while the patient sat at rest before exercise, at the end of stage I (3 minutes), at the subjectively determined point of maximal exercise and at 1,3 and 5 minutes after the termination of exercise. After undergoing treadmill exercise testing before antihypertensive therapy, the patients were randomly assigned to therapy with hydrochlorothiazide or alpha methyldopa. Antihypertensive therapy with each drug was continued for 4 weeks before the exercise test was repeated. Hydrochlorothiazide (50 mg once or twice a day) and alpha methyldopa (1.0 to 2.0 g in divided doses) were administered, the dosage depending on clinical responses. Each patient was then assigned to the opposite regimen for the next 4 weeks, and treadmill testing was repeated. Exercise-induced changes during antihypertensive therapy were assessed with Student’s t test. Results Cardiovascular responses during the study are summarized in Table 1 and Figures 1 to 3. The number of patients studied with each regimen are shown in Table I. Systolic pressure: Alpha methyldopa and hydrochlorothiazide reduced preexercise systolic pressure (P
TABLE I Exercise-Induced Changes in Cardiovascular Measurements Before and During Antihypertensive Therapy Total
Exercise Stage I (3 min)
Subjective Maximum
85 4 11.3 155 f 12.3 132 f 8.1 104 17.7
127 f 13.6 194 l 24.9 246 108 & f 46.3 12.5
161 f 17.4 218 f 24.4 349 111 f 40.7 13.2
88 f 134 f
11.5 16.2’
126 f18.3 184 f 17.9
158 f 19.3 207 f 33.7
116 93 f 7.6’ 14.3’
232 103 f 35.3 7.8
328 101 f 66.4 10.0*
83 130 90 107
124 173 102 214
155 f 18.4 ;(I; = ;2..’
Before Exercise
Recovery 3 Min
5 Min
104 f 11.7 160 f 17.2 165 f 21.9 104 12.2
101 f 11.2 150 f 14.9 151 f 21.3 103 12.3
122 f 15.7 171 f 36.6
109 f
210 94 f 58.2 11.5
166 ‘$6” zf ,“.I$ 49.8
103 137 96 142
f 11.4 f 22.9$ f 9.8 f 31.6
99 140 93 138
97 131 89 128
f 11.6 f 9.1’ f 7.1’ f 14.3+
1 Min
Duration (min)
Control Study (no. = 15) HR SP RK
125 f 20.9 189 f 25.7 234 101 f 51.8 11.1
8.4 f 2.23
Hydrochlorothiazide (no. = 13) HR SP RDPF
14.2
7.5 f 2.40
Alpha Methyldopa (no. = 14) HR ;; RPP
f 12.0 f 13.4‘ f 8.6’ f 19.9’
f 14.5 f 19.8+ f 6.9* f 36.3*
310 f 4iS.6t
114 165 92 187
f 15.2 f 23.2+ f 6.1+ f 29.2+
f 12.1 f 12.6’ f 6.1+ f 16.1+
8.2 f
1.94
Each figure represents the mean with respective standard deviation. P
326
August 1979
The Amerlcen Journal of CARDIOLOGY Volume 44
ANTIHYPERTENSIVE
THERAPY AND EXERCISE-LEE
Discussion
No Therapy Hydrochlorothiazide Alpha Methyl Dopa
Antihypertensive therapy and cardiovascular responses to dynamic exercise: In this study therapy with alpha methyldopa was associated with slower buildup, lower ceiling and more rapid recovery of arterial pressure in response to dynamic exercise (treadmill) in contrast to hydrochlorothiazide therapy, which failed to do so although both agents were equally effective in lowering resting arterial pressure. The degree of rise in rate-pressure product (an index of myocardial oxygen consumption) was significantly decreased with alpha methyldopa during exercise and the recovery phase but are not decreased with hydrochlorothiazide. The reduction of rate-pressure product associated with alpha methyldopa therapy was primarily due to reduced peak systolic pressure rather than to an effect on heart rate. The total duration of exercise (an index of work capacity) was unchanged with either hydrochlorothiazide or alpha methyldopa therapy. Previous studies: To our knowledge, there are few previous studies of the cardiovascular effects of antihypertensive therapy during exercise. Bruce et a1.6 reported divergent effects of antihypertensive therapy on cardiovascular responses of two groups (“patients” and “workers”) during upright exercise on treadmill. The divergence of cardiovascular responses to exercise was ascribed to the difference in the severity of hypertension of the two groups. The results of our study are in general agreement with those of the “workers” in their study. However, they did not include an individual evaluation of antihypertensive agents. A brief discussion of the studies of Shapiro’ and Lamid and Wolffs seems war-
*p<.os **p<.Ol ***p<.oo1
N S-Not significant
110 I” E E
100
90
n
PreExercise
Stage I (3 min)
Subjective Maximum
Postex 13 min)
NS
400l-
No Therapy Hydrochlorothiazide (Alpha Methyl Dopa
*p<.o5 35cl-
*p<.o5 **p<.o1
I
1 180 I-
8 7
***p<.oo1 N S-Not significant
I
3ocl-
200 l-
’
250l-
k =
TNS IT
16t l200I-
* h NS
140 150
120 -
** *+ 9
/ OL
Postex (5 min)
ranted, even though the stress or exercise used in their studies was different. Using psychologic stress and cold pressor tests, Shapiro7 demonstrated that antihypertensive therapy failed to decrease the increment of arterial pressure during “noxious stimuli” although the “ceiling” pressure was lowered. Lamid and Wolff8 found that the percentile increment of systolic and diastolic pressures during
**p<.Ol t**n<.OOl
220 I-
I” E E
Postex(1 min)
FIGURE 2. Effect of antihypertensive therapy on diastolic pressure. Each bar represents the mean value for each group at each time period with the respective standard deviation. Abbreviations as in Figure 1.
No Therapy Hydrochlorothiazide Alpha Methyl Dopa
240
ET AL.
Subjective Maximum
Postex (1 min)
Postex (3 min)
0/ILL
Postex (5 min)
FIGURE 1. Effect of antihypertensive therapy on systolic pressure. Each bar represents the mean value fw each group at each time period with the respective standard deviation. p = probability; Postex = postexercise.
PreExercise
Stage (3 i-h
I Subjoctiv‘e Maximum
Postex
(1 mid
Postex (3 min)
PI3stex 15mini
FIGURE 3. Effect of antihypertensive therapy on rate-pressure product (RPP) (heart rate X systolic pressure X lo-*). Each bar represents the mean value for each group at each time period with the respective standard deviation.
August 1979
The American Journal of CARDIOLOGY
Volume 44
327
ANTIHYPERTENSIVE THERAPY AND EXERCISE-LEE ET AL.
the stress of isometric handgrip contraction was not affected by therapeutic doses of various antihypertensive agents. However, they did not report the arterial pressure changes in absolute terms in their study. Clinical implications: Acute excessive elevation of systemic arterial pressure during exercise could be detrimental to the compromised heart and blood vessels, which are major target organs of hypertensive complications. Our data indicate that good control of resting arterial pressure does not necessarily provide
adequate protection against arterial pressure response during exercise. Alpha methyldopa controlled the arterial pressure during exercise better than hydrochlorothiazide. The difference could be ascribed to the different mode of antihypertensive action of these agents. This observation seems to be important for clinical management of hypertensive patients. Further studies on the effects of other antihypertensive agents that are commonly used alone or in combination are warranted.
References 1. Sannerstedt R: Hemodynamic response to exercise in patients with arterial hypertension. Acta Med Stand 180: Suppl 458:1-70, 1966 2. Atnery A, Julius S, Whitlock LS, Conway J: Influence of hypertension on the hemodynamic response to exercise. Circulation 36:231-237, 1967 3. Levy AM, Tabakln BS, Hanson JS: Hemodynamic responses to graded treadmill exercise in young untreated labile hypertensive patients. Circulation 351063-1072, 1967 4. Hammer J, Telemlng J, Shinebourne E: Effects of walking on blood pressure in systemic hypertension. Lancet 2: 114- 118, 1967 5. Bruce RA: Exercise testing of patients with coronary heart disease.
328
August
1979
The Arnerlcan
Journal of CARDIOLOGY
Ann Clin Res 3:323-332, 1971 6. Bruce RA, Eleady-Cote R, Bennett W, Kusumi F: Divergent effects of antihypertensive therapy on cardiovascular responses and left ventricular function during upright exercise. Am J Cardiol 30: 768-774, 1972 7. Shapiro AP: Pressor responses to noxious stimuli in hypertensive patients. Effects of reserpine and chlorothiazide. Circulation 26: 242-249, 1962 8. Lamid S, Wolff FW: Drug failure in reducing pressor effect of isometric handgrip stress test in hypertension. Am Heart J 36:211-215, 1973
Volume 44
WON R. LEE, MO, FACC LAY M. FOX, MD, FACC LAWRENCE M. SLOTKOFF, MD Washington, D. C.
The effects of alpha methyldopa and hydrochlorothiazide therapy on exercise induced changes in arterial pressure, heart rate, rate-pressure product and total duration of exercise were evaluated with graded treadmill exercise. Although both agents were equally effective In reducing resting arterial pressure, alpha methyldopa appeared to provide slower build-up, a lower celling and more rapld recovery of arterial pressure In response to exercise stress than did hydrochlorothiazide. Alpha methyldopa signlflcantly reduced the degree of rise of the rate-pressure product (an Index of myocardlal oxygen consumption) during the exercise and recovery phases, whereas hydrochlorothlazlde failed to&doso. The total duration of exercise (an index of work capacity) was unchanged with either hydrochlorothlazlde or alpha methykfopa. Therapy with alpha methyldopa presumably reduced myocardlal oxygen demand wlthout reducing work capacity.
The exaggerated arterial pressure response to exercise in untreated hypertensive patients has been well documented.14 However, the effects of antihypertensive therapy on this increased pressure response to exercise have not been clearly characterized. Cardiovascular effects of antihypertensive therapy during exercise may differ from one agent to another depending on the mode of antihypertensive action even if they are all equally effective on resting arterial pressure. In our study, hydrochlorothiazide and alpha methyldopa were evaluated individually and in series, in random fashion, with each subject serving as his own control. Multistage treadmill testing was used for exercise stress. Exercise-induced changes in arterial pressure, heart rate, rate-pressure product and total duration of exercise as an index of work capacity were assessed before and during antihypertensive therapy. Methods
From the Georgetown Medical Division, District of Columbia General Hospital, Washington, D.C. Manuscript received December 17, 1978; revised manuscript received March 5. 1979, accepted March 7, 1979 Address for reprints: Won R. Lee, MD, District of Columbia General Hospital, 19th 8 Massachusetts Avenue, Southeast, Washington, DC. 20003.
Patients: Fifteen patients with hypertension were enrolled in our study and were seen at our Hypertension Clinic. Hypertension was defined as a systolic pressure of 150 mm Hg or more or a diastolic pressure of 90 mm Hg or more by the fifth Korotkoff sound, or both, on three occasions while sitting. Twelve of the 15 patients were men, all were black, and their ages ranged from 26 to49 years (mean 40.2). None of the patients had taken any antihypertensive medication for the previous several months. After the initial evaluation, all patients were considered to have essential hypertension. All patients were asymptomatic, without clinically detectable coronary heart disease, congestive heart failure, stroke, significant obesity or diabetes mellitus. Three patients had early grade JI and five patients had grade I retinal change as assessed with the KeithWagener-Barker criteria. Five patients had left ventricular hypertrophy as judged from electrocardiographic voltage criteria only and none had S-T or T wave abnormalities at rest. Protocol: After informed consent was obtained from each patient, multistage treadmill testing according to the Bruce protocol5 was performed to a level of
August 1979
The American Journal of CARDlOLOGY
Volume 44
325
ANTIHYPERTENSIVETHERAPY AND EXERCISE-LEE ET AL
“self-determined
maximal effort.” A bipolar CBS electrocar-
significantly reduced the rise in systolic pressure during the build-up (P
diogram was monitored and recorded for heart rate and assessment of electrocardiographic changes. Arterial pressure
was measured with a clinical sphygmomanometer utilizing the fifth Korotkoff sound as diastolic pressure. Both the electrocardiogram and arterial pressure were recorded while the patient sat at rest before exercise, at the end of stage I (3 minutes), at the subjectively determined point of maximal exercise and at 1,3 and 5 minutes after the termination of exercise. After undergoing treadmill exercise testing before antihypertensive therapy, the patients were randomly assigned to therapy with hydrochlorothiazide or alpha methyldopa. Antihypertensive therapy with each drug was continued for 4 weeks before the exercise test was repeated. Hydrochlorothiazide (50 mg once or twice a day) and alpha methyldopa (1.0 to 2.0 g in divided doses) were administered, the dosage depending on clinical responses. Each patient was then assigned to the opposite regimen for the next 4 weeks, and treadmill testing was repeated. Exercise-induced changes during antihypertensive therapy were assessed with Student’s t test. Results Cardiovascular responses during the study are summarized in Table 1 and Figures 1 to 3. The number of patients studied with each regimen are shown in Table I. Systolic pressure: Alpha methyldopa and hydrochlorothiazide reduced preexercise systolic pressure (P
TABLE I Exercise-Induced Changes in Cardiovascular Measurements Before and During Antihypertensive Therapy Total
Exercise Stage I (3 min)
Subjective Maximum
85 4 11.3 155 f 12.3 132 f 8.1 104 17.7
127 f 13.6 194 l 24.9 246 108 & f 46.3 12.5
161 f 17.4 218 f 24.4 349 111 f 40.7 13.2
88 f 134 f
11.5 16.2’
126 f18.3 184 f 17.9
158 f 19.3 207 f 33.7
116 93 f 7.6’ 14.3’
232 103 f 35.3 7.8
328 101 f 66.4 10.0*
83 130 90 107
124 173 102 214
155 f 18.4 ;(I; = ;2..’
Before Exercise
Recovery 3 Min
5 Min
104 f 11.7 160 f 17.2 165 f 21.9 104 12.2
101 f 11.2 150 f 14.9 151 f 21.3 103 12.3
122 f 15.7 171 f 36.6
109 f
210 94 f 58.2 11.5
166 ‘$6” zf ,“.I$ 49.8
103 137 96 142
f 11.4 f 22.9$ f 9.8 f 31.6
99 140 93 138
97 131 89 128
f 11.6 f 9.1’ f 7.1’ f 14.3+
1 Min
Duration (min)
Control Study (no. = 15) HR SP RK
125 f 20.9 189 f 25.7 234 101 f 51.8 11.1
8.4 f 2.23
Hydrochlorothiazide (no. = 13) HR SP RDPF
14.2
7.5 f 2.40
Alpha Methyldopa (no. = 14) HR ;; RPP
f 12.0 f 13.4‘ f 8.6’ f 19.9’
f 14.5 f 19.8+ f 6.9* f 36.3*
310 f 4iS.6t
114 165 92 187
f 15.2 f 23.2+ f 6.1+ f 29.2+
f 12.1 f 12.6’ f 6.1+ f 16.1+
8.2 f
1.94
Each figure represents the mean with respective standard deviation. P
326
August 1979
The Amerlcen Journal of CARDIOLOGY Volume 44
ANTIHYPERTENSIVE
THERAPY AND EXERCISE-LEE
Discussion
No Therapy Hydrochlorothiazide Alpha Methyl Dopa
Antihypertensive therapy and cardiovascular responses to dynamic exercise: In this study therapy with alpha methyldopa was associated with slower buildup, lower ceiling and more rapid recovery of arterial pressure in response to dynamic exercise (treadmill) in contrast to hydrochlorothiazide therapy, which failed to do so although both agents were equally effective in lowering resting arterial pressure. The degree of rise in rate-pressure product (an index of myocardial oxygen consumption) was significantly decreased with alpha methyldopa during exercise and the recovery phase but are not decreased with hydrochlorothiazide. The reduction of rate-pressure product associated with alpha methyldopa therapy was primarily due to reduced peak systolic pressure rather than to an effect on heart rate. The total duration of exercise (an index of work capacity) was unchanged with either hydrochlorothiazide or alpha methyldopa therapy. Previous studies: To our knowledge, there are few previous studies of the cardiovascular effects of antihypertensive therapy during exercise. Bruce et a1.6 reported divergent effects of antihypertensive therapy on cardiovascular responses of two groups (“patients” and “workers”) during upright exercise on treadmill. The divergence of cardiovascular responses to exercise was ascribed to the difference in the severity of hypertension of the two groups. The results of our study are in general agreement with those of the “workers” in their study. However, they did not include an individual evaluation of antihypertensive agents. A brief discussion of the studies of Shapiro’ and Lamid and Wolffs seems war-
*p<.os **p<.Ol ***p<.oo1
N S-Not significant
110 I” E E
100
90
n
PreExercise
Stage I (3 min)
Subjective Maximum
Postex 13 min)
NS
400l-
No Therapy Hydrochlorothiazide (Alpha Methyl Dopa
*p<.o5 35cl-
*p<.o5 **p<.o1
I
1 180 I-
8 7
***p<.oo1 N S-Not significant
I
3ocl-
200 l-
’
250l-
k =
TNS IT
16t l200I-
* h NS
140 150
120 -
** *+ 9
/ OL
Postex (5 min)
ranted, even though the stress or exercise used in their studies was different. Using psychologic stress and cold pressor tests, Shapiro7 demonstrated that antihypertensive therapy failed to decrease the increment of arterial pressure during “noxious stimuli” although the “ceiling” pressure was lowered. Lamid and Wolff8 found that the percentile increment of systolic and diastolic pressures during
**p<.Ol t**n<.OOl
220 I-
I” E E
Postex(1 min)
FIGURE 2. Effect of antihypertensive therapy on diastolic pressure. Each bar represents the mean value for each group at each time period with the respective standard deviation. Abbreviations as in Figure 1.
No Therapy Hydrochlorothiazide Alpha Methyl Dopa
240
ET AL.
Subjective Maximum
Postex (1 min)
Postex (3 min)
0/ILL
Postex (5 min)
FIGURE 1. Effect of antihypertensive therapy on systolic pressure. Each bar represents the mean value fw each group at each time period with the respective standard deviation. p = probability; Postex = postexercise.
PreExercise
Stage (3 i-h
I Subjoctiv‘e Maximum
Postex
(1 mid
Postex (3 min)
PI3stex 15mini
FIGURE 3. Effect of antihypertensive therapy on rate-pressure product (RPP) (heart rate X systolic pressure X lo-*). Each bar represents the mean value for each group at each time period with the respective standard deviation.
August 1979
The American Journal of CARDIOLOGY
Volume 44
327
ANTIHYPERTENSIVE THERAPY AND EXERCISE-LEE ET AL.
the stress of isometric handgrip contraction was not affected by therapeutic doses of various antihypertensive agents. However, they did not report the arterial pressure changes in absolute terms in their study. Clinical implications: Acute excessive elevation of systemic arterial pressure during exercise could be detrimental to the compromised heart and blood vessels, which are major target organs of hypertensive complications. Our data indicate that good control of resting arterial pressure does not necessarily provide
adequate protection against arterial pressure response during exercise. Alpha methyldopa controlled the arterial pressure during exercise better than hydrochlorothiazide. The difference could be ascribed to the different mode of antihypertensive action of these agents. This observation seems to be important for clinical management of hypertensive patients. Further studies on the effects of other antihypertensive agents that are commonly used alone or in combination are warranted.
References 1. Sannerstedt R: Hemodynamic response to exercise in patients with arterial hypertension. Acta Med Stand 180: Suppl 458:1-70, 1966 2. Atnery A, Julius S, Whitlock LS, Conway J: Influence of hypertension on the hemodynamic response to exercise. Circulation 36:231-237, 1967 3. Levy AM, Tabakln BS, Hanson JS: Hemodynamic responses to graded treadmill exercise in young untreated labile hypertensive patients. Circulation 351063-1072, 1967 4. Hammer J, Telemlng J, Shinebourne E: Effects of walking on blood pressure in systemic hypertension. Lancet 2: 114- 118, 1967 5. Bruce RA: Exercise testing of patients with coronary heart disease.
328
August
1979
The Arnerlcan
Journal of CARDIOLOGY
Ann Clin Res 3:323-332, 1971 6. Bruce RA, Eleady-Cote R, Bennett W, Kusumi F: Divergent effects of antihypertensive therapy on cardiovascular responses and left ventricular function during upright exercise. Am J Cardiol 30: 768-774, 1972 7. Shapiro AP: Pressor responses to noxious stimuli in hypertensive patients. Effects of reserpine and chlorothiazide. Circulation 26: 242-249, 1962 8. Lamid S, Wolff FW: Drug failure in reducing pressor effect of isometric handgrip stress test in hypertension. Am Heart J 36:211-215, 1973
Volume 44